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Slide 1 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities.
Slide 2 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities.
Slide 3 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors.
Slide 4 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech
Slide 5 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose
Slide 6 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly
Slide 7 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200.
Slide 8 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission
Slide 9 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission
Slide 10 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953.
Slide 11 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953.
Slide 12 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission
Slide 13 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006.
Slide 14 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205
Slide 15 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533.
Slide 16 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012.
Slide 17 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days
Slide 18 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission
Slide 19 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel
Slide 20 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338.
Slide 21 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R A N D O M I Z E n = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712
Slide 22 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R A N D O M I Z E n = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission
Slide 23 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R A N D O M I Z E n = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Placebo BEV 15 mg/kg II Stratification variables: GOG performance status (PS) Stage/debulking status RANDOM I Z E 1:1:1 15 months Paclitaxel (P) 175 mg/m2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 III Maintenance (16 cycles) BEV 15 mg/kg Burger RA et al. N Engl J Med. 2011;365:2473-2483.
Slide 24 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R A N D O M I Z E n = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Placebo BEV 15 mg/kg II Stratification variables: GOG performance status (PS) Stage/debulking status RANDOM I Z E 1:1:1 15 months Paclitaxel (P) 175 mg/m2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 III Maintenance (16 cycles) BEV 15 mg/kg Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218: Investigator-assessed PFS + BEV (Arm II) CP (Arm I) *P-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 Burger RA et al. N Engl J Med. 2011;365:2473-2483.
Slide 25 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R A N D O M I Z E n = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Placebo BEV 15 mg/kg II Stratification variables: GOG performance status (PS) Stage/debulking status RANDOM I Z E 1:1:1 15 months Paclitaxel (P) 175 mg/m2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 III Maintenance (16 cycles) BEV 15 mg/kg Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218: Investigator-assessed PFS + BEV (Arm II) CP (Arm I) *P-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 CA-125 to Determine Progression Burger RA et al. N Engl J Med. 2011;365:2473-2483.
Slide 26 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R A N D O M I Z E n = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Placebo BEV 15 mg/kg II Stratification variables: GOG performance status (PS) Stage/debulking status RANDOM I Z E 1:1:1 15 months Paclitaxel (P) 175 mg/m2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 III Maintenance (16 cycles) BEV 15 mg/kg Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218: Investigator-assessed PFS + BEV (Arm II) CP (Arm I) *P-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 CA-125 to Determine Progression Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 Interim Survival Analysis Proportion Alive Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 48 aStratified analysis 625/625/623 442/432/437 173/162/171 46/39/40 No. at risk Burger RA et al. N Engl J Med. 2011;365:2473-2483.
Slide 27 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R A N D O M I Z E n = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Placebo BEV 15 mg/kg II Stratification variables: GOG performance status (PS) Stage/debulking status RANDOM I Z E 1:1:1 15 months Paclitaxel (P) 175 mg/m2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 III Maintenance (16 cycles) BEV 15 mg/kg Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218: Investigator-assessed PFS + BEV (Arm II) CP (Arm I) *P-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 CA-125 to Determine Progression Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 Interim Survival Analysis Proportion Alive Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 48 aStratified analysis 625/625/623 442/432/437 173/162/171 46/39/40 No. at risk Burger RA et al. N Engl J Med. 2011;365:2473-2483. ICON7: Study Design Stratification variables: Stage/surgery Time since surgery GCIG group *Might vary based on GCIG group **Omit cycle 1 bevacizumab if <4 weeks from surgery Paclitaxel 175 mg/m2 Carboplatin AUC 6* AVASTIN Carboplatin AUC 6* Paclitaxel 175 mg/m2 Arm A Arm B 12 months Front-line EOC, PP or FT cancer Stage I-IIA (Gr 3 or CC) Stage IIB/C Stage III Stage IV n=1528 Bevacizumab 7.5 mg/kg ** Primary endpoints: PFS Secondary endpoints: OS, RR, safety, QOL, cost-effectiveness, translational No IRC present Perren T et al. N Engl J Med. 2011;365:2484-2496. Perren et al. ESMO 2010.
Slide 28 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R A N D O M I Z E n = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Placebo BEV 15 mg/kg II Stratification variables: GOG performance status (PS) Stage/debulking status RANDOM I Z E 1:1:1 15 months Paclitaxel (P) 175 mg/m2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 III Maintenance (16 cycles) BEV 15 mg/kg Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218: Investigator-assessed PFS + BEV (Arm II) CP (Arm I) *P-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 CA-125 to Determine Progression Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 Interim Survival Analysis Proportion Alive Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 48 aStratified analysis 625/625/623 442/432/437 173/162/171 46/39/40 No. at risk Burger RA et al. N Engl J Med. 2011;365:2473-2483. ICON7: Study Design Stratification variables: Stage/surgery Time since surgery GCIG group *Might vary based on GCIG group **Omit cycle 1 bevacizumab if <4 weeks from surgery Paclitaxel 175 mg/m2 Carboplatin AUC 6* AVASTIN Carboplatin AUC 6* Paclitaxel 175 mg/m2 Arm A Arm B 12 months Front-line EOC, PP or FT cancer Stage I-IIA (Gr 3 or CC) Stage IIB/C Stage III Stage IV n=1528 Bevacizumab 7.5 mg/kg ** Primary endpoints: PFS Secondary endpoints: OS, RR, safety, QOL, cost-effectiveness, translational No IRC present Perren T et al. N Engl J Med. 2011;365:2484-2496. Perren et al. ESMO 2010. ICON 7 Summary of Updated Results Kristensen G et al. J Clin Oncol. 2011;29: suppl; abstr LBA5006). Perren T et al. N Engl J Med. 2011;365:2484-2496.
Slide 29 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R A N D O M I Z E n = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Placebo BEV 15 mg/kg II Stratification variables: GOG performance status (PS) Stage/debulking status RANDOM I Z E 1:1:1 15 months Paclitaxel (P) 175 mg/m2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 III Maintenance (16 cycles) BEV 15 mg/kg Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218: Investigator-assessed PFS + BEV (Arm II) CP (Arm I) *P-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 CA-125 to Determine Progression Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 Interim Survival Analysis Proportion Alive Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 48 aStratified analysis 625/625/623 442/432/437 173/162/171 46/39/40 No. at risk Burger RA et al. N Engl J Med. 2011;365:2473-2483. ICON7: Study Design Stratification variables: Stage/surgery Time since surgery GCIG group *Might vary based on GCIG group **Omit cycle 1 bevacizumab if <4 weeks from surgery Paclitaxel 175 mg/m2 Carboplatin AUC 6* AVASTIN Carboplatin AUC 6* Paclitaxel 175 mg/m2 Arm A Arm B 12 months Front-line EOC, PP or FT cancer Stage I-IIA (Gr 3 or CC) Stage IIB/C Stage III Stage IV n=1528 Bevacizumab 7.5 mg/kg ** Primary endpoints: PFS Secondary endpoints: OS, RR, safety, QOL, cost-effectiveness, translational No IRC present Perren T et al. N Engl J Med. 2011;365:2484-2496. Perren et al. ESMO 2010. ICON 7 Summary of Updated Results Kristensen G et al. J Clin Oncol. 2011;29: suppl; abstr LBA5006). Perren T et al. N Engl J Med. 2011;365:2484-2496. First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission
Slide 30 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R A N D O M I Z E n = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Placebo BEV 15 mg/kg II Stratification variables: GOG performance status (PS) Stage/debulking status RANDOM I Z E 1:1:1 15 months Paclitaxel (P) 175 mg/m2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 III Maintenance (16 cycles) BEV 15 mg/kg Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218: Investigator-assessed PFS + BEV (Arm II) CP (Arm I) *P-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 CA-125 to Determine Progression Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 Interim Survival Analysis Proportion Alive Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 48 aStratified analysis 625/625/623 442/432/437 173/162/171 46/39/40 No. at risk Burger RA et al. N Engl J Med. 2011;365:2473-2483. ICON7: Study Design Stratification variables: Stage/surgery Time since surgery GCIG group *Might vary based on GCIG group **Omit cycle 1 bevacizumab if <4 weeks from surgery Paclitaxel 175 mg/m2 Carboplatin AUC 6* AVASTIN Carboplatin AUC 6* Paclitaxel 175 mg/m2 Arm A Arm B 12 months Front-line EOC, PP or FT cancer Stage I-IIA (Gr 3 or CC) Stage IIB/C Stage III Stage IV n=1528 Bevacizumab 7.5 mg/kg ** Primary endpoints: PFS Secondary endpoints: OS, RR, safety, QOL, cost-effectiveness, translational No IRC present Perren T et al. N Engl J Med. 2011;365:2484-2496. Perren et al. ESMO 2010. ICON 7 Summary of Updated Results Kristensen G et al. J Clin Oncol. 2011;29: suppl; abstr LBA5006). Perren T et al. N Engl J Med. 2011;365:2484-2496. First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG 178—Investigating Paclitaxel as Consolidation Markman M et al. J Clin Oncol. 2003;21:2460-2465. 277 stage III/IV patients in complete clinical remission Paclitaxel 175 mg/m2 every 28 days × 3 months Paclitaxel 175 mg/m2 every 28 days × 12 months RANDOM I Z E CR = Complete response.
Slide 31 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R A N D O M I Z E n = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Placebo BEV 15 mg/kg II Stratification variables: GOG performance status (PS) Stage/debulking status RANDOM I Z E 1:1:1 15 months Paclitaxel (P) 175 mg/m2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 III Maintenance (16 cycles) BEV 15 mg/kg Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218: Investigator-assessed PFS + BEV (Arm II) CP (Arm I) *P-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 CA-125 to Determine Progression Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 Interim Survival Analysis Proportion Alive Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 48 aStratified analysis 625/625/623 442/432/437 173/162/171 46/39/40 No. at risk Burger RA et al. N Engl J Med. 2011;365:2473-2483. ICON7: Study Design Stratification variables: Stage/surgery Time since surgery GCIG group *Might vary based on GCIG group **Omit cycle 1 bevacizumab if <4 weeks from surgery Paclitaxel 175 mg/m2 Carboplatin AUC 6* AVASTIN Carboplatin AUC 6* Paclitaxel 175 mg/m2 Arm A Arm B 12 months Front-line EOC, PP or FT cancer Stage I-IIA (Gr 3 or CC) Stage IIB/C Stage III Stage IV n=1528 Bevacizumab 7.5 mg/kg ** Primary endpoints: PFS Secondary endpoints: OS, RR, safety, QOL, cost-effectiveness, translational No IRC present Perren T et al. N Engl J Med. 2011;365:2484-2496. Perren et al. ESMO 2010. ICON 7 Summary of Updated Results Kristensen G et al. J Clin Oncol. 2011;29: suppl; abstr LBA5006). Perren T et al. N Engl J Med. 2011;365:2484-2496. First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG 178—Investigating Paclitaxel as Consolidation Markman M et al. J Clin Oncol. 2003;21:2460-2465. 277 stage III/IV patients in complete clinical remission Paclitaxel 175 mg/m2 every 28 days × 3 months Paclitaxel 175 mg/m2 every 28 days × 12 months RANDOM I Z E CR = Complete response. Progression-free survival 0 20 40 60 80 100 0 12 24 36 48 Months after registration Paclitaxel 12 courses Paclitaxel 3 courses 110 At risk 112 Failed 20 34 Median, months 28 21 P = 0.0023 Percentage Markman M et al. J Clin Oncol. 2003;21:2460-2465. GOG 178
Slide 32 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R A N D O M I Z E n = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Placebo BEV 15 mg/kg II Stratification variables: GOG performance status (PS) Stage/debulking status RANDOM I Z E 1:1:1 15 months Paclitaxel (P) 175 mg/m2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 III Maintenance (16 cycles) BEV 15 mg/kg Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218: Investigator-assessed PFS + BEV (Arm II) CP (Arm I) *P-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 CA-125 to Determine Progression Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 Interim Survival Analysis Proportion Alive Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 48 aStratified analysis 625/625/623 442/432/437 173/162/171 46/39/40 No. at risk Burger RA et al. N Engl J Med. 2011;365:2473-2483. ICON7: Study Design Stratification variables: Stage/surgery Time since surgery GCIG group *Might vary based on GCIG group **Omit cycle 1 bevacizumab if <4 weeks from surgery Paclitaxel 175 mg/m2 Carboplatin AUC 6* AVASTIN Carboplatin AUC 6* Paclitaxel 175 mg/m2 Arm A Arm B 12 months Front-line EOC, PP or FT cancer Stage I-IIA (Gr 3 or CC) Stage IIB/C Stage III Stage IV n=1528 Bevacizumab 7.5 mg/kg ** Primary endpoints: PFS Secondary endpoints: OS, RR, safety, QOL, cost-effectiveness, translational No IRC present Perren T et al. N Engl J Med. 2011;365:2484-2496. Perren et al. ESMO 2010. ICON 7 Summary of Updated Results Kristensen G et al. J Clin Oncol. 2011;29: suppl; abstr LBA5006). Perren T et al. N Engl J Med. 2011;365:2484-2496. First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG 178—Investigating Paclitaxel as Consolidation Markman M et al. J Clin Oncol. 2003;21:2460-2465. 277 stage III/IV patients in complete clinical remission Paclitaxel 175 mg/m2 every 28 days × 3 months Paclitaxel 175 mg/m2 every 28 days × 12 months RANDOM I Z E CR = Complete response. Progression-free survival 0 20 40 60 80 100 0 12 24 36 48 Months after registration Paclitaxel 12 courses Paclitaxel 3 courses 110 At risk 112 Failed 20 34 Median, months 28 21 P = 0.0023 Percentage Markman M et al. J Clin Oncol. 2003;21:2460-2465. GOG 178 GOG-0212 Phase III Maintenance Therapy Trial Primary endpoint: survival Secondary endpoints: PFS, toxicity, QoL www.clinicaltrials.gov/ct2/show/NCT00108745. Macromolecular complex of paclitaxel poliglumex Patients with stage III/IV epithelial ovarian or primary peritoneal cancer, GOG PS ≤ 2, and complete response after surgery plus taxane and carboplatin (Planned n = 1400-1550) Paclitaxel Every 28 days for up to 12 courses No treatment Paclitaxel poliglumex Every 28 days for up to 12 courses
Slide 33 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R A N D O M I Z E n = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Placebo BEV 15 mg/kg II Stratification variables: GOG performance status (PS) Stage/debulking status RANDOM I Z E 1:1:1 15 months Paclitaxel (P) 175 mg/m2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 III Maintenance (16 cycles) BEV 15 mg/kg Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218: Investigator-assessed PFS + BEV (Arm II) CP (Arm I) *P-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 CA-125 to Determine Progression Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 Interim Survival Analysis Proportion Alive Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 48 aStratified analysis 625/625/623 442/432/437 173/162/171 46/39/40 No. at risk Burger RA et al. N Engl J Med. 2011;365:2473-2483. ICON7: Study Design Stratification variables: Stage/surgery Time since surgery GCIG group *Might vary based on GCIG group **Omit cycle 1 bevacizumab if <4 weeks from surgery Paclitaxel 175 mg/m2 Carboplatin AUC 6* AVASTIN Carboplatin AUC 6* Paclitaxel 175 mg/m2 Arm A Arm B 12 months Front-line EOC, PP or FT cancer Stage I-IIA (Gr 3 or CC) Stage IIB/C Stage III Stage IV n=1528 Bevacizumab 7.5 mg/kg ** Primary endpoints: PFS Secondary endpoints: OS, RR, safety, QOL, cost-effectiveness, translational No IRC present Perren T et al. N Engl J Med. 2011;365:2484-2496. Perren et al. ESMO 2010. ICON 7 Summary of Updated Results Kristensen G et al. J Clin Oncol. 2011;29: suppl; abstr LBA5006). Perren T et al. N Engl J Med. 2011;365:2484-2496. First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG 178—Investigating Paclitaxel as Consolidation Markman M et al. J Clin Oncol. 2003;21:2460-2465. 277 stage III/IV patients in complete clinical remission Paclitaxel 175 mg/m2 every 28 days × 3 months Paclitaxel 175 mg/m2 every 28 days × 12 months RANDOM I Z E CR = Complete response. Progression-free survival 0 20 40 60 80 100 0 12 24 36 48 Months after registration Paclitaxel 12 courses Paclitaxel 3 courses 110 At risk 112 Failed 20 34 Median, months 28 21 P = 0.0023 Percentage Markman M et al. J Clin Oncol. 2003;21:2460-2465. GOG 178 GOG-0212 Phase III Maintenance Therapy Trial Primary endpoint: survival Secondary endpoints: PFS, toxicity, QoL www.clinicaltrials.gov/ct2/show/NCT00108745. Macromolecular complex of paclitaxel poliglumex Patients with stage III/IV epithelial ovarian or primary peritoneal cancer, GOG PS ≤ 2, and complete response after surgery plus taxane and carboplatin (Planned n = 1400-1550) Paclitaxel Every 28 days for up to 12 courses No treatment Paclitaxel poliglumex Every 28 days for up to 12 courses Summary: Initial Treatment of Advanced Ovarian Cancer Surgery Attempt at maximal surgical cytoreduction Neoadjuvant chemo before surgery is an option for poor surgical candidates Chemotherapy 6-8 cycles taxane-platinum combination is standard IP admin benefits patients with low volume (optimal) disease but has increased toxicity NED patients treated with IP have a median survival of over 9 years Weekly (dose-dense) paclitaxel improves outcome in one study Confirmatory North American trials recently completed Bevacizumab during and after chemotherapy improves PFS but not OS
Slide 34 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R A N D O M I Z E n = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Placebo BEV 15 mg/kg II Stratification variables: GOG performance status (PS) Stage/debulking status RANDOM I Z E 1:1:1 15 months Paclitaxel (P) 175 mg/m2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 III Maintenance (16 cycles) BEV 15 mg/kg Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218: Investigator-assessed PFS + BEV (Arm II) CP (Arm I) *P-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 CA-125 to Determine Progression Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 Interim Survival Analysis Proportion Alive Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 48 aStratified analysis 625/625/623 442/432/437 173/162/171 46/39/40 No. at risk Burger RA et al. N Engl J Med. 2011;365:2473-2483. ICON7: Study Design Stratification variables: Stage/surgery Time since surgery GCIG group *Might vary based on GCIG group **Omit cycle 1 bevacizumab if <4 weeks from surgery Paclitaxel 175 mg/m2 Carboplatin AUC 6* AVASTIN Carboplatin AUC 6* Paclitaxel 175 mg/m2 Arm A Arm B 12 months Front-line EOC, PP or FT cancer Stage I-IIA (Gr 3 or CC) Stage IIB/C Stage III Stage IV n=1528 Bevacizumab 7.5 mg/kg ** Primary endpoints: PFS Secondary endpoints: OS, RR, safety, QOL, cost-effectiveness, translational No IRC present Perren T et al. N Engl J Med. 2011;365:2484-2496. Perren et al. ESMO 2010. ICON 7 Summary of Updated Results Kristensen G et al. J Clin Oncol. 2011;29: suppl; abstr LBA5006). Perren T et al. N Engl J Med. 2011;365:2484-2496. First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG 178—Investigating Paclitaxel as Consolidation Markman M et al. J Clin Oncol. 2003;21:2460-2465. 277 stage III/IV patients in complete clinical remission Paclitaxel 175 mg/m2 every 28 days × 3 months Paclitaxel 175 mg/m2 every 28 days × 12 months RANDOM I Z E CR = Complete response. Progression-free survival 0 20 40 60 80 100 0 12 24 36 48 Months after registration Paclitaxel 12 courses Paclitaxel 3 courses 110 At risk 112 Failed 20 34 Median, months 28 21 P = 0.0023 Percentage Markman M et al. J Clin Oncol. 2003;21:2460-2465. GOG 178 GOG-0212 Phase III Maintenance Therapy Trial Primary endpoint: survival Secondary endpoints: PFS, toxicity, QoL www.clinicaltrials.gov/ct2/show/NCT00108745. Macromolecular complex of paclitaxel poliglumex Patients with stage III/IV epithelial ovarian or primary peritoneal cancer, GOG PS ≤ 2, and complete response after surgery plus taxane and carboplatin (Planned n = 1400-1550) Paclitaxel Every 28 days for up to 12 courses No treatment Paclitaxel poliglumex Every 28 days for up to 12 courses Summary: Initial Treatment of Advanced Ovarian Cancer Surgery Attempt at maximal surgical cytoreduction Neoadjuvant chemo before surgery is an option for poor surgical candidates Chemotherapy 6-8 cycles taxane-platinum combination is standard IP admin benefits patients with low volume (optimal) disease but has increased toxicity NED patients treated with IP have a median survival of over 9 years Weekly (dose-dense) paclitaxel improves outcome in one study Confirmatory North American trials recently completed Bevacizumab during and after chemotherapy improves PFS but not OS Case Discussions
Slide 35 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R A N D O M I Z E n = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Placebo BEV 15 mg/kg II Stratification variables: GOG performance status (PS) Stage/debulking status RANDOM I Z E 1:1:1 15 months Paclitaxel (P) 175 mg/m2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 III Maintenance (16 cycles) BEV 15 mg/kg Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218: Investigator-assessed PFS + BEV (Arm II) CP (Arm I) *P-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 CA-125 to Determine Progression Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 Interim Survival Analysis Proportion Alive Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 48 aStratified analysis 625/625/623 442/432/437 173/162/171 46/39/40 No. at risk Burger RA et al. N Engl J Med. 2011;365:2473-2483. ICON7: Study Design Stratification variables: Stage/surgery Time since surgery GCIG group *Might vary based on GCIG group **Omit cycle 1 bevacizumab if <4 weeks from surgery Paclitaxel 175 mg/m2 Carboplatin AUC 6* AVASTIN Carboplatin AUC 6* Paclitaxel 175 mg/m2 Arm A Arm B 12 months Front-line EOC, PP or FT cancer Stage I-IIA (Gr 3 or CC) Stage IIB/C Stage III Stage IV n=1528 Bevacizumab 7.5 mg/kg ** Primary endpoints: PFS Secondary endpoints: OS, RR, safety, QOL, cost-effectiveness, translational No IRC present Perren T et al. N Engl J Med. 2011;365:2484-2496. Perren et al. ESMO 2010. ICON 7 Summary of Updated Results Kristensen G et al. J Clin Oncol. 2011;29: suppl; abstr LBA5006). Perren T et al. N Engl J Med. 2011;365:2484-2496. First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG 178—Investigating Paclitaxel as Consolidation Markman M et al. J Clin Oncol. 2003;21:2460-2465. 277 stage III/IV patients in complete clinical remission Paclitaxel 175 mg/m2 every 28 days × 3 months Paclitaxel 175 mg/m2 every 28 days × 12 months RANDOM I Z E CR = Complete response. Progression-free survival 0 20 40 60 80 100 0 12 24 36 48 Months after registration Paclitaxel 12 courses Paclitaxel 3 courses 110 At risk 112 Failed 20 34 Median, months 28 21 P = 0.0023 Percentage Markman M et al. J Clin Oncol. 2003;21:2460-2465. GOG 178 GOG-0212 Phase III Maintenance Therapy Trial Primary endpoint: survival Secondary endpoints: PFS, toxicity, QoL www.clinicaltrials.gov/ct2/show/NCT00108745. Macromolecular complex of paclitaxel poliglumex Patients with stage III/IV epithelial ovarian or primary peritoneal cancer, GOG PS ≤ 2, and complete response after surgery plus taxane and carboplatin (Planned n = 1400-1550) Paclitaxel Every 28 days for up to 12 courses No treatment Paclitaxel poliglumex Every 28 days for up to 12 courses Summary: Initial Treatment of Advanced Ovarian Cancer Surgery Attempt at maximal surgical cytoreduction Neoadjuvant chemo before surgery is an option for poor surgical candidates Chemotherapy 6-8 cycles taxane-platinum combination is standard IP admin benefits patients with low volume (optimal) disease but has increased toxicity NED patients treated with IP have a median survival of over 9 years Weekly (dose-dense) paclitaxel improves outcome in one study Confirmatory North American trials recently completed Bevacizumab during and after chemotherapy improves PFS but not OS Case Discussions Case 1: A Newly Diagnosed Patient With Ovarian Cancer 58 year old real estate broker with controlled hypertension presents with a pelvic mass, omental caking, and a CA125 of 2,056. She has no malnutrition or change in her weight. She is a PS=0. What would you recommend for this patient? Neoadjuvant chemotherapy Primary radical debulking surgery
Slide 36 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R A N D O M I Z E n = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Placebo BEV 15 mg/kg II Stratification variables: GOG performance status (PS) Stage/debulking status RANDOM I Z E 1:1:1 15 months Paclitaxel (P) 175 mg/m2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 III Maintenance (16 cycles) BEV 15 mg/kg Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218: Investigator-assessed PFS + BEV (Arm II) CP (Arm I) *P-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 CA-125 to Determine Progression Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 Interim Survival Analysis Proportion Alive Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 48 aStratified analysis 625/625/623 442/432/437 173/162/171 46/39/40 No. at risk Burger RA et al. N Engl J Med. 2011;365:2473-2483. ICON7: Study Design Stratification variables: Stage/surgery Time since surgery GCIG group *Might vary based on GCIG group **Omit cycle 1 bevacizumab if <4 weeks from surgery Paclitaxel 175 mg/m2 Carboplatin AUC 6* AVASTIN Carboplatin AUC 6* Paclitaxel 175 mg/m2 Arm A Arm B 12 months Front-line EOC, PP or FT cancer Stage I-IIA (Gr 3 or CC) Stage IIB/C Stage III Stage IV n=1528 Bevacizumab 7.5 mg/kg ** Primary endpoints: PFS Secondary endpoints: OS, RR, safety, QOL, cost-effectiveness, translational No IRC present Perren T et al. N Engl J Med. 2011;365:2484-2496. Perren et al. ESMO 2010. ICON 7 Summary of Updated Results Kristensen G et al. J Clin Oncol. 2011;29: suppl; abstr LBA5006). Perren T et al. N Engl J Med. 2011;365:2484-2496. First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG 178—Investigating Paclitaxel as Consolidation Markman M et al. J Clin Oncol. 2003;21:2460-2465. 277 stage III/IV patients in complete clinical remission Paclitaxel 175 mg/m2 every 28 days × 3 months Paclitaxel 175 mg/m2 every 28 days × 12 months RANDOM I Z E CR = Complete response. Progression-free survival 0 20 40 60 80 100 0 12 24 36 48 Months after registration Paclitaxel 12 courses Paclitaxel 3 courses 110 At risk 112 Failed 20 34 Median, months 28 21 P = 0.0023 Percentage Markman M et al. J Clin Oncol. 2003;21:2460-2465. GOG 178 GOG-0212 Phase III Maintenance Therapy Trial Primary endpoint: survival Secondary endpoints: PFS, toxicity, QoL www.clinicaltrials.gov/ct2/show/NCT00108745. Macromolecular complex of paclitaxel poliglumex Patients with stage III/IV epithelial ovarian or primary peritoneal cancer, GOG PS ≤ 2, and complete response after surgery plus taxane and carboplatin (Planned n = 1400-1550) Paclitaxel Every 28 days for up to 12 courses No treatment Paclitaxel poliglumex Every 28 days for up to 12 courses Summary: Initial Treatment of Advanced Ovarian Cancer Surgery Attempt at maximal surgical cytoreduction Neoadjuvant chemo before surgery is an option for poor surgical candidates Chemotherapy 6-8 cycles taxane-platinum combination is standard IP admin benefits patients with low volume (optimal) disease but has increased toxicity NED patients treated with IP have a median survival of over 9 years Weekly (dose-dense) paclitaxel improves outcome in one study Confirmatory North American trials recently completed Bevacizumab during and after chemotherapy improves PFS but not OS Case Discussions Case 1: A Newly Diagnosed Patient With Ovarian Cancer 58 year old real estate broker with controlled hypertension presents with a pelvic mass, omental caking, and a CA125 of 2,056. She has no malnutrition or change in her weight. She is a PS=0. What would you recommend for this patient? Neoadjuvant chemotherapy Primary radical debulking surgery What Would You Recommend for This Patient? Neoadjuvant chemotherapy Primary radical debulking surgery
Slide 37 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R A N D O M I Z E n = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Placebo BEV 15 mg/kg II Stratification variables: GOG performance status (PS) Stage/debulking status RANDOM I Z E 1:1:1 15 months Paclitaxel (P) 175 mg/m2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 III Maintenance (16 cycles) BEV 15 mg/kg Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218: Investigator-assessed PFS + BEV (Arm II) CP (Arm I) *P-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 CA-125 to Determine Progression Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 Interim Survival Analysis Proportion Alive Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 48 aStratified analysis 625/625/623 442/432/437 173/162/171 46/39/40 No. at risk Burger RA et al. N Engl J Med. 2011;365:2473-2483. ICON7: Study Design Stratification variables: Stage/surgery Time since surgery GCIG group *Might vary based on GCIG group **Omit cycle 1 bevacizumab if <4 weeks from surgery Paclitaxel 175 mg/m2 Carboplatin AUC 6* AVASTIN Carboplatin AUC 6* Paclitaxel 175 mg/m2 Arm A Arm B 12 months Front-line EOC, PP or FT cancer Stage I-IIA (Gr 3 or CC) Stage IIB/C Stage III Stage IV n=1528 Bevacizumab 7.5 mg/kg ** Primary endpoints: PFS Secondary endpoints: OS, RR, safety, QOL, cost-effectiveness, translational No IRC present Perren T et al. N Engl J Med. 2011;365:2484-2496. Perren et al. ESMO 2010. ICON 7 Summary of Updated Results Kristensen G et al. J Clin Oncol. 2011;29: suppl; abstr LBA5006). Perren T et al. N Engl J Med. 2011;365:2484-2496. First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG 178—Investigating Paclitaxel as Consolidation Markman M et al. J Clin Oncol. 2003;21:2460-2465. 277 stage III/IV patients in complete clinical remission Paclitaxel 175 mg/m2 every 28 days × 3 months Paclitaxel 175 mg/m2 every 28 days × 12 months RANDOM I Z E CR = Complete response. Progression-free survival 0 20 40 60 80 100 0 12 24 36 48 Months after registration Paclitaxel 12 courses Paclitaxel 3 courses 110 At risk 112 Failed 20 34 Median, months 28 21 P = 0.0023 Percentage Markman M et al. J Clin Oncol. 2003;21:2460-2465. GOG 178 GOG-0212 Phase III Maintenance Therapy Trial Primary endpoint: survival Secondary endpoints: PFS, toxicity, QoL www.clinicaltrials.gov/ct2/show/NCT00108745. Macromolecular complex of paclitaxel poliglumex Patients with stage III/IV epithelial ovarian or primary peritoneal cancer, GOG PS ≤ 2, and complete response after surgery plus taxane and carboplatin (Planned n = 1400-1550) Paclitaxel Every 28 days for up to 12 courses No treatment Paclitaxel poliglumex Every 28 days for up to 12 courses Summary: Initial Treatment of Advanced Ovarian Cancer Surgery Attempt at maximal surgical cytoreduction Neoadjuvant chemo before surgery is an option for poor surgical candidates Chemotherapy 6-8 cycles taxane-platinum combination is standard IP admin benefits patients with low volume (optimal) disease but has increased toxicity NED patients treated with IP have a median survival of over 9 years Weekly (dose-dense) paclitaxel improves outcome in one study Confirmatory North American trials recently completed Bevacizumab during and after chemotherapy improves PFS but not OS Case Discussions Case 1: A Newly Diagnosed Patient With Ovarian Cancer 58 year old real estate broker with controlled hypertension presents with a pelvic mass, omental caking, and a CA125 of 2,056. She has no malnutrition or change in her weight. She is a PS=0. What would you recommend for this patient? Neoadjuvant chemotherapy Primary radical debulking surgery What Would You Recommend for This Patient? Neoadjuvant chemotherapy Primary radical debulking surgery Primary Cytoreduction Meta-analysis: 53 studies (1989–1998) 81 cohorts (Stage III/IV) n = 6885 patients Results Expert centers have high optimal rates Optimal vs not: 11 mos (50% increase) Each 10%  in cytoreduction = 5.5%  in survival Platinum intensity = NS Bristow. J Clin Oncol. 2002;20:1248.
Slide 38 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R A N D O M I Z E n = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Placebo BEV 15 mg/kg II Stratification variables: GOG performance status (PS) Stage/debulking status RANDOM I Z E 1:1:1 15 months Paclitaxel (P) 175 mg/m2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 III Maintenance (16 cycles) BEV 15 mg/kg Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218: Investigator-assessed PFS + BEV (Arm II) CP (Arm I) *P-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 CA-125 to Determine Progression Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 Interim Survival Analysis Proportion Alive Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 48 aStratified analysis 625/625/623 442/432/437 173/162/171 46/39/40 No. at risk Burger RA et al. N Engl J Med. 2011;365:2473-2483. ICON7: Study Design Stratification variables: Stage/surgery Time since surgery GCIG group *Might vary based on GCIG group **Omit cycle 1 bevacizumab if <4 weeks from surgery Paclitaxel 175 mg/m2 Carboplatin AUC 6* AVASTIN Carboplatin AUC 6* Paclitaxel 175 mg/m2 Arm A Arm B 12 months Front-line EOC, PP or FT cancer Stage I-IIA (Gr 3 or CC) Stage IIB/C Stage III Stage IV n=1528 Bevacizumab 7.5 mg/kg ** Primary endpoints: PFS Secondary endpoints: OS, RR, safety, QOL, cost-effectiveness, translational No IRC present Perren T et al. N Engl J Med. 2011;365:2484-2496. Perren et al. ESMO 2010. ICON 7 Summary of Updated Results Kristensen G et al. J Clin Oncol. 2011;29: suppl; abstr LBA5006). Perren T et al. N Engl J Med. 2011;365:2484-2496. First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG 178—Investigating Paclitaxel as Consolidation Markman M et al. J Clin Oncol. 2003;21:2460-2465. 277 stage III/IV patients in complete clinical remission Paclitaxel 175 mg/m2 every 28 days × 3 months Paclitaxel 175 mg/m2 every 28 days × 12 months RANDOM I Z E CR = Complete response. Progression-free survival 0 20 40 60 80 100 0 12 24 36 48 Months after registration Paclitaxel 12 courses Paclitaxel 3 courses 110 At risk 112 Failed 20 34 Median, months 28 21 P = 0.0023 Percentage Markman M et al. J Clin Oncol. 2003;21:2460-2465. GOG 178 GOG-0212 Phase III Maintenance Therapy Trial Primary endpoint: survival Secondary endpoints: PFS, toxicity, QoL www.clinicaltrials.gov/ct2/show/NCT00108745. Macromolecular complex of paclitaxel poliglumex Patients with stage III/IV epithelial ovarian or primary peritoneal cancer, GOG PS ≤ 2, and complete response after surgery plus taxane and carboplatin (Planned n = 1400-1550) Paclitaxel Every 28 days for up to 12 courses No treatment Paclitaxel poliglumex Every 28 days for up to 12 courses Summary: Initial Treatment of Advanced Ovarian Cancer Surgery Attempt at maximal surgical cytoreduction Neoadjuvant chemo before surgery is an option for poor surgical candidates Chemotherapy 6-8 cycles taxane-platinum combination is standard IP admin benefits patients with low volume (optimal) disease but has increased toxicity NED patients treated with IP have a median survival of over 9 years Weekly (dose-dense) paclitaxel improves outcome in one study Confirmatory North American trials recently completed Bevacizumab during and after chemotherapy improves PFS but not OS Case Discussions Case 1: A Newly Diagnosed Patient With Ovarian Cancer 58 year old real estate broker with controlled hypertension presents with a pelvic mass, omental caking, and a CA125 of 2,056. She has no malnutrition or change in her weight. She is a PS=0. What would you recommend for this patient? Neoadjuvant chemotherapy Primary radical debulking surgery What Would You Recommend for This Patient? Neoadjuvant chemotherapy Primary radical debulking surgery Primary Cytoreduction Meta-analysis: 53 studies (1989–1998) 81 cohorts (Stage III/IV) n = 6885 patients Results Expert centers have high optimal rates Optimal vs not: 11 mos (50% increase) Each 10%  in cytoreduction = 5.5%  in survival Platinum intensity = NS Bristow. J Clin Oncol. 2002;20:1248. The Impact of Residual Tumor: What Is Optimal Debulking? % Progression-Free Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.52 (2.26; 2.81) >10 mm vs 1 mm – 10 mm: 1.36 (1.24; 1.50) log-rank: P<0.0001 % Overall Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.70 (2.37; 3.07) >10 mm vs 1 mm – 10 mm: 1.34 (1.21; 1.49) log-rank: P<0.0001 Generated from 3 prospective Phase III trials (OVAR 3,5, & 7) n = 3126 pts DuBois. Cancer. 2009;115:1234.
Slide 39 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R A N D O M I Z E n = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Placebo BEV 15 mg/kg II Stratification variables: GOG performance status (PS) Stage/debulking status RANDOM I Z E 1:1:1 15 months Paclitaxel (P) 175 mg/m2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 III Maintenance (16 cycles) BEV 15 mg/kg Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218: Investigator-assessed PFS + BEV (Arm II) CP (Arm I) *P-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 CA-125 to Determine Progression Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 Interim Survival Analysis Proportion Alive Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 48 aStratified analysis 625/625/623 442/432/437 173/162/171 46/39/40 No. at risk Burger RA et al. N Engl J Med. 2011;365:2473-2483. ICON7: Study Design Stratification variables: Stage/surgery Time since surgery GCIG group *Might vary based on GCIG group **Omit cycle 1 bevacizumab if <4 weeks from surgery Paclitaxel 175 mg/m2 Carboplatin AUC 6* AVASTIN Carboplatin AUC 6* Paclitaxel 175 mg/m2 Arm A Arm B 12 months Front-line EOC, PP or FT cancer Stage I-IIA (Gr 3 or CC) Stage IIB/C Stage III Stage IV n=1528 Bevacizumab 7.5 mg/kg ** Primary endpoints: PFS Secondary endpoints: OS, RR, safety, QOL, cost-effectiveness, translational No IRC present Perren T et al. N Engl J Med. 2011;365:2484-2496. Perren et al. ESMO 2010. ICON 7 Summary of Updated Results Kristensen G et al. J Clin Oncol. 2011;29: suppl; abstr LBA5006). Perren T et al. N Engl J Med. 2011;365:2484-2496. First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG 178—Investigating Paclitaxel as Consolidation Markman M et al. J Clin Oncol. 2003;21:2460-2465. 277 stage III/IV patients in complete clinical remission Paclitaxel 175 mg/m2 every 28 days × 3 months Paclitaxel 175 mg/m2 every 28 days × 12 months RANDOM I Z E CR = Complete response. Progression-free survival 0 20 40 60 80 100 0 12 24 36 48 Months after registration Paclitaxel 12 courses Paclitaxel 3 courses 110 At risk 112 Failed 20 34 Median, months 28 21 P = 0.0023 Percentage Markman M et al. J Clin Oncol. 2003;21:2460-2465. GOG 178 GOG-0212 Phase III Maintenance Therapy Trial Primary endpoint: survival Secondary endpoints: PFS, toxicity, QoL www.clinicaltrials.gov/ct2/show/NCT00108745. Macromolecular complex of paclitaxel poliglumex Patients with stage III/IV epithelial ovarian or primary peritoneal cancer, GOG PS ≤ 2, and complete response after surgery plus taxane and carboplatin (Planned n = 1400-1550) Paclitaxel Every 28 days for up to 12 courses No treatment Paclitaxel poliglumex Every 28 days for up to 12 courses Summary: Initial Treatment of Advanced Ovarian Cancer Surgery Attempt at maximal surgical cytoreduction Neoadjuvant chemo before surgery is an option for poor surgical candidates Chemotherapy 6-8 cycles taxane-platinum combination is standard IP admin benefits patients with low volume (optimal) disease but has increased toxicity NED patients treated with IP have a median survival of over 9 years Weekly (dose-dense) paclitaxel improves outcome in one study Confirmatory North American trials recently completed Bevacizumab during and after chemotherapy improves PFS but not OS Case Discussions Case 1: A Newly Diagnosed Patient With Ovarian Cancer 58 year old real estate broker with controlled hypertension presents with a pelvic mass, omental caking, and a CA125 of 2,056. She has no malnutrition or change in her weight. She is a PS=0. What would you recommend for this patient? Neoadjuvant chemotherapy Primary radical debulking surgery What Would You Recommend for This Patient? Neoadjuvant chemotherapy Primary radical debulking surgery Primary Cytoreduction Meta-analysis: 53 studies (1989–1998) 81 cohorts (Stage III/IV) n = 6885 patients Results Expert centers have high optimal rates Optimal vs not: 11 mos (50% increase) Each 10%  in cytoreduction = 5.5%  in survival Platinum intensity = NS Bristow. J Clin Oncol. 2002;20:1248. The Impact of Residual Tumor: What Is Optimal Debulking? % Progression-Free Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.52 (2.26; 2.81) >10 mm vs 1 mm – 10 mm: 1.36 (1.24; 1.50) log-rank: P<0.0001 % Overall Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.70 (2.37; 3.07) >10 mm vs 1 mm – 10 mm: 1.34 (1.21; 1.49) log-rank: P<0.0001 Generated from 3 prospective Phase III trials (OVAR 3,5, & 7) n = 3126 pts DuBois. Cancer. 2009;115:1234. Case 1 She has a TAH BSO, transverse colectomy, omentectomy and spends 7 days in the hospital (2 in the ICU). Except for an open wound with a wound-vac and getting 4 units of blood, she does well… The pathology shows a high-grade serous carcinoma. The surgeon noted small volume residual (5-9mm) disease throughout the abdomen. What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP
Slide 40 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R A N D O M I Z E n = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Placebo BEV 15 mg/kg II Stratification variables: GOG performance status (PS) Stage/debulking status RANDOM I Z E 1:1:1 15 months Paclitaxel (P) 175 mg/m2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 III Maintenance (16 cycles) BEV 15 mg/kg Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218: Investigator-assessed PFS + BEV (Arm II) CP (Arm I) *P-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 CA-125 to Determine Progression Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 Interim Survival Analysis Proportion Alive Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 48 aStratified analysis 625/625/623 442/432/437 173/162/171 46/39/40 No. at risk Burger RA et al. N Engl J Med. 2011;365:2473-2483. ICON7: Study Design Stratification variables: Stage/surgery Time since surgery GCIG group *Might vary based on GCIG group **Omit cycle 1 bevacizumab if <4 weeks from surgery Paclitaxel 175 mg/m2 Carboplatin AUC 6* AVASTIN Carboplatin AUC 6* Paclitaxel 175 mg/m2 Arm A Arm B 12 months Front-line EOC, PP or FT cancer Stage I-IIA (Gr 3 or CC) Stage IIB/C Stage III Stage IV n=1528 Bevacizumab 7.5 mg/kg ** Primary endpoints: PFS Secondary endpoints: OS, RR, safety, QOL, cost-effectiveness, translational No IRC present Perren T et al. N Engl J Med. 2011;365:2484-2496. Perren et al. ESMO 2010. ICON 7 Summary of Updated Results Kristensen G et al. J Clin Oncol. 2011;29: suppl; abstr LBA5006). Perren T et al. N Engl J Med. 2011;365:2484-2496. First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG 178—Investigating Paclitaxel as Consolidation Markman M et al. J Clin Oncol. 2003;21:2460-2465. 277 stage III/IV patients in complete clinical remission Paclitaxel 175 mg/m2 every 28 days × 3 months Paclitaxel 175 mg/m2 every 28 days × 12 months RANDOM I Z E CR = Complete response. Progression-free survival 0 20 40 60 80 100 0 12 24 36 48 Months after registration Paclitaxel 12 courses Paclitaxel 3 courses 110 At risk 112 Failed 20 34 Median, months 28 21 P = 0.0023 Percentage Markman M et al. J Clin Oncol. 2003;21:2460-2465. GOG 178 GOG-0212 Phase III Maintenance Therapy Trial Primary endpoint: survival Secondary endpoints: PFS, toxicity, QoL www.clinicaltrials.gov/ct2/show/NCT00108745. Macromolecular complex of paclitaxel poliglumex Patients with stage III/IV epithelial ovarian or primary peritoneal cancer, GOG PS ≤ 2, and complete response after surgery plus taxane and carboplatin (Planned n = 1400-1550) Paclitaxel Every 28 days for up to 12 courses No treatment Paclitaxel poliglumex Every 28 days for up to 12 courses Summary: Initial Treatment of Advanced Ovarian Cancer Surgery Attempt at maximal surgical cytoreduction Neoadjuvant chemo before surgery is an option for poor surgical candidates Chemotherapy 6-8 cycles taxane-platinum combination is standard IP admin benefits patients with low volume (optimal) disease but has increased toxicity NED patients treated with IP have a median survival of over 9 years Weekly (dose-dense) paclitaxel improves outcome in one study Confirmatory North American trials recently completed Bevacizumab during and after chemotherapy improves PFS but not OS Case Discussions Case 1: A Newly Diagnosed Patient With Ovarian Cancer 58 year old real estate broker with controlled hypertension presents with a pelvic mass, omental caking, and a CA125 of 2,056. She has no malnutrition or change in her weight. She is a PS=0. What would you recommend for this patient? Neoadjuvant chemotherapy Primary radical debulking surgery What Would You Recommend for This Patient? Neoadjuvant chemotherapy Primary radical debulking surgery Primary Cytoreduction Meta-analysis: 53 studies (1989–1998) 81 cohorts (Stage III/IV) n = 6885 patients Results Expert centers have high optimal rates Optimal vs not: 11 mos (50% increase) Each 10%  in cytoreduction = 5.5%  in survival Platinum intensity = NS Bristow. J Clin Oncol. 2002;20:1248. The Impact of Residual Tumor: What Is Optimal Debulking? % Progression-Free Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.52 (2.26; 2.81) >10 mm vs 1 mm – 10 mm: 1.36 (1.24; 1.50) log-rank: P<0.0001 % Overall Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.70 (2.37; 3.07) >10 mm vs 1 mm – 10 mm: 1.34 (1.21; 1.49) log-rank: P<0.0001 Generated from 3 prospective Phase III trials (OVAR 3,5, & 7) n = 3126 pts DuBois. Cancer. 2009;115:1234. Case 1 She has a TAH BSO, transverse colectomy, omentectomy and spends 7 days in the hospital (2 in the ICU). Except for an open wound with a wound-vac and getting 4 units of blood, she does well… The pathology shows a high-grade serous carcinoma. The surgeon noted small volume residual (5-9mm) disease throughout the abdomen. What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP Case 1 Question 2 What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP All the above answers are reasonable treatment choices. When would you start the bevacizumab? Cycle 1, 2 or 3? After the chemotherapy (maintenance)?
Slide 41 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R A N D O M I Z E n = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Placebo BEV 15 mg/kg II Stratification variables: GOG performance status (PS) Stage/debulking status RANDOM I Z E 1:1:1 15 months Paclitaxel (P) 175 mg/m2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 III Maintenance (16 cycles) BEV 15 mg/kg Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218: Investigator-assessed PFS + BEV (Arm II) CP (Arm I) *P-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 CA-125 to Determine Progression Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 Interim Survival Analysis Proportion Alive Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 48 aStratified analysis 625/625/623 442/432/437 173/162/171 46/39/40 No. at risk Burger RA et al. N Engl J Med. 2011;365:2473-2483. ICON7: Study Design Stratification variables: Stage/surgery Time since surgery GCIG group *Might vary based on GCIG group **Omit cycle 1 bevacizumab if <4 weeks from surgery Paclitaxel 175 mg/m2 Carboplatin AUC 6* AVASTIN Carboplatin AUC 6* Paclitaxel 175 mg/m2 Arm A Arm B 12 months Front-line EOC, PP or FT cancer Stage I-IIA (Gr 3 or CC) Stage IIB/C Stage III Stage IV n=1528 Bevacizumab 7.5 mg/kg ** Primary endpoints: PFS Secondary endpoints: OS, RR, safety, QOL, cost-effectiveness, translational No IRC present Perren T et al. N Engl J Med. 2011;365:2484-2496. Perren et al. ESMO 2010. ICON 7 Summary of Updated Results Kristensen G et al. J Clin Oncol. 2011;29: suppl; abstr LBA5006). Perren T et al. N Engl J Med. 2011;365:2484-2496. First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG 178—Investigating Paclitaxel as Consolidation Markman M et al. J Clin Oncol. 2003;21:2460-2465. 277 stage III/IV patients in complete clinical remission Paclitaxel 175 mg/m2 every 28 days × 3 months Paclitaxel 175 mg/m2 every 28 days × 12 months RANDOM I Z E CR = Complete response. Progression-free survival 0 20 40 60 80 100 0 12 24 36 48 Months after registration Paclitaxel 12 courses Paclitaxel 3 courses 110 At risk 112 Failed 20 34 Median, months 28 21 P = 0.0023 Percentage Markman M et al. J Clin Oncol. 2003;21:2460-2465. GOG 178 GOG-0212 Phase III Maintenance Therapy Trial Primary endpoint: survival Secondary endpoints: PFS, toxicity, QoL www.clinicaltrials.gov/ct2/show/NCT00108745. Macromolecular complex of paclitaxel poliglumex Patients with stage III/IV epithelial ovarian or primary peritoneal cancer, GOG PS ≤ 2, and complete response after surgery plus taxane and carboplatin (Planned n = 1400-1550) Paclitaxel Every 28 days for up to 12 courses No treatment Paclitaxel poliglumex Every 28 days for up to 12 courses Summary: Initial Treatment of Advanced Ovarian Cancer Surgery Attempt at maximal surgical cytoreduction Neoadjuvant chemo before surgery is an option for poor surgical candidates Chemotherapy 6-8 cycles taxane-platinum combination is standard IP admin benefits patients with low volume (optimal) disease but has increased toxicity NED patients treated with IP have a median survival of over 9 years Weekly (dose-dense) paclitaxel improves outcome in one study Confirmatory North American trials recently completed Bevacizumab during and after chemotherapy improves PFS but not OS Case Discussions Case 1: A Newly Diagnosed Patient With Ovarian Cancer 58 year old real estate broker with controlled hypertension presents with a pelvic mass, omental caking, and a CA125 of 2,056. She has no malnutrition or change in her weight. She is a PS=0. What would you recommend for this patient? Neoadjuvant chemotherapy Primary radical debulking surgery What Would You Recommend for This Patient? Neoadjuvant chemotherapy Primary radical debulking surgery Primary Cytoreduction Meta-analysis: 53 studies (1989–1998) 81 cohorts (Stage III/IV) n = 6885 patients Results Expert centers have high optimal rates Optimal vs not: 11 mos (50% increase) Each 10%  in cytoreduction = 5.5%  in survival Platinum intensity = NS Bristow. J Clin Oncol. 2002;20:1248. The Impact of Residual Tumor: What Is Optimal Debulking? % Progression-Free Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.52 (2.26; 2.81) >10 mm vs 1 mm – 10 mm: 1.36 (1.24; 1.50) log-rank: P<0.0001 % Overall Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.70 (2.37; 3.07) >10 mm vs 1 mm – 10 mm: 1.34 (1.21; 1.49) log-rank: P<0.0001 Generated from 3 prospective Phase III trials (OVAR 3,5, & 7) n = 3126 pts DuBois. Cancer. 2009;115:1234. Case 1 She has a TAH BSO, transverse colectomy, omentectomy and spends 7 days in the hospital (2 in the ICU). Except for an open wound with a wound-vac and getting 4 units of blood, she does well… The pathology shows a high-grade serous carcinoma. The surgeon noted small volume residual (5-9mm) disease throughout the abdomen. What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP Case 1 Question 2 What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP All the above answers are reasonable treatment choices. When would you start the bevacizumab? Cycle 1, 2 or 3? After the chemotherapy (maintenance)? Case 2: Platinum Sensitive Ovarian Cancer 52-year-old woman with high-grade serous carcinoma of the fallopian tube Optimally debulked in 2010 Treated with IV paclitaxel, IP cisplatin and IP paclitaxel completed June 2011 CA125 at presentation 5800 nadir post therapy 7 In 2012 : Increasing Ca125 (1200) Imaging: diffuse peritoneal carcinomatosis; pleural nodularity; mediastinal adenopathy Symptomatic: abdominal bloating, early satiety, and mild shortness of breath Disease free interval: 10-12 months Genetic testing: BRCA1/2 negative
Slide 42 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R A N D O M I Z E n = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Placebo BEV 15 mg/kg II Stratification variables: GOG performance status (PS) Stage/debulking status RANDOM I Z E 1:1:1 15 months Paclitaxel (P) 175 mg/m2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 III Maintenance (16 cycles) BEV 15 mg/kg Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218: Investigator-assessed PFS + BEV (Arm II) CP (Arm I) *P-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 CA-125 to Determine Progression Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 Interim Survival Analysis Proportion Alive Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 48 aStratified analysis 625/625/623 442/432/437 173/162/171 46/39/40 No. at risk Burger RA et al. N Engl J Med. 2011;365:2473-2483. ICON7: Study Design Stratification variables: Stage/surgery Time since surgery GCIG group *Might vary based on GCIG group **Omit cycle 1 bevacizumab if <4 weeks from surgery Paclitaxel 175 mg/m2 Carboplatin AUC 6* AVASTIN Carboplatin AUC 6* Paclitaxel 175 mg/m2 Arm A Arm B 12 months Front-line EOC, PP or FT cancer Stage I-IIA (Gr 3 or CC) Stage IIB/C Stage III Stage IV n=1528 Bevacizumab 7.5 mg/kg ** Primary endpoints: PFS Secondary endpoints: OS, RR, safety, QOL, cost-effectiveness, translational No IRC present Perren T et al. N Engl J Med. 2011;365:2484-2496. Perren et al. ESMO 2010. ICON 7 Summary of Updated Results Kristensen G et al. J Clin Oncol. 2011;29: suppl; abstr LBA5006). Perren T et al. N Engl J Med. 2011;365:2484-2496. First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG 178—Investigating Paclitaxel as Consolidation Markman M et al. J Clin Oncol. 2003;21:2460-2465. 277 stage III/IV patients in complete clinical remission Paclitaxel 175 mg/m2 every 28 days × 3 months Paclitaxel 175 mg/m2 every 28 days × 12 months RANDOM I Z E CR = Complete response. Progression-free survival 0 20 40 60 80 100 0 12 24 36 48 Months after registration Paclitaxel 12 courses Paclitaxel 3 courses 110 At risk 112 Failed 20 34 Median, months 28 21 P = 0.0023 Percentage Markman M et al. J Clin Oncol. 2003;21:2460-2465. GOG 178 GOG-0212 Phase III Maintenance Therapy Trial Primary endpoint: survival Secondary endpoints: PFS, toxicity, QoL www.clinicaltrials.gov/ct2/show/NCT00108745. Macromolecular complex of paclitaxel poliglumex Patients with stage III/IV epithelial ovarian or primary peritoneal cancer, GOG PS ≤ 2, and complete response after surgery plus taxane and carboplatin (Planned n = 1400-1550) Paclitaxel Every 28 days for up to 12 courses No treatment Paclitaxel poliglumex Every 28 days for up to 12 courses Summary: Initial Treatment of Advanced Ovarian Cancer Surgery Attempt at maximal surgical cytoreduction Neoadjuvant chemo before surgery is an option for poor surgical candidates Chemotherapy 6-8 cycles taxane-platinum combination is standard IP admin benefits patients with low volume (optimal) disease but has increased toxicity NED patients treated with IP have a median survival of over 9 years Weekly (dose-dense) paclitaxel improves outcome in one study Confirmatory North American trials recently completed Bevacizumab during and after chemotherapy improves PFS but not OS Case Discussions Case 1: A Newly Diagnosed Patient With Ovarian Cancer 58 year old real estate broker with controlled hypertension presents with a pelvic mass, omental caking, and a CA125 of 2,056. She has no malnutrition or change in her weight. She is a PS=0. What would you recommend for this patient? Neoadjuvant chemotherapy Primary radical debulking surgery What Would You Recommend for This Patient? Neoadjuvant chemotherapy Primary radical debulking surgery Primary Cytoreduction Meta-analysis: 53 studies (1989–1998) 81 cohorts (Stage III/IV) n = 6885 patients Results Expert centers have high optimal rates Optimal vs not: 11 mos (50% increase) Each 10%  in cytoreduction = 5.5%  in survival Platinum intensity = NS Bristow. J Clin Oncol. 2002;20:1248. The Impact of Residual Tumor: What Is Optimal Debulking? % Progression-Free Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.52 (2.26; 2.81) >10 mm vs 1 mm – 10 mm: 1.36 (1.24; 1.50) log-rank: P<0.0001 % Overall Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.70 (2.37; 3.07) >10 mm vs 1 mm – 10 mm: 1.34 (1.21; 1.49) log-rank: P<0.0001 Generated from 3 prospective Phase III trials (OVAR 3,5, & 7) n = 3126 pts DuBois. Cancer. 2009;115:1234. Case 1 She has a TAH BSO, transverse colectomy, omentectomy and spends 7 days in the hospital (2 in the ICU). Except for an open wound with a wound-vac and getting 4 units of blood, she does well… The pathology shows a high-grade serous carcinoma. The surgeon noted small volume residual (5-9mm) disease throughout the abdomen. What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP Case 1 Question 2 What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP All the above answers are reasonable treatment choices. When would you start the bevacizumab? Cycle 1, 2 or 3? After the chemotherapy (maintenance)? Case 2: Platinum Sensitive Ovarian Cancer 52-year-old woman with high-grade serous carcinoma of the fallopian tube Optimally debulked in 2010 Treated with IV paclitaxel, IP cisplatin and IP paclitaxel completed June 2011 CA125 at presentation 5800 nadir post therapy 7 In 2012 : Increasing Ca125 (1200) Imaging: diffuse peritoneal carcinomatosis; pleural nodularity; mediastinal adenopathy Symptomatic: abdominal bloating, early satiety, and mild shortness of breath Disease free interval: 10-12 months Genetic testing: BRCA1/2 negative Case 2 Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin PLD, carboplatin and bevacizumab Gemcitabine and carboplatin Gemcitabine, carboplatin and bevacizumab Paclitaxel and carboplatin Weekly paclitaxel and carboplatin Paclitaxel, carboplatin and PARP inhibitor
Slide 43 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R A N D O M I Z E n = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Placebo BEV 15 mg/kg II Stratification variables: GOG performance status (PS) Stage/debulking status RANDOM I Z E 1:1:1 15 months Paclitaxel (P) 175 mg/m2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 III Maintenance (16 cycles) BEV 15 mg/kg Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218: Investigator-assessed PFS + BEV (Arm II) CP (Arm I) *P-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 CA-125 to Determine Progression Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 Interim Survival Analysis Proportion Alive Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 48 aStratified analysis 625/625/623 442/432/437 173/162/171 46/39/40 No. at risk Burger RA et al. N Engl J Med. 2011;365:2473-2483. ICON7: Study Design Stratification variables: Stage/surgery Time since surgery GCIG group *Might vary based on GCIG group **Omit cycle 1 bevacizumab if <4 weeks from surgery Paclitaxel 175 mg/m2 Carboplatin AUC 6* AVASTIN Carboplatin AUC 6* Paclitaxel 175 mg/m2 Arm A Arm B 12 months Front-line EOC, PP or FT cancer Stage I-IIA (Gr 3 or CC) Stage IIB/C Stage III Stage IV n=1528 Bevacizumab 7.5 mg/kg ** Primary endpoints: PFS Secondary endpoints: OS, RR, safety, QOL, cost-effectiveness, translational No IRC present Perren T et al. N Engl J Med. 2011;365:2484-2496. Perren et al. ESMO 2010. ICON 7 Summary of Updated Results Kristensen G et al. J Clin Oncol. 2011;29: suppl; abstr LBA5006). Perren T et al. N Engl J Med. 2011;365:2484-2496. First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG 178—Investigating Paclitaxel as Consolidation Markman M et al. J Clin Oncol. 2003;21:2460-2465. 277 stage III/IV patients in complete clinical remission Paclitaxel 175 mg/m2 every 28 days × 3 months Paclitaxel 175 mg/m2 every 28 days × 12 months RANDOM I Z E CR = Complete response. Progression-free survival 0 20 40 60 80 100 0 12 24 36 48 Months after registration Paclitaxel 12 courses Paclitaxel 3 courses 110 At risk 112 Failed 20 34 Median, months 28 21 P = 0.0023 Percentage Markman M et al. J Clin Oncol. 2003;21:2460-2465. GOG 178 GOG-0212 Phase III Maintenance Therapy Trial Primary endpoint: survival Secondary endpoints: PFS, toxicity, QoL www.clinicaltrials.gov/ct2/show/NCT00108745. Macromolecular complex of paclitaxel poliglumex Patients with stage III/IV epithelial ovarian or primary peritoneal cancer, GOG PS ≤ 2, and complete response after surgery plus taxane and carboplatin (Planned n = 1400-1550) Paclitaxel Every 28 days for up to 12 courses No treatment Paclitaxel poliglumex Every 28 days for up to 12 courses Summary: Initial Treatment of Advanced Ovarian Cancer Surgery Attempt at maximal surgical cytoreduction Neoadjuvant chemo before surgery is an option for poor surgical candidates Chemotherapy 6-8 cycles taxane-platinum combination is standard IP admin benefits patients with low volume (optimal) disease but has increased toxicity NED patients treated with IP have a median survival of over 9 years Weekly (dose-dense) paclitaxel improves outcome in one study Confirmatory North American trials recently completed Bevacizumab during and after chemotherapy improves PFS but not OS Case Discussions Case 1: A Newly Diagnosed Patient With Ovarian Cancer 58 year old real estate broker with controlled hypertension presents with a pelvic mass, omental caking, and a CA125 of 2,056. She has no malnutrition or change in her weight. She is a PS=0. What would you recommend for this patient? Neoadjuvant chemotherapy Primary radical debulking surgery What Would You Recommend for This Patient? Neoadjuvant chemotherapy Primary radical debulking surgery Primary Cytoreduction Meta-analysis: 53 studies (1989–1998) 81 cohorts (Stage III/IV) n = 6885 patients Results Expert centers have high optimal rates Optimal vs not: 11 mos (50% increase) Each 10%  in cytoreduction = 5.5%  in survival Platinum intensity = NS Bristow. J Clin Oncol. 2002;20:1248. The Impact of Residual Tumor: What Is Optimal Debulking? % Progression-Free Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.52 (2.26; 2.81) >10 mm vs 1 mm – 10 mm: 1.36 (1.24; 1.50) log-rank: P<0.0001 % Overall Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.70 (2.37; 3.07) >10 mm vs 1 mm – 10 mm: 1.34 (1.21; 1.49) log-rank: P<0.0001 Generated from 3 prospective Phase III trials (OVAR 3,5, & 7) n = 3126 pts DuBois. Cancer. 2009;115:1234. Case 1 She has a TAH BSO, transverse colectomy, omentectomy and spends 7 days in the hospital (2 in the ICU). Except for an open wound with a wound-vac and getting 4 units of blood, she does well… The pathology shows a high-grade serous carcinoma. The surgeon noted small volume residual (5-9mm) disease throughout the abdomen. What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP Case 1 Question 2 What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP All the above answers are reasonable treatment choices. When would you start the bevacizumab? Cycle 1, 2 or 3? After the chemotherapy (maintenance)? Case 2: Platinum Sensitive Ovarian Cancer 52-year-old woman with high-grade serous carcinoma of the fallopian tube Optimally debulked in 2010 Treated with IV paclitaxel, IP cisplatin and IP paclitaxel completed June 2011 CA125 at presentation 5800 nadir post therapy 7 In 2012 : Increasing Ca125 (1200) Imaging: diffuse peritoneal carcinomatosis; pleural nodularity; mediastinal adenopathy Symptomatic: abdominal bloating, early satiety, and mild shortness of breath Disease free interval: 10-12 months Genetic testing: BRCA1/2 negative Case 2 Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin PLD, carboplatin and bevacizumab Gemcitabine and carboplatin Gemcitabine, carboplatin and bevacizumab Paclitaxel and carboplatin Weekly paclitaxel and carboplatin Paclitaxel, carboplatin and PARP inhibitor Case 2, Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin (PLD and carboplatin is a reasonable option based on results of the CALYPSO study showing superiority to paclitaxel and carboplatin) PLD, carboplatin and bevacizumab (PLD, carboplatin and bevacizumab has not been tested in a randomized phase III trial) Gemcitabine and carboplatin (Gemcitabine and carboplatin: this is reasonable based on a comparison with carboplatin alone (Pfisterer et.al. 2005) Gemcitabine, carboplatin and bevacizumab (Higher response rates and improved PFS are seen when bevacizumab is added to gem/carbo but OS is not improved (OCEANS trial) Paclitaxel and carboplatin (Paclitaxel and carboplatin can be used but based on prior taxane and results of CALYPSO, is used less) Weekly paclitaxel and carboplatin (Weekly paclitaxel has shown improved outcome when used with carboplatin for newly diagnosed patients but has not been rigorously tested in recurrent disease Paclitaxel, carboplatin and PARP inhibitor (PARP inhibitors are not yet FDA approved , so can only be obtained on a clinical trial. However, this is a very promising direction in ovarian cancer and a clinical trial of paclitaxel and carboplatin +/- olaparib showed improved PFS (Oza et.al. ASCO 2012)
Slide 44 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R A N D O M I Z E n = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Placebo BEV 15 mg/kg II Stratification variables: GOG performance status (PS) Stage/debulking status RANDOM I Z E 1:1:1 15 months Paclitaxel (P) 175 mg/m2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 III Maintenance (16 cycles) BEV 15 mg/kg Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218: Investigator-assessed PFS + BEV (Arm II) CP (Arm I) *P-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 CA-125 to Determine Progression Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 Interim Survival Analysis Proportion Alive Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 48 aStratified analysis 625/625/623 442/432/437 173/162/171 46/39/40 No. at risk Burger RA et al. N Engl J Med. 2011;365:2473-2483. ICON7: Study Design Stratification variables: Stage/surgery Time since surgery GCIG group *Might vary based on GCIG group **Omit cycle 1 bevacizumab if <4 weeks from surgery Paclitaxel 175 mg/m2 Carboplatin AUC 6* AVASTIN Carboplatin AUC 6* Paclitaxel 175 mg/m2 Arm A Arm B 12 months Front-line EOC, PP or FT cancer Stage I-IIA (Gr 3 or CC) Stage IIB/C Stage III Stage IV n=1528 Bevacizumab 7.5 mg/kg ** Primary endpoints: PFS Secondary endpoints: OS, RR, safety, QOL, cost-effectiveness, translational No IRC present Perren T et al. N Engl J Med. 2011;365:2484-2496. Perren et al. ESMO 2010. ICON 7 Summary of Updated Results Kristensen G et al. J Clin Oncol. 2011;29: suppl; abstr LBA5006). Perren T et al. N Engl J Med. 2011;365:2484-2496. First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG 178—Investigating Paclitaxel as Consolidation Markman M et al. J Clin Oncol. 2003;21:2460-2465. 277 stage III/IV patients in complete clinical remission Paclitaxel 175 mg/m2 every 28 days × 3 months Paclitaxel 175 mg/m2 every 28 days × 12 months RANDOM I Z E CR = Complete response. Progression-free survival 0 20 40 60 80 100 0 12 24 36 48 Months after registration Paclitaxel 12 courses Paclitaxel 3 courses 110 At risk 112 Failed 20 34 Median, months 28 21 P = 0.0023 Percentage Markman M et al. J Clin Oncol. 2003;21:2460-2465. GOG 178 GOG-0212 Phase III Maintenance Therapy Trial Primary endpoint: survival Secondary endpoints: PFS, toxicity, QoL www.clinicaltrials.gov/ct2/show/NCT00108745. Macromolecular complex of paclitaxel poliglumex Patients with stage III/IV epithelial ovarian or primary peritoneal cancer, GOG PS ≤ 2, and complete response after surgery plus taxane and carboplatin (Planned n = 1400-1550) Paclitaxel Every 28 days for up to 12 courses No treatment Paclitaxel poliglumex Every 28 days for up to 12 courses Summary: Initial Treatment of Advanced Ovarian Cancer Surgery Attempt at maximal surgical cytoreduction Neoadjuvant chemo before surgery is an option for poor surgical candidates Chemotherapy 6-8 cycles taxane-platinum combination is standard IP admin benefits patients with low volume (optimal) disease but has increased toxicity NED patients treated with IP have a median survival of over 9 years Weekly (dose-dense) paclitaxel improves outcome in one study Confirmatory North American trials recently completed Bevacizumab during and after chemotherapy improves PFS but not OS Case Discussions Case 1: A Newly Diagnosed Patient With Ovarian Cancer 58 year old real estate broker with controlled hypertension presents with a pelvic mass, omental caking, and a CA125 of 2,056. She has no malnutrition or change in her weight. She is a PS=0. What would you recommend for this patient? Neoadjuvant chemotherapy Primary radical debulking surgery What Would You Recommend for This Patient? Neoadjuvant chemotherapy Primary radical debulking surgery Primary Cytoreduction Meta-analysis: 53 studies (1989–1998) 81 cohorts (Stage III/IV) n = 6885 patients Results Expert centers have high optimal rates Optimal vs not: 11 mos (50% increase) Each 10%  in cytoreduction = 5.5%  in survival Platinum intensity = NS Bristow. J Clin Oncol. 2002;20:1248. The Impact of Residual Tumor: What Is Optimal Debulking? % Progression-Free Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.52 (2.26; 2.81) >10 mm vs 1 mm – 10 mm: 1.36 (1.24; 1.50) log-rank: P<0.0001 % Overall Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.70 (2.37; 3.07) >10 mm vs 1 mm – 10 mm: 1.34 (1.21; 1.49) log-rank: P<0.0001 Generated from 3 prospective Phase III trials (OVAR 3,5, & 7) n = 3126 pts DuBois. Cancer. 2009;115:1234. Case 1 She has a TAH BSO, transverse colectomy, omentectomy and spends 7 days in the hospital (2 in the ICU). Except for an open wound with a wound-vac and getting 4 units of blood, she does well… The pathology shows a high-grade serous carcinoma. The surgeon noted small volume residual (5-9mm) disease throughout the abdomen. What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP Case 1 Question 2 What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP All the above answers are reasonable treatment choices. When would you start the bevacizumab? Cycle 1, 2 or 3? After the chemotherapy (maintenance)? Case 2: Platinum Sensitive Ovarian Cancer 52-year-old woman with high-grade serous carcinoma of the fallopian tube Optimally debulked in 2010 Treated with IV paclitaxel, IP cisplatin and IP paclitaxel completed June 2011 CA125 at presentation 5800 nadir post therapy 7 In 2012 : Increasing Ca125 (1200) Imaging: diffuse peritoneal carcinomatosis; pleural nodularity; mediastinal adenopathy Symptomatic: abdominal bloating, early satiety, and mild shortness of breath Disease free interval: 10-12 months Genetic testing: BRCA1/2 negative Case 2 Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin PLD, carboplatin and bevacizumab Gemcitabine and carboplatin Gemcitabine, carboplatin and bevacizumab Paclitaxel and carboplatin Weekly paclitaxel and carboplatin Paclitaxel, carboplatin and PARP inhibitor Case 2, Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin (PLD and carboplatin is a reasonable option based on results of the CALYPSO study showing superiority to paclitaxel and carboplatin) PLD, carboplatin and bevacizumab (PLD, carboplatin and bevacizumab has not been tested in a randomized phase III trial) Gemcitabine and carboplatin (Gemcitabine and carboplatin: this is reasonable based on a comparison with carboplatin alone (Pfisterer et.al. 2005) Gemcitabine, carboplatin and bevacizumab (Higher response rates and improved PFS are seen when bevacizumab is added to gem/carbo but OS is not improved (OCEANS trial) Paclitaxel and carboplatin (Paclitaxel and carboplatin can be used but based on prior taxane and results of CALYPSO, is used less) Weekly paclitaxel and carboplatin (Weekly paclitaxel has shown improved outcome when used with carboplatin for newly diagnosed patients but has not been rigorously tested in recurrent disease Paclitaxel, carboplatin and PARP inhibitor (PARP inhibitors are not yet FDA approved , so can only be obtained on a clinical trial. However, this is a very promising direction in ovarian cancer and a clinical trial of paclitaxel and carboplatin +/- olaparib showed improved PFS (Oza et.al. ASCO 2012) She Asks You Whether There Is Any Role for Surgery for Her Which of the following are true regarding secondary debulking? It is not considered for patients like her who relapse 10-12 months after completing initial chemotherapy The finding of carcinomatosis is a relatively strong contraindication to secondary debulking surgery Survival is improved for secondary debulking even if all disease can’t be removed at surgery Mediastinal and pleural disease are relatively strong contraindications to secondary debulking surgery 1 and 3 2 and 4 All of the above
Slide 45 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R A N D O M I Z E n = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Placebo BEV 15 mg/kg II Stratification variables: GOG performance status (PS) Stage/debulking status RANDOM I Z E 1:1:1 15 months Paclitaxel (P) 175 mg/m2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 III Maintenance (16 cycles) BEV 15 mg/kg Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218: Investigator-assessed PFS + BEV (Arm II) CP (Arm I) *P-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 CA-125 to Determine Progression Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 Interim Survival Analysis Proportion Alive Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 48 aStratified analysis 625/625/623 442/432/437 173/162/171 46/39/40 No. at risk Burger RA et al. N Engl J Med. 2011;365:2473-2483. ICON7: Study Design Stratification variables: Stage/surgery Time since surgery GCIG group *Might vary based on GCIG group **Omit cycle 1 bevacizumab if <4 weeks from surgery Paclitaxel 175 mg/m2 Carboplatin AUC 6* AVASTIN Carboplatin AUC 6* Paclitaxel 175 mg/m2 Arm A Arm B 12 months Front-line EOC, PP or FT cancer Stage I-IIA (Gr 3 or CC) Stage IIB/C Stage III Stage IV n=1528 Bevacizumab 7.5 mg/kg ** Primary endpoints: PFS Secondary endpoints: OS, RR, safety, QOL, cost-effectiveness, translational No IRC present Perren T et al. N Engl J Med. 2011;365:2484-2496. Perren et al. ESMO 2010. ICON 7 Summary of Updated Results Kristensen G et al. J Clin Oncol. 2011;29: suppl; abstr LBA5006). Perren T et al. N Engl J Med. 2011;365:2484-2496. First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG 178—Investigating Paclitaxel as Consolidation Markman M et al. J Clin Oncol. 2003;21:2460-2465. 277 stage III/IV patients in complete clinical remission Paclitaxel 175 mg/m2 every 28 days × 3 months Paclitaxel 175 mg/m2 every 28 days × 12 months RANDOM I Z E CR = Complete response. Progression-free survival 0 20 40 60 80 100 0 12 24 36 48 Months after registration Paclitaxel 12 courses Paclitaxel 3 courses 110 At risk 112 Failed 20 34 Median, months 28 21 P = 0.0023 Percentage Markman M et al. J Clin Oncol. 2003;21:2460-2465. GOG 178 GOG-0212 Phase III Maintenance Therapy Trial Primary endpoint: survival Secondary endpoints: PFS, toxicity, QoL www.clinicaltrials.gov/ct2/show/NCT00108745. Macromolecular complex of paclitaxel poliglumex Patients with stage III/IV epithelial ovarian or primary peritoneal cancer, GOG PS ≤ 2, and complete response after surgery plus taxane and carboplatin (Planned n = 1400-1550) Paclitaxel Every 28 days for up to 12 courses No treatment Paclitaxel poliglumex Every 28 days for up to 12 courses Summary: Initial Treatment of Advanced Ovarian Cancer Surgery Attempt at maximal surgical cytoreduction Neoadjuvant chemo before surgery is an option for poor surgical candidates Chemotherapy 6-8 cycles taxane-platinum combination is standard IP admin benefits patients with low volume (optimal) disease but has increased toxicity NED patients treated with IP have a median survival of over 9 years Weekly (dose-dense) paclitaxel improves outcome in one study Confirmatory North American trials recently completed Bevacizumab during and after chemotherapy improves PFS but not OS Case Discussions Case 1: A Newly Diagnosed Patient With Ovarian Cancer 58 year old real estate broker with controlled hypertension presents with a pelvic mass, omental caking, and a CA125 of 2,056. She has no malnutrition or change in her weight. She is a PS=0. What would you recommend for this patient? Neoadjuvant chemotherapy Primary radical debulking surgery What Would You Recommend for This Patient? Neoadjuvant chemotherapy Primary radical debulking surgery Primary Cytoreduction Meta-analysis: 53 studies (1989–1998) 81 cohorts (Stage III/IV) n = 6885 patients Results Expert centers have high optimal rates Optimal vs not: 11 mos (50% increase) Each 10%  in cytoreduction = 5.5%  in survival Platinum intensity = NS Bristow. J Clin Oncol. 2002;20:1248. The Impact of Residual Tumor: What Is Optimal Debulking? % Progression-Free Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.52 (2.26; 2.81) >10 mm vs 1 mm – 10 mm: 1.36 (1.24; 1.50) log-rank: P<0.0001 % Overall Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.70 (2.37; 3.07) >10 mm vs 1 mm – 10 mm: 1.34 (1.21; 1.49) log-rank: P<0.0001 Generated from 3 prospective Phase III trials (OVAR 3,5, & 7) n = 3126 pts DuBois. Cancer. 2009;115:1234. Case 1 She has a TAH BSO, transverse colectomy, omentectomy and spends 7 days in the hospital (2 in the ICU). Except for an open wound with a wound-vac and getting 4 units of blood, she does well… The pathology shows a high-grade serous carcinoma. The surgeon noted small volume residual (5-9mm) disease throughout the abdomen. What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP Case 1 Question 2 What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP All the above answers are reasonable treatment choices. When would you start the bevacizumab? Cycle 1, 2 or 3? After the chemotherapy (maintenance)? Case 2: Platinum Sensitive Ovarian Cancer 52-year-old woman with high-grade serous carcinoma of the fallopian tube Optimally debulked in 2010 Treated with IV paclitaxel, IP cisplatin and IP paclitaxel completed June 2011 CA125 at presentation 5800 nadir post therapy 7 In 2012 : Increasing Ca125 (1200) Imaging: diffuse peritoneal carcinomatosis; pleural nodularity; mediastinal adenopathy Symptomatic: abdominal bloating, early satiety, and mild shortness of breath Disease free interval: 10-12 months Genetic testing: BRCA1/2 negative Case 2 Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin PLD, carboplatin and bevacizumab Gemcitabine and carboplatin Gemcitabine, carboplatin and bevacizumab Paclitaxel and carboplatin Weekly paclitaxel and carboplatin Paclitaxel, carboplatin and PARP inhibitor Case 2, Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin (PLD and carboplatin is a reasonable option based on results of the CALYPSO study showing superiority to paclitaxel and carboplatin) PLD, carboplatin and bevacizumab (PLD, carboplatin and bevacizumab has not been tested in a randomized phase III trial) Gemcitabine and carboplatin (Gemcitabine and carboplatin: this is reasonable based on a comparison with carboplatin alone (Pfisterer et.al. 2005) Gemcitabine, carboplatin and bevacizumab (Higher response rates and improved PFS are seen when bevacizumab is added to gem/carbo but OS is not improved (OCEANS trial) Paclitaxel and carboplatin (Paclitaxel and carboplatin can be used but based on prior taxane and results of CALYPSO, is used less) Weekly paclitaxel and carboplatin (Weekly paclitaxel has shown improved outcome when used with carboplatin for newly diagnosed patients but has not been rigorously tested in recurrent disease Paclitaxel, carboplatin and PARP inhibitor (PARP inhibitors are not yet FDA approved , so can only be obtained on a clinical trial. However, this is a very promising direction in ovarian cancer and a clinical trial of paclitaxel and carboplatin +/- olaparib showed improved PFS (Oza et.al. ASCO 2012) She Asks You Whether There Is Any Role for Surgery for Her Which of the following are true regarding secondary debulking? It is not considered for patients like her who relapse 10-12 months after completing initial chemotherapy The finding of carcinomatosis is a relatively strong contraindication to secondary debulking surgery Survival is improved for secondary debulking even if all disease can’t be removed at surgery Mediastinal and pleural disease are relatively strong contraindications to secondary debulking surgery 1 and 3 2 and 4 All of the above Secondary Debulking Candidate Selection Onda et al. J Cancer. 2005;92:1026.
Slide 46 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R A N D O M I Z E n = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Placebo BEV 15 mg/kg II Stratification variables: GOG performance status (PS) Stage/debulking status RANDOM I Z E 1:1:1 15 months Paclitaxel (P) 175 mg/m2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 III Maintenance (16 cycles) BEV 15 mg/kg Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218: Investigator-assessed PFS + BEV (Arm II) CP (Arm I) *P-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 CA-125 to Determine Progression Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 Interim Survival Analysis Proportion Alive Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 48 aStratified analysis 625/625/623 442/432/437 173/162/171 46/39/40 No. at risk Burger RA et al. N Engl J Med. 2011;365:2473-2483. ICON7: Study Design Stratification variables: Stage/surgery Time since surgery GCIG group *Might vary based on GCIG group **Omit cycle 1 bevacizumab if <4 weeks from surgery Paclitaxel 175 mg/m2 Carboplatin AUC 6* AVASTIN Carboplatin AUC 6* Paclitaxel 175 mg/m2 Arm A Arm B 12 months Front-line EOC, PP or FT cancer Stage I-IIA (Gr 3 or CC) Stage IIB/C Stage III Stage IV n=1528 Bevacizumab 7.5 mg/kg ** Primary endpoints: PFS Secondary endpoints: OS, RR, safety, QOL, cost-effectiveness, translational No IRC present Perren T et al. N Engl J Med. 2011;365:2484-2496. Perren et al. ESMO 2010. ICON 7 Summary of Updated Results Kristensen G et al. J Clin Oncol. 2011;29: suppl; abstr LBA5006). Perren T et al. N Engl J Med. 2011;365:2484-2496. First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG 178—Investigating Paclitaxel as Consolidation Markman M et al. J Clin Oncol. 2003;21:2460-2465. 277 stage III/IV patients in complete clinical remission Paclitaxel 175 mg/m2 every 28 days × 3 months Paclitaxel 175 mg/m2 every 28 days × 12 months RANDOM I Z E CR = Complete response. Progression-free survival 0 20 40 60 80 100 0 12 24 36 48 Months after registration Paclitaxel 12 courses Paclitaxel 3 courses 110 At risk 112 Failed 20 34 Median, months 28 21 P = 0.0023 Percentage Markman M et al. J Clin Oncol. 2003;21:2460-2465. GOG 178 GOG-0212 Phase III Maintenance Therapy Trial Primary endpoint: survival Secondary endpoints: PFS, toxicity, QoL www.clinicaltrials.gov/ct2/show/NCT00108745. Macromolecular complex of paclitaxel poliglumex Patients with stage III/IV epithelial ovarian or primary peritoneal cancer, GOG PS ≤ 2, and complete response after surgery plus taxane and carboplatin (Planned n = 1400-1550) Paclitaxel Every 28 days for up to 12 courses No treatment Paclitaxel poliglumex Every 28 days for up to 12 courses Summary: Initial Treatment of Advanced Ovarian Cancer Surgery Attempt at maximal surgical cytoreduction Neoadjuvant chemo before surgery is an option for poor surgical candidates Chemotherapy 6-8 cycles taxane-platinum combination is standard IP admin benefits patients with low volume (optimal) disease but has increased toxicity NED patients treated with IP have a median survival of over 9 years Weekly (dose-dense) paclitaxel improves outcome in one study Confirmatory North American trials recently completed Bevacizumab during and after chemotherapy improves PFS but not OS Case Discussions Case 1: A Newly Diagnosed Patient With Ovarian Cancer 58 year old real estate broker with controlled hypertension presents with a pelvic mass, omental caking, and a CA125 of 2,056. She has no malnutrition or change in her weight. She is a PS=0. What would you recommend for this patient? Neoadjuvant chemotherapy Primary radical debulking surgery What Would You Recommend for This Patient? Neoadjuvant chemotherapy Primary radical debulking surgery Primary Cytoreduction Meta-analysis: 53 studies (1989–1998) 81 cohorts (Stage III/IV) n = 6885 patients Results Expert centers have high optimal rates Optimal vs not: 11 mos (50% increase) Each 10%  in cytoreduction = 5.5%  in survival Platinum intensity = NS Bristow. J Clin Oncol. 2002;20:1248. The Impact of Residual Tumor: What Is Optimal Debulking? % Progression-Free Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.52 (2.26; 2.81) >10 mm vs 1 mm – 10 mm: 1.36 (1.24; 1.50) log-rank: P<0.0001 % Overall Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.70 (2.37; 3.07) >10 mm vs 1 mm – 10 mm: 1.34 (1.21; 1.49) log-rank: P<0.0001 Generated from 3 prospective Phase III trials (OVAR 3,5, & 7) n = 3126 pts DuBois. Cancer. 2009;115:1234. Case 1 She has a TAH BSO, transverse colectomy, omentectomy and spends 7 days in the hospital (2 in the ICU). Except for an open wound with a wound-vac and getting 4 units of blood, she does well… The pathology shows a high-grade serous carcinoma. The surgeon noted small volume residual (5-9mm) disease throughout the abdomen. What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP Case 1 Question 2 What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP All the above answers are reasonable treatment choices. When would you start the bevacizumab? Cycle 1, 2 or 3? After the chemotherapy (maintenance)? Case 2: Platinum Sensitive Ovarian Cancer 52-year-old woman with high-grade serous carcinoma of the fallopian tube Optimally debulked in 2010 Treated with IV paclitaxel, IP cisplatin and IP paclitaxel completed June 2011 CA125 at presentation 5800 nadir post therapy 7 In 2012 : Increasing Ca125 (1200) Imaging: diffuse peritoneal carcinomatosis; pleural nodularity; mediastinal adenopathy Symptomatic: abdominal bloating, early satiety, and mild shortness of breath Disease free interval: 10-12 months Genetic testing: BRCA1/2 negative Case 2 Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin PLD, carboplatin and bevacizumab Gemcitabine and carboplatin Gemcitabine, carboplatin and bevacizumab Paclitaxel and carboplatin Weekly paclitaxel and carboplatin Paclitaxel, carboplatin and PARP inhibitor Case 2, Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin (PLD and carboplatin is a reasonable option based on results of the CALYPSO study showing superiority to paclitaxel and carboplatin) PLD, carboplatin and bevacizumab (PLD, carboplatin and bevacizumab has not been tested in a randomized phase III trial) Gemcitabine and carboplatin (Gemcitabine and carboplatin: this is reasonable based on a comparison with carboplatin alone (Pfisterer et.al. 2005) Gemcitabine, carboplatin and bevacizumab (Higher response rates and improved PFS are seen when bevacizumab is added to gem/carbo but OS is not improved (OCEANS trial) Paclitaxel and carboplatin (Paclitaxel and carboplatin can be used but based on prior taxane and results of CALYPSO, is used less) Weekly paclitaxel and carboplatin (Weekly paclitaxel has shown improved outcome when used with carboplatin for newly diagnosed patients but has not been rigorously tested in recurrent disease Paclitaxel, carboplatin and PARP inhibitor (PARP inhibitors are not yet FDA approved , so can only be obtained on a clinical trial. However, this is a very promising direction in ovarian cancer and a clinical trial of paclitaxel and carboplatin +/- olaparib showed improved PFS (Oza et.al. ASCO 2012) She Asks You Whether There Is Any Role for Surgery for Her Which of the following are true regarding secondary debulking? It is not considered for patients like her who relapse 10-12 months after completing initial chemotherapy The finding of carcinomatosis is a relatively strong contraindication to secondary debulking surgery Survival is improved for secondary debulking even if all disease can’t be removed at surgery Mediastinal and pleural disease are relatively strong contraindications to secondary debulking surgery 1 and 3 2 and 4 All of the above Secondary Debulking Candidate Selection Onda et al. J Cancer. 2005;92:1026. Pujade-Lauraine, Ann Oncol. 2011;22(Supplement 8):viii61–viii64.
Slide 47 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R A N D O M I Z E n = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Placebo BEV 15 mg/kg II Stratification variables: GOG performance status (PS) Stage/debulking status RANDOM I Z E 1:1:1 15 months Paclitaxel (P) 175 mg/m2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 III Maintenance (16 cycles) BEV 15 mg/kg Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218: Investigator-assessed PFS + BEV (Arm II) CP (Arm I) *P-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 CA-125 to Determine Progression Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 Interim Survival Analysis Proportion Alive Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 48 aStratified analysis 625/625/623 442/432/437 173/162/171 46/39/40 No. at risk Burger RA et al. N Engl J Med. 2011;365:2473-2483. ICON7: Study Design Stratification variables: Stage/surgery Time since surgery GCIG group *Might vary based on GCIG group **Omit cycle 1 bevacizumab if <4 weeks from surgery Paclitaxel 175 mg/m2 Carboplatin AUC 6* AVASTIN Carboplatin AUC 6* Paclitaxel 175 mg/m2 Arm A Arm B 12 months Front-line EOC, PP or FT cancer Stage I-IIA (Gr 3 or CC) Stage IIB/C Stage III Stage IV n=1528 Bevacizumab 7.5 mg/kg ** Primary endpoints: PFS Secondary endpoints: OS, RR, safety, QOL, cost-effectiveness, translational No IRC present Perren T et al. N Engl J Med. 2011;365:2484-2496. Perren et al. ESMO 2010. ICON 7 Summary of Updated Results Kristensen G et al. J Clin Oncol. 2011;29: suppl; abstr LBA5006). Perren T et al. N Engl J Med. 2011;365:2484-2496. First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG 178—Investigating Paclitaxel as Consolidation Markman M et al. J Clin Oncol. 2003;21:2460-2465. 277 stage III/IV patients in complete clinical remission Paclitaxel 175 mg/m2 every 28 days × 3 months Paclitaxel 175 mg/m2 every 28 days × 12 months RANDOM I Z E CR = Complete response. Progression-free survival 0 20 40 60 80 100 0 12 24 36 48 Months after registration Paclitaxel 12 courses Paclitaxel 3 courses 110 At risk 112 Failed 20 34 Median, months 28 21 P = 0.0023 Percentage Markman M et al. J Clin Oncol. 2003;21:2460-2465. GOG 178 GOG-0212 Phase III Maintenance Therapy Trial Primary endpoint: survival Secondary endpoints: PFS, toxicity, QoL www.clinicaltrials.gov/ct2/show/NCT00108745. Macromolecular complex of paclitaxel poliglumex Patients with stage III/IV epithelial ovarian or primary peritoneal cancer, GOG PS ≤ 2, and complete response after surgery plus taxane and carboplatin (Planned n = 1400-1550) Paclitaxel Every 28 days for up to 12 courses No treatment Paclitaxel poliglumex Every 28 days for up to 12 courses Summary: Initial Treatment of Advanced Ovarian Cancer Surgery Attempt at maximal surgical cytoreduction Neoadjuvant chemo before surgery is an option for poor surgical candidates Chemotherapy 6-8 cycles taxane-platinum combination is standard IP admin benefits patients with low volume (optimal) disease but has increased toxicity NED patients treated with IP have a median survival of over 9 years Weekly (dose-dense) paclitaxel improves outcome in one study Confirmatory North American trials recently completed Bevacizumab during and after chemotherapy improves PFS but not OS Case Discussions Case 1: A Newly Diagnosed Patient With Ovarian Cancer 58 year old real estate broker with controlled hypertension presents with a pelvic mass, omental caking, and a CA125 of 2,056. She has no malnutrition or change in her weight. She is a PS=0. What would you recommend for this patient? Neoadjuvant chemotherapy Primary radical debulking surgery What Would You Recommend for This Patient? Neoadjuvant chemotherapy Primary radical debulking surgery Primary Cytoreduction Meta-analysis: 53 studies (1989–1998) 81 cohorts (Stage III/IV) n = 6885 patients Results Expert centers have high optimal rates Optimal vs not: 11 mos (50% increase) Each 10%  in cytoreduction = 5.5%  in survival Platinum intensity = NS Bristow. J Clin Oncol. 2002;20:1248. The Impact of Residual Tumor: What Is Optimal Debulking? % Progression-Free Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.52 (2.26; 2.81) >10 mm vs 1 mm – 10 mm: 1.36 (1.24; 1.50) log-rank: P<0.0001 % Overall Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.70 (2.37; 3.07) >10 mm vs 1 mm – 10 mm: 1.34 (1.21; 1.49) log-rank: P<0.0001 Generated from 3 prospective Phase III trials (OVAR 3,5, & 7) n = 3126 pts DuBois. Cancer. 2009;115:1234. Case 1 She has a TAH BSO, transverse colectomy, omentectomy and spends 7 days in the hospital (2 in the ICU). Except for an open wound with a wound-vac and getting 4 units of blood, she does well… The pathology shows a high-grade serous carcinoma. The surgeon noted small volume residual (5-9mm) disease throughout the abdomen. What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP Case 1 Question 2 What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP All the above answers are reasonable treatment choices. When would you start the bevacizumab? Cycle 1, 2 or 3? After the chemotherapy (maintenance)? Case 2: Platinum Sensitive Ovarian Cancer 52-year-old woman with high-grade serous carcinoma of the fallopian tube Optimally debulked in 2010 Treated with IV paclitaxel, IP cisplatin and IP paclitaxel completed June 2011 CA125 at presentation 5800 nadir post therapy 7 In 2012 : Increasing Ca125 (1200) Imaging: diffuse peritoneal carcinomatosis; pleural nodularity; mediastinal adenopathy Symptomatic: abdominal bloating, early satiety, and mild shortness of breath Disease free interval: 10-12 months Genetic testing: BRCA1/2 negative Case 2 Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin PLD, carboplatin and bevacizumab Gemcitabine and carboplatin Gemcitabine, carboplatin and bevacizumab Paclitaxel and carboplatin Weekly paclitaxel and carboplatin Paclitaxel, carboplatin and PARP inhibitor Case 2, Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin (PLD and carboplatin is a reasonable option based on results of the CALYPSO study showing superiority to paclitaxel and carboplatin) PLD, carboplatin and bevacizumab (PLD, carboplatin and bevacizumab has not been tested in a randomized phase III trial) Gemcitabine and carboplatin (Gemcitabine and carboplatin: this is reasonable based on a comparison with carboplatin alone (Pfisterer et.al. 2005) Gemcitabine, carboplatin and bevacizumab (Higher response rates and improved PFS are seen when bevacizumab is added to gem/carbo but OS is not improved (OCEANS trial) Paclitaxel and carboplatin (Paclitaxel and carboplatin can be used but based on prior taxane and results of CALYPSO, is used less) Weekly paclitaxel and carboplatin (Weekly paclitaxel has shown improved outcome when used with carboplatin for newly diagnosed patients but has not been rigorously tested in recurrent disease Paclitaxel, carboplatin and PARP inhibitor (PARP inhibitors are not yet FDA approved , so can only be obtained on a clinical trial. However, this is a very promising direction in ovarian cancer and a clinical trial of paclitaxel and carboplatin +/- olaparib showed improved PFS (Oza et.al. ASCO 2012) She Asks You Whether There Is Any Role for Surgery for Her Which of the following are true regarding secondary debulking? It is not considered for patients like her who relapse 10-12 months after completing initial chemotherapy The finding of carcinomatosis is a relatively strong contraindication to secondary debulking surgery Survival is improved for secondary debulking even if all disease can’t be removed at surgery Mediastinal and pleural disease are relatively strong contraindications to secondary debulking surgery 1 and 3 2 and 4 All of the above Secondary Debulking Candidate Selection Onda et al. J Cancer. 2005;92:1026. Pujade-Lauraine, Ann Oncol. 2011;22(Supplement 8):viii61–viii64. RANDOM I Z E GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: ≤ 0.5 cm > 0.5-2 cm PLD 30 mg/m2 Carboplatin AUC = 5 q 28 days x 6 Paclitaxel 175 mg/m2 Carboplatin AUC = 5 q 21 days x 6 GCIG = Gynecologic Cancer Intergroup PFS = progression-free survival PLD = pegylated liposomal doxorubicin Accrual 864 pts PFS primary endpoint Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329.
Slide 48 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R A N D O M I Z E n = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Placebo BEV 15 mg/kg II Stratification variables: GOG performance status (PS) Stage/debulking status RANDOM I Z E 1:1:1 15 months Paclitaxel (P) 175 mg/m2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 III Maintenance (16 cycles) BEV 15 mg/kg Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218: Investigator-assessed PFS + BEV (Arm II) CP (Arm I) *P-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 CA-125 to Determine Progression Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 Interim Survival Analysis Proportion Alive Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 48 aStratified analysis 625/625/623 442/432/437 173/162/171 46/39/40 No. at risk Burger RA et al. N Engl J Med. 2011;365:2473-2483. ICON7: Study Design Stratification variables: Stage/surgery Time since surgery GCIG group *Might vary based on GCIG group **Omit cycle 1 bevacizumab if <4 weeks from surgery Paclitaxel 175 mg/m2 Carboplatin AUC 6* AVASTIN Carboplatin AUC 6* Paclitaxel 175 mg/m2 Arm A Arm B 12 months Front-line EOC, PP or FT cancer Stage I-IIA (Gr 3 or CC) Stage IIB/C Stage III Stage IV n=1528 Bevacizumab 7.5 mg/kg ** Primary endpoints: PFS Secondary endpoints: OS, RR, safety, QOL, cost-effectiveness, translational No IRC present Perren T et al. N Engl J Med. 2011;365:2484-2496. Perren et al. ESMO 2010. ICON 7 Summary of Updated Results Kristensen G et al. J Clin Oncol. 2011;29: suppl; abstr LBA5006). Perren T et al. N Engl J Med. 2011;365:2484-2496. First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG 178—Investigating Paclitaxel as Consolidation Markman M et al. J Clin Oncol. 2003;21:2460-2465. 277 stage III/IV patients in complete clinical remission Paclitaxel 175 mg/m2 every 28 days × 3 months Paclitaxel 175 mg/m2 every 28 days × 12 months RANDOM I Z E CR = Complete response. Progression-free survival 0 20 40 60 80 100 0 12 24 36 48 Months after registration Paclitaxel 12 courses Paclitaxel 3 courses 110 At risk 112 Failed 20 34 Median, months 28 21 P = 0.0023 Percentage Markman M et al. J Clin Oncol. 2003;21:2460-2465. GOG 178 GOG-0212 Phase III Maintenance Therapy Trial Primary endpoint: survival Secondary endpoints: PFS, toxicity, QoL www.clinicaltrials.gov/ct2/show/NCT00108745. Macromolecular complex of paclitaxel poliglumex Patients with stage III/IV epithelial ovarian or primary peritoneal cancer, GOG PS ≤ 2, and complete response after surgery plus taxane and carboplatin (Planned n = 1400-1550) Paclitaxel Every 28 days for up to 12 courses No treatment Paclitaxel poliglumex Every 28 days for up to 12 courses Summary: Initial Treatment of Advanced Ovarian Cancer Surgery Attempt at maximal surgical cytoreduction Neoadjuvant chemo before surgery is an option for poor surgical candidates Chemotherapy 6-8 cycles taxane-platinum combination is standard IP admin benefits patients with low volume (optimal) disease but has increased toxicity NED patients treated with IP have a median survival of over 9 years Weekly (dose-dense) paclitaxel improves outcome in one study Confirmatory North American trials recently completed Bevacizumab during and after chemotherapy improves PFS but not OS Case Discussions Case 1: A Newly Diagnosed Patient With Ovarian Cancer 58 year old real estate broker with controlled hypertension presents with a pelvic mass, omental caking, and a CA125 of 2,056. She has no malnutrition or change in her weight. She is a PS=0. What would you recommend for this patient? Neoadjuvant chemotherapy Primary radical debulking surgery What Would You Recommend for This Patient? Neoadjuvant chemotherapy Primary radical debulking surgery Primary Cytoreduction Meta-analysis: 53 studies (1989–1998) 81 cohorts (Stage III/IV) n = 6885 patients Results Expert centers have high optimal rates Optimal vs not: 11 mos (50% increase) Each 10%  in cytoreduction = 5.5%  in survival Platinum intensity = NS Bristow. J Clin Oncol. 2002;20:1248. The Impact of Residual Tumor: What Is Optimal Debulking? % Progression-Free Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.52 (2.26; 2.81) >10 mm vs 1 mm – 10 mm: 1.36 (1.24; 1.50) log-rank: P<0.0001 % Overall Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.70 (2.37; 3.07) >10 mm vs 1 mm – 10 mm: 1.34 (1.21; 1.49) log-rank: P<0.0001 Generated from 3 prospective Phase III trials (OVAR 3,5, & 7) n = 3126 pts DuBois. Cancer. 2009;115:1234. Case 1 She has a TAH BSO, transverse colectomy, omentectomy and spends 7 days in the hospital (2 in the ICU). Except for an open wound with a wound-vac and getting 4 units of blood, she does well… The pathology shows a high-grade serous carcinoma. The surgeon noted small volume residual (5-9mm) disease throughout the abdomen. What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP Case 1 Question 2 What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP All the above answers are reasonable treatment choices. When would you start the bevacizumab? Cycle 1, 2 or 3? After the chemotherapy (maintenance)? Case 2: Platinum Sensitive Ovarian Cancer 52-year-old woman with high-grade serous carcinoma of the fallopian tube Optimally debulked in 2010 Treated with IV paclitaxel, IP cisplatin and IP paclitaxel completed June 2011 CA125 at presentation 5800 nadir post therapy 7 In 2012 : Increasing Ca125 (1200) Imaging: diffuse peritoneal carcinomatosis; pleural nodularity; mediastinal adenopathy Symptomatic: abdominal bloating, early satiety, and mild shortness of breath Disease free interval: 10-12 months Genetic testing: BRCA1/2 negative Case 2 Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin PLD, carboplatin and bevacizumab Gemcitabine and carboplatin Gemcitabine, carboplatin and bevacizumab Paclitaxel and carboplatin Weekly paclitaxel and carboplatin Paclitaxel, carboplatin and PARP inhibitor Case 2, Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin (PLD and carboplatin is a reasonable option based on results of the CALYPSO study showing superiority to paclitaxel and carboplatin) PLD, carboplatin and bevacizumab (PLD, carboplatin and bevacizumab has not been tested in a randomized phase III trial) Gemcitabine and carboplatin (Gemcitabine and carboplatin: this is reasonable based on a comparison with carboplatin alone (Pfisterer et.al. 2005) Gemcitabine, carboplatin and bevacizumab (Higher response rates and improved PFS are seen when bevacizumab is added to gem/carbo but OS is not improved (OCEANS trial) Paclitaxel and carboplatin (Paclitaxel and carboplatin can be used but based on prior taxane and results of CALYPSO, is used less) Weekly paclitaxel and carboplatin (Weekly paclitaxel has shown improved outcome when used with carboplatin for newly diagnosed patients but has not been rigorously tested in recurrent disease Paclitaxel, carboplatin and PARP inhibitor (PARP inhibitors are not yet FDA approved , so can only be obtained on a clinical trial. However, this is a very promising direction in ovarian cancer and a clinical trial of paclitaxel and carboplatin +/- olaparib showed improved PFS (Oza et.al. ASCO 2012) She Asks You Whether There Is Any Role for Surgery for Her Which of the following are true regarding secondary debulking? It is not considered for patients like her who relapse 10-12 months after completing initial chemotherapy The finding of carcinomatosis is a relatively strong contraindication to secondary debulking surgery Survival is improved for secondary debulking even if all disease can’t be removed at surgery Mediastinal and pleural disease are relatively strong contraindications to secondary debulking surgery 1 and 3 2 and 4 All of the above Secondary Debulking Candidate Selection Onda et al. J Cancer. 2005;92:1026. Pujade-Lauraine, Ann Oncol. 2011;22(Supplement 8):viii61–viii64. RANDOM I Z E GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: ≤ 0.5 cm > 0.5-2 cm PLD 30 mg/m2 Carboplatin AUC = 5 q 28 days x 6 Paclitaxel 175 mg/m2 Carboplatin AUC = 5 q 21 days x 6 GCIG = Gynecologic Cancer Intergroup PFS = progression-free survival PLD = pegylated liposomal doxorubicin Accrual 864 pts PFS primary endpoint Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. GCIG CALYPSO Trial Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329.
Slide 49 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R A N D O M I Z E n = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Placebo BEV 15 mg/kg II Stratification variables: GOG performance status (PS) Stage/debulking status RANDOM I Z E 1:1:1 15 months Paclitaxel (P) 175 mg/m2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 III Maintenance (16 cycles) BEV 15 mg/kg Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218: Investigator-assessed PFS + BEV (Arm II) CP (Arm I) *P-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 CA-125 to Determine Progression Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 Interim Survival Analysis Proportion Alive Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 48 aStratified analysis 625/625/623 442/432/437 173/162/171 46/39/40 No. at risk Burger RA et al. N Engl J Med. 2011;365:2473-2483. ICON7: Study Design Stratification variables: Stage/surgery Time since surgery GCIG group *Might vary based on GCIG group **Omit cycle 1 bevacizumab if <4 weeks from surgery Paclitaxel 175 mg/m2 Carboplatin AUC 6* AVASTIN Carboplatin AUC 6* Paclitaxel 175 mg/m2 Arm A Arm B 12 months Front-line EOC, PP or FT cancer Stage I-IIA (Gr 3 or CC) Stage IIB/C Stage III Stage IV n=1528 Bevacizumab 7.5 mg/kg ** Primary endpoints: PFS Secondary endpoints: OS, RR, safety, QOL, cost-effectiveness, translational No IRC present Perren T et al. N Engl J Med. 2011;365:2484-2496. Perren et al. ESMO 2010. ICON 7 Summary of Updated Results Kristensen G et al. J Clin Oncol. 2011;29: suppl; abstr LBA5006). Perren T et al. N Engl J Med. 2011;365:2484-2496. First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG 178—Investigating Paclitaxel as Consolidation Markman M et al. J Clin Oncol. 2003;21:2460-2465. 277 stage III/IV patients in complete clinical remission Paclitaxel 175 mg/m2 every 28 days × 3 months Paclitaxel 175 mg/m2 every 28 days × 12 months RANDOM I Z E CR = Complete response. Progression-free survival 0 20 40 60 80 100 0 12 24 36 48 Months after registration Paclitaxel 12 courses Paclitaxel 3 courses 110 At risk 112 Failed 20 34 Median, months 28 21 P = 0.0023 Percentage Markman M et al. J Clin Oncol. 2003;21:2460-2465. GOG 178 GOG-0212 Phase III Maintenance Therapy Trial Primary endpoint: survival Secondary endpoints: PFS, toxicity, QoL www.clinicaltrials.gov/ct2/show/NCT00108745. Macromolecular complex of paclitaxel poliglumex Patients with stage III/IV epithelial ovarian or primary peritoneal cancer, GOG PS ≤ 2, and complete response after surgery plus taxane and carboplatin (Planned n = 1400-1550) Paclitaxel Every 28 days for up to 12 courses No treatment Paclitaxel poliglumex Every 28 days for up to 12 courses Summary: Initial Treatment of Advanced Ovarian Cancer Surgery Attempt at maximal surgical cytoreduction Neoadjuvant chemo before surgery is an option for poor surgical candidates Chemotherapy 6-8 cycles taxane-platinum combination is standard IP admin benefits patients with low volume (optimal) disease but has increased toxicity NED patients treated with IP have a median survival of over 9 years Weekly (dose-dense) paclitaxel improves outcome in one study Confirmatory North American trials recently completed Bevacizumab during and after chemotherapy improves PFS but not OS Case Discussions Case 1: A Newly Diagnosed Patient With Ovarian Cancer 58 year old real estate broker with controlled hypertension presents with a pelvic mass, omental caking, and a CA125 of 2,056. She has no malnutrition or change in her weight. She is a PS=0. What would you recommend for this patient? Neoadjuvant chemotherapy Primary radical debulking surgery What Would You Recommend for This Patient? Neoadjuvant chemotherapy Primary radical debulking surgery Primary Cytoreduction Meta-analysis: 53 studies (1989–1998) 81 cohorts (Stage III/IV) n = 6885 patients Results Expert centers have high optimal rates Optimal vs not: 11 mos (50% increase) Each 10%  in cytoreduction = 5.5%  in survival Platinum intensity = NS Bristow. J Clin Oncol. 2002;20:1248. The Impact of Residual Tumor: What Is Optimal Debulking? % Progression-Free Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.52 (2.26; 2.81) >10 mm vs 1 mm – 10 mm: 1.36 (1.24; 1.50) log-rank: P<0.0001 % Overall Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.70 (2.37; 3.07) >10 mm vs 1 mm – 10 mm: 1.34 (1.21; 1.49) log-rank: P<0.0001 Generated from 3 prospective Phase III trials (OVAR 3,5, & 7) n = 3126 pts DuBois. Cancer. 2009;115:1234. Case 1 She has a TAH BSO, transverse colectomy, omentectomy and spends 7 days in the hospital (2 in the ICU). Except for an open wound with a wound-vac and getting 4 units of blood, she does well… The pathology shows a high-grade serous carcinoma. The surgeon noted small volume residual (5-9mm) disease throughout the abdomen. What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP Case 1 Question 2 What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP All the above answers are reasonable treatment choices. When would you start the bevacizumab? Cycle 1, 2 or 3? After the chemotherapy (maintenance)? Case 2: Platinum Sensitive Ovarian Cancer 52-year-old woman with high-grade serous carcinoma of the fallopian tube Optimally debulked in 2010 Treated with IV paclitaxel, IP cisplatin and IP paclitaxel completed June 2011 CA125 at presentation 5800 nadir post therapy 7 In 2012 : Increasing Ca125 (1200) Imaging: diffuse peritoneal carcinomatosis; pleural nodularity; mediastinal adenopathy Symptomatic: abdominal bloating, early satiety, and mild shortness of breath Disease free interval: 10-12 months Genetic testing: BRCA1/2 negative Case 2 Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin PLD, carboplatin and bevacizumab Gemcitabine and carboplatin Gemcitabine, carboplatin and bevacizumab Paclitaxel and carboplatin Weekly paclitaxel and carboplatin Paclitaxel, carboplatin and PARP inhibitor Case 2, Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin (PLD and carboplatin is a reasonable option based on results of the CALYPSO study showing superiority to paclitaxel and carboplatin) PLD, carboplatin and bevacizumab (PLD, carboplatin and bevacizumab has not been tested in a randomized phase III trial) Gemcitabine and carboplatin (Gemcitabine and carboplatin: this is reasonable based on a comparison with carboplatin alone (Pfisterer et.al. 2005) Gemcitabine, carboplatin and bevacizumab (Higher response rates and improved PFS are seen when bevacizumab is added to gem/carbo but OS is not improved (OCEANS trial) Paclitaxel and carboplatin (Paclitaxel and carboplatin can be used but based on prior taxane and results of CALYPSO, is used less) Weekly paclitaxel and carboplatin (Weekly paclitaxel has shown improved outcome when used with carboplatin for newly diagnosed patients but has not been rigorously tested in recurrent disease Paclitaxel, carboplatin and PARP inhibitor (PARP inhibitors are not yet FDA approved , so can only be obtained on a clinical trial. However, this is a very promising direction in ovarian cancer and a clinical trial of paclitaxel and carboplatin +/- olaparib showed improved PFS (Oza et.al. ASCO 2012) She Asks You Whether There Is Any Role for Surgery for Her Which of the following are true regarding secondary debulking? It is not considered for patients like her who relapse 10-12 months after completing initial chemotherapy The finding of carcinomatosis is a relatively strong contraindication to secondary debulking surgery Survival is improved for secondary debulking even if all disease can’t be removed at surgery Mediastinal and pleural disease are relatively strong contraindications to secondary debulking surgery 1 and 3 2 and 4 All of the above Secondary Debulking Candidate Selection Onda et al. J Cancer. 2005;92:1026. Pujade-Lauraine, Ann Oncol. 2011;22(Supplement 8):viii61–viii64. RANDOM I Z E GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: ≤ 0.5 cm > 0.5-2 cm PLD 30 mg/m2 Carboplatin AUC = 5 q 28 days x 6 Paclitaxel 175 mg/m2 Carboplatin AUC = 5 q 21 days x 6 GCIG = Gynecologic Cancer Intergroup PFS = progression-free survival PLD = pegylated liposomal doxorubicin Accrual 864 pts PFS primary endpoint Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. GCIG CALYPSO Trial Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. Selected Non-hematologic Toxicities During Treatment Alopecia *P< 0.001 Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329.
Slide 50 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R A N D O M I Z E n = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Placebo BEV 15 mg/kg II Stratification variables: GOG performance status (PS) Stage/debulking status RANDOM I Z E 1:1:1 15 months Paclitaxel (P) 175 mg/m2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 III Maintenance (16 cycles) BEV 15 mg/kg Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218: Investigator-assessed PFS + BEV (Arm II) CP (Arm I) *P-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 CA-125 to Determine Progression Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 Interim Survival Analysis Proportion Alive Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 48 aStratified analysis 625/625/623 442/432/437 173/162/171 46/39/40 No. at risk Burger RA et al. N Engl J Med. 2011;365:2473-2483. ICON7: Study Design Stratification variables: Stage/surgery Time since surgery GCIG group *Might vary based on GCIG group **Omit cycle 1 bevacizumab if <4 weeks from surgery Paclitaxel 175 mg/m2 Carboplatin AUC 6* AVASTIN Carboplatin AUC 6* Paclitaxel 175 mg/m2 Arm A Arm B 12 months Front-line EOC, PP or FT cancer Stage I-IIA (Gr 3 or CC) Stage IIB/C Stage III Stage IV n=1528 Bevacizumab 7.5 mg/kg ** Primary endpoints: PFS Secondary endpoints: OS, RR, safety, QOL, cost-effectiveness, translational No IRC present Perren T et al. N Engl J Med. 2011;365:2484-2496. Perren et al. ESMO 2010. ICON 7 Summary of Updated Results Kristensen G et al. J Clin Oncol. 2011;29: suppl; abstr LBA5006). Perren T et al. N Engl J Med. 2011;365:2484-2496. First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG 178—Investigating Paclitaxel as Consolidation Markman M et al. J Clin Oncol. 2003;21:2460-2465. 277 stage III/IV patients in complete clinical remission Paclitaxel 175 mg/m2 every 28 days × 3 months Paclitaxel 175 mg/m2 every 28 days × 12 months RANDOM I Z E CR = Complete response. Progression-free survival 0 20 40 60 80 100 0 12 24 36 48 Months after registration Paclitaxel 12 courses Paclitaxel 3 courses 110 At risk 112 Failed 20 34 Median, months 28 21 P = 0.0023 Percentage Markman M et al. J Clin Oncol. 2003;21:2460-2465. GOG 178 GOG-0212 Phase III Maintenance Therapy Trial Primary endpoint: survival Secondary endpoints: PFS, toxicity, QoL www.clinicaltrials.gov/ct2/show/NCT00108745. Macromolecular complex of paclitaxel poliglumex Patients with stage III/IV epithelial ovarian or primary peritoneal cancer, GOG PS ≤ 2, and complete response after surgery plus taxane and carboplatin (Planned n = 1400-1550) Paclitaxel Every 28 days for up to 12 courses No treatment Paclitaxel poliglumex Every 28 days for up to 12 courses Summary: Initial Treatment of Advanced Ovarian Cancer Surgery Attempt at maximal surgical cytoreduction Neoadjuvant chemo before surgery is an option for poor surgical candidates Chemotherapy 6-8 cycles taxane-platinum combination is standard IP admin benefits patients with low volume (optimal) disease but has increased toxicity NED patients treated with IP have a median survival of over 9 years Weekly (dose-dense) paclitaxel improves outcome in one study Confirmatory North American trials recently completed Bevacizumab during and after chemotherapy improves PFS but not OS Case Discussions Case 1: A Newly Diagnosed Patient With Ovarian Cancer 58 year old real estate broker with controlled hypertension presents with a pelvic mass, omental caking, and a CA125 of 2,056. She has no malnutrition or change in her weight. She is a PS=0. What would you recommend for this patient? Neoadjuvant chemotherapy Primary radical debulking surgery What Would You Recommend for This Patient? Neoadjuvant chemotherapy Primary radical debulking surgery Primary Cytoreduction Meta-analysis: 53 studies (1989–1998) 81 cohorts (Stage III/IV) n = 6885 patients Results Expert centers have high optimal rates Optimal vs not: 11 mos (50% increase) Each 10%  in cytoreduction = 5.5%  in survival Platinum intensity = NS Bristow. J Clin Oncol. 2002;20:1248. The Impact of Residual Tumor: What Is Optimal Debulking? % Progression-Free Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.52 (2.26; 2.81) >10 mm vs 1 mm – 10 mm: 1.36 (1.24; 1.50) log-rank: P<0.0001 % Overall Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.70 (2.37; 3.07) >10 mm vs 1 mm – 10 mm: 1.34 (1.21; 1.49) log-rank: P<0.0001 Generated from 3 prospective Phase III trials (OVAR 3,5, & 7) n = 3126 pts DuBois. Cancer. 2009;115:1234. Case 1 She has a TAH BSO, transverse colectomy, omentectomy and spends 7 days in the hospital (2 in the ICU). Except for an open wound with a wound-vac and getting 4 units of blood, she does well… The pathology shows a high-grade serous carcinoma. The surgeon noted small volume residual (5-9mm) disease throughout the abdomen. What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP Case 1 Question 2 What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP All the above answers are reasonable treatment choices. When would you start the bevacizumab? Cycle 1, 2 or 3? After the chemotherapy (maintenance)? Case 2: Platinum Sensitive Ovarian Cancer 52-year-old woman with high-grade serous carcinoma of the fallopian tube Optimally debulked in 2010 Treated with IV paclitaxel, IP cisplatin and IP paclitaxel completed June 2011 CA125 at presentation 5800 nadir post therapy 7 In 2012 : Increasing Ca125 (1200) Imaging: diffuse peritoneal carcinomatosis; pleural nodularity; mediastinal adenopathy Symptomatic: abdominal bloating, early satiety, and mild shortness of breath Disease free interval: 10-12 months Genetic testing: BRCA1/2 negative Case 2 Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin PLD, carboplatin and bevacizumab Gemcitabine and carboplatin Gemcitabine, carboplatin and bevacizumab Paclitaxel and carboplatin Weekly paclitaxel and carboplatin Paclitaxel, carboplatin and PARP inhibitor Case 2, Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin (PLD and carboplatin is a reasonable option based on results of the CALYPSO study showing superiority to paclitaxel and carboplatin) PLD, carboplatin and bevacizumab (PLD, carboplatin and bevacizumab has not been tested in a randomized phase III trial) Gemcitabine and carboplatin (Gemcitabine and carboplatin: this is reasonable based on a comparison with carboplatin alone (Pfisterer et.al. 2005) Gemcitabine, carboplatin and bevacizumab (Higher response rates and improved PFS are seen when bevacizumab is added to gem/carbo but OS is not improved (OCEANS trial) Paclitaxel and carboplatin (Paclitaxel and carboplatin can be used but based on prior taxane and results of CALYPSO, is used less) Weekly paclitaxel and carboplatin (Weekly paclitaxel has shown improved outcome when used with carboplatin for newly diagnosed patients but has not been rigorously tested in recurrent disease Paclitaxel, carboplatin and PARP inhibitor (PARP inhibitors are not yet FDA approved , so can only be obtained on a clinical trial. However, this is a very promising direction in ovarian cancer and a clinical trial of paclitaxel and carboplatin +/- olaparib showed improved PFS (Oza et.al. ASCO 2012) She Asks You Whether There Is Any Role for Surgery for Her Which of the following are true regarding secondary debulking? It is not considered for patients like her who relapse 10-12 months after completing initial chemotherapy The finding of carcinomatosis is a relatively strong contraindication to secondary debulking surgery Survival is improved for secondary debulking even if all disease can’t be removed at surgery Mediastinal and pleural disease are relatively strong contraindications to secondary debulking surgery 1 and 3 2 and 4 All of the above Secondary Debulking Candidate Selection Onda et al. J Cancer. 2005;92:1026. Pujade-Lauraine, Ann Oncol. 2011;22(Supplement 8):viii61–viii64. RANDOM I Z E GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: ≤ 0.5 cm > 0.5-2 cm PLD 30 mg/m2 Carboplatin AUC = 5 q 28 days x 6 Paclitaxel 175 mg/m2 Carboplatin AUC = 5 q 21 days x 6 GCIG = Gynecologic Cancer Intergroup PFS = progression-free survival PLD = pegylated liposomal doxorubicin Accrual 864 pts PFS primary endpoint Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. GCIG CALYPSO Trial Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. Selected Non-hematologic Toxicities During Treatment Alopecia *P< 0.001 Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. Targeted Agents in Ovarian Cancer Signaling/Angiogenesis Bevacizumab/Aflibercept RTKI’s: Pazopanib Cabozantinib Sorafenib, etc Cediranib Nintedanib Trebananib, MEDI-3617 PI3K/Akt/mTOR MEKi Folate: Vintafolide (EC-145) Farletuzumab NKTR-102 Taxanes/epothilones Immunotherapy – vaccines and inducers EP-100 PARPi ErbB3
Slide 51 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R A N D O M I Z E n = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Placebo BEV 15 mg/kg II Stratification variables: GOG performance status (PS) Stage/debulking status RANDOM I Z E 1:1:1 15 months Paclitaxel (P) 175 mg/m2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 III Maintenance (16 cycles) BEV 15 mg/kg Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218: Investigator-assessed PFS + BEV (Arm II) CP (Arm I) *P-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 CA-125 to Determine Progression Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 Interim Survival Analysis Proportion Alive Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 48 aStratified analysis 625/625/623 442/432/437 173/162/171 46/39/40 No. at risk Burger RA et al. N Engl J Med. 2011;365:2473-2483. ICON7: Study Design Stratification variables: Stage/surgery Time since surgery GCIG group *Might vary based on GCIG group **Omit cycle 1 bevacizumab if <4 weeks from surgery Paclitaxel 175 mg/m2 Carboplatin AUC 6* AVASTIN Carboplatin AUC 6* Paclitaxel 175 mg/m2 Arm A Arm B 12 months Front-line EOC, PP or FT cancer Stage I-IIA (Gr 3 or CC) Stage IIB/C Stage III Stage IV n=1528 Bevacizumab 7.5 mg/kg ** Primary endpoints: PFS Secondary endpoints: OS, RR, safety, QOL, cost-effectiveness, translational No IRC present Perren T et al. N Engl J Med. 2011;365:2484-2496. Perren et al. ESMO 2010. ICON 7 Summary of Updated Results Kristensen G et al. J Clin Oncol. 2011;29: suppl; abstr LBA5006). Perren T et al. N Engl J Med. 2011;365:2484-2496. First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG 178—Investigating Paclitaxel as Consolidation Markman M et al. J Clin Oncol. 2003;21:2460-2465. 277 stage III/IV patients in complete clinical remission Paclitaxel 175 mg/m2 every 28 days × 3 months Paclitaxel 175 mg/m2 every 28 days × 12 months RANDOM I Z E CR = Complete response. Progression-free survival 0 20 40 60 80 100 0 12 24 36 48 Months after registration Paclitaxel 12 courses Paclitaxel 3 courses 110 At risk 112 Failed 20 34 Median, months 28 21 P = 0.0023 Percentage Markman M et al. J Clin Oncol. 2003;21:2460-2465. GOG 178 GOG-0212 Phase III Maintenance Therapy Trial Primary endpoint: survival Secondary endpoints: PFS, toxicity, QoL www.clinicaltrials.gov/ct2/show/NCT00108745. Macromolecular complex of paclitaxel poliglumex Patients with stage III/IV epithelial ovarian or primary peritoneal cancer, GOG PS ≤ 2, and complete response after surgery plus taxane and carboplatin (Planned n = 1400-1550) Paclitaxel Every 28 days for up to 12 courses No treatment Paclitaxel poliglumex Every 28 days for up to 12 courses Summary: Initial Treatment of Advanced Ovarian Cancer Surgery Attempt at maximal surgical cytoreduction Neoadjuvant chemo before surgery is an option for poor surgical candidates Chemotherapy 6-8 cycles taxane-platinum combination is standard IP admin benefits patients with low volume (optimal) disease but has increased toxicity NED patients treated with IP have a median survival of over 9 years Weekly (dose-dense) paclitaxel improves outcome in one study Confirmatory North American trials recently completed Bevacizumab during and after chemotherapy improves PFS but not OS Case Discussions Case 1: A Newly Diagnosed Patient With Ovarian Cancer 58 year old real estate broker with controlled hypertension presents with a pelvic mass, omental caking, and a CA125 of 2,056. She has no malnutrition or change in her weight. She is a PS=0. What would you recommend for this patient? Neoadjuvant chemotherapy Primary radical debulking surgery What Would You Recommend for This Patient? Neoadjuvant chemotherapy Primary radical debulking surgery Primary Cytoreduction Meta-analysis: 53 studies (1989–1998) 81 cohorts (Stage III/IV) n = 6885 patients Results Expert centers have high optimal rates Optimal vs not: 11 mos (50% increase) Each 10%  in cytoreduction = 5.5%  in survival Platinum intensity = NS Bristow. J Clin Oncol. 2002;20:1248. The Impact of Residual Tumor: What Is Optimal Debulking? % Progression-Free Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.52 (2.26; 2.81) >10 mm vs 1 mm – 10 mm: 1.36 (1.24; 1.50) log-rank: P<0.0001 % Overall Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.70 (2.37; 3.07) >10 mm vs 1 mm – 10 mm: 1.34 (1.21; 1.49) log-rank: P<0.0001 Generated from 3 prospective Phase III trials (OVAR 3,5, & 7) n = 3126 pts DuBois. Cancer. 2009;115:1234. Case 1 She has a TAH BSO, transverse colectomy, omentectomy and spends 7 days in the hospital (2 in the ICU). Except for an open wound with a wound-vac and getting 4 units of blood, she does well… The pathology shows a high-grade serous carcinoma. The surgeon noted small volume residual (5-9mm) disease throughout the abdomen. What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP Case 1 Question 2 What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP All the above answers are reasonable treatment choices. When would you start the bevacizumab? Cycle 1, 2 or 3? After the chemotherapy (maintenance)? Case 2: Platinum Sensitive Ovarian Cancer 52-year-old woman with high-grade serous carcinoma of the fallopian tube Optimally debulked in 2010 Treated with IV paclitaxel, IP cisplatin and IP paclitaxel completed June 2011 CA125 at presentation 5800 nadir post therapy 7 In 2012 : Increasing Ca125 (1200) Imaging: diffuse peritoneal carcinomatosis; pleural nodularity; mediastinal adenopathy Symptomatic: abdominal bloating, early satiety, and mild shortness of breath Disease free interval: 10-12 months Genetic testing: BRCA1/2 negative Case 2 Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin PLD, carboplatin and bevacizumab Gemcitabine and carboplatin Gemcitabine, carboplatin and bevacizumab Paclitaxel and carboplatin Weekly paclitaxel and carboplatin Paclitaxel, carboplatin and PARP inhibitor Case 2, Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin (PLD and carboplatin is a reasonable option based on results of the CALYPSO study showing superiority to paclitaxel and carboplatin) PLD, carboplatin and bevacizumab (PLD, carboplatin and bevacizumab has not been tested in a randomized phase III trial) Gemcitabine and carboplatin (Gemcitabine and carboplatin: this is reasonable based on a comparison with carboplatin alone (Pfisterer et.al. 2005) Gemcitabine, carboplatin and bevacizumab (Higher response rates and improved PFS are seen when bevacizumab is added to gem/carbo but OS is not improved (OCEANS trial) Paclitaxel and carboplatin (Paclitaxel and carboplatin can be used but based on prior taxane and results of CALYPSO, is used less) Weekly paclitaxel and carboplatin (Weekly paclitaxel has shown improved outcome when used with carboplatin for newly diagnosed patients but has not been rigorously tested in recurrent disease Paclitaxel, carboplatin and PARP inhibitor (PARP inhibitors are not yet FDA approved , so can only be obtained on a clinical trial. However, this is a very promising direction in ovarian cancer and a clinical trial of paclitaxel and carboplatin +/- olaparib showed improved PFS (Oza et.al. ASCO 2012) She Asks You Whether There Is Any Role for Surgery for Her Which of the following are true regarding secondary debulking? It is not considered for patients like her who relapse 10-12 months after completing initial chemotherapy The finding of carcinomatosis is a relatively strong contraindication to secondary debulking surgery Survival is improved for secondary debulking even if all disease can’t be removed at surgery Mediastinal and pleural disease are relatively strong contraindications to secondary debulking surgery 1 and 3 2 and 4 All of the above Secondary Debulking Candidate Selection Onda et al. J Cancer. 2005;92:1026. Pujade-Lauraine, Ann Oncol. 2011;22(Supplement 8):viii61–viii64. RANDOM I Z E GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: ≤ 0.5 cm > 0.5-2 cm PLD 30 mg/m2 Carboplatin AUC = 5 q 28 days x 6 Paclitaxel 175 mg/m2 Carboplatin AUC = 5 q 21 days x 6 GCIG = Gynecologic Cancer Intergroup PFS = progression-free survival PLD = pegylated liposomal doxorubicin Accrual 864 pts PFS primary endpoint Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. GCIG CALYPSO Trial Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. Selected Non-hematologic Toxicities During Treatment Alopecia *P< 0.001 Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. Targeted Agents in Ovarian Cancer Signaling/Angiogenesis Bevacizumab/Aflibercept RTKI’s: Pazopanib Cabozantinib Sorafenib, etc Cediranib Nintedanib Trebananib, MEDI-3617 PI3K/Akt/mTOR MEKi Folate: Vintafolide (EC-145) Farletuzumab NKTR-102 Taxanes/epothilones Immunotherapy – vaccines and inducers EP-100 PARPi ErbB3 CG + PL OCEANS: Study schema CG for 6 (up to 10) cycles Stratification variables: Platinum-free interval (6–12 vs >12 months) Cytoreductive surgery for recurrent disease (yes vs no) Platinum-sensitive recurrent OCa Measurable disease ECOG 0/1 No prior chemo for recurrent OC No prior BV (n=484) BV = bevacizumab; PL = placebo aEpithelial ovarian, primary peritoneal, or fallopian tube cancer G 1000 mg/m2, d1 & 8 C AUC 4 PL q3w until progression C AUC 4 BV 15 mg/kg q3w until progression G 1000 mg/m2, d1 & 8 CG + BV Aghajanian C et al. J Clin Oncol. 2012;30:2039-2045.
Slide 52 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R A N D O M I Z E n = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Placebo BEV 15 mg/kg II Stratification variables: GOG performance status (PS) Stage/debulking status RANDOM I Z E 1:1:1 15 months Paclitaxel (P) 175 mg/m2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 III Maintenance (16 cycles) BEV 15 mg/kg Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218: Investigator-assessed PFS + BEV (Arm II) CP (Arm I) *P-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 CA-125 to Determine Progression Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 Interim Survival Analysis Proportion Alive Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 48 aStratified analysis 625/625/623 442/432/437 173/162/171 46/39/40 No. at risk Burger RA et al. N Engl J Med. 2011;365:2473-2483. ICON7: Study Design Stratification variables: Stage/surgery Time since surgery GCIG group *Might vary based on GCIG group **Omit cycle 1 bevacizumab if <4 weeks from surgery Paclitaxel 175 mg/m2 Carboplatin AUC 6* AVASTIN Carboplatin AUC 6* Paclitaxel 175 mg/m2 Arm A Arm B 12 months Front-line EOC, PP or FT cancer Stage I-IIA (Gr 3 or CC) Stage IIB/C Stage III Stage IV n=1528 Bevacizumab 7.5 mg/kg ** Primary endpoints: PFS Secondary endpoints: OS, RR, safety, QOL, cost-effectiveness, translational No IRC present Perren T et al. N Engl J Med. 2011;365:2484-2496. Perren et al. ESMO 2010. ICON 7 Summary of Updated Results Kristensen G et al. J Clin Oncol. 2011;29: suppl; abstr LBA5006). Perren T et al. N Engl J Med. 2011;365:2484-2496. First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG 178—Investigating Paclitaxel as Consolidation Markman M et al. J Clin Oncol. 2003;21:2460-2465. 277 stage III/IV patients in complete clinical remission Paclitaxel 175 mg/m2 every 28 days × 3 months Paclitaxel 175 mg/m2 every 28 days × 12 months RANDOM I Z E CR = Complete response. Progression-free survival 0 20 40 60 80 100 0 12 24 36 48 Months after registration Paclitaxel 12 courses Paclitaxel 3 courses 110 At risk 112 Failed 20 34 Median, months 28 21 P = 0.0023 Percentage Markman M et al. J Clin Oncol. 2003;21:2460-2465. GOG 178 GOG-0212 Phase III Maintenance Therapy Trial Primary endpoint: survival Secondary endpoints: PFS, toxicity, QoL www.clinicaltrials.gov/ct2/show/NCT00108745. Macromolecular complex of paclitaxel poliglumex Patients with stage III/IV epithelial ovarian or primary peritoneal cancer, GOG PS ≤ 2, and complete response after surgery plus taxane and carboplatin (Planned n = 1400-1550) Paclitaxel Every 28 days for up to 12 courses No treatment Paclitaxel poliglumex Every 28 days for up to 12 courses Summary: Initial Treatment of Advanced Ovarian Cancer Surgery Attempt at maximal surgical cytoreduction Neoadjuvant chemo before surgery is an option for poor surgical candidates Chemotherapy 6-8 cycles taxane-platinum combination is standard IP admin benefits patients with low volume (optimal) disease but has increased toxicity NED patients treated with IP have a median survival of over 9 years Weekly (dose-dense) paclitaxel improves outcome in one study Confirmatory North American trials recently completed Bevacizumab during and after chemotherapy improves PFS but not OS Case Discussions Case 1: A Newly Diagnosed Patient With Ovarian Cancer 58 year old real estate broker with controlled hypertension presents with a pelvic mass, omental caking, and a CA125 of 2,056. She has no malnutrition or change in her weight. She is a PS=0. What would you recommend for this patient? Neoadjuvant chemotherapy Primary radical debulking surgery What Would You Recommend for This Patient? Neoadjuvant chemotherapy Primary radical debulking surgery Primary Cytoreduction Meta-analysis: 53 studies (1989–1998) 81 cohorts (Stage III/IV) n = 6885 patients Results Expert centers have high optimal rates Optimal vs not: 11 mos (50% increase) Each 10%  in cytoreduction = 5.5%  in survival Platinum intensity = NS Bristow. J Clin Oncol. 2002;20:1248. The Impact of Residual Tumor: What Is Optimal Debulking? % Progression-Free Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.52 (2.26; 2.81) >10 mm vs 1 mm – 10 mm: 1.36 (1.24; 1.50) log-rank: P<0.0001 % Overall Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.70 (2.37; 3.07) >10 mm vs 1 mm – 10 mm: 1.34 (1.21; 1.49) log-rank: P<0.0001 Generated from 3 prospective Phase III trials (OVAR 3,5, & 7) n = 3126 pts DuBois. Cancer. 2009;115:1234. Case 1 She has a TAH BSO, transverse colectomy, omentectomy and spends 7 days in the hospital (2 in the ICU). Except for an open wound with a wound-vac and getting 4 units of blood, she does well… The pathology shows a high-grade serous carcinoma. The surgeon noted small volume residual (5-9mm) disease throughout the abdomen. What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP Case 1 Question 2 What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP All the above answers are reasonable treatment choices. When would you start the bevacizumab? Cycle 1, 2 or 3? After the chemotherapy (maintenance)? Case 2: Platinum Sensitive Ovarian Cancer 52-year-old woman with high-grade serous carcinoma of the fallopian tube Optimally debulked in 2010 Treated with IV paclitaxel, IP cisplatin and IP paclitaxel completed June 2011 CA125 at presentation 5800 nadir post therapy 7 In 2012 : Increasing Ca125 (1200) Imaging: diffuse peritoneal carcinomatosis; pleural nodularity; mediastinal adenopathy Symptomatic: abdominal bloating, early satiety, and mild shortness of breath Disease free interval: 10-12 months Genetic testing: BRCA1/2 negative Case 2 Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin PLD, carboplatin and bevacizumab Gemcitabine and carboplatin Gemcitabine, carboplatin and bevacizumab Paclitaxel and carboplatin Weekly paclitaxel and carboplatin Paclitaxel, carboplatin and PARP inhibitor Case 2, Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin (PLD and carboplatin is a reasonable option based on results of the CALYPSO study showing superiority to paclitaxel and carboplatin) PLD, carboplatin and bevacizumab (PLD, carboplatin and bevacizumab has not been tested in a randomized phase III trial) Gemcitabine and carboplatin (Gemcitabine and carboplatin: this is reasonable based on a comparison with carboplatin alone (Pfisterer et.al. 2005) Gemcitabine, carboplatin and bevacizumab (Higher response rates and improved PFS are seen when bevacizumab is added to gem/carbo but OS is not improved (OCEANS trial) Paclitaxel and carboplatin (Paclitaxel and carboplatin can be used but based on prior taxane and results of CALYPSO, is used less) Weekly paclitaxel and carboplatin (Weekly paclitaxel has shown improved outcome when used with carboplatin for newly diagnosed patients but has not been rigorously tested in recurrent disease Paclitaxel, carboplatin and PARP inhibitor (PARP inhibitors are not yet FDA approved , so can only be obtained on a clinical trial. However, this is a very promising direction in ovarian cancer and a clinical trial of paclitaxel and carboplatin +/- olaparib showed improved PFS (Oza et.al. ASCO 2012) She Asks You Whether There Is Any Role for Surgery for Her Which of the following are true regarding secondary debulking? It is not considered for patients like her who relapse 10-12 months after completing initial chemotherapy The finding of carcinomatosis is a relatively strong contraindication to secondary debulking surgery Survival is improved for secondary debulking even if all disease can’t be removed at surgery Mediastinal and pleural disease are relatively strong contraindications to secondary debulking surgery 1 and 3 2 and 4 All of the above Secondary Debulking Candidate Selection Onda et al. J Cancer. 2005;92:1026. Pujade-Lauraine, Ann Oncol. 2011;22(Supplement 8):viii61–viii64. RANDOM I Z E GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: ≤ 0.5 cm > 0.5-2 cm PLD 30 mg/m2 Carboplatin AUC = 5 q 28 days x 6 Paclitaxel 175 mg/m2 Carboplatin AUC = 5 q 21 days x 6 GCIG = Gynecologic Cancer Intergroup PFS = progression-free survival PLD = pegylated liposomal doxorubicin Accrual 864 pts PFS primary endpoint Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. GCIG CALYPSO Trial Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. Selected Non-hematologic Toxicities During Treatment Alopecia *P< 0.001 Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. Targeted Agents in Ovarian Cancer Signaling/Angiogenesis Bevacizumab/Aflibercept RTKI’s: Pazopanib Cabozantinib Sorafenib, etc Cediranib Nintedanib Trebananib, MEDI-3617 PI3K/Akt/mTOR MEKi Folate: Vintafolide (EC-145) Farletuzumab NKTR-102 Taxanes/epothilones Immunotherapy – vaccines and inducers EP-100 PARPi ErbB3 CG + PL OCEANS: Study schema CG for 6 (up to 10) cycles Stratification variables: Platinum-free interval (6–12 vs >12 months) Cytoreductive surgery for recurrent disease (yes vs no) Platinum-sensitive recurrent OCa Measurable disease ECOG 0/1 No prior chemo for recurrent OC No prior BV (n=484) BV = bevacizumab; PL = placebo aEpithelial ovarian, primary peritoneal, or fallopian tube cancer G 1000 mg/m2, d1 & 8 C AUC 4 PL q3w until progression C AUC 4 BV 15 mg/kg q3w until progression G 1000 mg/m2, d1 & 8 CG + BV Aghajanian C et al. J Clin Oncol. 2012;30:2039-2045. 242 177 45 11 3 0 CG + PL OCEANS: Primary Analysis of PFS Months No. at risk 242 203 92 33 11 0 CG + BV 1.0 0.8 0.6 0.4 0.2 0 Proportion progression free 0 6 12 18 24 30 Aghajanian C et al. J Clin Oncol. 2012;30:2039-2045.
Slide 53 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R A N D O M I Z E n = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Placebo BEV 15 mg/kg II Stratification variables: GOG performance status (PS) Stage/debulking status RANDOM I Z E 1:1:1 15 months Paclitaxel (P) 175 mg/m2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 III Maintenance (16 cycles) BEV 15 mg/kg Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218: Investigator-assessed PFS + BEV (Arm II) CP (Arm I) *P-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 CA-125 to Determine Progression Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 Interim Survival Analysis Proportion Alive Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 48 aStratified analysis 625/625/623 442/432/437 173/162/171 46/39/40 No. at risk Burger RA et al. N Engl J Med. 2011;365:2473-2483. ICON7: Study Design Stratification variables: Stage/surgery Time since surgery GCIG group *Might vary based on GCIG group **Omit cycle 1 bevacizumab if <4 weeks from surgery Paclitaxel 175 mg/m2 Carboplatin AUC 6* AVASTIN Carboplatin AUC 6* Paclitaxel 175 mg/m2 Arm A Arm B 12 months Front-line EOC, PP or FT cancer Stage I-IIA (Gr 3 or CC) Stage IIB/C Stage III Stage IV n=1528 Bevacizumab 7.5 mg/kg ** Primary endpoints: PFS Secondary endpoints: OS, RR, safety, QOL, cost-effectiveness, translational No IRC present Perren T et al. N Engl J Med. 2011;365:2484-2496. Perren et al. ESMO 2010. ICON 7 Summary of Updated Results Kristensen G et al. J Clin Oncol. 2011;29: suppl; abstr LBA5006). Perren T et al. N Engl J Med. 2011;365:2484-2496. First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG 178—Investigating Paclitaxel as Consolidation Markman M et al. J Clin Oncol. 2003;21:2460-2465. 277 stage III/IV patients in complete clinical remission Paclitaxel 175 mg/m2 every 28 days × 3 months Paclitaxel 175 mg/m2 every 28 days × 12 months RANDOM I Z E CR = Complete response. Progression-free survival 0 20 40 60 80 100 0 12 24 36 48 Months after registration Paclitaxel 12 courses Paclitaxel 3 courses 110 At risk 112 Failed 20 34 Median, months 28 21 P = 0.0023 Percentage Markman M et al. J Clin Oncol. 2003;21:2460-2465. GOG 178 GOG-0212 Phase III Maintenance Therapy Trial Primary endpoint: survival Secondary endpoints: PFS, toxicity, QoL www.clinicaltrials.gov/ct2/show/NCT00108745. Macromolecular complex of paclitaxel poliglumex Patients with stage III/IV epithelial ovarian or primary peritoneal cancer, GOG PS ≤ 2, and complete response after surgery plus taxane and carboplatin (Planned n = 1400-1550) Paclitaxel Every 28 days for up to 12 courses No treatment Paclitaxel poliglumex Every 28 days for up to 12 courses Summary: Initial Treatment of Advanced Ovarian Cancer Surgery Attempt at maximal surgical cytoreduction Neoadjuvant chemo before surgery is an option for poor surgical candidates Chemotherapy 6-8 cycles taxane-platinum combination is standard IP admin benefits patients with low volume (optimal) disease but has increased toxicity NED patients treated with IP have a median survival of over 9 years Weekly (dose-dense) paclitaxel improves outcome in one study Confirmatory North American trials recently completed Bevacizumab during and after chemotherapy improves PFS but not OS Case Discussions Case 1: A Newly Diagnosed Patient With Ovarian Cancer 58 year old real estate broker with controlled hypertension presents with a pelvic mass, omental caking, and a CA125 of 2,056. She has no malnutrition or change in her weight. She is a PS=0. What would you recommend for this patient? Neoadjuvant chemotherapy Primary radical debulking surgery What Would You Recommend for This Patient? Neoadjuvant chemotherapy Primary radical debulking surgery Primary Cytoreduction Meta-analysis: 53 studies (1989–1998) 81 cohorts (Stage III/IV) n = 6885 patients Results Expert centers have high optimal rates Optimal vs not: 11 mos (50% increase) Each 10%  in cytoreduction = 5.5%  in survival Platinum intensity = NS Bristow. J Clin Oncol. 2002;20:1248. The Impact of Residual Tumor: What Is Optimal Debulking? % Progression-Free Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.52 (2.26; 2.81) >10 mm vs 1 mm – 10 mm: 1.36 (1.24; 1.50) log-rank: P<0.0001 % Overall Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.70 (2.37; 3.07) >10 mm vs 1 mm – 10 mm: 1.34 (1.21; 1.49) log-rank: P<0.0001 Generated from 3 prospective Phase III trials (OVAR 3,5, & 7) n = 3126 pts DuBois. Cancer. 2009;115:1234. Case 1 She has a TAH BSO, transverse colectomy, omentectomy and spends 7 days in the hospital (2 in the ICU). Except for an open wound with a wound-vac and getting 4 units of blood, she does well… The pathology shows a high-grade serous carcinoma. The surgeon noted small volume residual (5-9mm) disease throughout the abdomen. What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP Case 1 Question 2 What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP All the above answers are reasonable treatment choices. When would you start the bevacizumab? Cycle 1, 2 or 3? After the chemotherapy (maintenance)? Case 2: Platinum Sensitive Ovarian Cancer 52-year-old woman with high-grade serous carcinoma of the fallopian tube Optimally debulked in 2010 Treated with IV paclitaxel, IP cisplatin and IP paclitaxel completed June 2011 CA125 at presentation 5800 nadir post therapy 7 In 2012 : Increasing Ca125 (1200) Imaging: diffuse peritoneal carcinomatosis; pleural nodularity; mediastinal adenopathy Symptomatic: abdominal bloating, early satiety, and mild shortness of breath Disease free interval: 10-12 months Genetic testing: BRCA1/2 negative Case 2 Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin PLD, carboplatin and bevacizumab Gemcitabine and carboplatin Gemcitabine, carboplatin and bevacizumab Paclitaxel and carboplatin Weekly paclitaxel and carboplatin Paclitaxel, carboplatin and PARP inhibitor Case 2, Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin (PLD and carboplatin is a reasonable option based on results of the CALYPSO study showing superiority to paclitaxel and carboplatin) PLD, carboplatin and bevacizumab (PLD, carboplatin and bevacizumab has not been tested in a randomized phase III trial) Gemcitabine and carboplatin (Gemcitabine and carboplatin: this is reasonable based on a comparison with carboplatin alone (Pfisterer et.al. 2005) Gemcitabine, carboplatin and bevacizumab (Higher response rates and improved PFS are seen when bevacizumab is added to gem/carbo but OS is not improved (OCEANS trial) Paclitaxel and carboplatin (Paclitaxel and carboplatin can be used but based on prior taxane and results of CALYPSO, is used less) Weekly paclitaxel and carboplatin (Weekly paclitaxel has shown improved outcome when used with carboplatin for newly diagnosed patients but has not been rigorously tested in recurrent disease Paclitaxel, carboplatin and PARP inhibitor (PARP inhibitors are not yet FDA approved , so can only be obtained on a clinical trial. However, this is a very promising direction in ovarian cancer and a clinical trial of paclitaxel and carboplatin +/- olaparib showed improved PFS (Oza et.al. ASCO 2012) She Asks You Whether There Is Any Role for Surgery for Her Which of the following are true regarding secondary debulking? It is not considered for patients like her who relapse 10-12 months after completing initial chemotherapy The finding of carcinomatosis is a relatively strong contraindication to secondary debulking surgery Survival is improved for secondary debulking even if all disease can’t be removed at surgery Mediastinal and pleural disease are relatively strong contraindications to secondary debulking surgery 1 and 3 2 and 4 All of the above Secondary Debulking Candidate Selection Onda et al. J Cancer. 2005;92:1026. Pujade-Lauraine, Ann Oncol. 2011;22(Supplement 8):viii61–viii64. RANDOM I Z E GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: ≤ 0.5 cm > 0.5-2 cm PLD 30 mg/m2 Carboplatin AUC = 5 q 28 days x 6 Paclitaxel 175 mg/m2 Carboplatin AUC = 5 q 21 days x 6 GCIG = Gynecologic Cancer Intergroup PFS = progression-free survival PLD = pegylated liposomal doxorubicin Accrual 864 pts PFS primary endpoint Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. GCIG CALYPSO Trial Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. Selected Non-hematologic Toxicities During Treatment Alopecia *P< 0.001 Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. Targeted Agents in Ovarian Cancer Signaling/Angiogenesis Bevacizumab/Aflibercept RTKI’s: Pazopanib Cabozantinib Sorafenib, etc Cediranib Nintedanib Trebananib, MEDI-3617 PI3K/Akt/mTOR MEKi Folate: Vintafolide (EC-145) Farletuzumab NKTR-102 Taxanes/epothilones Immunotherapy – vaccines and inducers EP-100 PARPi ErbB3 CG + PL OCEANS: Study schema CG for 6 (up to 10) cycles Stratification variables: Platinum-free interval (6–12 vs >12 months) Cytoreductive surgery for recurrent disease (yes vs no) Platinum-sensitive recurrent OCa Measurable disease ECOG 0/1 No prior chemo for recurrent OC No prior BV (n=484) BV = bevacizumab; PL = placebo aEpithelial ovarian, primary peritoneal, or fallopian tube cancer G 1000 mg/m2, d1 & 8 C AUC 4 PL q3w until progression C AUC 4 BV 15 mg/kg q3w until progression G 1000 mg/m2, d1 & 8 CG + BV Aghajanian C et al. J Clin Oncol. 2012;30:2039-2045. 242 177 45 11 3 0 CG + PL OCEANS: Primary Analysis of PFS Months No. at risk 242 203 92 33 11 0 CG + BV 1.0 0.8 0.6 0.4 0.2 0 Proportion progression free 0 6 12 18 24 30 Aghajanian C et al. J Clin Oncol. 2012;30:2039-2045. 1.0 0.8 0.6 0.4 0.2 0 OCEANS: Third Interim OS Analysisa 0 6 12 18 24 30 36 42 48 54 60 242 235 221 190 159 117 77 44 23 7 0 242 239 226 201 171 127 78 48 27 7 0 Number at risk: GC + PL GC + BV aData cutoff date: March 30, 2012. Median follow-up 41.9 months in PL arm and 42.3 months in BV arm, with 286 deaths (59.1% of patients) Proportion surviving Months Aghajanian et al. ESMO 2012.
Slide 54 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R A N D O M I Z E n = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Placebo BEV 15 mg/kg II Stratification variables: GOG performance status (PS) Stage/debulking status RANDOM I Z E 1:1:1 15 months Paclitaxel (P) 175 mg/m2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 III Maintenance (16 cycles) BEV 15 mg/kg Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218: Investigator-assessed PFS + BEV (Arm II) CP (Arm I) *P-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 CA-125 to Determine Progression Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 Interim Survival Analysis Proportion Alive Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 48 aStratified analysis 625/625/623 442/432/437 173/162/171 46/39/40 No. at risk Burger RA et al. N Engl J Med. 2011;365:2473-2483. ICON7: Study Design Stratification variables: Stage/surgery Time since surgery GCIG group *Might vary based on GCIG group **Omit cycle 1 bevacizumab if <4 weeks from surgery Paclitaxel 175 mg/m2 Carboplatin AUC 6* AVASTIN Carboplatin AUC 6* Paclitaxel 175 mg/m2 Arm A Arm B 12 months Front-line EOC, PP or FT cancer Stage I-IIA (Gr 3 or CC) Stage IIB/C Stage III Stage IV n=1528 Bevacizumab 7.5 mg/kg ** Primary endpoints: PFS Secondary endpoints: OS, RR, safety, QOL, cost-effectiveness, translational No IRC present Perren T et al. N Engl J Med. 2011;365:2484-2496. Perren et al. ESMO 2010. ICON 7 Summary of Updated Results Kristensen G et al. J Clin Oncol. 2011;29: suppl; abstr LBA5006). Perren T et al. N Engl J Med. 2011;365:2484-2496. First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG 178—Investigating Paclitaxel as Consolidation Markman M et al. J Clin Oncol. 2003;21:2460-2465. 277 stage III/IV patients in complete clinical remission Paclitaxel 175 mg/m2 every 28 days × 3 months Paclitaxel 175 mg/m2 every 28 days × 12 months RANDOM I Z E CR = Complete response. Progression-free survival 0 20 40 60 80 100 0 12 24 36 48 Months after registration Paclitaxel 12 courses Paclitaxel 3 courses 110 At risk 112 Failed 20 34 Median, months 28 21 P = 0.0023 Percentage Markman M et al. J Clin Oncol. 2003;21:2460-2465. GOG 178 GOG-0212 Phase III Maintenance Therapy Trial Primary endpoint: survival Secondary endpoints: PFS, toxicity, QoL www.clinicaltrials.gov/ct2/show/NCT00108745. Macromolecular complex of paclitaxel poliglumex Patients with stage III/IV epithelial ovarian or primary peritoneal cancer, GOG PS ≤ 2, and complete response after surgery plus taxane and carboplatin (Planned n = 1400-1550) Paclitaxel Every 28 days for up to 12 courses No treatment Paclitaxel poliglumex Every 28 days for up to 12 courses Summary: Initial Treatment of Advanced Ovarian Cancer Surgery Attempt at maximal surgical cytoreduction Neoadjuvant chemo before surgery is an option for poor surgical candidates Chemotherapy 6-8 cycles taxane-platinum combination is standard IP admin benefits patients with low volume (optimal) disease but has increased toxicity NED patients treated with IP have a median survival of over 9 years Weekly (dose-dense) paclitaxel improves outcome in one study Confirmatory North American trials recently completed Bevacizumab during and after chemotherapy improves PFS but not OS Case Discussions Case 1: A Newly Diagnosed Patient With Ovarian Cancer 58 year old real estate broker with controlled hypertension presents with a pelvic mass, omental caking, and a CA125 of 2,056. She has no malnutrition or change in her weight. She is a PS=0. What would you recommend for this patient? Neoadjuvant chemotherapy Primary radical debulking surgery What Would You Recommend for This Patient? Neoadjuvant chemotherapy Primary radical debulking surgery Primary Cytoreduction Meta-analysis: 53 studies (1989–1998) 81 cohorts (Stage III/IV) n = 6885 patients Results Expert centers have high optimal rates Optimal vs not: 11 mos (50% increase) Each 10%  in cytoreduction = 5.5%  in survival Platinum intensity = NS Bristow. J Clin Oncol. 2002;20:1248. The Impact of Residual Tumor: What Is Optimal Debulking? % Progression-Free Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.52 (2.26; 2.81) >10 mm vs 1 mm – 10 mm: 1.36 (1.24; 1.50) log-rank: P<0.0001 % Overall Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.70 (2.37; 3.07) >10 mm vs 1 mm – 10 mm: 1.34 (1.21; 1.49) log-rank: P<0.0001 Generated from 3 prospective Phase III trials (OVAR 3,5, & 7) n = 3126 pts DuBois. Cancer. 2009;115:1234. Case 1 She has a TAH BSO, transverse colectomy, omentectomy and spends 7 days in the hospital (2 in the ICU). Except for an open wound with a wound-vac and getting 4 units of blood, she does well… The pathology shows a high-grade serous carcinoma. The surgeon noted small volume residual (5-9mm) disease throughout the abdomen. What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP Case 1 Question 2 What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP All the above answers are reasonable treatment choices. When would you start the bevacizumab? Cycle 1, 2 or 3? After the chemotherapy (maintenance)? Case 2: Platinum Sensitive Ovarian Cancer 52-year-old woman with high-grade serous carcinoma of the fallopian tube Optimally debulked in 2010 Treated with IV paclitaxel, IP cisplatin and IP paclitaxel completed June 2011 CA125 at presentation 5800 nadir post therapy 7 In 2012 : Increasing Ca125 (1200) Imaging: diffuse peritoneal carcinomatosis; pleural nodularity; mediastinal adenopathy Symptomatic: abdominal bloating, early satiety, and mild shortness of breath Disease free interval: 10-12 months Genetic testing: BRCA1/2 negative Case 2 Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin PLD, carboplatin and bevacizumab Gemcitabine and carboplatin Gemcitabine, carboplatin and bevacizumab Paclitaxel and carboplatin Weekly paclitaxel and carboplatin Paclitaxel, carboplatin and PARP inhibitor Case 2, Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin (PLD and carboplatin is a reasonable option based on results of the CALYPSO study showing superiority to paclitaxel and carboplatin) PLD, carboplatin and bevacizumab (PLD, carboplatin and bevacizumab has not been tested in a randomized phase III trial) Gemcitabine and carboplatin (Gemcitabine and carboplatin: this is reasonable based on a comparison with carboplatin alone (Pfisterer et.al. 2005) Gemcitabine, carboplatin and bevacizumab (Higher response rates and improved PFS are seen when bevacizumab is added to gem/carbo but OS is not improved (OCEANS trial) Paclitaxel and carboplatin (Paclitaxel and carboplatin can be used but based on prior taxane and results of CALYPSO, is used less) Weekly paclitaxel and carboplatin (Weekly paclitaxel has shown improved outcome when used with carboplatin for newly diagnosed patients but has not been rigorously tested in recurrent disease Paclitaxel, carboplatin and PARP inhibitor (PARP inhibitors are not yet FDA approved , so can only be obtained on a clinical trial. However, this is a very promising direction in ovarian cancer and a clinical trial of paclitaxel and carboplatin +/- olaparib showed improved PFS (Oza et.al. ASCO 2012) She Asks You Whether There Is Any Role for Surgery for Her Which of the following are true regarding secondary debulking? It is not considered for patients like her who relapse 10-12 months after completing initial chemotherapy The finding of carcinomatosis is a relatively strong contraindication to secondary debulking surgery Survival is improved for secondary debulking even if all disease can’t be removed at surgery Mediastinal and pleural disease are relatively strong contraindications to secondary debulking surgery 1 and 3 2 and 4 All of the above Secondary Debulking Candidate Selection Onda et al. J Cancer. 2005;92:1026. Pujade-Lauraine, Ann Oncol. 2011;22(Supplement 8):viii61–viii64. RANDOM I Z E GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: ≤ 0.5 cm > 0.5-2 cm PLD 30 mg/m2 Carboplatin AUC = 5 q 28 days x 6 Paclitaxel 175 mg/m2 Carboplatin AUC = 5 q 21 days x 6 GCIG = Gynecologic Cancer Intergroup PFS = progression-free survival PLD = pegylated liposomal doxorubicin Accrual 864 pts PFS primary endpoint Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. GCIG CALYPSO Trial Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. Selected Non-hematologic Toxicities During Treatment Alopecia *P< 0.001 Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. Targeted Agents in Ovarian Cancer Signaling/Angiogenesis Bevacizumab/Aflibercept RTKI’s: Pazopanib Cabozantinib Sorafenib, etc Cediranib Nintedanib Trebananib, MEDI-3617 PI3K/Akt/mTOR MEKi Folate: Vintafolide (EC-145) Farletuzumab NKTR-102 Taxanes/epothilones Immunotherapy – vaccines and inducers EP-100 PARPi ErbB3 CG + PL OCEANS: Study schema CG for 6 (up to 10) cycles Stratification variables: Platinum-free interval (6–12 vs >12 months) Cytoreductive surgery for recurrent disease (yes vs no) Platinum-sensitive recurrent OCa Measurable disease ECOG 0/1 No prior chemo for recurrent OC No prior BV (n=484) BV = bevacizumab; PL = placebo aEpithelial ovarian, primary peritoneal, or fallopian tube cancer G 1000 mg/m2, d1 & 8 C AUC 4 PL q3w until progression C AUC 4 BV 15 mg/kg q3w until progression G 1000 mg/m2, d1 & 8 CG + BV Aghajanian C et al. J Clin Oncol. 2012;30:2039-2045. 242 177 45 11 3 0 CG + PL OCEANS: Primary Analysis of PFS Months No. at risk 242 203 92 33 11 0 CG + BV 1.0 0.8 0.6 0.4 0.2 0 Proportion progression free 0 6 12 18 24 30 Aghajanian C et al. J Clin Oncol. 2012;30:2039-2045. 1.0 0.8 0.6 0.4 0.2 0 OCEANS: Third Interim OS Analysisa 0 6 12 18 24 30 36 42 48 54 60 242 235 221 190 159 117 77 44 23 7 0 242 239 226 201 171 127 78 48 27 7 0 Number at risk: GC + PL GC + BV aData cutoff date: March 30, 2012. Median follow-up 41.9 months in PL arm and 42.3 months in BV arm, with 286 deaths (59.1% of patients) Proportion surviving Months Aghajanian et al. ESMO 2012. Asymptomatic relapse Single-agent farletuzumab Until progression Single-agent ORR Compare lengths of first and second remissions Farletuzumab - MORAb-003-002 Phase II: Design Epithelial Ovarian Cancer First platinum-sensitive relapse First remission of 6-18 months Evaluable disease by CA125 Symptomatic relapse Original Carbo/Taxane regimen Plus farletuzumab x 6 Farletuzumab maintenance Rx For responders Combination ORR White AJ et al. J Clin Oncol. 2010;28(15s):Abstract 5001.
Slide 55 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R A N D O M I Z E n = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Placebo BEV 15 mg/kg II Stratification variables: GOG performance status (PS) Stage/debulking status RANDOM I Z E 1:1:1 15 months Paclitaxel (P) 175 mg/m2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 III Maintenance (16 cycles) BEV 15 mg/kg Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218: Investigator-assessed PFS + BEV (Arm II) CP (Arm I) *P-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 CA-125 to Determine Progression Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 Interim Survival Analysis Proportion Alive Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 48 aStratified analysis 625/625/623 442/432/437 173/162/171 46/39/40 No. at risk Burger RA et al. N Engl J Med. 2011;365:2473-2483. ICON7: Study Design Stratification variables: Stage/surgery Time since surgery GCIG group *Might vary based on GCIG group **Omit cycle 1 bevacizumab if <4 weeks from surgery Paclitaxel 175 mg/m2 Carboplatin AUC 6* AVASTIN Carboplatin AUC 6* Paclitaxel 175 mg/m2 Arm A Arm B 12 months Front-line EOC, PP or FT cancer Stage I-IIA (Gr 3 or CC) Stage IIB/C Stage III Stage IV n=1528 Bevacizumab 7.5 mg/kg ** Primary endpoints: PFS Secondary endpoints: OS, RR, safety, QOL, cost-effectiveness, translational No IRC present Perren T et al. N Engl J Med. 2011;365:2484-2496. Perren et al. ESMO 2010. ICON 7 Summary of Updated Results Kristensen G et al. J Clin Oncol. 2011;29: suppl; abstr LBA5006). Perren T et al. N Engl J Med. 2011;365:2484-2496. First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG 178—Investigating Paclitaxel as Consolidation Markman M et al. J Clin Oncol. 2003;21:2460-2465. 277 stage III/IV patients in complete clinical remission Paclitaxel 175 mg/m2 every 28 days × 3 months Paclitaxel 175 mg/m2 every 28 days × 12 months RANDOM I Z E CR = Complete response. Progression-free survival 0 20 40 60 80 100 0 12 24 36 48 Months after registration Paclitaxel 12 courses Paclitaxel 3 courses 110 At risk 112 Failed 20 34 Median, months 28 21 P = 0.0023 Percentage Markman M et al. J Clin Oncol. 2003;21:2460-2465. GOG 178 GOG-0212 Phase III Maintenance Therapy Trial Primary endpoint: survival Secondary endpoints: PFS, toxicity, QoL www.clinicaltrials.gov/ct2/show/NCT00108745. Macromolecular complex of paclitaxel poliglumex Patients with stage III/IV epithelial ovarian or primary peritoneal cancer, GOG PS ≤ 2, and complete response after surgery plus taxane and carboplatin (Planned n = 1400-1550) Paclitaxel Every 28 days for up to 12 courses No treatment Paclitaxel poliglumex Every 28 days for up to 12 courses Summary: Initial Treatment of Advanced Ovarian Cancer Surgery Attempt at maximal surgical cytoreduction Neoadjuvant chemo before surgery is an option for poor surgical candidates Chemotherapy 6-8 cycles taxane-platinum combination is standard IP admin benefits patients with low volume (optimal) disease but has increased toxicity NED patients treated with IP have a median survival of over 9 years Weekly (dose-dense) paclitaxel improves outcome in one study Confirmatory North American trials recently completed Bevacizumab during and after chemotherapy improves PFS but not OS Case Discussions Case 1: A Newly Diagnosed Patient With Ovarian Cancer 58 year old real estate broker with controlled hypertension presents with a pelvic mass, omental caking, and a CA125 of 2,056. She has no malnutrition or change in her weight. She is a PS=0. What would you recommend for this patient? Neoadjuvant chemotherapy Primary radical debulking surgery What Would You Recommend for This Patient? Neoadjuvant chemotherapy Primary radical debulking surgery Primary Cytoreduction Meta-analysis: 53 studies (1989–1998) 81 cohorts (Stage III/IV) n = 6885 patients Results Expert centers have high optimal rates Optimal vs not: 11 mos (50% increase) Each 10%  in cytoreduction = 5.5%  in survival Platinum intensity = NS Bristow. J Clin Oncol. 2002;20:1248. The Impact of Residual Tumor: What Is Optimal Debulking? % Progression-Free Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.52 (2.26; 2.81) >10 mm vs 1 mm – 10 mm: 1.36 (1.24; 1.50) log-rank: P<0.0001 % Overall Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.70 (2.37; 3.07) >10 mm vs 1 mm – 10 mm: 1.34 (1.21; 1.49) log-rank: P<0.0001 Generated from 3 prospective Phase III trials (OVAR 3,5, & 7) n = 3126 pts DuBois. Cancer. 2009;115:1234. Case 1 She has a TAH BSO, transverse colectomy, omentectomy and spends 7 days in the hospital (2 in the ICU). Except for an open wound with a wound-vac and getting 4 units of blood, she does well… The pathology shows a high-grade serous carcinoma. The surgeon noted small volume residual (5-9mm) disease throughout the abdomen. What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP Case 1 Question 2 What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP All the above answers are reasonable treatment choices. When would you start the bevacizumab? Cycle 1, 2 or 3? After the chemotherapy (maintenance)? Case 2: Platinum Sensitive Ovarian Cancer 52-year-old woman with high-grade serous carcinoma of the fallopian tube Optimally debulked in 2010 Treated with IV paclitaxel, IP cisplatin and IP paclitaxel completed June 2011 CA125 at presentation 5800 nadir post therapy 7 In 2012 : Increasing Ca125 (1200) Imaging: diffuse peritoneal carcinomatosis; pleural nodularity; mediastinal adenopathy Symptomatic: abdominal bloating, early satiety, and mild shortness of breath Disease free interval: 10-12 months Genetic testing: BRCA1/2 negative Case 2 Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin PLD, carboplatin and bevacizumab Gemcitabine and carboplatin Gemcitabine, carboplatin and bevacizumab Paclitaxel and carboplatin Weekly paclitaxel and carboplatin Paclitaxel, carboplatin and PARP inhibitor Case 2, Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin (PLD and carboplatin is a reasonable option based on results of the CALYPSO study showing superiority to paclitaxel and carboplatin) PLD, carboplatin and bevacizumab (PLD, carboplatin and bevacizumab has not been tested in a randomized phase III trial) Gemcitabine and carboplatin (Gemcitabine and carboplatin: this is reasonable based on a comparison with carboplatin alone (Pfisterer et.al. 2005) Gemcitabine, carboplatin and bevacizumab (Higher response rates and improved PFS are seen when bevacizumab is added to gem/carbo but OS is not improved (OCEANS trial) Paclitaxel and carboplatin (Paclitaxel and carboplatin can be used but based on prior taxane and results of CALYPSO, is used less) Weekly paclitaxel and carboplatin (Weekly paclitaxel has shown improved outcome when used with carboplatin for newly diagnosed patients but has not been rigorously tested in recurrent disease Paclitaxel, carboplatin and PARP inhibitor (PARP inhibitors are not yet FDA approved , so can only be obtained on a clinical trial. However, this is a very promising direction in ovarian cancer and a clinical trial of paclitaxel and carboplatin +/- olaparib showed improved PFS (Oza et.al. ASCO 2012) She Asks You Whether There Is Any Role for Surgery for Her Which of the following are true regarding secondary debulking? It is not considered for patients like her who relapse 10-12 months after completing initial chemotherapy The finding of carcinomatosis is a relatively strong contraindication to secondary debulking surgery Survival is improved for secondary debulking even if all disease can’t be removed at surgery Mediastinal and pleural disease are relatively strong contraindications to secondary debulking surgery 1 and 3 2 and 4 All of the above Secondary Debulking Candidate Selection Onda et al. J Cancer. 2005;92:1026. Pujade-Lauraine, Ann Oncol. 2011;22(Supplement 8):viii61–viii64. RANDOM I Z E GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: ≤ 0.5 cm > 0.5-2 cm PLD 30 mg/m2 Carboplatin AUC = 5 q 28 days x 6 Paclitaxel 175 mg/m2 Carboplatin AUC = 5 q 21 days x 6 GCIG = Gynecologic Cancer Intergroup PFS = progression-free survival PLD = pegylated liposomal doxorubicin Accrual 864 pts PFS primary endpoint Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. GCIG CALYPSO Trial Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. Selected Non-hematologic Toxicities During Treatment Alopecia *P< 0.001 Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. Targeted Agents in Ovarian Cancer Signaling/Angiogenesis Bevacizumab/Aflibercept RTKI’s: Pazopanib Cabozantinib Sorafenib, etc Cediranib Nintedanib Trebananib, MEDI-3617 PI3K/Akt/mTOR MEKi Folate: Vintafolide (EC-145) Farletuzumab NKTR-102 Taxanes/epothilones Immunotherapy – vaccines and inducers EP-100 PARPi ErbB3 CG + PL OCEANS: Study schema CG for 6 (up to 10) cycles Stratification variables: Platinum-free interval (6–12 vs >12 months) Cytoreductive surgery for recurrent disease (yes vs no) Platinum-sensitive recurrent OCa Measurable disease ECOG 0/1 No prior chemo for recurrent OC No prior BV (n=484) BV = bevacizumab; PL = placebo aEpithelial ovarian, primary peritoneal, or fallopian tube cancer G 1000 mg/m2, d1 & 8 C AUC 4 PL q3w until progression C AUC 4 BV 15 mg/kg q3w until progression G 1000 mg/m2, d1 & 8 CG + BV Aghajanian C et al. J Clin Oncol. 2012;30:2039-2045. 242 177 45 11 3 0 CG + PL OCEANS: Primary Analysis of PFS Months No. at risk 242 203 92 33 11 0 CG + BV 1.0 0.8 0.6 0.4 0.2 0 Proportion progression free 0 6 12 18 24 30 Aghajanian C et al. J Clin Oncol. 2012;30:2039-2045. 1.0 0.8 0.6 0.4 0.2 0 OCEANS: Third Interim OS Analysisa 0 6 12 18 24 30 36 42 48 54 60 242 235 221 190 159 117 77 44 23 7 0 242 239 226 201 171 127 78 48 27 7 0 Number at risk: GC + PL GC + BV aData cutoff date: March 30, 2012. Median follow-up 41.9 months in PL arm and 42.3 months in BV arm, with 286 deaths (59.1% of patients) Proportion surviving Months Aghajanian et al. ESMO 2012. Asymptomatic relapse Single-agent farletuzumab Until progression Single-agent ORR Compare lengths of first and second remissions Farletuzumab - MORAb-003-002 Phase II: Design Epithelial Ovarian Cancer First platinum-sensitive relapse First remission of 6-18 months Evaluable disease by CA125 Symptomatic relapse Original Carbo/Taxane regimen Plus farletuzumab x 6 Farletuzumab maintenance Rx For responders Combination ORR White AJ et al. J Clin Oncol. 2010;28(15s):Abstract 5001. MorAb-003-002: Study Conclusions Overall response rate 70% Response rate similar in early (6-12 month) and late (12+ months) recurrent patients High rates of CA-125 normalization (89%) 1/5 patients had a PFI2 ≥ PFI1 Phase III studies Platinum-sensitive: fully enrolled Platinum-resistant (weekly paclitaxel): met futility endpoint White AJ et al. J Clin Oncol. 2010;28(15s):Abstract 5001.
Slide 56 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R A N D O M I Z E n = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Placebo BEV 15 mg/kg II Stratification variables: GOG performance status (PS) Stage/debulking status RANDOM I Z E 1:1:1 15 months Paclitaxel (P) 175 mg/m2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 III Maintenance (16 cycles) BEV 15 mg/kg Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218: Investigator-assessed PFS + BEV (Arm II) CP (Arm I) *P-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 CA-125 to Determine Progression Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 Interim Survival Analysis Proportion Alive Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 48 aStratified analysis 625/625/623 442/432/437 173/162/171 46/39/40 No. at risk Burger RA et al. N Engl J Med. 2011;365:2473-2483. ICON7: Study Design Stratification variables: Stage/surgery Time since surgery GCIG group *Might vary based on GCIG group **Omit cycle 1 bevacizumab if <4 weeks from surgery Paclitaxel 175 mg/m2 Carboplatin AUC 6* AVASTIN Carboplatin AUC 6* Paclitaxel 175 mg/m2 Arm A Arm B 12 months Front-line EOC, PP or FT cancer Stage I-IIA (Gr 3 or CC) Stage IIB/C Stage III Stage IV n=1528 Bevacizumab 7.5 mg/kg ** Primary endpoints: PFS Secondary endpoints: OS, RR, safety, QOL, cost-effectiveness, translational No IRC present Perren T et al. N Engl J Med. 2011;365:2484-2496. Perren et al. ESMO 2010. ICON 7 Summary of Updated Results Kristensen G et al. J Clin Oncol. 2011;29: suppl; abstr LBA5006). Perren T et al. N Engl J Med. 2011;365:2484-2496. First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG 178—Investigating Paclitaxel as Consolidation Markman M et al. J Clin Oncol. 2003;21:2460-2465. 277 stage III/IV patients in complete clinical remission Paclitaxel 175 mg/m2 every 28 days × 3 months Paclitaxel 175 mg/m2 every 28 days × 12 months RANDOM I Z E CR = Complete response. Progression-free survival 0 20 40 60 80 100 0 12 24 36 48 Months after registration Paclitaxel 12 courses Paclitaxel 3 courses 110 At risk 112 Failed 20 34 Median, months 28 21 P = 0.0023 Percentage Markman M et al. J Clin Oncol. 2003;21:2460-2465. GOG 178 GOG-0212 Phase III Maintenance Therapy Trial Primary endpoint: survival Secondary endpoints: PFS, toxicity, QoL www.clinicaltrials.gov/ct2/show/NCT00108745. Macromolecular complex of paclitaxel poliglumex Patients with stage III/IV epithelial ovarian or primary peritoneal cancer, GOG PS ≤ 2, and complete response after surgery plus taxane and carboplatin (Planned n = 1400-1550) Paclitaxel Every 28 days for up to 12 courses No treatment Paclitaxel poliglumex Every 28 days for up to 12 courses Summary: Initial Treatment of Advanced Ovarian Cancer Surgery Attempt at maximal surgical cytoreduction Neoadjuvant chemo before surgery is an option for poor surgical candidates Chemotherapy 6-8 cycles taxane-platinum combination is standard IP admin benefits patients with low volume (optimal) disease but has increased toxicity NED patients treated with IP have a median survival of over 9 years Weekly (dose-dense) paclitaxel improves outcome in one study Confirmatory North American trials recently completed Bevacizumab during and after chemotherapy improves PFS but not OS Case Discussions Case 1: A Newly Diagnosed Patient With Ovarian Cancer 58 year old real estate broker with controlled hypertension presents with a pelvic mass, omental caking, and a CA125 of 2,056. She has no malnutrition or change in her weight. She is a PS=0. What would you recommend for this patient? Neoadjuvant chemotherapy Primary radical debulking surgery What Would You Recommend for This Patient? Neoadjuvant chemotherapy Primary radical debulking surgery Primary Cytoreduction Meta-analysis: 53 studies (1989–1998) 81 cohorts (Stage III/IV) n = 6885 patients Results Expert centers have high optimal rates Optimal vs not: 11 mos (50% increase) Each 10%  in cytoreduction = 5.5%  in survival Platinum intensity = NS Bristow. J Clin Oncol. 2002;20:1248. The Impact of Residual Tumor: What Is Optimal Debulking? % Progression-Free Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.52 (2.26; 2.81) >10 mm vs 1 mm – 10 mm: 1.36 (1.24; 1.50) log-rank: P<0.0001 % Overall Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.70 (2.37; 3.07) >10 mm vs 1 mm – 10 mm: 1.34 (1.21; 1.49) log-rank: P<0.0001 Generated from 3 prospective Phase III trials (OVAR 3,5, & 7) n = 3126 pts DuBois. Cancer. 2009;115:1234. Case 1 She has a TAH BSO, transverse colectomy, omentectomy and spends 7 days in the hospital (2 in the ICU). Except for an open wound with a wound-vac and getting 4 units of blood, she does well… The pathology shows a high-grade serous carcinoma. The surgeon noted small volume residual (5-9mm) disease throughout the abdomen. What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP Case 1 Question 2 What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP All the above answers are reasonable treatment choices. When would you start the bevacizumab? Cycle 1, 2 or 3? After the chemotherapy (maintenance)? Case 2: Platinum Sensitive Ovarian Cancer 52-year-old woman with high-grade serous carcinoma of the fallopian tube Optimally debulked in 2010 Treated with IV paclitaxel, IP cisplatin and IP paclitaxel completed June 2011 CA125 at presentation 5800 nadir post therapy 7 In 2012 : Increasing Ca125 (1200) Imaging: diffuse peritoneal carcinomatosis; pleural nodularity; mediastinal adenopathy Symptomatic: abdominal bloating, early satiety, and mild shortness of breath Disease free interval: 10-12 months Genetic testing: BRCA1/2 negative Case 2 Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin PLD, carboplatin and bevacizumab Gemcitabine and carboplatin Gemcitabine, carboplatin and bevacizumab Paclitaxel and carboplatin Weekly paclitaxel and carboplatin Paclitaxel, carboplatin and PARP inhibitor Case 2, Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin (PLD and carboplatin is a reasonable option based on results of the CALYPSO study showing superiority to paclitaxel and carboplatin) PLD, carboplatin and bevacizumab (PLD, carboplatin and bevacizumab has not been tested in a randomized phase III trial) Gemcitabine and carboplatin (Gemcitabine and carboplatin: this is reasonable based on a comparison with carboplatin alone (Pfisterer et.al. 2005) Gemcitabine, carboplatin and bevacizumab (Higher response rates and improved PFS are seen when bevacizumab is added to gem/carbo but OS is not improved (OCEANS trial) Paclitaxel and carboplatin (Paclitaxel and carboplatin can be used but based on prior taxane and results of CALYPSO, is used less) Weekly paclitaxel and carboplatin (Weekly paclitaxel has shown improved outcome when used with carboplatin for newly diagnosed patients but has not been rigorously tested in recurrent disease Paclitaxel, carboplatin and PARP inhibitor (PARP inhibitors are not yet FDA approved , so can only be obtained on a clinical trial. However, this is a very promising direction in ovarian cancer and a clinical trial of paclitaxel and carboplatin +/- olaparib showed improved PFS (Oza et.al. ASCO 2012) She Asks You Whether There Is Any Role for Surgery for Her Which of the following are true regarding secondary debulking? It is not considered for patients like her who relapse 10-12 months after completing initial chemotherapy The finding of carcinomatosis is a relatively strong contraindication to secondary debulking surgery Survival is improved for secondary debulking even if all disease can’t be removed at surgery Mediastinal and pleural disease are relatively strong contraindications to secondary debulking surgery 1 and 3 2 and 4 All of the above Secondary Debulking Candidate Selection Onda et al. J Cancer. 2005;92:1026. Pujade-Lauraine, Ann Oncol. 2011;22(Supplement 8):viii61–viii64. RANDOM I Z E GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: ≤ 0.5 cm > 0.5-2 cm PLD 30 mg/m2 Carboplatin AUC = 5 q 28 days x 6 Paclitaxel 175 mg/m2 Carboplatin AUC = 5 q 21 days x 6 GCIG = Gynecologic Cancer Intergroup PFS = progression-free survival PLD = pegylated liposomal doxorubicin Accrual 864 pts PFS primary endpoint Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. GCIG CALYPSO Trial Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. Selected Non-hematologic Toxicities During Treatment Alopecia *P< 0.001 Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. Targeted Agents in Ovarian Cancer Signaling/Angiogenesis Bevacizumab/Aflibercept RTKI’s: Pazopanib Cabozantinib Sorafenib, etc Cediranib Nintedanib Trebananib, MEDI-3617 PI3K/Akt/mTOR MEKi Folate: Vintafolide (EC-145) Farletuzumab NKTR-102 Taxanes/epothilones Immunotherapy – vaccines and inducers EP-100 PARPi ErbB3 CG + PL OCEANS: Study schema CG for 6 (up to 10) cycles Stratification variables: Platinum-free interval (6–12 vs >12 months) Cytoreductive surgery for recurrent disease (yes vs no) Platinum-sensitive recurrent OCa Measurable disease ECOG 0/1 No prior chemo for recurrent OC No prior BV (n=484) BV = bevacizumab; PL = placebo aEpithelial ovarian, primary peritoneal, or fallopian tube cancer G 1000 mg/m2, d1 & 8 C AUC 4 PL q3w until progression C AUC 4 BV 15 mg/kg q3w until progression G 1000 mg/m2, d1 & 8 CG + BV Aghajanian C et al. J Clin Oncol. 2012;30:2039-2045. 242 177 45 11 3 0 CG + PL OCEANS: Primary Analysis of PFS Months No. at risk 242 203 92 33 11 0 CG + BV 1.0 0.8 0.6 0.4 0.2 0 Proportion progression free 0 6 12 18 24 30 Aghajanian C et al. J Clin Oncol. 2012;30:2039-2045. 1.0 0.8 0.6 0.4 0.2 0 OCEANS: Third Interim OS Analysisa 0 6 12 18 24 30 36 42 48 54 60 242 235 221 190 159 117 77 44 23 7 0 242 239 226 201 171 127 78 48 27 7 0 Number at risk: GC + PL GC + BV aData cutoff date: March 30, 2012. Median follow-up 41.9 months in PL arm and 42.3 months in BV arm, with 286 deaths (59.1% of patients) Proportion surviving Months Aghajanian et al. ESMO 2012. Asymptomatic relapse Single-agent farletuzumab Until progression Single-agent ORR Compare lengths of first and second remissions Farletuzumab - MORAb-003-002 Phase II: Design Epithelial Ovarian Cancer First platinum-sensitive relapse First remission of 6-18 months Evaluable disease by CA125 Symptomatic relapse Original Carbo/Taxane regimen Plus farletuzumab x 6 Farletuzumab maintenance Rx For responders Combination ORR White AJ et al. J Clin Oncol. 2010;28(15s):Abstract 5001. MorAb-003-002: Study Conclusions Overall response rate 70% Response rate similar in early (6-12 month) and late (12+ months) recurrent patients High rates of CA-125 normalization (89%) 1/5 patients had a PFI2 ≥ PFI1 Phase III studies Platinum-sensitive: fully enrolled Platinum-resistant (weekly paclitaxel): met futility endpoint White AJ et al. J Clin Oncol. 2010;28(15s):Abstract 5001. n=66 Randomized, Open-label, Phase II Study in Patients With Platinum-sensitive, Advanced Serous Ovarian Cancer Paclitaxel 175 mg/m2 (iv, d1) + carboplatin AUC6 (iv d1) Randomization (1:1) All patients followed for objective radiologic progression and survival Maintenance phase Olaparib 400 mg bid continuously Completion of 4–6 x 21-day cycles of chemotherapy Arm B Arm A n=81 n=81 n=55 Multinational study; 43 sites in 12 countries * Capsule formulation Patients with: Platinum-sensitive advanced ovarian cancer A serous histology or serous component Measurable disease ≤3 previous platinum-containing regimens Progression free for ≥6 months following completion of last platinum-containing regimen Maintenance phase No further study treatment Olaparib 200 mg bid* (d1–10 every 21 days) + paclitaxel 175 mg/m2 (iv, d1) + carboplatin AUC4 (iv, d1) Oza A. ASCO 2012; Abstract 5001.
Slide 57 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R A N D O M I Z E n = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Placebo BEV 15 mg/kg II Stratification variables: GOG performance status (PS) Stage/debulking status RANDOM I Z E 1:1:1 15 months Paclitaxel (P) 175 mg/m2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 III Maintenance (16 cycles) BEV 15 mg/kg Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218: Investigator-assessed PFS + BEV (Arm II) CP (Arm I) *P-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 CA-125 to Determine Progression Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 Interim Survival Analysis Proportion Alive Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 48 aStratified analysis 625/625/623 442/432/437 173/162/171 46/39/40 No. at risk Burger RA et al. N Engl J Med. 2011;365:2473-2483. ICON7: Study Design Stratification variables: Stage/surgery Time since surgery GCIG group *Might vary based on GCIG group **Omit cycle 1 bevacizumab if <4 weeks from surgery Paclitaxel 175 mg/m2 Carboplatin AUC 6* AVASTIN Carboplatin AUC 6* Paclitaxel 175 mg/m2 Arm A Arm B 12 months Front-line EOC, PP or FT cancer Stage I-IIA (Gr 3 or CC) Stage IIB/C Stage III Stage IV n=1528 Bevacizumab 7.5 mg/kg ** Primary endpoints: PFS Secondary endpoints: OS, RR, safety, QOL, cost-effectiveness, translational No IRC present Perren T et al. N Engl J Med. 2011;365:2484-2496. Perren et al. ESMO 2010. ICON 7 Summary of Updated Results Kristensen G et al. J Clin Oncol. 2011;29: suppl; abstr LBA5006). Perren T et al. N Engl J Med. 2011;365:2484-2496. First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG 178—Investigating Paclitaxel as Consolidation Markman M et al. J Clin Oncol. 2003;21:2460-2465. 277 stage III/IV patients in complete clinical remission Paclitaxel 175 mg/m2 every 28 days × 3 months Paclitaxel 175 mg/m2 every 28 days × 12 months RANDOM I Z E CR = Complete response. Progression-free survival 0 20 40 60 80 100 0 12 24 36 48 Months after registration Paclitaxel 12 courses Paclitaxel 3 courses 110 At risk 112 Failed 20 34 Median, months 28 21 P = 0.0023 Percentage Markman M et al. J Clin Oncol. 2003;21:2460-2465. GOG 178 GOG-0212 Phase III Maintenance Therapy Trial Primary endpoint: survival Secondary endpoints: PFS, toxicity, QoL www.clinicaltrials.gov/ct2/show/NCT00108745. Macromolecular complex of paclitaxel poliglumex Patients with stage III/IV epithelial ovarian or primary peritoneal cancer, GOG PS ≤ 2, and complete response after surgery plus taxane and carboplatin (Planned n = 1400-1550) Paclitaxel Every 28 days for up to 12 courses No treatment Paclitaxel poliglumex Every 28 days for up to 12 courses Summary: Initial Treatment of Advanced Ovarian Cancer Surgery Attempt at maximal surgical cytoreduction Neoadjuvant chemo before surgery is an option for poor surgical candidates Chemotherapy 6-8 cycles taxane-platinum combination is standard IP admin benefits patients with low volume (optimal) disease but has increased toxicity NED patients treated with IP have a median survival of over 9 years Weekly (dose-dense) paclitaxel improves outcome in one study Confirmatory North American trials recently completed Bevacizumab during and after chemotherapy improves PFS but not OS Case Discussions Case 1: A Newly Diagnosed Patient With Ovarian Cancer 58 year old real estate broker with controlled hypertension presents with a pelvic mass, omental caking, and a CA125 of 2,056. She has no malnutrition or change in her weight. She is a PS=0. What would you recommend for this patient? Neoadjuvant chemotherapy Primary radical debulking surgery What Would You Recommend for This Patient? Neoadjuvant chemotherapy Primary radical debulking surgery Primary Cytoreduction Meta-analysis: 53 studies (1989–1998) 81 cohorts (Stage III/IV) n = 6885 patients Results Expert centers have high optimal rates Optimal vs not: 11 mos (50% increase) Each 10%  in cytoreduction = 5.5%  in survival Platinum intensity = NS Bristow. J Clin Oncol. 2002;20:1248. The Impact of Residual Tumor: What Is Optimal Debulking? % Progression-Free Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.52 (2.26; 2.81) >10 mm vs 1 mm – 10 mm: 1.36 (1.24; 1.50) log-rank: P<0.0001 % Overall Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.70 (2.37; 3.07) >10 mm vs 1 mm – 10 mm: 1.34 (1.21; 1.49) log-rank: P<0.0001 Generated from 3 prospective Phase III trials (OVAR 3,5, & 7) n = 3126 pts DuBois. Cancer. 2009;115:1234. Case 1 She has a TAH BSO, transverse colectomy, omentectomy and spends 7 days in the hospital (2 in the ICU). Except for an open wound with a wound-vac and getting 4 units of blood, she does well… The pathology shows a high-grade serous carcinoma. The surgeon noted small volume residual (5-9mm) disease throughout the abdomen. What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP Case 1 Question 2 What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP All the above answers are reasonable treatment choices. When would you start the bevacizumab? Cycle 1, 2 or 3? After the chemotherapy (maintenance)? Case 2: Platinum Sensitive Ovarian Cancer 52-year-old woman with high-grade serous carcinoma of the fallopian tube Optimally debulked in 2010 Treated with IV paclitaxel, IP cisplatin and IP paclitaxel completed June 2011 CA125 at presentation 5800 nadir post therapy 7 In 2012 : Increasing Ca125 (1200) Imaging: diffuse peritoneal carcinomatosis; pleural nodularity; mediastinal adenopathy Symptomatic: abdominal bloating, early satiety, and mild shortness of breath Disease free interval: 10-12 months Genetic testing: BRCA1/2 negative Case 2 Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin PLD, carboplatin and bevacizumab Gemcitabine and carboplatin Gemcitabine, carboplatin and bevacizumab Paclitaxel and carboplatin Weekly paclitaxel and carboplatin Paclitaxel, carboplatin and PARP inhibitor Case 2, Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin (PLD and carboplatin is a reasonable option based on results of the CALYPSO study showing superiority to paclitaxel and carboplatin) PLD, carboplatin and bevacizumab (PLD, carboplatin and bevacizumab has not been tested in a randomized phase III trial) Gemcitabine and carboplatin (Gemcitabine and carboplatin: this is reasonable based on a comparison with carboplatin alone (Pfisterer et.al. 2005) Gemcitabine, carboplatin and bevacizumab (Higher response rates and improved PFS are seen when bevacizumab is added to gem/carbo but OS is not improved (OCEANS trial) Paclitaxel and carboplatin (Paclitaxel and carboplatin can be used but based on prior taxane and results of CALYPSO, is used less) Weekly paclitaxel and carboplatin (Weekly paclitaxel has shown improved outcome when used with carboplatin for newly diagnosed patients but has not been rigorously tested in recurrent disease Paclitaxel, carboplatin and PARP inhibitor (PARP inhibitors are not yet FDA approved , so can only be obtained on a clinical trial. However, this is a very promising direction in ovarian cancer and a clinical trial of paclitaxel and carboplatin +/- olaparib showed improved PFS (Oza et.al. ASCO 2012) She Asks You Whether There Is Any Role for Surgery for Her Which of the following are true regarding secondary debulking? It is not considered for patients like her who relapse 10-12 months after completing initial chemotherapy The finding of carcinomatosis is a relatively strong contraindication to secondary debulking surgery Survival is improved for secondary debulking even if all disease can’t be removed at surgery Mediastinal and pleural disease are relatively strong contraindications to secondary debulking surgery 1 and 3 2 and 4 All of the above Secondary Debulking Candidate Selection Onda et al. J Cancer. 2005;92:1026. Pujade-Lauraine, Ann Oncol. 2011;22(Supplement 8):viii61–viii64. RANDOM I Z E GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: ≤ 0.5 cm > 0.5-2 cm PLD 30 mg/m2 Carboplatin AUC = 5 q 28 days x 6 Paclitaxel 175 mg/m2 Carboplatin AUC = 5 q 21 days x 6 GCIG = Gynecologic Cancer Intergroup PFS = progression-free survival PLD = pegylated liposomal doxorubicin Accrual 864 pts PFS primary endpoint Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. GCIG CALYPSO Trial Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. Selected Non-hematologic Toxicities During Treatment Alopecia *P< 0.001 Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. Targeted Agents in Ovarian Cancer Signaling/Angiogenesis Bevacizumab/Aflibercept RTKI’s: Pazopanib Cabozantinib Sorafenib, etc Cediranib Nintedanib Trebananib, MEDI-3617 PI3K/Akt/mTOR MEKi Folate: Vintafolide (EC-145) Farletuzumab NKTR-102 Taxanes/epothilones Immunotherapy – vaccines and inducers EP-100 PARPi ErbB3 CG + PL OCEANS: Study schema CG for 6 (up to 10) cycles Stratification variables: Platinum-free interval (6–12 vs >12 months) Cytoreductive surgery for recurrent disease (yes vs no) Platinum-sensitive recurrent OCa Measurable disease ECOG 0/1 No prior chemo for recurrent OC No prior BV (n=484) BV = bevacizumab; PL = placebo aEpithelial ovarian, primary peritoneal, or fallopian tube cancer G 1000 mg/m2, d1 & 8 C AUC 4 PL q3w until progression C AUC 4 BV 15 mg/kg q3w until progression G 1000 mg/m2, d1 & 8 CG + BV Aghajanian C et al. J Clin Oncol. 2012;30:2039-2045. 242 177 45 11 3 0 CG + PL OCEANS: Primary Analysis of PFS Months No. at risk 242 203 92 33 11 0 CG + BV 1.0 0.8 0.6 0.4 0.2 0 Proportion progression free 0 6 12 18 24 30 Aghajanian C et al. J Clin Oncol. 2012;30:2039-2045. 1.0 0.8 0.6 0.4 0.2 0 OCEANS: Third Interim OS Analysisa 0 6 12 18 24 30 36 42 48 54 60 242 235 221 190 159 117 77 44 23 7 0 242 239 226 201 171 127 78 48 27 7 0 Number at risk: GC + PL GC + BV aData cutoff date: March 30, 2012. Median follow-up 41.9 months in PL arm and 42.3 months in BV arm, with 286 deaths (59.1% of patients) Proportion surviving Months Aghajanian et al. ESMO 2012. Asymptomatic relapse Single-agent farletuzumab Until progression Single-agent ORR Compare lengths of first and second remissions Farletuzumab - MORAb-003-002 Phase II: Design Epithelial Ovarian Cancer First platinum-sensitive relapse First remission of 6-18 months Evaluable disease by CA125 Symptomatic relapse Original Carbo/Taxane regimen Plus farletuzumab x 6 Farletuzumab maintenance Rx For responders Combination ORR White AJ et al. J Clin Oncol. 2010;28(15s):Abstract 5001. MorAb-003-002: Study Conclusions Overall response rate 70% Response rate similar in early (6-12 month) and late (12+ months) recurrent patients High rates of CA-125 normalization (89%) 1/5 patients had a PFI2 ≥ PFI1 Phase III studies Platinum-sensitive: fully enrolled Platinum-resistant (weekly paclitaxel): met futility endpoint White AJ et al. J Clin Oncol. 2010;28(15s):Abstract 5001. n=66 Randomized, Open-label, Phase II Study in Patients With Platinum-sensitive, Advanced Serous Ovarian Cancer Paclitaxel 175 mg/m2 (iv, d1) + carboplatin AUC6 (iv d1) Randomization (1:1) All patients followed for objective radiologic progression and survival Maintenance phase Olaparib 400 mg bid continuously Completion of 4–6 x 21-day cycles of chemotherapy Arm B Arm A n=81 n=81 n=55 Multinational study; 43 sites in 12 countries * Capsule formulation Patients with: Platinum-sensitive advanced ovarian cancer A serous histology or serous component Measurable disease ≤3 previous platinum-containing regimens Progression free for ≥6 months following completion of last platinum-containing regimen Maintenance phase No further study treatment Olaparib 200 mg bid* (d1–10 every 21 days) + paclitaxel 175 mg/m2 (iv, d1) + carboplatin AUC4 (iv, d1) Oza A. ASCO 2012; Abstract 5001. Paclitaxel Carboplatin (P/C) vs P/C Plus Olaparib (O/P/C) In Platinum Sensitive Recurrent Ovarian Cancer: PFS Time from randomization (months) 0 Proportion of patients progression free 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 2 4 6 8 10 12 16 20 Number of patients at risk Olaparib + P + C (AUC4) P + C (AUC6) 14 18 81 80 76 71 55 37 34 3 0 20 0 81 68 65 57 40 18 15 2 0 8 1 O/P/C P/C Oza A. ASCO 2012; Abstract 5001.
Slide 58 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R A N D O M I Z E n = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Placebo BEV 15 mg/kg II Stratification variables: GOG performance status (PS) Stage/debulking status RANDOM I Z E 1:1:1 15 months Paclitaxel (P) 175 mg/m2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 III Maintenance (16 cycles) BEV 15 mg/kg Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218: Investigator-assessed PFS + BEV (Arm II) CP (Arm I) *P-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 CA-125 to Determine Progression Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 Interim Survival Analysis Proportion Alive Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 48 aStratified analysis 625/625/623 442/432/437 173/162/171 46/39/40 No. at risk Burger RA et al. N Engl J Med. 2011;365:2473-2483. ICON7: Study Design Stratification variables: Stage/surgery Time since surgery GCIG group *Might vary based on GCIG group **Omit cycle 1 bevacizumab if <4 weeks from surgery Paclitaxel 175 mg/m2 Carboplatin AUC 6* AVASTIN Carboplatin AUC 6* Paclitaxel 175 mg/m2 Arm A Arm B 12 months Front-line EOC, PP or FT cancer Stage I-IIA (Gr 3 or CC) Stage IIB/C Stage III Stage IV n=1528 Bevacizumab 7.5 mg/kg ** Primary endpoints: PFS Secondary endpoints: OS, RR, safety, QOL, cost-effectiveness, translational No IRC present Perren T et al. N Engl J Med. 2011;365:2484-2496. Perren et al. ESMO 2010. ICON 7 Summary of Updated Results Kristensen G et al. J Clin Oncol. 2011;29: suppl; abstr LBA5006). Perren T et al. N Engl J Med. 2011;365:2484-2496. First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG 178—Investigating Paclitaxel as Consolidation Markman M et al. J Clin Oncol. 2003;21:2460-2465. 277 stage III/IV patients in complete clinical remission Paclitaxel 175 mg/m2 every 28 days × 3 months Paclitaxel 175 mg/m2 every 28 days × 12 months RANDOM I Z E CR = Complete response. Progression-free survival 0 20 40 60 80 100 0 12 24 36 48 Months after registration Paclitaxel 12 courses Paclitaxel 3 courses 110 At risk 112 Failed 20 34 Median, months 28 21 P = 0.0023 Percentage Markman M et al. J Clin Oncol. 2003;21:2460-2465. GOG 178 GOG-0212 Phase III Maintenance Therapy Trial Primary endpoint: survival Secondary endpoints: PFS, toxicity, QoL www.clinicaltrials.gov/ct2/show/NCT00108745. Macromolecular complex of paclitaxel poliglumex Patients with stage III/IV epithelial ovarian or primary peritoneal cancer, GOG PS ≤ 2, and complete response after surgery plus taxane and carboplatin (Planned n = 1400-1550) Paclitaxel Every 28 days for up to 12 courses No treatment Paclitaxel poliglumex Every 28 days for up to 12 courses Summary: Initial Treatment of Advanced Ovarian Cancer Surgery Attempt at maximal surgical cytoreduction Neoadjuvant chemo before surgery is an option for poor surgical candidates Chemotherapy 6-8 cycles taxane-platinum combination is standard IP admin benefits patients with low volume (optimal) disease but has increased toxicity NED patients treated with IP have a median survival of over 9 years Weekly (dose-dense) paclitaxel improves outcome in one study Confirmatory North American trials recently completed Bevacizumab during and after chemotherapy improves PFS but not OS Case Discussions Case 1: A Newly Diagnosed Patient With Ovarian Cancer 58 year old real estate broker with controlled hypertension presents with a pelvic mass, omental caking, and a CA125 of 2,056. She has no malnutrition or change in her weight. She is a PS=0. What would you recommend for this patient? Neoadjuvant chemotherapy Primary radical debulking surgery What Would You Recommend for This Patient? Neoadjuvant chemotherapy Primary radical debulking surgery Primary Cytoreduction Meta-analysis: 53 studies (1989–1998) 81 cohorts (Stage III/IV) n = 6885 patients Results Expert centers have high optimal rates Optimal vs not: 11 mos (50% increase) Each 10%  in cytoreduction = 5.5%  in survival Platinum intensity = NS Bristow. J Clin Oncol. 2002;20:1248. The Impact of Residual Tumor: What Is Optimal Debulking? % Progression-Free Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.52 (2.26; 2.81) >10 mm vs 1 mm – 10 mm: 1.36 (1.24; 1.50) log-rank: P<0.0001 % Overall Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.70 (2.37; 3.07) >10 mm vs 1 mm – 10 mm: 1.34 (1.21; 1.49) log-rank: P<0.0001 Generated from 3 prospective Phase III trials (OVAR 3,5, & 7) n = 3126 pts DuBois. Cancer. 2009;115:1234. Case 1 She has a TAH BSO, transverse colectomy, omentectomy and spends 7 days in the hospital (2 in the ICU). Except for an open wound with a wound-vac and getting 4 units of blood, she does well… The pathology shows a high-grade serous carcinoma. The surgeon noted small volume residual (5-9mm) disease throughout the abdomen. What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP Case 1 Question 2 What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP All the above answers are reasonable treatment choices. When would you start the bevacizumab? Cycle 1, 2 or 3? After the chemotherapy (maintenance)? Case 2: Platinum Sensitive Ovarian Cancer 52-year-old woman with high-grade serous carcinoma of the fallopian tube Optimally debulked in 2010 Treated with IV paclitaxel, IP cisplatin and IP paclitaxel completed June 2011 CA125 at presentation 5800 nadir post therapy 7 In 2012 : Increasing Ca125 (1200) Imaging: diffuse peritoneal carcinomatosis; pleural nodularity; mediastinal adenopathy Symptomatic: abdominal bloating, early satiety, and mild shortness of breath Disease free interval: 10-12 months Genetic testing: BRCA1/2 negative Case 2 Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin PLD, carboplatin and bevacizumab Gemcitabine and carboplatin Gemcitabine, carboplatin and bevacizumab Paclitaxel and carboplatin Weekly paclitaxel and carboplatin Paclitaxel, carboplatin and PARP inhibitor Case 2, Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin (PLD and carboplatin is a reasonable option based on results of the CALYPSO study showing superiority to paclitaxel and carboplatin) PLD, carboplatin and bevacizumab (PLD, carboplatin and bevacizumab has not been tested in a randomized phase III trial) Gemcitabine and carboplatin (Gemcitabine and carboplatin: this is reasonable based on a comparison with carboplatin alone (Pfisterer et.al. 2005) Gemcitabine, carboplatin and bevacizumab (Higher response rates and improved PFS are seen when bevacizumab is added to gem/carbo but OS is not improved (OCEANS trial) Paclitaxel and carboplatin (Paclitaxel and carboplatin can be used but based on prior taxane and results of CALYPSO, is used less) Weekly paclitaxel and carboplatin (Weekly paclitaxel has shown improved outcome when used with carboplatin for newly diagnosed patients but has not been rigorously tested in recurrent disease Paclitaxel, carboplatin and PARP inhibitor (PARP inhibitors are not yet FDA approved , so can only be obtained on a clinical trial. However, this is a very promising direction in ovarian cancer and a clinical trial of paclitaxel and carboplatin +/- olaparib showed improved PFS (Oza et.al. ASCO 2012) She Asks You Whether There Is Any Role for Surgery for Her Which of the following are true regarding secondary debulking? It is not considered for patients like her who relapse 10-12 months after completing initial chemotherapy The finding of carcinomatosis is a relatively strong contraindication to secondary debulking surgery Survival is improved for secondary debulking even if all disease can’t be removed at surgery Mediastinal and pleural disease are relatively strong contraindications to secondary debulking surgery 1 and 3 2 and 4 All of the above Secondary Debulking Candidate Selection Onda et al. J Cancer. 2005;92:1026. Pujade-Lauraine, Ann Oncol. 2011;22(Supplement 8):viii61–viii64. RANDOM I Z E GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: ≤ 0.5 cm > 0.5-2 cm PLD 30 mg/m2 Carboplatin AUC = 5 q 28 days x 6 Paclitaxel 175 mg/m2 Carboplatin AUC = 5 q 21 days x 6 GCIG = Gynecologic Cancer Intergroup PFS = progression-free survival PLD = pegylated liposomal doxorubicin Accrual 864 pts PFS primary endpoint Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. GCIG CALYPSO Trial Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. Selected Non-hematologic Toxicities During Treatment Alopecia *P< 0.001 Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. Targeted Agents in Ovarian Cancer Signaling/Angiogenesis Bevacizumab/Aflibercept RTKI’s: Pazopanib Cabozantinib Sorafenib, etc Cediranib Nintedanib Trebananib, MEDI-3617 PI3K/Akt/mTOR MEKi Folate: Vintafolide (EC-145) Farletuzumab NKTR-102 Taxanes/epothilones Immunotherapy – vaccines and inducers EP-100 PARPi ErbB3 CG + PL OCEANS: Study schema CG for 6 (up to 10) cycles Stratification variables: Platinum-free interval (6–12 vs >12 months) Cytoreductive surgery for recurrent disease (yes vs no) Platinum-sensitive recurrent OCa Measurable disease ECOG 0/1 No prior chemo for recurrent OC No prior BV (n=484) BV = bevacizumab; PL = placebo aEpithelial ovarian, primary peritoneal, or fallopian tube cancer G 1000 mg/m2, d1 & 8 C AUC 4 PL q3w until progression C AUC 4 BV 15 mg/kg q3w until progression G 1000 mg/m2, d1 & 8 CG + BV Aghajanian C et al. J Clin Oncol. 2012;30:2039-2045. 242 177 45 11 3 0 CG + PL OCEANS: Primary Analysis of PFS Months No. at risk 242 203 92 33 11 0 CG + BV 1.0 0.8 0.6 0.4 0.2 0 Proportion progression free 0 6 12 18 24 30 Aghajanian C et al. J Clin Oncol. 2012;30:2039-2045. 1.0 0.8 0.6 0.4 0.2 0 OCEANS: Third Interim OS Analysisa 0 6 12 18 24 30 36 42 48 54 60 242 235 221 190 159 117 77 44 23 7 0 242 239 226 201 171 127 78 48 27 7 0 Number at risk: GC + PL GC + BV aData cutoff date: March 30, 2012. Median follow-up 41.9 months in PL arm and 42.3 months in BV arm, with 286 deaths (59.1% of patients) Proportion surviving Months Aghajanian et al. ESMO 2012. Asymptomatic relapse Single-agent farletuzumab Until progression Single-agent ORR Compare lengths of first and second remissions Farletuzumab - MORAb-003-002 Phase II: Design Epithelial Ovarian Cancer First platinum-sensitive relapse First remission of 6-18 months Evaluable disease by CA125 Symptomatic relapse Original Carbo/Taxane regimen Plus farletuzumab x 6 Farletuzumab maintenance Rx For responders Combination ORR White AJ et al. J Clin Oncol. 2010;28(15s):Abstract 5001. MorAb-003-002: Study Conclusions Overall response rate 70% Response rate similar in early (6-12 month) and late (12+ months) recurrent patients High rates of CA-125 normalization (89%) 1/5 patients had a PFI2 ≥ PFI1 Phase III studies Platinum-sensitive: fully enrolled Platinum-resistant (weekly paclitaxel): met futility endpoint White AJ et al. J Clin Oncol. 2010;28(15s):Abstract 5001. n=66 Randomized, Open-label, Phase II Study in Patients With Platinum-sensitive, Advanced Serous Ovarian Cancer Paclitaxel 175 mg/m2 (iv, d1) + carboplatin AUC6 (iv d1) Randomization (1:1) All patients followed for objective radiologic progression and survival Maintenance phase Olaparib 400 mg bid continuously Completion of 4–6 x 21-day cycles of chemotherapy Arm B Arm A n=81 n=81 n=55 Multinational study; 43 sites in 12 countries * Capsule formulation Patients with: Platinum-sensitive advanced ovarian cancer A serous histology or serous component Measurable disease ≤3 previous platinum-containing regimens Progression free for ≥6 months following completion of last platinum-containing regimen Maintenance phase No further study treatment Olaparib 200 mg bid* (d1–10 every 21 days) + paclitaxel 175 mg/m2 (iv, d1) + carboplatin AUC4 (iv, d1) Oza A. ASCO 2012; Abstract 5001. Paclitaxel Carboplatin (P/C) vs P/C Plus Olaparib (O/P/C) In Platinum Sensitive Recurrent Ovarian Cancer: PFS Time from randomization (months) 0 Proportion of patients progression free 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 2 4 6 8 10 12 16 20 Number of patients at risk Olaparib + P + C (AUC4) P + C (AUC6) 14 18 81 80 76 71 55 37 34 3 0 20 0 81 68 65 57 40 18 15 2 0 8 1 O/P/C P/C Oza A. ASCO 2012; Abstract 5001. GOG 9927: Phase I Combination Platinum sensitive recurrent EOC Chemotherapy based on CALYPSO Primary endpoint: 1st or 2nd cycle DLT Secondary endpoints: RR, PFS, Toxicity TR: PARPi in PBMCs, BRCA status PLD 30 mg/m2 Carboplatin AUC 5 Arm I Veliparib PO daily continuously Cycles: 28 days Planned administration: 6 cycles Arm II Veliparib PO daily D1-7 Cycles: 28 days Planned administration: 6 cycles www.clinicaltrials.gov/ct2/show/NCT01459380.
Slide 59 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R A N D O M I Z E n = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Placebo BEV 15 mg/kg II Stratification variables: GOG performance status (PS) Stage/debulking status RANDOM I Z E 1:1:1 15 months Paclitaxel (P) 175 mg/m2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 III Maintenance (16 cycles) BEV 15 mg/kg Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218: Investigator-assessed PFS + BEV (Arm II) CP (Arm I) *P-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 CA-125 to Determine Progression Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 Interim Survival Analysis Proportion Alive Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 48 aStratified analysis 625/625/623 442/432/437 173/162/171 46/39/40 No. at risk Burger RA et al. N Engl J Med. 2011;365:2473-2483. ICON7: Study Design Stratification variables: Stage/surgery Time since surgery GCIG group *Might vary based on GCIG group **Omit cycle 1 bevacizumab if <4 weeks from surgery Paclitaxel 175 mg/m2 Carboplatin AUC 6* AVASTIN Carboplatin AUC 6* Paclitaxel 175 mg/m2 Arm A Arm B 12 months Front-line EOC, PP or FT cancer Stage I-IIA (Gr 3 or CC) Stage IIB/C Stage III Stage IV n=1528 Bevacizumab 7.5 mg/kg ** Primary endpoints: PFS Secondary endpoints: OS, RR, safety, QOL, cost-effectiveness, translational No IRC present Perren T et al. N Engl J Med. 2011;365:2484-2496. Perren et al. ESMO 2010. ICON 7 Summary of Updated Results Kristensen G et al. J Clin Oncol. 2011;29: suppl; abstr LBA5006). Perren T et al. N Engl J Med. 2011;365:2484-2496. First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG 178—Investigating Paclitaxel as Consolidation Markman M et al. J Clin Oncol. 2003;21:2460-2465. 277 stage III/IV patients in complete clinical remission Paclitaxel 175 mg/m2 every 28 days × 3 months Paclitaxel 175 mg/m2 every 28 days × 12 months RANDOM I Z E CR = Complete response. Progression-free survival 0 20 40 60 80 100 0 12 24 36 48 Months after registration Paclitaxel 12 courses Paclitaxel 3 courses 110 At risk 112 Failed 20 34 Median, months 28 21 P = 0.0023 Percentage Markman M et al. J Clin Oncol. 2003;21:2460-2465. GOG 178 GOG-0212 Phase III Maintenance Therapy Trial Primary endpoint: survival Secondary endpoints: PFS, toxicity, QoL www.clinicaltrials.gov/ct2/show/NCT00108745. Macromolecular complex of paclitaxel poliglumex Patients with stage III/IV epithelial ovarian or primary peritoneal cancer, GOG PS ≤ 2, and complete response after surgery plus taxane and carboplatin (Planned n = 1400-1550) Paclitaxel Every 28 days for up to 12 courses No treatment Paclitaxel poliglumex Every 28 days for up to 12 courses Summary: Initial Treatment of Advanced Ovarian Cancer Surgery Attempt at maximal surgical cytoreduction Neoadjuvant chemo before surgery is an option for poor surgical candidates Chemotherapy 6-8 cycles taxane-platinum combination is standard IP admin benefits patients with low volume (optimal) disease but has increased toxicity NED patients treated with IP have a median survival of over 9 years Weekly (dose-dense) paclitaxel improves outcome in one study Confirmatory North American trials recently completed Bevacizumab during and after chemotherapy improves PFS but not OS Case Discussions Case 1: A Newly Diagnosed Patient With Ovarian Cancer 58 year old real estate broker with controlled hypertension presents with a pelvic mass, omental caking, and a CA125 of 2,056. She has no malnutrition or change in her weight. She is a PS=0. What would you recommend for this patient? Neoadjuvant chemotherapy Primary radical debulking surgery What Would You Recommend for This Patient? Neoadjuvant chemotherapy Primary radical debulking surgery Primary Cytoreduction Meta-analysis: 53 studies (1989–1998) 81 cohorts (Stage III/IV) n = 6885 patients Results Expert centers have high optimal rates Optimal vs not: 11 mos (50% increase) Each 10%  in cytoreduction = 5.5%  in survival Platinum intensity = NS Bristow. J Clin Oncol. 2002;20:1248. The Impact of Residual Tumor: What Is Optimal Debulking? % Progression-Free Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.52 (2.26; 2.81) >10 mm vs 1 mm – 10 mm: 1.36 (1.24; 1.50) log-rank: P<0.0001 % Overall Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.70 (2.37; 3.07) >10 mm vs 1 mm – 10 mm: 1.34 (1.21; 1.49) log-rank: P<0.0001 Generated from 3 prospective Phase III trials (OVAR 3,5, & 7) n = 3126 pts DuBois. Cancer. 2009;115:1234. Case 1 She has a TAH BSO, transverse colectomy, omentectomy and spends 7 days in the hospital (2 in the ICU). Except for an open wound with a wound-vac and getting 4 units of blood, she does well… The pathology shows a high-grade serous carcinoma. The surgeon noted small volume residual (5-9mm) disease throughout the abdomen. What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP Case 1 Question 2 What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP All the above answers are reasonable treatment choices. When would you start the bevacizumab? Cycle 1, 2 or 3? After the chemotherapy (maintenance)? Case 2: Platinum Sensitive Ovarian Cancer 52-year-old woman with high-grade serous carcinoma of the fallopian tube Optimally debulked in 2010 Treated with IV paclitaxel, IP cisplatin and IP paclitaxel completed June 2011 CA125 at presentation 5800 nadir post therapy 7 In 2012 : Increasing Ca125 (1200) Imaging: diffuse peritoneal carcinomatosis; pleural nodularity; mediastinal adenopathy Symptomatic: abdominal bloating, early satiety, and mild shortness of breath Disease free interval: 10-12 months Genetic testing: BRCA1/2 negative Case 2 Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin PLD, carboplatin and bevacizumab Gemcitabine and carboplatin Gemcitabine, carboplatin and bevacizumab Paclitaxel and carboplatin Weekly paclitaxel and carboplatin Paclitaxel, carboplatin and PARP inhibitor Case 2, Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin (PLD and carboplatin is a reasonable option based on results of the CALYPSO study showing superiority to paclitaxel and carboplatin) PLD, carboplatin and bevacizumab (PLD, carboplatin and bevacizumab has not been tested in a randomized phase III trial) Gemcitabine and carboplatin (Gemcitabine and carboplatin: this is reasonable based on a comparison with carboplatin alone (Pfisterer et.al. 2005) Gemcitabine, carboplatin and bevacizumab (Higher response rates and improved PFS are seen when bevacizumab is added to gem/carbo but OS is not improved (OCEANS trial) Paclitaxel and carboplatin (Paclitaxel and carboplatin can be used but based on prior taxane and results of CALYPSO, is used less) Weekly paclitaxel and carboplatin (Weekly paclitaxel has shown improved outcome when used with carboplatin for newly diagnosed patients but has not been rigorously tested in recurrent disease Paclitaxel, carboplatin and PARP inhibitor (PARP inhibitors are not yet FDA approved , so can only be obtained on a clinical trial. However, this is a very promising direction in ovarian cancer and a clinical trial of paclitaxel and carboplatin +/- olaparib showed improved PFS (Oza et.al. ASCO 2012) She Asks You Whether There Is Any Role for Surgery for Her Which of the following are true regarding secondary debulking? It is not considered for patients like her who relapse 10-12 months after completing initial chemotherapy The finding of carcinomatosis is a relatively strong contraindication to secondary debulking surgery Survival is improved for secondary debulking even if all disease can’t be removed at surgery Mediastinal and pleural disease are relatively strong contraindications to secondary debulking surgery 1 and 3 2 and 4 All of the above Secondary Debulking Candidate Selection Onda et al. J Cancer. 2005;92:1026. Pujade-Lauraine, Ann Oncol. 2011;22(Supplement 8):viii61–viii64. RANDOM I Z E GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: ≤ 0.5 cm > 0.5-2 cm PLD 30 mg/m2 Carboplatin AUC = 5 q 28 days x 6 Paclitaxel 175 mg/m2 Carboplatin AUC = 5 q 21 days x 6 GCIG = Gynecologic Cancer Intergroup PFS = progression-free survival PLD = pegylated liposomal doxorubicin Accrual 864 pts PFS primary endpoint Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. GCIG CALYPSO Trial Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. Selected Non-hematologic Toxicities During Treatment Alopecia *P< 0.001 Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. Targeted Agents in Ovarian Cancer Signaling/Angiogenesis Bevacizumab/Aflibercept RTKI’s: Pazopanib Cabozantinib Sorafenib, etc Cediranib Nintedanib Trebananib, MEDI-3617 PI3K/Akt/mTOR MEKi Folate: Vintafolide (EC-145) Farletuzumab NKTR-102 Taxanes/epothilones Immunotherapy – vaccines and inducers EP-100 PARPi ErbB3 CG + PL OCEANS: Study schema CG for 6 (up to 10) cycles Stratification variables: Platinum-free interval (6–12 vs >12 months) Cytoreductive surgery for recurrent disease (yes vs no) Platinum-sensitive recurrent OCa Measurable disease ECOG 0/1 No prior chemo for recurrent OC No prior BV (n=484) BV = bevacizumab; PL = placebo aEpithelial ovarian, primary peritoneal, or fallopian tube cancer G 1000 mg/m2, d1 & 8 C AUC 4 PL q3w until progression C AUC 4 BV 15 mg/kg q3w until progression G 1000 mg/m2, d1 & 8 CG + BV Aghajanian C et al. J Clin Oncol. 2012;30:2039-2045. 242 177 45 11 3 0 CG + PL OCEANS: Primary Analysis of PFS Months No. at risk 242 203 92 33 11 0 CG + BV 1.0 0.8 0.6 0.4 0.2 0 Proportion progression free 0 6 12 18 24 30 Aghajanian C et al. J Clin Oncol. 2012;30:2039-2045. 1.0 0.8 0.6 0.4 0.2 0 OCEANS: Third Interim OS Analysisa 0 6 12 18 24 30 36 42 48 54 60 242 235 221 190 159 117 77 44 23 7 0 242 239 226 201 171 127 78 48 27 7 0 Number at risk: GC + PL GC + BV aData cutoff date: March 30, 2012. Median follow-up 41.9 months in PL arm and 42.3 months in BV arm, with 286 deaths (59.1% of patients) Proportion surviving Months Aghajanian et al. ESMO 2012. Asymptomatic relapse Single-agent farletuzumab Until progression Single-agent ORR Compare lengths of first and second remissions Farletuzumab - MORAb-003-002 Phase II: Design Epithelial Ovarian Cancer First platinum-sensitive relapse First remission of 6-18 months Evaluable disease by CA125 Symptomatic relapse Original Carbo/Taxane regimen Plus farletuzumab x 6 Farletuzumab maintenance Rx For responders Combination ORR White AJ et al. J Clin Oncol. 2010;28(15s):Abstract 5001. MorAb-003-002: Study Conclusions Overall response rate 70% Response rate similar in early (6-12 month) and late (12+ months) recurrent patients High rates of CA-125 normalization (89%) 1/5 patients had a PFI2 ≥ PFI1 Phase III studies Platinum-sensitive: fully enrolled Platinum-resistant (weekly paclitaxel): met futility endpoint White AJ et al. J Clin Oncol. 2010;28(15s):Abstract 5001. n=66 Randomized, Open-label, Phase II Study in Patients With Platinum-sensitive, Advanced Serous Ovarian Cancer Paclitaxel 175 mg/m2 (iv, d1) + carboplatin AUC6 (iv d1) Randomization (1:1) All patients followed for objective radiologic progression and survival Maintenance phase Olaparib 400 mg bid continuously Completion of 4–6 x 21-day cycles of chemotherapy Arm B Arm A n=81 n=81 n=55 Multinational study; 43 sites in 12 countries * Capsule formulation Patients with: Platinum-sensitive advanced ovarian cancer A serous histology or serous component Measurable disease ≤3 previous platinum-containing regimens Progression free for ≥6 months following completion of last platinum-containing regimen Maintenance phase No further study treatment Olaparib 200 mg bid* (d1–10 every 21 days) + paclitaxel 175 mg/m2 (iv, d1) + carboplatin AUC4 (iv, d1) Oza A. ASCO 2012; Abstract 5001. Paclitaxel Carboplatin (P/C) vs P/C Plus Olaparib (O/P/C) In Platinum Sensitive Recurrent Ovarian Cancer: PFS Time from randomization (months) 0 Proportion of patients progression free 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 2 4 6 8 10 12 16 20 Number of patients at risk Olaparib + P + C (AUC4) P + C (AUC6) 14 18 81 80 76 71 55 37 34 3 0 20 0 81 68 65 57 40 18 15 2 0 8 1 O/P/C P/C Oza A. ASCO 2012; Abstract 5001. GOG 9927: Phase I Combination Platinum sensitive recurrent EOC Chemotherapy based on CALYPSO Primary endpoint: 1st or 2nd cycle DLT Secondary endpoints: RR, PFS, Toxicity TR: PARPi in PBMCs, BRCA status PLD 30 mg/m2 Carboplatin AUC 5 Arm I Veliparib PO daily continuously Cycles: 28 days Planned administration: 6 cycles Arm II Veliparib PO daily D1-7 Cycles: 28 days Planned administration: 6 cycles www.clinicaltrials.gov/ct2/show/NCT01459380. Summary for Platinum-sensitive Recurrent Ovarian Cancer Consider Secondary Debulking Platinum retreatment is standard Treatment with a platinum-based doublet improves response rate, progression-free survival, and possibly overall survival Options: Taxane Carboplatin: Paclitaxel, Docetaxel (?), Weekly Paclitaxel (?) Gemcitabine Carboplatin +/- Bevacizumab PLD Carboplatin
Slide 60 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R A N D O M I Z E n = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Placebo BEV 15 mg/kg II Stratification variables: GOG performance status (PS) Stage/debulking status RANDOM I Z E 1:1:1 15 months Paclitaxel (P) 175 mg/m2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 III Maintenance (16 cycles) BEV 15 mg/kg Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218: Investigator-assessed PFS + BEV (Arm II) CP (Arm I) *P-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 CA-125 to Determine Progression Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 Interim Survival Analysis Proportion Alive Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 48 aStratified analysis 625/625/623 442/432/437 173/162/171 46/39/40 No. at risk Burger RA et al. N Engl J Med. 2011;365:2473-2483. ICON7: Study Design Stratification variables: Stage/surgery Time since surgery GCIG group *Might vary based on GCIG group **Omit cycle 1 bevacizumab if <4 weeks from surgery Paclitaxel 175 mg/m2 Carboplatin AUC 6* AVASTIN Carboplatin AUC 6* Paclitaxel 175 mg/m2 Arm A Arm B 12 months Front-line EOC, PP or FT cancer Stage I-IIA (Gr 3 or CC) Stage IIB/C Stage III Stage IV n=1528 Bevacizumab 7.5 mg/kg ** Primary endpoints: PFS Secondary endpoints: OS, RR, safety, QOL, cost-effectiveness, translational No IRC present Perren T et al. N Engl J Med. 2011;365:2484-2496. Perren et al. ESMO 2010. ICON 7 Summary of Updated Results Kristensen G et al. J Clin Oncol. 2011;29: suppl; abstr LBA5006). Perren T et al. N Engl J Med. 2011;365:2484-2496. First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG 178—Investigating Paclitaxel as Consolidation Markman M et al. J Clin Oncol. 2003;21:2460-2465. 277 stage III/IV patients in complete clinical remission Paclitaxel 175 mg/m2 every 28 days × 3 months Paclitaxel 175 mg/m2 every 28 days × 12 months RANDOM I Z E CR = Complete response. Progression-free survival 0 20 40 60 80 100 0 12 24 36 48 Months after registration Paclitaxel 12 courses Paclitaxel 3 courses 110 At risk 112 Failed 20 34 Median, months 28 21 P = 0.0023 Percentage Markman M et al. J Clin Oncol. 2003;21:2460-2465. GOG 178 GOG-0212 Phase III Maintenance Therapy Trial Primary endpoint: survival Secondary endpoints: PFS, toxicity, QoL www.clinicaltrials.gov/ct2/show/NCT00108745. Macromolecular complex of paclitaxel poliglumex Patients with stage III/IV epithelial ovarian or primary peritoneal cancer, GOG PS ≤ 2, and complete response after surgery plus taxane and carboplatin (Planned n = 1400-1550) Paclitaxel Every 28 days for up to 12 courses No treatment Paclitaxel poliglumex Every 28 days for up to 12 courses Summary: Initial Treatment of Advanced Ovarian Cancer Surgery Attempt at maximal surgical cytoreduction Neoadjuvant chemo before surgery is an option for poor surgical candidates Chemotherapy 6-8 cycles taxane-platinum combination is standard IP admin benefits patients with low volume (optimal) disease but has increased toxicity NED patients treated with IP have a median survival of over 9 years Weekly (dose-dense) paclitaxel improves outcome in one study Confirmatory North American trials recently completed Bevacizumab during and after chemotherapy improves PFS but not OS Case Discussions Case 1: A Newly Diagnosed Patient With Ovarian Cancer 58 year old real estate broker with controlled hypertension presents with a pelvic mass, omental caking, and a CA125 of 2,056. She has no malnutrition or change in her weight. She is a PS=0. What would you recommend for this patient? Neoadjuvant chemotherapy Primary radical debulking surgery What Would You Recommend for This Patient? Neoadjuvant chemotherapy Primary radical debulking surgery Primary Cytoreduction Meta-analysis: 53 studies (1989–1998) 81 cohorts (Stage III/IV) n = 6885 patients Results Expert centers have high optimal rates Optimal vs not: 11 mos (50% increase) Each 10%  in cytoreduction = 5.5%  in survival Platinum intensity = NS Bristow. J Clin Oncol. 2002;20:1248. The Impact of Residual Tumor: What Is Optimal Debulking? % Progression-Free Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.52 (2.26; 2.81) >10 mm vs 1 mm – 10 mm: 1.36 (1.24; 1.50) log-rank: P<0.0001 % Overall Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.70 (2.37; 3.07) >10 mm vs 1 mm – 10 mm: 1.34 (1.21; 1.49) log-rank: P<0.0001 Generated from 3 prospective Phase III trials (OVAR 3,5, & 7) n = 3126 pts DuBois. Cancer. 2009;115:1234. Case 1 She has a TAH BSO, transverse colectomy, omentectomy and spends 7 days in the hospital (2 in the ICU). Except for an open wound with a wound-vac and getting 4 units of blood, she does well… The pathology shows a high-grade serous carcinoma. The surgeon noted small volume residual (5-9mm) disease throughout the abdomen. What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP Case 1 Question 2 What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP All the above answers are reasonable treatment choices. When would you start the bevacizumab? Cycle 1, 2 or 3? After the chemotherapy (maintenance)? Case 2: Platinum Sensitive Ovarian Cancer 52-year-old woman with high-grade serous carcinoma of the fallopian tube Optimally debulked in 2010 Treated with IV paclitaxel, IP cisplatin and IP paclitaxel completed June 2011 CA125 at presentation 5800 nadir post therapy 7 In 2012 : Increasing Ca125 (1200) Imaging: diffuse peritoneal carcinomatosis; pleural nodularity; mediastinal adenopathy Symptomatic: abdominal bloating, early satiety, and mild shortness of breath Disease free interval: 10-12 months Genetic testing: BRCA1/2 negative Case 2 Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin PLD, carboplatin and bevacizumab Gemcitabine and carboplatin Gemcitabine, carboplatin and bevacizumab Paclitaxel and carboplatin Weekly paclitaxel and carboplatin Paclitaxel, carboplatin and PARP inhibitor Case 2, Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin (PLD and carboplatin is a reasonable option based on results of the CALYPSO study showing superiority to paclitaxel and carboplatin) PLD, carboplatin and bevacizumab (PLD, carboplatin and bevacizumab has not been tested in a randomized phase III trial) Gemcitabine and carboplatin (Gemcitabine and carboplatin: this is reasonable based on a comparison with carboplatin alone (Pfisterer et.al. 2005) Gemcitabine, carboplatin and bevacizumab (Higher response rates and improved PFS are seen when bevacizumab is added to gem/carbo but OS is not improved (OCEANS trial) Paclitaxel and carboplatin (Paclitaxel and carboplatin can be used but based on prior taxane and results of CALYPSO, is used less) Weekly paclitaxel and carboplatin (Weekly paclitaxel has shown improved outcome when used with carboplatin for newly diagnosed patients but has not been rigorously tested in recurrent disease Paclitaxel, carboplatin and PARP inhibitor (PARP inhibitors are not yet FDA approved , so can only be obtained on a clinical trial. However, this is a very promising direction in ovarian cancer and a clinical trial of paclitaxel and carboplatin +/- olaparib showed improved PFS (Oza et.al. ASCO 2012) She Asks You Whether There Is Any Role for Surgery for Her Which of the following are true regarding secondary debulking? It is not considered for patients like her who relapse 10-12 months after completing initial chemotherapy The finding of carcinomatosis is a relatively strong contraindication to secondary debulking surgery Survival is improved for secondary debulking even if all disease can’t be removed at surgery Mediastinal and pleural disease are relatively strong contraindications to secondary debulking surgery 1 and 3 2 and 4 All of the above Secondary Debulking Candidate Selection Onda et al. J Cancer. 2005;92:1026. Pujade-Lauraine, Ann Oncol. 2011;22(Supplement 8):viii61–viii64. RANDOM I Z E GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: ≤ 0.5 cm > 0.5-2 cm PLD 30 mg/m2 Carboplatin AUC = 5 q 28 days x 6 Paclitaxel 175 mg/m2 Carboplatin AUC = 5 q 21 days x 6 GCIG = Gynecologic Cancer Intergroup PFS = progression-free survival PLD = pegylated liposomal doxorubicin Accrual 864 pts PFS primary endpoint Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. GCIG CALYPSO Trial Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. Selected Non-hematologic Toxicities During Treatment Alopecia *P< 0.001 Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. Targeted Agents in Ovarian Cancer Signaling/Angiogenesis Bevacizumab/Aflibercept RTKI’s: Pazopanib Cabozantinib Sorafenib, etc Cediranib Nintedanib Trebananib, MEDI-3617 PI3K/Akt/mTOR MEKi Folate: Vintafolide (EC-145) Farletuzumab NKTR-102 Taxanes/epothilones Immunotherapy – vaccines and inducers EP-100 PARPi ErbB3 CG + PL OCEANS: Study schema CG for 6 (up to 10) cycles Stratification variables: Platinum-free interval (6–12 vs >12 months) Cytoreductive surgery for recurrent disease (yes vs no) Platinum-sensitive recurrent OCa Measurable disease ECOG 0/1 No prior chemo for recurrent OC No prior BV (n=484) BV = bevacizumab; PL = placebo aEpithelial ovarian, primary peritoneal, or fallopian tube cancer G 1000 mg/m2, d1 & 8 C AUC 4 PL q3w until progression C AUC 4 BV 15 mg/kg q3w until progression G 1000 mg/m2, d1 & 8 CG + BV Aghajanian C et al. J Clin Oncol. 2012;30:2039-2045. 242 177 45 11 3 0 CG + PL OCEANS: Primary Analysis of PFS Months No. at risk 242 203 92 33 11 0 CG + BV 1.0 0.8 0.6 0.4 0.2 0 Proportion progression free 0 6 12 18 24 30 Aghajanian C et al. J Clin Oncol. 2012;30:2039-2045. 1.0 0.8 0.6 0.4 0.2 0 OCEANS: Third Interim OS Analysisa 0 6 12 18 24 30 36 42 48 54 60 242 235 221 190 159 117 77 44 23 7 0 242 239 226 201 171 127 78 48 27 7 0 Number at risk: GC + PL GC + BV aData cutoff date: March 30, 2012. Median follow-up 41.9 months in PL arm and 42.3 months in BV arm, with 286 deaths (59.1% of patients) Proportion surviving Months Aghajanian et al. ESMO 2012. Asymptomatic relapse Single-agent farletuzumab Until progression Single-agent ORR Compare lengths of first and second remissions Farletuzumab - MORAb-003-002 Phase II: Design Epithelial Ovarian Cancer First platinum-sensitive relapse First remission of 6-18 months Evaluable disease by CA125 Symptomatic relapse Original Carbo/Taxane regimen Plus farletuzumab x 6 Farletuzumab maintenance Rx For responders Combination ORR White AJ et al. J Clin Oncol. 2010;28(15s):Abstract 5001. MorAb-003-002: Study Conclusions Overall response rate 70% Response rate similar in early (6-12 month) and late (12+ months) recurrent patients High rates of CA-125 normalization (89%) 1/5 patients had a PFI2 ≥ PFI1 Phase III studies Platinum-sensitive: fully enrolled Platinum-resistant (weekly paclitaxel): met futility endpoint White AJ et al. J Clin Oncol. 2010;28(15s):Abstract 5001. n=66 Randomized, Open-label, Phase II Study in Patients With Platinum-sensitive, Advanced Serous Ovarian Cancer Paclitaxel 175 mg/m2 (iv, d1) + carboplatin AUC6 (iv d1) Randomization (1:1) All patients followed for objective radiologic progression and survival Maintenance phase Olaparib 400 mg bid continuously Completion of 4–6 x 21-day cycles of chemotherapy Arm B Arm A n=81 n=81 n=55 Multinational study; 43 sites in 12 countries * Capsule formulation Patients with: Platinum-sensitive advanced ovarian cancer A serous histology or serous component Measurable disease ≤3 previous platinum-containing regimens Progression free for ≥6 months following completion of last platinum-containing regimen Maintenance phase No further study treatment Olaparib 200 mg bid* (d1–10 every 21 days) + paclitaxel 175 mg/m2 (iv, d1) + carboplatin AUC4 (iv, d1) Oza A. ASCO 2012; Abstract 5001. Paclitaxel Carboplatin (P/C) vs P/C Plus Olaparib (O/P/C) In Platinum Sensitive Recurrent Ovarian Cancer: PFS Time from randomization (months) 0 Proportion of patients progression free 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 2 4 6 8 10 12 16 20 Number of patients at risk Olaparib + P + C (AUC4) P + C (AUC6) 14 18 81 80 76 71 55 37 34 3 0 20 0 81 68 65 57 40 18 15 2 0 8 1 O/P/C P/C Oza A. ASCO 2012; Abstract 5001. GOG 9927: Phase I Combination Platinum sensitive recurrent EOC Chemotherapy based on CALYPSO Primary endpoint: 1st or 2nd cycle DLT Secondary endpoints: RR, PFS, Toxicity TR: PARPi in PBMCs, BRCA status PLD 30 mg/m2 Carboplatin AUC 5 Arm I Veliparib PO daily continuously Cycles: 28 days Planned administration: 6 cycles Arm II Veliparib PO daily D1-7 Cycles: 28 days Planned administration: 6 cycles www.clinicaltrials.gov/ct2/show/NCT01459380. Summary for Platinum-sensitive Recurrent Ovarian Cancer Consider Secondary Debulking Platinum retreatment is standard Treatment with a platinum-based doublet improves response rate, progression-free survival, and possibly overall survival Options: Taxane Carboplatin: Paclitaxel, Docetaxel (?), Weekly Paclitaxel (?) Gemcitabine Carboplatin +/- Bevacizumab PLD Carboplatin Case 3: Platinum Resistant Ovarian Cancer 60-year-old woman with extensive pelvic and peritoneal implants, ascites and large volume disease at the root of the mesentery Diagnosis of ovarian cancer made by paracentesis Deemed unresectable by a gynecologic oncologist Treated with neoadjuvant paclitaxel and carboplatin x 3 without response Then treated with topotecan (daily x 5 regimen) x 3 without response Required paracentesis weekly for palliation CA-125=6916 What treatment would you recommend?
Slide 61 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R A N D O M I Z E n = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Placebo BEV 15 mg/kg II Stratification variables: GOG performance status (PS) Stage/debulking status RANDOM I Z E 1:1:1 15 months Paclitaxel (P) 175 mg/m2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 III Maintenance (16 cycles) BEV 15 mg/kg Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218: Investigator-assessed PFS + BEV (Arm II) CP (Arm I) *P-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 CA-125 to Determine Progression Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 Interim Survival Analysis Proportion Alive Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 48 aStratified analysis 625/625/623 442/432/437 173/162/171 46/39/40 No. at risk Burger RA et al. N Engl J Med. 2011;365:2473-2483. ICON7: Study Design Stratification variables: Stage/surgery Time since surgery GCIG group *Might vary based on GCIG group **Omit cycle 1 bevacizumab if <4 weeks from surgery Paclitaxel 175 mg/m2 Carboplatin AUC 6* AVASTIN Carboplatin AUC 6* Paclitaxel 175 mg/m2 Arm A Arm B 12 months Front-line EOC, PP or FT cancer Stage I-IIA (Gr 3 or CC) Stage IIB/C Stage III Stage IV n=1528 Bevacizumab 7.5 mg/kg ** Primary endpoints: PFS Secondary endpoints: OS, RR, safety, QOL, cost-effectiveness, translational No IRC present Perren T et al. N Engl J Med. 2011;365:2484-2496. Perren et al. ESMO 2010. ICON 7 Summary of Updated Results Kristensen G et al. J Clin Oncol. 2011;29: suppl; abstr LBA5006). Perren T et al. N Engl J Med. 2011;365:2484-2496. First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG 178—Investigating Paclitaxel as Consolidation Markman M et al. J Clin Oncol. 2003;21:2460-2465. 277 stage III/IV patients in complete clinical remission Paclitaxel 175 mg/m2 every 28 days × 3 months Paclitaxel 175 mg/m2 every 28 days × 12 months RANDOM I Z E CR = Complete response. Progression-free survival 0 20 40 60 80 100 0 12 24 36 48 Months after registration Paclitaxel 12 courses Paclitaxel 3 courses 110 At risk 112 Failed 20 34 Median, months 28 21 P = 0.0023 Percentage Markman M et al. J Clin Oncol. 2003;21:2460-2465. GOG 178 GOG-0212 Phase III Maintenance Therapy Trial Primary endpoint: survival Secondary endpoints: PFS, toxicity, QoL www.clinicaltrials.gov/ct2/show/NCT00108745. Macromolecular complex of paclitaxel poliglumex Patients with stage III/IV epithelial ovarian or primary peritoneal cancer, GOG PS ≤ 2, and complete response after surgery plus taxane and carboplatin (Planned n = 1400-1550) Paclitaxel Every 28 days for up to 12 courses No treatment Paclitaxel poliglumex Every 28 days for up to 12 courses Summary: Initial Treatment of Advanced Ovarian Cancer Surgery Attempt at maximal surgical cytoreduction Neoadjuvant chemo before surgery is an option for poor surgical candidates Chemotherapy 6-8 cycles taxane-platinum combination is standard IP admin benefits patients with low volume (optimal) disease but has increased toxicity NED patients treated with IP have a median survival of over 9 years Weekly (dose-dense) paclitaxel improves outcome in one study Confirmatory North American trials recently completed Bevacizumab during and after chemotherapy improves PFS but not OS Case Discussions Case 1: A Newly Diagnosed Patient With Ovarian Cancer 58 year old real estate broker with controlled hypertension presents with a pelvic mass, omental caking, and a CA125 of 2,056. She has no malnutrition or change in her weight. She is a PS=0. What would you recommend for this patient? Neoadjuvant chemotherapy Primary radical debulking surgery What Would You Recommend for This Patient? Neoadjuvant chemotherapy Primary radical debulking surgery Primary Cytoreduction Meta-analysis: 53 studies (1989–1998) 81 cohorts (Stage III/IV) n = 6885 patients Results Expert centers have high optimal rates Optimal vs not: 11 mos (50% increase) Each 10%  in cytoreduction = 5.5%  in survival Platinum intensity = NS Bristow. J Clin Oncol. 2002;20:1248. The Impact of Residual Tumor: What Is Optimal Debulking? % Progression-Free Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.52 (2.26; 2.81) >10 mm vs 1 mm – 10 mm: 1.36 (1.24; 1.50) log-rank: P<0.0001 % Overall Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.70 (2.37; 3.07) >10 mm vs 1 mm – 10 mm: 1.34 (1.21; 1.49) log-rank: P<0.0001 Generated from 3 prospective Phase III trials (OVAR 3,5, & 7) n = 3126 pts DuBois. Cancer. 2009;115:1234. Case 1 She has a TAH BSO, transverse colectomy, omentectomy and spends 7 days in the hospital (2 in the ICU). Except for an open wound with a wound-vac and getting 4 units of blood, she does well… The pathology shows a high-grade serous carcinoma. The surgeon noted small volume residual (5-9mm) disease throughout the abdomen. What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP Case 1 Question 2 What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP All the above answers are reasonable treatment choices. When would you start the bevacizumab? Cycle 1, 2 or 3? After the chemotherapy (maintenance)? Case 2: Platinum Sensitive Ovarian Cancer 52-year-old woman with high-grade serous carcinoma of the fallopian tube Optimally debulked in 2010 Treated with IV paclitaxel, IP cisplatin and IP paclitaxel completed June 2011 CA125 at presentation 5800 nadir post therapy 7 In 2012 : Increasing Ca125 (1200) Imaging: diffuse peritoneal carcinomatosis; pleural nodularity; mediastinal adenopathy Symptomatic: abdominal bloating, early satiety, and mild shortness of breath Disease free interval: 10-12 months Genetic testing: BRCA1/2 negative Case 2 Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin PLD, carboplatin and bevacizumab Gemcitabine and carboplatin Gemcitabine, carboplatin and bevacizumab Paclitaxel and carboplatin Weekly paclitaxel and carboplatin Paclitaxel, carboplatin and PARP inhibitor Case 2, Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin (PLD and carboplatin is a reasonable option based on results of the CALYPSO study showing superiority to paclitaxel and carboplatin) PLD, carboplatin and bevacizumab (PLD, carboplatin and bevacizumab has not been tested in a randomized phase III trial) Gemcitabine and carboplatin (Gemcitabine and carboplatin: this is reasonable based on a comparison with carboplatin alone (Pfisterer et.al. 2005) Gemcitabine, carboplatin and bevacizumab (Higher response rates and improved PFS are seen when bevacizumab is added to gem/carbo but OS is not improved (OCEANS trial) Paclitaxel and carboplatin (Paclitaxel and carboplatin can be used but based on prior taxane and results of CALYPSO, is used less) Weekly paclitaxel and carboplatin (Weekly paclitaxel has shown improved outcome when used with carboplatin for newly diagnosed patients but has not been rigorously tested in recurrent disease Paclitaxel, carboplatin and PARP inhibitor (PARP inhibitors are not yet FDA approved , so can only be obtained on a clinical trial. However, this is a very promising direction in ovarian cancer and a clinical trial of paclitaxel and carboplatin +/- olaparib showed improved PFS (Oza et.al. ASCO 2012) She Asks You Whether There Is Any Role for Surgery for Her Which of the following are true regarding secondary debulking? It is not considered for patients like her who relapse 10-12 months after completing initial chemotherapy The finding of carcinomatosis is a relatively strong contraindication to secondary debulking surgery Survival is improved for secondary debulking even if all disease can’t be removed at surgery Mediastinal and pleural disease are relatively strong contraindications to secondary debulking surgery 1 and 3 2 and 4 All of the above Secondary Debulking Candidate Selection Onda et al. J Cancer. 2005;92:1026. Pujade-Lauraine, Ann Oncol. 2011;22(Supplement 8):viii61–viii64. RANDOM I Z E GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: ≤ 0.5 cm > 0.5-2 cm PLD 30 mg/m2 Carboplatin AUC = 5 q 28 days x 6 Paclitaxel 175 mg/m2 Carboplatin AUC = 5 q 21 days x 6 GCIG = Gynecologic Cancer Intergroup PFS = progression-free survival PLD = pegylated liposomal doxorubicin Accrual 864 pts PFS primary endpoint Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. GCIG CALYPSO Trial Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. Selected Non-hematologic Toxicities During Treatment Alopecia *P< 0.001 Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. Targeted Agents in Ovarian Cancer Signaling/Angiogenesis Bevacizumab/Aflibercept RTKI’s: Pazopanib Cabozantinib Sorafenib, etc Cediranib Nintedanib Trebananib, MEDI-3617 PI3K/Akt/mTOR MEKi Folate: Vintafolide (EC-145) Farletuzumab NKTR-102 Taxanes/epothilones Immunotherapy – vaccines and inducers EP-100 PARPi ErbB3 CG + PL OCEANS: Study schema CG for 6 (up to 10) cycles Stratification variables: Platinum-free interval (6–12 vs >12 months) Cytoreductive surgery for recurrent disease (yes vs no) Platinum-sensitive recurrent OCa Measurable disease ECOG 0/1 No prior chemo for recurrent OC No prior BV (n=484) BV = bevacizumab; PL = placebo aEpithelial ovarian, primary peritoneal, or fallopian tube cancer G 1000 mg/m2, d1 & 8 C AUC 4 PL q3w until progression C AUC 4 BV 15 mg/kg q3w until progression G 1000 mg/m2, d1 & 8 CG + BV Aghajanian C et al. J Clin Oncol. 2012;30:2039-2045. 242 177 45 11 3 0 CG + PL OCEANS: Primary Analysis of PFS Months No. at risk 242 203 92 33 11 0 CG + BV 1.0 0.8 0.6 0.4 0.2 0 Proportion progression free 0 6 12 18 24 30 Aghajanian C et al. J Clin Oncol. 2012;30:2039-2045. 1.0 0.8 0.6 0.4 0.2 0 OCEANS: Third Interim OS Analysisa 0 6 12 18 24 30 36 42 48 54 60 242 235 221 190 159 117 77 44 23 7 0 242 239 226 201 171 127 78 48 27 7 0 Number at risk: GC + PL GC + BV aData cutoff date: March 30, 2012. Median follow-up 41.9 months in PL arm and 42.3 months in BV arm, with 286 deaths (59.1% of patients) Proportion surviving Months Aghajanian et al. ESMO 2012. Asymptomatic relapse Single-agent farletuzumab Until progression Single-agent ORR Compare lengths of first and second remissions Farletuzumab - MORAb-003-002 Phase II: Design Epithelial Ovarian Cancer First platinum-sensitive relapse First remission of 6-18 months Evaluable disease by CA125 Symptomatic relapse Original Carbo/Taxane regimen Plus farletuzumab x 6 Farletuzumab maintenance Rx For responders Combination ORR White AJ et al. J Clin Oncol. 2010;28(15s):Abstract 5001. MorAb-003-002: Study Conclusions Overall response rate 70% Response rate similar in early (6-12 month) and late (12+ months) recurrent patients High rates of CA-125 normalization (89%) 1/5 patients had a PFI2 ≥ PFI1 Phase III studies Platinum-sensitive: fully enrolled Platinum-resistant (weekly paclitaxel): met futility endpoint White AJ et al. J Clin Oncol. 2010;28(15s):Abstract 5001. n=66 Randomized, Open-label, Phase II Study in Patients With Platinum-sensitive, Advanced Serous Ovarian Cancer Paclitaxel 175 mg/m2 (iv, d1) + carboplatin AUC6 (iv d1) Randomization (1:1) All patients followed for objective radiologic progression and survival Maintenance phase Olaparib 400 mg bid continuously Completion of 4–6 x 21-day cycles of chemotherapy Arm B Arm A n=81 n=81 n=55 Multinational study; 43 sites in 12 countries * Capsule formulation Patients with: Platinum-sensitive advanced ovarian cancer A serous histology or serous component Measurable disease ≤3 previous platinum-containing regimens Progression free for ≥6 months following completion of last platinum-containing regimen Maintenance phase No further study treatment Olaparib 200 mg bid* (d1–10 every 21 days) + paclitaxel 175 mg/m2 (iv, d1) + carboplatin AUC4 (iv, d1) Oza A. ASCO 2012; Abstract 5001. Paclitaxel Carboplatin (P/C) vs P/C Plus Olaparib (O/P/C) In Platinum Sensitive Recurrent Ovarian Cancer: PFS Time from randomization (months) 0 Proportion of patients progression free 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 2 4 6 8 10 12 16 20 Number of patients at risk Olaparib + P + C (AUC4) P + C (AUC6) 14 18 81 80 76 71 55 37 34 3 0 20 0 81 68 65 57 40 18 15 2 0 8 1 O/P/C P/C Oza A. ASCO 2012; Abstract 5001. GOG 9927: Phase I Combination Platinum sensitive recurrent EOC Chemotherapy based on CALYPSO Primary endpoint: 1st or 2nd cycle DLT Secondary endpoints: RR, PFS, Toxicity TR: PARPi in PBMCs, BRCA status PLD 30 mg/m2 Carboplatin AUC 5 Arm I Veliparib PO daily continuously Cycles: 28 days Planned administration: 6 cycles Arm II Veliparib PO daily D1-7 Cycles: 28 days Planned administration: 6 cycles www.clinicaltrials.gov/ct2/show/NCT01459380. Summary for Platinum-sensitive Recurrent Ovarian Cancer Consider Secondary Debulking Platinum retreatment is standard Treatment with a platinum-based doublet improves response rate, progression-free survival, and possibly overall survival Options: Taxane Carboplatin: Paclitaxel, Docetaxel (?), Weekly Paclitaxel (?) Gemcitabine Carboplatin +/- Bevacizumab PLD Carboplatin Case 3: Platinum Resistant Ovarian Cancer 60-year-old woman with extensive pelvic and peritoneal implants, ascites and large volume disease at the root of the mesentery Diagnosis of ovarian cancer made by paracentesis Deemed unresectable by a gynecologic oncologist Treated with neoadjuvant paclitaxel and carboplatin x 3 without response Then treated with topotecan (daily x 5 regimen) x 3 without response Required paracentesis weekly for palliation CA-125=6916 What treatment would you recommend? Case 3 Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) Weekly paclitaxel Gemcitabine Bevacizumab Weekly paclitaxel and bevacizumab Gemcitabine, carboplatin and bevacizumab
Slide 62 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R A N D O M I Z E n = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Placebo BEV 15 mg/kg II Stratification variables: GOG performance status (PS) Stage/debulking status RANDOM I Z E 1:1:1 15 months Paclitaxel (P) 175 mg/m2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 III Maintenance (16 cycles) BEV 15 mg/kg Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218: Investigator-assessed PFS + BEV (Arm II) CP (Arm I) *P-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 CA-125 to Determine Progression Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 Interim Survival Analysis Proportion Alive Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 48 aStratified analysis 625/625/623 442/432/437 173/162/171 46/39/40 No. at risk Burger RA et al. N Engl J Med. 2011;365:2473-2483. ICON7: Study Design Stratification variables: Stage/surgery Time since surgery GCIG group *Might vary based on GCIG group **Omit cycle 1 bevacizumab if <4 weeks from surgery Paclitaxel 175 mg/m2 Carboplatin AUC 6* AVASTIN Carboplatin AUC 6* Paclitaxel 175 mg/m2 Arm A Arm B 12 months Front-line EOC, PP or FT cancer Stage I-IIA (Gr 3 or CC) Stage IIB/C Stage III Stage IV n=1528 Bevacizumab 7.5 mg/kg ** Primary endpoints: PFS Secondary endpoints: OS, RR, safety, QOL, cost-effectiveness, translational No IRC present Perren T et al. N Engl J Med. 2011;365:2484-2496. Perren et al. ESMO 2010. ICON 7 Summary of Updated Results Kristensen G et al. J Clin Oncol. 2011;29: suppl; abstr LBA5006). Perren T et al. N Engl J Med. 2011;365:2484-2496. First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG 178—Investigating Paclitaxel as Consolidation Markman M et al. J Clin Oncol. 2003;21:2460-2465. 277 stage III/IV patients in complete clinical remission Paclitaxel 175 mg/m2 every 28 days × 3 months Paclitaxel 175 mg/m2 every 28 days × 12 months RANDOM I Z E CR = Complete response. Progression-free survival 0 20 40 60 80 100 0 12 24 36 48 Months after registration Paclitaxel 12 courses Paclitaxel 3 courses 110 At risk 112 Failed 20 34 Median, months 28 21 P = 0.0023 Percentage Markman M et al. J Clin Oncol. 2003;21:2460-2465. GOG 178 GOG-0212 Phase III Maintenance Therapy Trial Primary endpoint: survival Secondary endpoints: PFS, toxicity, QoL www.clinicaltrials.gov/ct2/show/NCT00108745. Macromolecular complex of paclitaxel poliglumex Patients with stage III/IV epithelial ovarian or primary peritoneal cancer, GOG PS ≤ 2, and complete response after surgery plus taxane and carboplatin (Planned n = 1400-1550) Paclitaxel Every 28 days for up to 12 courses No treatment Paclitaxel poliglumex Every 28 days for up to 12 courses Summary: Initial Treatment of Advanced Ovarian Cancer Surgery Attempt at maximal surgical cytoreduction Neoadjuvant chemo before surgery is an option for poor surgical candidates Chemotherapy 6-8 cycles taxane-platinum combination is standard IP admin benefits patients with low volume (optimal) disease but has increased toxicity NED patients treated with IP have a median survival of over 9 years Weekly (dose-dense) paclitaxel improves outcome in one study Confirmatory North American trials recently completed Bevacizumab during and after chemotherapy improves PFS but not OS Case Discussions Case 1: A Newly Diagnosed Patient With Ovarian Cancer 58 year old real estate broker with controlled hypertension presents with a pelvic mass, omental caking, and a CA125 of 2,056. She has no malnutrition or change in her weight. She is a PS=0. What would you recommend for this patient? Neoadjuvant chemotherapy Primary radical debulking surgery What Would You Recommend for This Patient? Neoadjuvant chemotherapy Primary radical debulking surgery Primary Cytoreduction Meta-analysis: 53 studies (1989–1998) 81 cohorts (Stage III/IV) n = 6885 patients Results Expert centers have high optimal rates Optimal vs not: 11 mos (50% increase) Each 10%  in cytoreduction = 5.5%  in survival Platinum intensity = NS Bristow. J Clin Oncol. 2002;20:1248. The Impact of Residual Tumor: What Is Optimal Debulking? % Progression-Free Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.52 (2.26; 2.81) >10 mm vs 1 mm – 10 mm: 1.36 (1.24; 1.50) log-rank: P<0.0001 % Overall Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.70 (2.37; 3.07) >10 mm vs 1 mm – 10 mm: 1.34 (1.21; 1.49) log-rank: P<0.0001 Generated from 3 prospective Phase III trials (OVAR 3,5, & 7) n = 3126 pts DuBois. Cancer. 2009;115:1234. Case 1 She has a TAH BSO, transverse colectomy, omentectomy and spends 7 days in the hospital (2 in the ICU). Except for an open wound with a wound-vac and getting 4 units of blood, she does well… The pathology shows a high-grade serous carcinoma. The surgeon noted small volume residual (5-9mm) disease throughout the abdomen. What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP Case 1 Question 2 What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP All the above answers are reasonable treatment choices. When would you start the bevacizumab? Cycle 1, 2 or 3? After the chemotherapy (maintenance)? Case 2: Platinum Sensitive Ovarian Cancer 52-year-old woman with high-grade serous carcinoma of the fallopian tube Optimally debulked in 2010 Treated with IV paclitaxel, IP cisplatin and IP paclitaxel completed June 2011 CA125 at presentation 5800 nadir post therapy 7 In 2012 : Increasing Ca125 (1200) Imaging: diffuse peritoneal carcinomatosis; pleural nodularity; mediastinal adenopathy Symptomatic: abdominal bloating, early satiety, and mild shortness of breath Disease free interval: 10-12 months Genetic testing: BRCA1/2 negative Case 2 Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin PLD, carboplatin and bevacizumab Gemcitabine and carboplatin Gemcitabine, carboplatin and bevacizumab Paclitaxel and carboplatin Weekly paclitaxel and carboplatin Paclitaxel, carboplatin and PARP inhibitor Case 2, Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin (PLD and carboplatin is a reasonable option based on results of the CALYPSO study showing superiority to paclitaxel and carboplatin) PLD, carboplatin and bevacizumab (PLD, carboplatin and bevacizumab has not been tested in a randomized phase III trial) Gemcitabine and carboplatin (Gemcitabine and carboplatin: this is reasonable based on a comparison with carboplatin alone (Pfisterer et.al. 2005) Gemcitabine, carboplatin and bevacizumab (Higher response rates and improved PFS are seen when bevacizumab is added to gem/carbo but OS is not improved (OCEANS trial) Paclitaxel and carboplatin (Paclitaxel and carboplatin can be used but based on prior taxane and results of CALYPSO, is used less) Weekly paclitaxel and carboplatin (Weekly paclitaxel has shown improved outcome when used with carboplatin for newly diagnosed patients but has not been rigorously tested in recurrent disease Paclitaxel, carboplatin and PARP inhibitor (PARP inhibitors are not yet FDA approved , so can only be obtained on a clinical trial. However, this is a very promising direction in ovarian cancer and a clinical trial of paclitaxel and carboplatin +/- olaparib showed improved PFS (Oza et.al. ASCO 2012) She Asks You Whether There Is Any Role for Surgery for Her Which of the following are true regarding secondary debulking? It is not considered for patients like her who relapse 10-12 months after completing initial chemotherapy The finding of carcinomatosis is a relatively strong contraindication to secondary debulking surgery Survival is improved for secondary debulking even if all disease can’t be removed at surgery Mediastinal and pleural disease are relatively strong contraindications to secondary debulking surgery 1 and 3 2 and 4 All of the above Secondary Debulking Candidate Selection Onda et al. J Cancer. 2005;92:1026. Pujade-Lauraine, Ann Oncol. 2011;22(Supplement 8):viii61–viii64. RANDOM I Z E GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: ≤ 0.5 cm > 0.5-2 cm PLD 30 mg/m2 Carboplatin AUC = 5 q 28 days x 6 Paclitaxel 175 mg/m2 Carboplatin AUC = 5 q 21 days x 6 GCIG = Gynecologic Cancer Intergroup PFS = progression-free survival PLD = pegylated liposomal doxorubicin Accrual 864 pts PFS primary endpoint Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. GCIG CALYPSO Trial Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. Selected Non-hematologic Toxicities During Treatment Alopecia *P< 0.001 Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. Targeted Agents in Ovarian Cancer Signaling/Angiogenesis Bevacizumab/Aflibercept RTKI’s: Pazopanib Cabozantinib Sorafenib, etc Cediranib Nintedanib Trebananib, MEDI-3617 PI3K/Akt/mTOR MEKi Folate: Vintafolide (EC-145) Farletuzumab NKTR-102 Taxanes/epothilones Immunotherapy – vaccines and inducers EP-100 PARPi ErbB3 CG + PL OCEANS: Study schema CG for 6 (up to 10) cycles Stratification variables: Platinum-free interval (6–12 vs >12 months) Cytoreductive surgery for recurrent disease (yes vs no) Platinum-sensitive recurrent OCa Measurable disease ECOG 0/1 No prior chemo for recurrent OC No prior BV (n=484) BV = bevacizumab; PL = placebo aEpithelial ovarian, primary peritoneal, or fallopian tube cancer G 1000 mg/m2, d1 & 8 C AUC 4 PL q3w until progression C AUC 4 BV 15 mg/kg q3w until progression G 1000 mg/m2, d1 & 8 CG + BV Aghajanian C et al. J Clin Oncol. 2012;30:2039-2045. 242 177 45 11 3 0 CG + PL OCEANS: Primary Analysis of PFS Months No. at risk 242 203 92 33 11 0 CG + BV 1.0 0.8 0.6 0.4 0.2 0 Proportion progression free 0 6 12 18 24 30 Aghajanian C et al. J Clin Oncol. 2012;30:2039-2045. 1.0 0.8 0.6 0.4 0.2 0 OCEANS: Third Interim OS Analysisa 0 6 12 18 24 30 36 42 48 54 60 242 235 221 190 159 117 77 44 23 7 0 242 239 226 201 171 127 78 48 27 7 0 Number at risk: GC + PL GC + BV aData cutoff date: March 30, 2012. Median follow-up 41.9 months in PL arm and 42.3 months in BV arm, with 286 deaths (59.1% of patients) Proportion surviving Months Aghajanian et al. ESMO 2012. Asymptomatic relapse Single-agent farletuzumab Until progression Single-agent ORR Compare lengths of first and second remissions Farletuzumab - MORAb-003-002 Phase II: Design Epithelial Ovarian Cancer First platinum-sensitive relapse First remission of 6-18 months Evaluable disease by CA125 Symptomatic relapse Original Carbo/Taxane regimen Plus farletuzumab x 6 Farletuzumab maintenance Rx For responders Combination ORR White AJ et al. J Clin Oncol. 2010;28(15s):Abstract 5001. MorAb-003-002: Study Conclusions Overall response rate 70% Response rate similar in early (6-12 month) and late (12+ months) recurrent patients High rates of CA-125 normalization (89%) 1/5 patients had a PFI2 ≥ PFI1 Phase III studies Platinum-sensitive: fully enrolled Platinum-resistant (weekly paclitaxel): met futility endpoint White AJ et al. J Clin Oncol. 2010;28(15s):Abstract 5001. n=66 Randomized, Open-label, Phase II Study in Patients With Platinum-sensitive, Advanced Serous Ovarian Cancer Paclitaxel 175 mg/m2 (iv, d1) + carboplatin AUC6 (iv d1) Randomization (1:1) All patients followed for objective radiologic progression and survival Maintenance phase Olaparib 400 mg bid continuously Completion of 4–6 x 21-day cycles of chemotherapy Arm B Arm A n=81 n=81 n=55 Multinational study; 43 sites in 12 countries * Capsule formulation Patients with: Platinum-sensitive advanced ovarian cancer A serous histology or serous component Measurable disease ≤3 previous platinum-containing regimens Progression free for ≥6 months following completion of last platinum-containing regimen Maintenance phase No further study treatment Olaparib 200 mg bid* (d1–10 every 21 days) + paclitaxel 175 mg/m2 (iv, d1) + carboplatin AUC4 (iv, d1) Oza A. ASCO 2012; Abstract 5001. Paclitaxel Carboplatin (P/C) vs P/C Plus Olaparib (O/P/C) In Platinum Sensitive Recurrent Ovarian Cancer: PFS Time from randomization (months) 0 Proportion of patients progression free 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 2 4 6 8 10 12 16 20 Number of patients at risk Olaparib + P + C (AUC4) P + C (AUC6) 14 18 81 80 76 71 55 37 34 3 0 20 0 81 68 65 57 40 18 15 2 0 8 1 O/P/C P/C Oza A. ASCO 2012; Abstract 5001. GOG 9927: Phase I Combination Platinum sensitive recurrent EOC Chemotherapy based on CALYPSO Primary endpoint: 1st or 2nd cycle DLT Secondary endpoints: RR, PFS, Toxicity TR: PARPi in PBMCs, BRCA status PLD 30 mg/m2 Carboplatin AUC 5 Arm I Veliparib PO daily continuously Cycles: 28 days Planned administration: 6 cycles Arm II Veliparib PO daily D1-7 Cycles: 28 days Planned administration: 6 cycles www.clinicaltrials.gov/ct2/show/NCT01459380. Summary for Platinum-sensitive Recurrent Ovarian Cancer Consider Secondary Debulking Platinum retreatment is standard Treatment with a platinum-based doublet improves response rate, progression-free survival, and possibly overall survival Options: Taxane Carboplatin: Paclitaxel, Docetaxel (?), Weekly Paclitaxel (?) Gemcitabine Carboplatin +/- Bevacizumab PLD Carboplatin Case 3: Platinum Resistant Ovarian Cancer 60-year-old woman with extensive pelvic and peritoneal implants, ascites and large volume disease at the root of the mesentery Diagnosis of ovarian cancer made by paracentesis Deemed unresectable by a gynecologic oncologist Treated with neoadjuvant paclitaxel and carboplatin x 3 without response Then treated with topotecan (daily x 5 regimen) x 3 without response Required paracentesis weekly for palliation CA-125=6916 What treatment would you recommend? Case 3 Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) Weekly paclitaxel Gemcitabine Bevacizumab Weekly paclitaxel and bevacizumab Gemcitabine, carboplatin and bevacizumab Case 3 Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) (PLD is a reasonable choice but expected response rate is 6-16% in a less heavily pretreated population) Weekly paclitaxel (Weekly paclitaxel is also a reasonable option. In GOG protocol 126-N weekly paclitaxel had a response rate of 21% although eligibility limited to one prior treatment regimen) Gemcitabine (although single agent gemcitabine is not FDA approved for treatment of ovarian cancer, the combination of gemcitabine and carboplatin is approved for platinum sensitive patients thus gemcitabine alone is frequently used. Response rates in this population are expected to be less than 10%) Bevacizumab (Bevacizumab is a reasonable choice. In GOG protocol 170D bevacizumab showed a response rate of 21% in this population) Weekly paclitaxel and bevacizumab (Based on Aurelia, the combination of weekly paclitaxel and bevacizumab would be expected to have a higher response rate than weekly paclitaxel alone. Survival data is not yet available. It is not yet clear whether sequential chemotherapy and bevacizumab or the combination is preferable) Gemcitabine, carboplatin and bevacizumab (platinum-based therapy is not indicated in this patient with platinum-refractory disease.)
Slide 63 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R A N D O M I Z E n = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Placebo BEV 15 mg/kg II Stratification variables: GOG performance status (PS) Stage/debulking status RANDOM I Z E 1:1:1 15 months Paclitaxel (P) 175 mg/m2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 III Maintenance (16 cycles) BEV 15 mg/kg Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218: Investigator-assessed PFS + BEV (Arm II) CP (Arm I) *P-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 CA-125 to Determine Progression Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 Interim Survival Analysis Proportion Alive Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 48 aStratified analysis 625/625/623 442/432/437 173/162/171 46/39/40 No. at risk Burger RA et al. N Engl J Med. 2011;365:2473-2483. ICON7: Study Design Stratification variables: Stage/surgery Time since surgery GCIG group *Might vary based on GCIG group **Omit cycle 1 bevacizumab if <4 weeks from surgery Paclitaxel 175 mg/m2 Carboplatin AUC 6* AVASTIN Carboplatin AUC 6* Paclitaxel 175 mg/m2 Arm A Arm B 12 months Front-line EOC, PP or FT cancer Stage I-IIA (Gr 3 or CC) Stage IIB/C Stage III Stage IV n=1528 Bevacizumab 7.5 mg/kg ** Primary endpoints: PFS Secondary endpoints: OS, RR, safety, QOL, cost-effectiveness, translational No IRC present Perren T et al. N Engl J Med. 2011;365:2484-2496. Perren et al. ESMO 2010. ICON 7 Summary of Updated Results Kristensen G et al. J Clin Oncol. 2011;29: suppl; abstr LBA5006). Perren T et al. N Engl J Med. 2011;365:2484-2496. First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG 178—Investigating Paclitaxel as Consolidation Markman M et al. J Clin Oncol. 2003;21:2460-2465. 277 stage III/IV patients in complete clinical remission Paclitaxel 175 mg/m2 every 28 days × 3 months Paclitaxel 175 mg/m2 every 28 days × 12 months RANDOM I Z E CR = Complete response. Progression-free survival 0 20 40 60 80 100 0 12 24 36 48 Months after registration Paclitaxel 12 courses Paclitaxel 3 courses 110 At risk 112 Failed 20 34 Median, months 28 21 P = 0.0023 Percentage Markman M et al. J Clin Oncol. 2003;21:2460-2465. GOG 178 GOG-0212 Phase III Maintenance Therapy Trial Primary endpoint: survival Secondary endpoints: PFS, toxicity, QoL www.clinicaltrials.gov/ct2/show/NCT00108745. Macromolecular complex of paclitaxel poliglumex Patients with stage III/IV epithelial ovarian or primary peritoneal cancer, GOG PS ≤ 2, and complete response after surgery plus taxane and carboplatin (Planned n = 1400-1550) Paclitaxel Every 28 days for up to 12 courses No treatment Paclitaxel poliglumex Every 28 days for up to 12 courses Summary: Initial Treatment of Advanced Ovarian Cancer Surgery Attempt at maximal surgical cytoreduction Neoadjuvant chemo before surgery is an option for poor surgical candidates Chemotherapy 6-8 cycles taxane-platinum combination is standard IP admin benefits patients with low volume (optimal) disease but has increased toxicity NED patients treated with IP have a median survival of over 9 years Weekly (dose-dense) paclitaxel improves outcome in one study Confirmatory North American trials recently completed Bevacizumab during and after chemotherapy improves PFS but not OS Case Discussions Case 1: A Newly Diagnosed Patient With Ovarian Cancer 58 year old real estate broker with controlled hypertension presents with a pelvic mass, omental caking, and a CA125 of 2,056. She has no malnutrition or change in her weight. She is a PS=0. What would you recommend for this patient? Neoadjuvant chemotherapy Primary radical debulking surgery What Would You Recommend for This Patient? Neoadjuvant chemotherapy Primary radical debulking surgery Primary Cytoreduction Meta-analysis: 53 studies (1989–1998) 81 cohorts (Stage III/IV) n = 6885 patients Results Expert centers have high optimal rates Optimal vs not: 11 mos (50% increase) Each 10%  in cytoreduction = 5.5%  in survival Platinum intensity = NS Bristow. J Clin Oncol. 2002;20:1248. The Impact of Residual Tumor: What Is Optimal Debulking? % Progression-Free Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.52 (2.26; 2.81) >10 mm vs 1 mm – 10 mm: 1.36 (1.24; 1.50) log-rank: P<0.0001 % Overall Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.70 (2.37; 3.07) >10 mm vs 1 mm – 10 mm: 1.34 (1.21; 1.49) log-rank: P<0.0001 Generated from 3 prospective Phase III trials (OVAR 3,5, & 7) n = 3126 pts DuBois. Cancer. 2009;115:1234. Case 1 She has a TAH BSO, transverse colectomy, omentectomy and spends 7 days in the hospital (2 in the ICU). Except for an open wound with a wound-vac and getting 4 units of blood, she does well… The pathology shows a high-grade serous carcinoma. The surgeon noted small volume residual (5-9mm) disease throughout the abdomen. What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP Case 1 Question 2 What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP All the above answers are reasonable treatment choices. When would you start the bevacizumab? Cycle 1, 2 or 3? After the chemotherapy (maintenance)? Case 2: Platinum Sensitive Ovarian Cancer 52-year-old woman with high-grade serous carcinoma of the fallopian tube Optimally debulked in 2010 Treated with IV paclitaxel, IP cisplatin and IP paclitaxel completed June 2011 CA125 at presentation 5800 nadir post therapy 7 In 2012 : Increasing Ca125 (1200) Imaging: diffuse peritoneal carcinomatosis; pleural nodularity; mediastinal adenopathy Symptomatic: abdominal bloating, early satiety, and mild shortness of breath Disease free interval: 10-12 months Genetic testing: BRCA1/2 negative Case 2 Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin PLD, carboplatin and bevacizumab Gemcitabine and carboplatin Gemcitabine, carboplatin and bevacizumab Paclitaxel and carboplatin Weekly paclitaxel and carboplatin Paclitaxel, carboplatin and PARP inhibitor Case 2, Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin (PLD and carboplatin is a reasonable option based on results of the CALYPSO study showing superiority to paclitaxel and carboplatin) PLD, carboplatin and bevacizumab (PLD, carboplatin and bevacizumab has not been tested in a randomized phase III trial) Gemcitabine and carboplatin (Gemcitabine and carboplatin: this is reasonable based on a comparison with carboplatin alone (Pfisterer et.al. 2005) Gemcitabine, carboplatin and bevacizumab (Higher response rates and improved PFS are seen when bevacizumab is added to gem/carbo but OS is not improved (OCEANS trial) Paclitaxel and carboplatin (Paclitaxel and carboplatin can be used but based on prior taxane and results of CALYPSO, is used less) Weekly paclitaxel and carboplatin (Weekly paclitaxel has shown improved outcome when used with carboplatin for newly diagnosed patients but has not been rigorously tested in recurrent disease Paclitaxel, carboplatin and PARP inhibitor (PARP inhibitors are not yet FDA approved , so can only be obtained on a clinical trial. However, this is a very promising direction in ovarian cancer and a clinical trial of paclitaxel and carboplatin +/- olaparib showed improved PFS (Oza et.al. ASCO 2012) She Asks You Whether There Is Any Role for Surgery for Her Which of the following are true regarding secondary debulking? It is not considered for patients like her who relapse 10-12 months after completing initial chemotherapy The finding of carcinomatosis is a relatively strong contraindication to secondary debulking surgery Survival is improved for secondary debulking even if all disease can’t be removed at surgery Mediastinal and pleural disease are relatively strong contraindications to secondary debulking surgery 1 and 3 2 and 4 All of the above Secondary Debulking Candidate Selection Onda et al. J Cancer. 2005;92:1026. Pujade-Lauraine, Ann Oncol. 2011;22(Supplement 8):viii61–viii64. RANDOM I Z E GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: ≤ 0.5 cm > 0.5-2 cm PLD 30 mg/m2 Carboplatin AUC = 5 q 28 days x 6 Paclitaxel 175 mg/m2 Carboplatin AUC = 5 q 21 days x 6 GCIG = Gynecologic Cancer Intergroup PFS = progression-free survival PLD = pegylated liposomal doxorubicin Accrual 864 pts PFS primary endpoint Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. GCIG CALYPSO Trial Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. Selected Non-hematologic Toxicities During Treatment Alopecia *P< 0.001 Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. Targeted Agents in Ovarian Cancer Signaling/Angiogenesis Bevacizumab/Aflibercept RTKI’s: Pazopanib Cabozantinib Sorafenib, etc Cediranib Nintedanib Trebananib, MEDI-3617 PI3K/Akt/mTOR MEKi Folate: Vintafolide (EC-145) Farletuzumab NKTR-102 Taxanes/epothilones Immunotherapy – vaccines and inducers EP-100 PARPi ErbB3 CG + PL OCEANS: Study schema CG for 6 (up to 10) cycles Stratification variables: Platinum-free interval (6–12 vs >12 months) Cytoreductive surgery for recurrent disease (yes vs no) Platinum-sensitive recurrent OCa Measurable disease ECOG 0/1 No prior chemo for recurrent OC No prior BV (n=484) BV = bevacizumab; PL = placebo aEpithelial ovarian, primary peritoneal, or fallopian tube cancer G 1000 mg/m2, d1 & 8 C AUC 4 PL q3w until progression C AUC 4 BV 15 mg/kg q3w until progression G 1000 mg/m2, d1 & 8 CG + BV Aghajanian C et al. J Clin Oncol. 2012;30:2039-2045. 242 177 45 11 3 0 CG + PL OCEANS: Primary Analysis of PFS Months No. at risk 242 203 92 33 11 0 CG + BV 1.0 0.8 0.6 0.4 0.2 0 Proportion progression free 0 6 12 18 24 30 Aghajanian C et al. J Clin Oncol. 2012;30:2039-2045. 1.0 0.8 0.6 0.4 0.2 0 OCEANS: Third Interim OS Analysisa 0 6 12 18 24 30 36 42 48 54 60 242 235 221 190 159 117 77 44 23 7 0 242 239 226 201 171 127 78 48 27 7 0 Number at risk: GC + PL GC + BV aData cutoff date: March 30, 2012. Median follow-up 41.9 months in PL arm and 42.3 months in BV arm, with 286 deaths (59.1% of patients) Proportion surviving Months Aghajanian et al. ESMO 2012. Asymptomatic relapse Single-agent farletuzumab Until progression Single-agent ORR Compare lengths of first and second remissions Farletuzumab - MORAb-003-002 Phase II: Design Epithelial Ovarian Cancer First platinum-sensitive relapse First remission of 6-18 months Evaluable disease by CA125 Symptomatic relapse Original Carbo/Taxane regimen Plus farletuzumab x 6 Farletuzumab maintenance Rx For responders Combination ORR White AJ et al. J Clin Oncol. 2010;28(15s):Abstract 5001. MorAb-003-002: Study Conclusions Overall response rate 70% Response rate similar in early (6-12 month) and late (12+ months) recurrent patients High rates of CA-125 normalization (89%) 1/5 patients had a PFI2 ≥ PFI1 Phase III studies Platinum-sensitive: fully enrolled Platinum-resistant (weekly paclitaxel): met futility endpoint White AJ et al. J Clin Oncol. 2010;28(15s):Abstract 5001. n=66 Randomized, Open-label, Phase II Study in Patients With Platinum-sensitive, Advanced Serous Ovarian Cancer Paclitaxel 175 mg/m2 (iv, d1) + carboplatin AUC6 (iv d1) Randomization (1:1) All patients followed for objective radiologic progression and survival Maintenance phase Olaparib 400 mg bid continuously Completion of 4–6 x 21-day cycles of chemotherapy Arm B Arm A n=81 n=81 n=55 Multinational study; 43 sites in 12 countries * Capsule formulation Patients with: Platinum-sensitive advanced ovarian cancer A serous histology or serous component Measurable disease ≤3 previous platinum-containing regimens Progression free for ≥6 months following completion of last platinum-containing regimen Maintenance phase No further study treatment Olaparib 200 mg bid* (d1–10 every 21 days) + paclitaxel 175 mg/m2 (iv, d1) + carboplatin AUC4 (iv, d1) Oza A. ASCO 2012; Abstract 5001. Paclitaxel Carboplatin (P/C) vs P/C Plus Olaparib (O/P/C) In Platinum Sensitive Recurrent Ovarian Cancer: PFS Time from randomization (months) 0 Proportion of patients progression free 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 2 4 6 8 10 12 16 20 Number of patients at risk Olaparib + P + C (AUC4) P + C (AUC6) 14 18 81 80 76 71 55 37 34 3 0 20 0 81 68 65 57 40 18 15 2 0 8 1 O/P/C P/C Oza A. ASCO 2012; Abstract 5001. GOG 9927: Phase I Combination Platinum sensitive recurrent EOC Chemotherapy based on CALYPSO Primary endpoint: 1st or 2nd cycle DLT Secondary endpoints: RR, PFS, Toxicity TR: PARPi in PBMCs, BRCA status PLD 30 mg/m2 Carboplatin AUC 5 Arm I Veliparib PO daily continuously Cycles: 28 days Planned administration: 6 cycles Arm II Veliparib PO daily D1-7 Cycles: 28 days Planned administration: 6 cycles www.clinicaltrials.gov/ct2/show/NCT01459380. Summary for Platinum-sensitive Recurrent Ovarian Cancer Consider Secondary Debulking Platinum retreatment is standard Treatment with a platinum-based doublet improves response rate, progression-free survival, and possibly overall survival Options: Taxane Carboplatin: Paclitaxel, Docetaxel (?), Weekly Paclitaxel (?) Gemcitabine Carboplatin +/- Bevacizumab PLD Carboplatin Case 3: Platinum Resistant Ovarian Cancer 60-year-old woman with extensive pelvic and peritoneal implants, ascites and large volume disease at the root of the mesentery Diagnosis of ovarian cancer made by paracentesis Deemed unresectable by a gynecologic oncologist Treated with neoadjuvant paclitaxel and carboplatin x 3 without response Then treated with topotecan (daily x 5 regimen) x 3 without response Required paracentesis weekly for palliation CA-125=6916 What treatment would you recommend? Case 3 Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) Weekly paclitaxel Gemcitabine Bevacizumab Weekly paclitaxel and bevacizumab Gemcitabine, carboplatin and bevacizumab Case 3 Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) (PLD is a reasonable choice but expected response rate is 6-16% in a less heavily pretreated population) Weekly paclitaxel (Weekly paclitaxel is also a reasonable option. In GOG protocol 126-N weekly paclitaxel had a response rate of 21% although eligibility limited to one prior treatment regimen) Gemcitabine (although single agent gemcitabine is not FDA approved for treatment of ovarian cancer, the combination of gemcitabine and carboplatin is approved for platinum sensitive patients thus gemcitabine alone is frequently used. Response rates in this population are expected to be less than 10%) Bevacizumab (Bevacizumab is a reasonable choice. In GOG protocol 170D bevacizumab showed a response rate of 21% in this population) Weekly paclitaxel and bevacizumab (Based on Aurelia, the combination of weekly paclitaxel and bevacizumab would be expected to have a higher response rate than weekly paclitaxel alone. Survival data is not yet available. It is not yet clear whether sequential chemotherapy and bevacizumab or the combination is preferable) Gemcitabine, carboplatin and bevacizumab (platinum-based therapy is not indicated in this patient with platinum-refractory disease.) Assume You Will Be Using Treatment With Bevacizumab: Which of the Following Are True Statements About Bevacizumab for Her 1. She will be at increased risk for bowel perforation 2. There is an increased risk of thrombo-embolic phenomena with bevacizumab 3. The response rate of ovarian cancer to single-agent bevacizumab is greater than for any other solid tumors tested to date 4. Hypertension and proteinuria are common side effects of bevacizumab 5. All of the above All the above are true statements in this case.
Slide 64 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R A N D O M I Z E n = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Placebo BEV 15 mg/kg II Stratification variables: GOG performance status (PS) Stage/debulking status RANDOM I Z E 1:1:1 15 months Paclitaxel (P) 175 mg/m2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 III Maintenance (16 cycles) BEV 15 mg/kg Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218: Investigator-assessed PFS + BEV (Arm II) CP (Arm I) *P-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 CA-125 to Determine Progression Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 Interim Survival Analysis Proportion Alive Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 48 aStratified analysis 625/625/623 442/432/437 173/162/171 46/39/40 No. at risk Burger RA et al. N Engl J Med. 2011;365:2473-2483. ICON7: Study Design Stratification variables: Stage/surgery Time since surgery GCIG group *Might vary based on GCIG group **Omit cycle 1 bevacizumab if <4 weeks from surgery Paclitaxel 175 mg/m2 Carboplatin AUC 6* AVASTIN Carboplatin AUC 6* Paclitaxel 175 mg/m2 Arm A Arm B 12 months Front-line EOC, PP or FT cancer Stage I-IIA (Gr 3 or CC) Stage IIB/C Stage III Stage IV n=1528 Bevacizumab 7.5 mg/kg ** Primary endpoints: PFS Secondary endpoints: OS, RR, safety, QOL, cost-effectiveness, translational No IRC present Perren T et al. N Engl J Med. 2011;365:2484-2496. Perren et al. ESMO 2010. ICON 7 Summary of Updated Results Kristensen G et al. J Clin Oncol. 2011;29: suppl; abstr LBA5006). Perren T et al. N Engl J Med. 2011;365:2484-2496. First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG 178—Investigating Paclitaxel as Consolidation Markman M et al. J Clin Oncol. 2003;21:2460-2465. 277 stage III/IV patients in complete clinical remission Paclitaxel 175 mg/m2 every 28 days × 3 months Paclitaxel 175 mg/m2 every 28 days × 12 months RANDOM I Z E CR = Complete response. Progression-free survival 0 20 40 60 80 100 0 12 24 36 48 Months after registration Paclitaxel 12 courses Paclitaxel 3 courses 110 At risk 112 Failed 20 34 Median, months 28 21 P = 0.0023 Percentage Markman M et al. J Clin Oncol. 2003;21:2460-2465. GOG 178 GOG-0212 Phase III Maintenance Therapy Trial Primary endpoint: survival Secondary endpoints: PFS, toxicity, QoL www.clinicaltrials.gov/ct2/show/NCT00108745. Macromolecular complex of paclitaxel poliglumex Patients with stage III/IV epithelial ovarian or primary peritoneal cancer, GOG PS ≤ 2, and complete response after surgery plus taxane and carboplatin (Planned n = 1400-1550) Paclitaxel Every 28 days for up to 12 courses No treatment Paclitaxel poliglumex Every 28 days for up to 12 courses Summary: Initial Treatment of Advanced Ovarian Cancer Surgery Attempt at maximal surgical cytoreduction Neoadjuvant chemo before surgery is an option for poor surgical candidates Chemotherapy 6-8 cycles taxane-platinum combination is standard IP admin benefits patients with low volume (optimal) disease but has increased toxicity NED patients treated with IP have a median survival of over 9 years Weekly (dose-dense) paclitaxel improves outcome in one study Confirmatory North American trials recently completed Bevacizumab during and after chemotherapy improves PFS but not OS Case Discussions Case 1: A Newly Diagnosed Patient With Ovarian Cancer 58 year old real estate broker with controlled hypertension presents with a pelvic mass, omental caking, and a CA125 of 2,056. She has no malnutrition or change in her weight. She is a PS=0. What would you recommend for this patient? Neoadjuvant chemotherapy Primary radical debulking surgery What Would You Recommend for This Patient? Neoadjuvant chemotherapy Primary radical debulking surgery Primary Cytoreduction Meta-analysis: 53 studies (1989–1998) 81 cohorts (Stage III/IV) n = 6885 patients Results Expert centers have high optimal rates Optimal vs not: 11 mos (50% increase) Each 10%  in cytoreduction = 5.5%  in survival Platinum intensity = NS Bristow. J Clin Oncol. 2002;20:1248. The Impact of Residual Tumor: What Is Optimal Debulking? % Progression-Free Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.52 (2.26; 2.81) >10 mm vs 1 mm – 10 mm: 1.36 (1.24; 1.50) log-rank: P<0.0001 % Overall Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.70 (2.37; 3.07) >10 mm vs 1 mm – 10 mm: 1.34 (1.21; 1.49) log-rank: P<0.0001 Generated from 3 prospective Phase III trials (OVAR 3,5, & 7) n = 3126 pts DuBois. Cancer. 2009;115:1234. Case 1 She has a TAH BSO, transverse colectomy, omentectomy and spends 7 days in the hospital (2 in the ICU). Except for an open wound with a wound-vac and getting 4 units of blood, she does well… The pathology shows a high-grade serous carcinoma. The surgeon noted small volume residual (5-9mm) disease throughout the abdomen. What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP Case 1 Question 2 What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP All the above answers are reasonable treatment choices. When would you start the bevacizumab? Cycle 1, 2 or 3? After the chemotherapy (maintenance)? Case 2: Platinum Sensitive Ovarian Cancer 52-year-old woman with high-grade serous carcinoma of the fallopian tube Optimally debulked in 2010 Treated with IV paclitaxel, IP cisplatin and IP paclitaxel completed June 2011 CA125 at presentation 5800 nadir post therapy 7 In 2012 : Increasing Ca125 (1200) Imaging: diffuse peritoneal carcinomatosis; pleural nodularity; mediastinal adenopathy Symptomatic: abdominal bloating, early satiety, and mild shortness of breath Disease free interval: 10-12 months Genetic testing: BRCA1/2 negative Case 2 Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin PLD, carboplatin and bevacizumab Gemcitabine and carboplatin Gemcitabine, carboplatin and bevacizumab Paclitaxel and carboplatin Weekly paclitaxel and carboplatin Paclitaxel, carboplatin and PARP inhibitor Case 2, Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin (PLD and carboplatin is a reasonable option based on results of the CALYPSO study showing superiority to paclitaxel and carboplatin) PLD, carboplatin and bevacizumab (PLD, carboplatin and bevacizumab has not been tested in a randomized phase III trial) Gemcitabine and carboplatin (Gemcitabine and carboplatin: this is reasonable based on a comparison with carboplatin alone (Pfisterer et.al. 2005) Gemcitabine, carboplatin and bevacizumab (Higher response rates and improved PFS are seen when bevacizumab is added to gem/carbo but OS is not improved (OCEANS trial) Paclitaxel and carboplatin (Paclitaxel and carboplatin can be used but based on prior taxane and results of CALYPSO, is used less) Weekly paclitaxel and carboplatin (Weekly paclitaxel has shown improved outcome when used with carboplatin for newly diagnosed patients but has not been rigorously tested in recurrent disease Paclitaxel, carboplatin and PARP inhibitor (PARP inhibitors are not yet FDA approved , so can only be obtained on a clinical trial. However, this is a very promising direction in ovarian cancer and a clinical trial of paclitaxel and carboplatin +/- olaparib showed improved PFS (Oza et.al. ASCO 2012) She Asks You Whether There Is Any Role for Surgery for Her Which of the following are true regarding secondary debulking? It is not considered for patients like her who relapse 10-12 months after completing initial chemotherapy The finding of carcinomatosis is a relatively strong contraindication to secondary debulking surgery Survival is improved for secondary debulking even if all disease can’t be removed at surgery Mediastinal and pleural disease are relatively strong contraindications to secondary debulking surgery 1 and 3 2 and 4 All of the above Secondary Debulking Candidate Selection Onda et al. J Cancer. 2005;92:1026. Pujade-Lauraine, Ann Oncol. 2011;22(Supplement 8):viii61–viii64. RANDOM I Z E GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: ≤ 0.5 cm > 0.5-2 cm PLD 30 mg/m2 Carboplatin AUC = 5 q 28 days x 6 Paclitaxel 175 mg/m2 Carboplatin AUC = 5 q 21 days x 6 GCIG = Gynecologic Cancer Intergroup PFS = progression-free survival PLD = pegylated liposomal doxorubicin Accrual 864 pts PFS primary endpoint Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. GCIG CALYPSO Trial Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. Selected Non-hematologic Toxicities During Treatment Alopecia *P< 0.001 Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. Targeted Agents in Ovarian Cancer Signaling/Angiogenesis Bevacizumab/Aflibercept RTKI’s: Pazopanib Cabozantinib Sorafenib, etc Cediranib Nintedanib Trebananib, MEDI-3617 PI3K/Akt/mTOR MEKi Folate: Vintafolide (EC-145) Farletuzumab NKTR-102 Taxanes/epothilones Immunotherapy – vaccines and inducers EP-100 PARPi ErbB3 CG + PL OCEANS: Study schema CG for 6 (up to 10) cycles Stratification variables: Platinum-free interval (6–12 vs >12 months) Cytoreductive surgery for recurrent disease (yes vs no) Platinum-sensitive recurrent OCa Measurable disease ECOG 0/1 No prior chemo for recurrent OC No prior BV (n=484) BV = bevacizumab; PL = placebo aEpithelial ovarian, primary peritoneal, or fallopian tube cancer G 1000 mg/m2, d1 & 8 C AUC 4 PL q3w until progression C AUC 4 BV 15 mg/kg q3w until progression G 1000 mg/m2, d1 & 8 CG + BV Aghajanian C et al. J Clin Oncol. 2012;30:2039-2045. 242 177 45 11 3 0 CG + PL OCEANS: Primary Analysis of PFS Months No. at risk 242 203 92 33 11 0 CG + BV 1.0 0.8 0.6 0.4 0.2 0 Proportion progression free 0 6 12 18 24 30 Aghajanian C et al. J Clin Oncol. 2012;30:2039-2045. 1.0 0.8 0.6 0.4 0.2 0 OCEANS: Third Interim OS Analysisa 0 6 12 18 24 30 36 42 48 54 60 242 235 221 190 159 117 77 44 23 7 0 242 239 226 201 171 127 78 48 27 7 0 Number at risk: GC + PL GC + BV aData cutoff date: March 30, 2012. Median follow-up 41.9 months in PL arm and 42.3 months in BV arm, with 286 deaths (59.1% of patients) Proportion surviving Months Aghajanian et al. ESMO 2012. Asymptomatic relapse Single-agent farletuzumab Until progression Single-agent ORR Compare lengths of first and second remissions Farletuzumab - MORAb-003-002 Phase II: Design Epithelial Ovarian Cancer First platinum-sensitive relapse First remission of 6-18 months Evaluable disease by CA125 Symptomatic relapse Original Carbo/Taxane regimen Plus farletuzumab x 6 Farletuzumab maintenance Rx For responders Combination ORR White AJ et al. J Clin Oncol. 2010;28(15s):Abstract 5001. MorAb-003-002: Study Conclusions Overall response rate 70% Response rate similar in early (6-12 month) and late (12+ months) recurrent patients High rates of CA-125 normalization (89%) 1/5 patients had a PFI2 ≥ PFI1 Phase III studies Platinum-sensitive: fully enrolled Platinum-resistant (weekly paclitaxel): met futility endpoint White AJ et al. J Clin Oncol. 2010;28(15s):Abstract 5001. n=66 Randomized, Open-label, Phase II Study in Patients With Platinum-sensitive, Advanced Serous Ovarian Cancer Paclitaxel 175 mg/m2 (iv, d1) + carboplatin AUC6 (iv d1) Randomization (1:1) All patients followed for objective radiologic progression and survival Maintenance phase Olaparib 400 mg bid continuously Completion of 4–6 x 21-day cycles of chemotherapy Arm B Arm A n=81 n=81 n=55 Multinational study; 43 sites in 12 countries * Capsule formulation Patients with: Platinum-sensitive advanced ovarian cancer A serous histology or serous component Measurable disease ≤3 previous platinum-containing regimens Progression free for ≥6 months following completion of last platinum-containing regimen Maintenance phase No further study treatment Olaparib 200 mg bid* (d1–10 every 21 days) + paclitaxel 175 mg/m2 (iv, d1) + carboplatin AUC4 (iv, d1) Oza A. ASCO 2012; Abstract 5001. Paclitaxel Carboplatin (P/C) vs P/C Plus Olaparib (O/P/C) In Platinum Sensitive Recurrent Ovarian Cancer: PFS Time from randomization (months) 0 Proportion of patients progression free 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 2 4 6 8 10 12 16 20 Number of patients at risk Olaparib + P + C (AUC4) P + C (AUC6) 14 18 81 80 76 71 55 37 34 3 0 20 0 81 68 65 57 40 18 15 2 0 8 1 O/P/C P/C Oza A. ASCO 2012; Abstract 5001. GOG 9927: Phase I Combination Platinum sensitive recurrent EOC Chemotherapy based on CALYPSO Primary endpoint: 1st or 2nd cycle DLT Secondary endpoints: RR, PFS, Toxicity TR: PARPi in PBMCs, BRCA status PLD 30 mg/m2 Carboplatin AUC 5 Arm I Veliparib PO daily continuously Cycles: 28 days Planned administration: 6 cycles Arm II Veliparib PO daily D1-7 Cycles: 28 days Planned administration: 6 cycles www.clinicaltrials.gov/ct2/show/NCT01459380. Summary for Platinum-sensitive Recurrent Ovarian Cancer Consider Secondary Debulking Platinum retreatment is standard Treatment with a platinum-based doublet improves response rate, progression-free survival, and possibly overall survival Options: Taxane Carboplatin: Paclitaxel, Docetaxel (?), Weekly Paclitaxel (?) Gemcitabine Carboplatin +/- Bevacizumab PLD Carboplatin Case 3: Platinum Resistant Ovarian Cancer 60-year-old woman with extensive pelvic and peritoneal implants, ascites and large volume disease at the root of the mesentery Diagnosis of ovarian cancer made by paracentesis Deemed unresectable by a gynecologic oncologist Treated with neoadjuvant paclitaxel and carboplatin x 3 without response Then treated with topotecan (daily x 5 regimen) x 3 without response Required paracentesis weekly for palliation CA-125=6916 What treatment would you recommend? Case 3 Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) Weekly paclitaxel Gemcitabine Bevacizumab Weekly paclitaxel and bevacizumab Gemcitabine, carboplatin and bevacizumab Case 3 Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) (PLD is a reasonable choice but expected response rate is 6-16% in a less heavily pretreated population) Weekly paclitaxel (Weekly paclitaxel is also a reasonable option. In GOG protocol 126-N weekly paclitaxel had a response rate of 21% although eligibility limited to one prior treatment regimen) Gemcitabine (although single agent gemcitabine is not FDA approved for treatment of ovarian cancer, the combination of gemcitabine and carboplatin is approved for platinum sensitive patients thus gemcitabine alone is frequently used. Response rates in this population are expected to be less than 10%) Bevacizumab (Bevacizumab is a reasonable choice. In GOG protocol 170D bevacizumab showed a response rate of 21% in this population) Weekly paclitaxel and bevacizumab (Based on Aurelia, the combination of weekly paclitaxel and bevacizumab would be expected to have a higher response rate than weekly paclitaxel alone. Survival data is not yet available. It is not yet clear whether sequential chemotherapy and bevacizumab or the combination is preferable) Gemcitabine, carboplatin and bevacizumab (platinum-based therapy is not indicated in this patient with platinum-refractory disease.) Assume You Will Be Using Treatment With Bevacizumab: Which of the Following Are True Statements About Bevacizumab for Her 1. She will be at increased risk for bowel perforation 2. There is an increased risk of thrombo-embolic phenomena with bevacizumab 3. The response rate of ovarian cancer to single-agent bevacizumab is greater than for any other solid tumors tested to date 4. Hypertension and proteinuria are common side effects of bevacizumab 5. All of the above All the above are true statements in this case. Annals of Oncology 22 (Supplement 8): viii61–viii64, 2011.
Slide 65 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R A N D O M I Z E n = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Placebo BEV 15 mg/kg II Stratification variables: GOG performance status (PS) Stage/debulking status RANDOM I Z E 1:1:1 15 months Paclitaxel (P) 175 mg/m2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 III Maintenance (16 cycles) BEV 15 mg/kg Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218: Investigator-assessed PFS + BEV (Arm II) CP (Arm I) *P-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 CA-125 to Determine Progression Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 Interim Survival Analysis Proportion Alive Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 48 aStratified analysis 625/625/623 442/432/437 173/162/171 46/39/40 No. at risk Burger RA et al. N Engl J Med. 2011;365:2473-2483. ICON7: Study Design Stratification variables: Stage/surgery Time since surgery GCIG group *Might vary based on GCIG group **Omit cycle 1 bevacizumab if <4 weeks from surgery Paclitaxel 175 mg/m2 Carboplatin AUC 6* AVASTIN Carboplatin AUC 6* Paclitaxel 175 mg/m2 Arm A Arm B 12 months Front-line EOC, PP or FT cancer Stage I-IIA (Gr 3 or CC) Stage IIB/C Stage III Stage IV n=1528 Bevacizumab 7.5 mg/kg ** Primary endpoints: PFS Secondary endpoints: OS, RR, safety, QOL, cost-effectiveness, translational No IRC present Perren T et al. N Engl J Med. 2011;365:2484-2496. Perren et al. ESMO 2010. ICON 7 Summary of Updated Results Kristensen G et al. J Clin Oncol. 2011;29: suppl; abstr LBA5006). Perren T et al. N Engl J Med. 2011;365:2484-2496. First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG 178—Investigating Paclitaxel as Consolidation Markman M et al. J Clin Oncol. 2003;21:2460-2465. 277 stage III/IV patients in complete clinical remission Paclitaxel 175 mg/m2 every 28 days × 3 months Paclitaxel 175 mg/m2 every 28 days × 12 months RANDOM I Z E CR = Complete response. Progression-free survival 0 20 40 60 80 100 0 12 24 36 48 Months after registration Paclitaxel 12 courses Paclitaxel 3 courses 110 At risk 112 Failed 20 34 Median, months 28 21 P = 0.0023 Percentage Markman M et al. J Clin Oncol. 2003;21:2460-2465. GOG 178 GOG-0212 Phase III Maintenance Therapy Trial Primary endpoint: survival Secondary endpoints: PFS, toxicity, QoL www.clinicaltrials.gov/ct2/show/NCT00108745. Macromolecular complex of paclitaxel poliglumex Patients with stage III/IV epithelial ovarian or primary peritoneal cancer, GOG PS ≤ 2, and complete response after surgery plus taxane and carboplatin (Planned n = 1400-1550) Paclitaxel Every 28 days for up to 12 courses No treatment Paclitaxel poliglumex Every 28 days for up to 12 courses Summary: Initial Treatment of Advanced Ovarian Cancer Surgery Attempt at maximal surgical cytoreduction Neoadjuvant chemo before surgery is an option for poor surgical candidates Chemotherapy 6-8 cycles taxane-platinum combination is standard IP admin benefits patients with low volume (optimal) disease but has increased toxicity NED patients treated with IP have a median survival of over 9 years Weekly (dose-dense) paclitaxel improves outcome in one study Confirmatory North American trials recently completed Bevacizumab during and after chemotherapy improves PFS but not OS Case Discussions Case 1: A Newly Diagnosed Patient With Ovarian Cancer 58 year old real estate broker with controlled hypertension presents with a pelvic mass, omental caking, and a CA125 of 2,056. She has no malnutrition or change in her weight. She is a PS=0. What would you recommend for this patient? Neoadjuvant chemotherapy Primary radical debulking surgery What Would You Recommend for This Patient? Neoadjuvant chemotherapy Primary radical debulking surgery Primary Cytoreduction Meta-analysis: 53 studies (1989–1998) 81 cohorts (Stage III/IV) n = 6885 patients Results Expert centers have high optimal rates Optimal vs not: 11 mos (50% increase) Each 10%  in cytoreduction = 5.5%  in survival Platinum intensity = NS Bristow. J Clin Oncol. 2002;20:1248. The Impact of Residual Tumor: What Is Optimal Debulking? % Progression-Free Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.52 (2.26; 2.81) >10 mm vs 1 mm – 10 mm: 1.36 (1.24; 1.50) log-rank: P<0.0001 % Overall Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.70 (2.37; 3.07) >10 mm vs 1 mm – 10 mm: 1.34 (1.21; 1.49) log-rank: P<0.0001 Generated from 3 prospective Phase III trials (OVAR 3,5, & 7) n = 3126 pts DuBois. Cancer. 2009;115:1234. Case 1 She has a TAH BSO, transverse colectomy, omentectomy and spends 7 days in the hospital (2 in the ICU). Except for an open wound with a wound-vac and getting 4 units of blood, she does well… The pathology shows a high-grade serous carcinoma. The surgeon noted small volume residual (5-9mm) disease throughout the abdomen. What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP Case 1 Question 2 What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP All the above answers are reasonable treatment choices. When would you start the bevacizumab? Cycle 1, 2 or 3? After the chemotherapy (maintenance)? Case 2: Platinum Sensitive Ovarian Cancer 52-year-old woman with high-grade serous carcinoma of the fallopian tube Optimally debulked in 2010 Treated with IV paclitaxel, IP cisplatin and IP paclitaxel completed June 2011 CA125 at presentation 5800 nadir post therapy 7 In 2012 : Increasing Ca125 (1200) Imaging: diffuse peritoneal carcinomatosis; pleural nodularity; mediastinal adenopathy Symptomatic: abdominal bloating, early satiety, and mild shortness of breath Disease free interval: 10-12 months Genetic testing: BRCA1/2 negative Case 2 Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin PLD, carboplatin and bevacizumab Gemcitabine and carboplatin Gemcitabine, carboplatin and bevacizumab Paclitaxel and carboplatin Weekly paclitaxel and carboplatin Paclitaxel, carboplatin and PARP inhibitor Case 2, Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin (PLD and carboplatin is a reasonable option based on results of the CALYPSO study showing superiority to paclitaxel and carboplatin) PLD, carboplatin and bevacizumab (PLD, carboplatin and bevacizumab has not been tested in a randomized phase III trial) Gemcitabine and carboplatin (Gemcitabine and carboplatin: this is reasonable based on a comparison with carboplatin alone (Pfisterer et.al. 2005) Gemcitabine, carboplatin and bevacizumab (Higher response rates and improved PFS are seen when bevacizumab is added to gem/carbo but OS is not improved (OCEANS trial) Paclitaxel and carboplatin (Paclitaxel and carboplatin can be used but based on prior taxane and results of CALYPSO, is used less) Weekly paclitaxel and carboplatin (Weekly paclitaxel has shown improved outcome when used with carboplatin for newly diagnosed patients but has not been rigorously tested in recurrent disease Paclitaxel, carboplatin and PARP inhibitor (PARP inhibitors are not yet FDA approved , so can only be obtained on a clinical trial. However, this is a very promising direction in ovarian cancer and a clinical trial of paclitaxel and carboplatin +/- olaparib showed improved PFS (Oza et.al. ASCO 2012) She Asks You Whether There Is Any Role for Surgery for Her Which of the following are true regarding secondary debulking? It is not considered for patients like her who relapse 10-12 months after completing initial chemotherapy The finding of carcinomatosis is a relatively strong contraindication to secondary debulking surgery Survival is improved for secondary debulking even if all disease can’t be removed at surgery Mediastinal and pleural disease are relatively strong contraindications to secondary debulking surgery 1 and 3 2 and 4 All of the above Secondary Debulking Candidate Selection Onda et al. J Cancer. 2005;92:1026. Pujade-Lauraine, Ann Oncol. 2011;22(Supplement 8):viii61–viii64. RANDOM I Z E GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: ≤ 0.5 cm > 0.5-2 cm PLD 30 mg/m2 Carboplatin AUC = 5 q 28 days x 6 Paclitaxel 175 mg/m2 Carboplatin AUC = 5 q 21 days x 6 GCIG = Gynecologic Cancer Intergroup PFS = progression-free survival PLD = pegylated liposomal doxorubicin Accrual 864 pts PFS primary endpoint Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. GCIG CALYPSO Trial Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. Selected Non-hematologic Toxicities During Treatment Alopecia *P< 0.001 Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. Targeted Agents in Ovarian Cancer Signaling/Angiogenesis Bevacizumab/Aflibercept RTKI’s: Pazopanib Cabozantinib Sorafenib, etc Cediranib Nintedanib Trebananib, MEDI-3617 PI3K/Akt/mTOR MEKi Folate: Vintafolide (EC-145) Farletuzumab NKTR-102 Taxanes/epothilones Immunotherapy – vaccines and inducers EP-100 PARPi ErbB3 CG + PL OCEANS: Study schema CG for 6 (up to 10) cycles Stratification variables: Platinum-free interval (6–12 vs >12 months) Cytoreductive surgery for recurrent disease (yes vs no) Platinum-sensitive recurrent OCa Measurable disease ECOG 0/1 No prior chemo for recurrent OC No prior BV (n=484) BV = bevacizumab; PL = placebo aEpithelial ovarian, primary peritoneal, or fallopian tube cancer G 1000 mg/m2, d1 & 8 C AUC 4 PL q3w until progression C AUC 4 BV 15 mg/kg q3w until progression G 1000 mg/m2, d1 & 8 CG + BV Aghajanian C et al. J Clin Oncol. 2012;30:2039-2045. 242 177 45 11 3 0 CG + PL OCEANS: Primary Analysis of PFS Months No. at risk 242 203 92 33 11 0 CG + BV 1.0 0.8 0.6 0.4 0.2 0 Proportion progression free 0 6 12 18 24 30 Aghajanian C et al. J Clin Oncol. 2012;30:2039-2045. 1.0 0.8 0.6 0.4 0.2 0 OCEANS: Third Interim OS Analysisa 0 6 12 18 24 30 36 42 48 54 60 242 235 221 190 159 117 77 44 23 7 0 242 239 226 201 171 127 78 48 27 7 0 Number at risk: GC + PL GC + BV aData cutoff date: March 30, 2012. Median follow-up 41.9 months in PL arm and 42.3 months in BV arm, with 286 deaths (59.1% of patients) Proportion surviving Months Aghajanian et al. ESMO 2012. Asymptomatic relapse Single-agent farletuzumab Until progression Single-agent ORR Compare lengths of first and second remissions Farletuzumab - MORAb-003-002 Phase II: Design Epithelial Ovarian Cancer First platinum-sensitive relapse First remission of 6-18 months Evaluable disease by CA125 Symptomatic relapse Original Carbo/Taxane regimen Plus farletuzumab x 6 Farletuzumab maintenance Rx For responders Combination ORR White AJ et al. J Clin Oncol. 2010;28(15s):Abstract 5001. MorAb-003-002: Study Conclusions Overall response rate 70% Response rate similar in early (6-12 month) and late (12+ months) recurrent patients High rates of CA-125 normalization (89%) 1/5 patients had a PFI2 ≥ PFI1 Phase III studies Platinum-sensitive: fully enrolled Platinum-resistant (weekly paclitaxel): met futility endpoint White AJ et al. J Clin Oncol. 2010;28(15s):Abstract 5001. n=66 Randomized, Open-label, Phase II Study in Patients With Platinum-sensitive, Advanced Serous Ovarian Cancer Paclitaxel 175 mg/m2 (iv, d1) + carboplatin AUC6 (iv d1) Randomization (1:1) All patients followed for objective radiologic progression and survival Maintenance phase Olaparib 400 mg bid continuously Completion of 4–6 x 21-day cycles of chemotherapy Arm B Arm A n=81 n=81 n=55 Multinational study; 43 sites in 12 countries * Capsule formulation Patients with: Platinum-sensitive advanced ovarian cancer A serous histology or serous component Measurable disease ≤3 previous platinum-containing regimens Progression free for ≥6 months following completion of last platinum-containing regimen Maintenance phase No further study treatment Olaparib 200 mg bid* (d1–10 every 21 days) + paclitaxel 175 mg/m2 (iv, d1) + carboplatin AUC4 (iv, d1) Oza A. ASCO 2012; Abstract 5001. Paclitaxel Carboplatin (P/C) vs P/C Plus Olaparib (O/P/C) In Platinum Sensitive Recurrent Ovarian Cancer: PFS Time from randomization (months) 0 Proportion of patients progression free 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 2 4 6 8 10 12 16 20 Number of patients at risk Olaparib + P + C (AUC4) P + C (AUC6) 14 18 81 80 76 71 55 37 34 3 0 20 0 81 68 65 57 40 18 15 2 0 8 1 O/P/C P/C Oza A. ASCO 2012; Abstract 5001. GOG 9927: Phase I Combination Platinum sensitive recurrent EOC Chemotherapy based on CALYPSO Primary endpoint: 1st or 2nd cycle DLT Secondary endpoints: RR, PFS, Toxicity TR: PARPi in PBMCs, BRCA status PLD 30 mg/m2 Carboplatin AUC 5 Arm I Veliparib PO daily continuously Cycles: 28 days Planned administration: 6 cycles Arm II Veliparib PO daily D1-7 Cycles: 28 days Planned administration: 6 cycles www.clinicaltrials.gov/ct2/show/NCT01459380. Summary for Platinum-sensitive Recurrent Ovarian Cancer Consider Secondary Debulking Platinum retreatment is standard Treatment with a platinum-based doublet improves response rate, progression-free survival, and possibly overall survival Options: Taxane Carboplatin: Paclitaxel, Docetaxel (?), Weekly Paclitaxel (?) Gemcitabine Carboplatin +/- Bevacizumab PLD Carboplatin Case 3: Platinum Resistant Ovarian Cancer 60-year-old woman with extensive pelvic and peritoneal implants, ascites and large volume disease at the root of the mesentery Diagnosis of ovarian cancer made by paracentesis Deemed unresectable by a gynecologic oncologist Treated with neoadjuvant paclitaxel and carboplatin x 3 without response Then treated with topotecan (daily x 5 regimen) x 3 without response Required paracentesis weekly for palliation CA-125=6916 What treatment would you recommend? Case 3 Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) Weekly paclitaxel Gemcitabine Bevacizumab Weekly paclitaxel and bevacizumab Gemcitabine, carboplatin and bevacizumab Case 3 Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) (PLD is a reasonable choice but expected response rate is 6-16% in a less heavily pretreated population) Weekly paclitaxel (Weekly paclitaxel is also a reasonable option. In GOG protocol 126-N weekly paclitaxel had a response rate of 21% although eligibility limited to one prior treatment regimen) Gemcitabine (although single agent gemcitabine is not FDA approved for treatment of ovarian cancer, the combination of gemcitabine and carboplatin is approved for platinum sensitive patients thus gemcitabine alone is frequently used. Response rates in this population are expected to be less than 10%) Bevacizumab (Bevacizumab is a reasonable choice. In GOG protocol 170D bevacizumab showed a response rate of 21% in this population) Weekly paclitaxel and bevacizumab (Based on Aurelia, the combination of weekly paclitaxel and bevacizumab would be expected to have a higher response rate than weekly paclitaxel alone. Survival data is not yet available. It is not yet clear whether sequential chemotherapy and bevacizumab or the combination is preferable) Gemcitabine, carboplatin and bevacizumab (platinum-based therapy is not indicated in this patient with platinum-refractory disease.) Assume You Will Be Using Treatment With Bevacizumab: Which of the Following Are True Statements About Bevacizumab for Her 1. She will be at increased risk for bowel perforation 2. There is an increased risk of thrombo-embolic phenomena with bevacizumab 3. The response rate of ovarian cancer to single-agent bevacizumab is greater than for any other solid tumors tested to date 4. Hypertension and proteinuria are common side effects of bevacizumab 5. All of the above All the above are true statements in this case. Annals of Oncology 22 (Supplement 8): viii61–viii64, 2011. Active Agents in Ovarian Cancer
Slide 66 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R A N D O M I Z E n = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Placebo BEV 15 mg/kg II Stratification variables: GOG performance status (PS) Stage/debulking status RANDOM I Z E 1:1:1 15 months Paclitaxel (P) 175 mg/m2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 III Maintenance (16 cycles) BEV 15 mg/kg Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218: Investigator-assessed PFS + BEV (Arm II) CP (Arm I) *P-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 CA-125 to Determine Progression Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 Interim Survival Analysis Proportion Alive Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 48 aStratified analysis 625/625/623 442/432/437 173/162/171 46/39/40 No. at risk Burger RA et al. N Engl J Med. 2011;365:2473-2483. ICON7: Study Design Stratification variables: Stage/surgery Time since surgery GCIG group *Might vary based on GCIG group **Omit cycle 1 bevacizumab if <4 weeks from surgery Paclitaxel 175 mg/m2 Carboplatin AUC 6* AVASTIN Carboplatin AUC 6* Paclitaxel 175 mg/m2 Arm A Arm B 12 months Front-line EOC, PP or FT cancer Stage I-IIA (Gr 3 or CC) Stage IIB/C Stage III Stage IV n=1528 Bevacizumab 7.5 mg/kg ** Primary endpoints: PFS Secondary endpoints: OS, RR, safety, QOL, cost-effectiveness, translational No IRC present Perren T et al. N Engl J Med. 2011;365:2484-2496. Perren et al. ESMO 2010. ICON 7 Summary of Updated Results Kristensen G et al. J Clin Oncol. 2011;29: suppl; abstr LBA5006). Perren T et al. N Engl J Med. 2011;365:2484-2496. First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG 178—Investigating Paclitaxel as Consolidation Markman M et al. J Clin Oncol. 2003;21:2460-2465. 277 stage III/IV patients in complete clinical remission Paclitaxel 175 mg/m2 every 28 days × 3 months Paclitaxel 175 mg/m2 every 28 days × 12 months RANDOM I Z E CR = Complete response. Progression-free survival 0 20 40 60 80 100 0 12 24 36 48 Months after registration Paclitaxel 12 courses Paclitaxel 3 courses 110 At risk 112 Failed 20 34 Median, months 28 21 P = 0.0023 Percentage Markman M et al. J Clin Oncol. 2003;21:2460-2465. GOG 178 GOG-0212 Phase III Maintenance Therapy Trial Primary endpoint: survival Secondary endpoints: PFS, toxicity, QoL www.clinicaltrials.gov/ct2/show/NCT00108745. Macromolecular complex of paclitaxel poliglumex Patients with stage III/IV epithelial ovarian or primary peritoneal cancer, GOG PS ≤ 2, and complete response after surgery plus taxane and carboplatin (Planned n = 1400-1550) Paclitaxel Every 28 days for up to 12 courses No treatment Paclitaxel poliglumex Every 28 days for up to 12 courses Summary: Initial Treatment of Advanced Ovarian Cancer Surgery Attempt at maximal surgical cytoreduction Neoadjuvant chemo before surgery is an option for poor surgical candidates Chemotherapy 6-8 cycles taxane-platinum combination is standard IP admin benefits patients with low volume (optimal) disease but has increased toxicity NED patients treated with IP have a median survival of over 9 years Weekly (dose-dense) paclitaxel improves outcome in one study Confirmatory North American trials recently completed Bevacizumab during and after chemotherapy improves PFS but not OS Case Discussions Case 1: A Newly Diagnosed Patient With Ovarian Cancer 58 year old real estate broker with controlled hypertension presents with a pelvic mass, omental caking, and a CA125 of 2,056. She has no malnutrition or change in her weight. She is a PS=0. What would you recommend for this patient? Neoadjuvant chemotherapy Primary radical debulking surgery What Would You Recommend for This Patient? Neoadjuvant chemotherapy Primary radical debulking surgery Primary Cytoreduction Meta-analysis: 53 studies (1989–1998) 81 cohorts (Stage III/IV) n = 6885 patients Results Expert centers have high optimal rates Optimal vs not: 11 mos (50% increase) Each 10%  in cytoreduction = 5.5%  in survival Platinum intensity = NS Bristow. J Clin Oncol. 2002;20:1248. The Impact of Residual Tumor: What Is Optimal Debulking? % Progression-Free Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.52 (2.26; 2.81) >10 mm vs 1 mm – 10 mm: 1.36 (1.24; 1.50) log-rank: P<0.0001 % Overall Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.70 (2.37; 3.07) >10 mm vs 1 mm – 10 mm: 1.34 (1.21; 1.49) log-rank: P<0.0001 Generated from 3 prospective Phase III trials (OVAR 3,5, & 7) n = 3126 pts DuBois. Cancer. 2009;115:1234. Case 1 She has a TAH BSO, transverse colectomy, omentectomy and spends 7 days in the hospital (2 in the ICU). Except for an open wound with a wound-vac and getting 4 units of blood, she does well… The pathology shows a high-grade serous carcinoma. The surgeon noted small volume residual (5-9mm) disease throughout the abdomen. What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP Case 1 Question 2 What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP All the above answers are reasonable treatment choices. When would you start the bevacizumab? Cycle 1, 2 or 3? After the chemotherapy (maintenance)? Case 2: Platinum Sensitive Ovarian Cancer 52-year-old woman with high-grade serous carcinoma of the fallopian tube Optimally debulked in 2010 Treated with IV paclitaxel, IP cisplatin and IP paclitaxel completed June 2011 CA125 at presentation 5800 nadir post therapy 7 In 2012 : Increasing Ca125 (1200) Imaging: diffuse peritoneal carcinomatosis; pleural nodularity; mediastinal adenopathy Symptomatic: abdominal bloating, early satiety, and mild shortness of breath Disease free interval: 10-12 months Genetic testing: BRCA1/2 negative Case 2 Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin PLD, carboplatin and bevacizumab Gemcitabine and carboplatin Gemcitabine, carboplatin and bevacizumab Paclitaxel and carboplatin Weekly paclitaxel and carboplatin Paclitaxel, carboplatin and PARP inhibitor Case 2, Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin (PLD and carboplatin is a reasonable option based on results of the CALYPSO study showing superiority to paclitaxel and carboplatin) PLD, carboplatin and bevacizumab (PLD, carboplatin and bevacizumab has not been tested in a randomized phase III trial) Gemcitabine and carboplatin (Gemcitabine and carboplatin: this is reasonable based on a comparison with carboplatin alone (Pfisterer et.al. 2005) Gemcitabine, carboplatin and bevacizumab (Higher response rates and improved PFS are seen when bevacizumab is added to gem/carbo but OS is not improved (OCEANS trial) Paclitaxel and carboplatin (Paclitaxel and carboplatin can be used but based on prior taxane and results of CALYPSO, is used less) Weekly paclitaxel and carboplatin (Weekly paclitaxel has shown improved outcome when used with carboplatin for newly diagnosed patients but has not been rigorously tested in recurrent disease Paclitaxel, carboplatin and PARP inhibitor (PARP inhibitors are not yet FDA approved , so can only be obtained on a clinical trial. However, this is a very promising direction in ovarian cancer and a clinical trial of paclitaxel and carboplatin +/- olaparib showed improved PFS (Oza et.al. ASCO 2012) She Asks You Whether There Is Any Role for Surgery for Her Which of the following are true regarding secondary debulking? It is not considered for patients like her who relapse 10-12 months after completing initial chemotherapy The finding of carcinomatosis is a relatively strong contraindication to secondary debulking surgery Survival is improved for secondary debulking even if all disease can’t be removed at surgery Mediastinal and pleural disease are relatively strong contraindications to secondary debulking surgery 1 and 3 2 and 4 All of the above Secondary Debulking Candidate Selection Onda et al. J Cancer. 2005;92:1026. Pujade-Lauraine, Ann Oncol. 2011;22(Supplement 8):viii61–viii64. RANDOM I Z E GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: ≤ 0.5 cm > 0.5-2 cm PLD 30 mg/m2 Carboplatin AUC = 5 q 28 days x 6 Paclitaxel 175 mg/m2 Carboplatin AUC = 5 q 21 days x 6 GCIG = Gynecologic Cancer Intergroup PFS = progression-free survival PLD = pegylated liposomal doxorubicin Accrual 864 pts PFS primary endpoint Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. GCIG CALYPSO Trial Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. Selected Non-hematologic Toxicities During Treatment Alopecia *P< 0.001 Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. Targeted Agents in Ovarian Cancer Signaling/Angiogenesis Bevacizumab/Aflibercept RTKI’s: Pazopanib Cabozantinib Sorafenib, etc Cediranib Nintedanib Trebananib, MEDI-3617 PI3K/Akt/mTOR MEKi Folate: Vintafolide (EC-145) Farletuzumab NKTR-102 Taxanes/epothilones Immunotherapy – vaccines and inducers EP-100 PARPi ErbB3 CG + PL OCEANS: Study schema CG for 6 (up to 10) cycles Stratification variables: Platinum-free interval (6–12 vs >12 months) Cytoreductive surgery for recurrent disease (yes vs no) Platinum-sensitive recurrent OCa Measurable disease ECOG 0/1 No prior chemo for recurrent OC No prior BV (n=484) BV = bevacizumab; PL = placebo aEpithelial ovarian, primary peritoneal, or fallopian tube cancer G 1000 mg/m2, d1 & 8 C AUC 4 PL q3w until progression C AUC 4 BV 15 mg/kg q3w until progression G 1000 mg/m2, d1 & 8 CG + BV Aghajanian C et al. J Clin Oncol. 2012;30:2039-2045. 242 177 45 11 3 0 CG + PL OCEANS: Primary Analysis of PFS Months No. at risk 242 203 92 33 11 0 CG + BV 1.0 0.8 0.6 0.4 0.2 0 Proportion progression free 0 6 12 18 24 30 Aghajanian C et al. J Clin Oncol. 2012;30:2039-2045. 1.0 0.8 0.6 0.4 0.2 0 OCEANS: Third Interim OS Analysisa 0 6 12 18 24 30 36 42 48 54 60 242 235 221 190 159 117 77 44 23 7 0 242 239 226 201 171 127 78 48 27 7 0 Number at risk: GC + PL GC + BV aData cutoff date: March 30, 2012. Median follow-up 41.9 months in PL arm and 42.3 months in BV arm, with 286 deaths (59.1% of patients) Proportion surviving Months Aghajanian et al. ESMO 2012. Asymptomatic relapse Single-agent farletuzumab Until progression Single-agent ORR Compare lengths of first and second remissions Farletuzumab - MORAb-003-002 Phase II: Design Epithelial Ovarian Cancer First platinum-sensitive relapse First remission of 6-18 months Evaluable disease by CA125 Symptomatic relapse Original Carbo/Taxane regimen Plus farletuzumab x 6 Farletuzumab maintenance Rx For responders Combination ORR White AJ et al. J Clin Oncol. 2010;28(15s):Abstract 5001. MorAb-003-002: Study Conclusions Overall response rate 70% Response rate similar in early (6-12 month) and late (12+ months) recurrent patients High rates of CA-125 normalization (89%) 1/5 patients had a PFI2 ≥ PFI1 Phase III studies Platinum-sensitive: fully enrolled Platinum-resistant (weekly paclitaxel): met futility endpoint White AJ et al. J Clin Oncol. 2010;28(15s):Abstract 5001. n=66 Randomized, Open-label, Phase II Study in Patients With Platinum-sensitive, Advanced Serous Ovarian Cancer Paclitaxel 175 mg/m2 (iv, d1) + carboplatin AUC6 (iv d1) Randomization (1:1) All patients followed for objective radiologic progression and survival Maintenance phase Olaparib 400 mg bid continuously Completion of 4–6 x 21-day cycles of chemotherapy Arm B Arm A n=81 n=81 n=55 Multinational study; 43 sites in 12 countries * Capsule formulation Patients with: Platinum-sensitive advanced ovarian cancer A serous histology or serous component Measurable disease ≤3 previous platinum-containing regimens Progression free for ≥6 months following completion of last platinum-containing regimen Maintenance phase No further study treatment Olaparib 200 mg bid* (d1–10 every 21 days) + paclitaxel 175 mg/m2 (iv, d1) + carboplatin AUC4 (iv, d1) Oza A. ASCO 2012; Abstract 5001. Paclitaxel Carboplatin (P/C) vs P/C Plus Olaparib (O/P/C) In Platinum Sensitive Recurrent Ovarian Cancer: PFS Time from randomization (months) 0 Proportion of patients progression free 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 2 4 6 8 10 12 16 20 Number of patients at risk Olaparib + P + C (AUC4) P + C (AUC6) 14 18 81 80 76 71 55 37 34 3 0 20 0 81 68 65 57 40 18 15 2 0 8 1 O/P/C P/C Oza A. ASCO 2012; Abstract 5001. GOG 9927: Phase I Combination Platinum sensitive recurrent EOC Chemotherapy based on CALYPSO Primary endpoint: 1st or 2nd cycle DLT Secondary endpoints: RR, PFS, Toxicity TR: PARPi in PBMCs, BRCA status PLD 30 mg/m2 Carboplatin AUC 5 Arm I Veliparib PO daily continuously Cycles: 28 days Planned administration: 6 cycles Arm II Veliparib PO daily D1-7 Cycles: 28 days Planned administration: 6 cycles www.clinicaltrials.gov/ct2/show/NCT01459380. Summary for Platinum-sensitive Recurrent Ovarian Cancer Consider Secondary Debulking Platinum retreatment is standard Treatment with a platinum-based doublet improves response rate, progression-free survival, and possibly overall survival Options: Taxane Carboplatin: Paclitaxel, Docetaxel (?), Weekly Paclitaxel (?) Gemcitabine Carboplatin +/- Bevacizumab PLD Carboplatin Case 3: Platinum Resistant Ovarian Cancer 60-year-old woman with extensive pelvic and peritoneal implants, ascites and large volume disease at the root of the mesentery Diagnosis of ovarian cancer made by paracentesis Deemed unresectable by a gynecologic oncologist Treated with neoadjuvant paclitaxel and carboplatin x 3 without response Then treated with topotecan (daily x 5 regimen) x 3 without response Required paracentesis weekly for palliation CA-125=6916 What treatment would you recommend? Case 3 Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) Weekly paclitaxel Gemcitabine Bevacizumab Weekly paclitaxel and bevacizumab Gemcitabine, carboplatin and bevacizumab Case 3 Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) (PLD is a reasonable choice but expected response rate is 6-16% in a less heavily pretreated population) Weekly paclitaxel (Weekly paclitaxel is also a reasonable option. In GOG protocol 126-N weekly paclitaxel had a response rate of 21% although eligibility limited to one prior treatment regimen) Gemcitabine (although single agent gemcitabine is not FDA approved for treatment of ovarian cancer, the combination of gemcitabine and carboplatin is approved for platinum sensitive patients thus gemcitabine alone is frequently used. Response rates in this population are expected to be less than 10%) Bevacizumab (Bevacizumab is a reasonable choice. In GOG protocol 170D bevacizumab showed a response rate of 21% in this population) Weekly paclitaxel and bevacizumab (Based on Aurelia, the combination of weekly paclitaxel and bevacizumab would be expected to have a higher response rate than weekly paclitaxel alone. Survival data is not yet available. It is not yet clear whether sequential chemotherapy and bevacizumab or the combination is preferable) Gemcitabine, carboplatin and bevacizumab (platinum-based therapy is not indicated in this patient with platinum-refractory disease.) Assume You Will Be Using Treatment With Bevacizumab: Which of the Following Are True Statements About Bevacizumab for Her 1. She will be at increased risk for bowel perforation 2. There is an increased risk of thrombo-embolic phenomena with bevacizumab 3. The response rate of ovarian cancer to single-agent bevacizumab is greater than for any other solid tumors tested to date 4. Hypertension and proteinuria are common side effects of bevacizumab 5. All of the above All the above are true statements in this case. Annals of Oncology 22 (Supplement 8): viii61–viii64, 2011. Active Agents in Ovarian Cancer Platinum-resistant Ovarian Cancer Cytotoxic Therapy Thresholds: 10%, 25% *Median of 3 prior lines *1 prior line Vergote IB et al. J Clin Oncol 2010;28:15s(suppl; abstr 5013).
Slide 67 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R A N D O M I Z E n = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Placebo BEV 15 mg/kg II Stratification variables: GOG performance status (PS) Stage/debulking status RANDOM I Z E 1:1:1 15 months Paclitaxel (P) 175 mg/m2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 III Maintenance (16 cycles) BEV 15 mg/kg Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218: Investigator-assessed PFS + BEV (Arm II) CP (Arm I) *P-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 CA-125 to Determine Progression Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 Interim Survival Analysis Proportion Alive Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 48 aStratified analysis 625/625/623 442/432/437 173/162/171 46/39/40 No. at risk Burger RA et al. N Engl J Med. 2011;365:2473-2483. ICON7: Study Design Stratification variables: Stage/surgery Time since surgery GCIG group *Might vary based on GCIG group **Omit cycle 1 bevacizumab if <4 weeks from surgery Paclitaxel 175 mg/m2 Carboplatin AUC 6* AVASTIN Carboplatin AUC 6* Paclitaxel 175 mg/m2 Arm A Arm B 12 months Front-line EOC, PP or FT cancer Stage I-IIA (Gr 3 or CC) Stage IIB/C Stage III Stage IV n=1528 Bevacizumab 7.5 mg/kg ** Primary endpoints: PFS Secondary endpoints: OS, RR, safety, QOL, cost-effectiveness, translational No IRC present Perren T et al. N Engl J Med. 2011;365:2484-2496. Perren et al. ESMO 2010. ICON 7 Summary of Updated Results Kristensen G et al. J Clin Oncol. 2011;29: suppl; abstr LBA5006). Perren T et al. N Engl J Med. 2011;365:2484-2496. First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG 178—Investigating Paclitaxel as Consolidation Markman M et al. J Clin Oncol. 2003;21:2460-2465. 277 stage III/IV patients in complete clinical remission Paclitaxel 175 mg/m2 every 28 days × 3 months Paclitaxel 175 mg/m2 every 28 days × 12 months RANDOM I Z E CR = Complete response. Progression-free survival 0 20 40 60 80 100 0 12 24 36 48 Months after registration Paclitaxel 12 courses Paclitaxel 3 courses 110 At risk 112 Failed 20 34 Median, months 28 21 P = 0.0023 Percentage Markman M et al. J Clin Oncol. 2003;21:2460-2465. GOG 178 GOG-0212 Phase III Maintenance Therapy Trial Primary endpoint: survival Secondary endpoints: PFS, toxicity, QoL www.clinicaltrials.gov/ct2/show/NCT00108745. Macromolecular complex of paclitaxel poliglumex Patients with stage III/IV epithelial ovarian or primary peritoneal cancer, GOG PS ≤ 2, and complete response after surgery plus taxane and carboplatin (Planned n = 1400-1550) Paclitaxel Every 28 days for up to 12 courses No treatment Paclitaxel poliglumex Every 28 days for up to 12 courses Summary: Initial Treatment of Advanced Ovarian Cancer Surgery Attempt at maximal surgical cytoreduction Neoadjuvant chemo before surgery is an option for poor surgical candidates Chemotherapy 6-8 cycles taxane-platinum combination is standard IP admin benefits patients with low volume (optimal) disease but has increased toxicity NED patients treated with IP have a median survival of over 9 years Weekly (dose-dense) paclitaxel improves outcome in one study Confirmatory North American trials recently completed Bevacizumab during and after chemotherapy improves PFS but not OS Case Discussions Case 1: A Newly Diagnosed Patient With Ovarian Cancer 58 year old real estate broker with controlled hypertension presents with a pelvic mass, omental caking, and a CA125 of 2,056. She has no malnutrition or change in her weight. She is a PS=0. What would you recommend for this patient? Neoadjuvant chemotherapy Primary radical debulking surgery What Would You Recommend for This Patient? Neoadjuvant chemotherapy Primary radical debulking surgery Primary Cytoreduction Meta-analysis: 53 studies (1989–1998) 81 cohorts (Stage III/IV) n = 6885 patients Results Expert centers have high optimal rates Optimal vs not: 11 mos (50% increase) Each 10%  in cytoreduction = 5.5%  in survival Platinum intensity = NS Bristow. J Clin Oncol. 2002;20:1248. The Impact of Residual Tumor: What Is Optimal Debulking? % Progression-Free Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.52 (2.26; 2.81) >10 mm vs 1 mm – 10 mm: 1.36 (1.24; 1.50) log-rank: P<0.0001 % Overall Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.70 (2.37; 3.07) >10 mm vs 1 mm – 10 mm: 1.34 (1.21; 1.49) log-rank: P<0.0001 Generated from 3 prospective Phase III trials (OVAR 3,5, & 7) n = 3126 pts DuBois. Cancer. 2009;115:1234. Case 1 She has a TAH BSO, transverse colectomy, omentectomy and spends 7 days in the hospital (2 in the ICU). Except for an open wound with a wound-vac and getting 4 units of blood, she does well… The pathology shows a high-grade serous carcinoma. The surgeon noted small volume residual (5-9mm) disease throughout the abdomen. What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP Case 1 Question 2 What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP All the above answers are reasonable treatment choices. When would you start the bevacizumab? Cycle 1, 2 or 3? After the chemotherapy (maintenance)? Case 2: Platinum Sensitive Ovarian Cancer 52-year-old woman with high-grade serous carcinoma of the fallopian tube Optimally debulked in 2010 Treated with IV paclitaxel, IP cisplatin and IP paclitaxel completed June 2011 CA125 at presentation 5800 nadir post therapy 7 In 2012 : Increasing Ca125 (1200) Imaging: diffuse peritoneal carcinomatosis; pleural nodularity; mediastinal adenopathy Symptomatic: abdominal bloating, early satiety, and mild shortness of breath Disease free interval: 10-12 months Genetic testing: BRCA1/2 negative Case 2 Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin PLD, carboplatin and bevacizumab Gemcitabine and carboplatin Gemcitabine, carboplatin and bevacizumab Paclitaxel and carboplatin Weekly paclitaxel and carboplatin Paclitaxel, carboplatin and PARP inhibitor Case 2, Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin (PLD and carboplatin is a reasonable option based on results of the CALYPSO study showing superiority to paclitaxel and carboplatin) PLD, carboplatin and bevacizumab (PLD, carboplatin and bevacizumab has not been tested in a randomized phase III trial) Gemcitabine and carboplatin (Gemcitabine and carboplatin: this is reasonable based on a comparison with carboplatin alone (Pfisterer et.al. 2005) Gemcitabine, carboplatin and bevacizumab (Higher response rates and improved PFS are seen when bevacizumab is added to gem/carbo but OS is not improved (OCEANS trial) Paclitaxel and carboplatin (Paclitaxel and carboplatin can be used but based on prior taxane and results of CALYPSO, is used less) Weekly paclitaxel and carboplatin (Weekly paclitaxel has shown improved outcome when used with carboplatin for newly diagnosed patients but has not been rigorously tested in recurrent disease Paclitaxel, carboplatin and PARP inhibitor (PARP inhibitors are not yet FDA approved , so can only be obtained on a clinical trial. However, this is a very promising direction in ovarian cancer and a clinical trial of paclitaxel and carboplatin +/- olaparib showed improved PFS (Oza et.al. ASCO 2012) She Asks You Whether There Is Any Role for Surgery for Her Which of the following are true regarding secondary debulking? It is not considered for patients like her who relapse 10-12 months after completing initial chemotherapy The finding of carcinomatosis is a relatively strong contraindication to secondary debulking surgery Survival is improved for secondary debulking even if all disease can’t be removed at surgery Mediastinal and pleural disease are relatively strong contraindications to secondary debulking surgery 1 and 3 2 and 4 All of the above Secondary Debulking Candidate Selection Onda et al. J Cancer. 2005;92:1026. Pujade-Lauraine, Ann Oncol. 2011;22(Supplement 8):viii61–viii64. RANDOM I Z E GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: ≤ 0.5 cm > 0.5-2 cm PLD 30 mg/m2 Carboplatin AUC = 5 q 28 days x 6 Paclitaxel 175 mg/m2 Carboplatin AUC = 5 q 21 days x 6 GCIG = Gynecologic Cancer Intergroup PFS = progression-free survival PLD = pegylated liposomal doxorubicin Accrual 864 pts PFS primary endpoint Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. GCIG CALYPSO Trial Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. Selected Non-hematologic Toxicities During Treatment Alopecia *P< 0.001 Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. Targeted Agents in Ovarian Cancer Signaling/Angiogenesis Bevacizumab/Aflibercept RTKI’s: Pazopanib Cabozantinib Sorafenib, etc Cediranib Nintedanib Trebananib, MEDI-3617 PI3K/Akt/mTOR MEKi Folate: Vintafolide (EC-145) Farletuzumab NKTR-102 Taxanes/epothilones Immunotherapy – vaccines and inducers EP-100 PARPi ErbB3 CG + PL OCEANS: Study schema CG for 6 (up to 10) cycles Stratification variables: Platinum-free interval (6–12 vs >12 months) Cytoreductive surgery for recurrent disease (yes vs no) Platinum-sensitive recurrent OCa Measurable disease ECOG 0/1 No prior chemo for recurrent OC No prior BV (n=484) BV = bevacizumab; PL = placebo aEpithelial ovarian, primary peritoneal, or fallopian tube cancer G 1000 mg/m2, d1 & 8 C AUC 4 PL q3w until progression C AUC 4 BV 15 mg/kg q3w until progression G 1000 mg/m2, d1 & 8 CG + BV Aghajanian C et al. J Clin Oncol. 2012;30:2039-2045. 242 177 45 11 3 0 CG + PL OCEANS: Primary Analysis of PFS Months No. at risk 242 203 92 33 11 0 CG + BV 1.0 0.8 0.6 0.4 0.2 0 Proportion progression free 0 6 12 18 24 30 Aghajanian C et al. J Clin Oncol. 2012;30:2039-2045. 1.0 0.8 0.6 0.4 0.2 0 OCEANS: Third Interim OS Analysisa 0 6 12 18 24 30 36 42 48 54 60 242 235 221 190 159 117 77 44 23 7 0 242 239 226 201 171 127 78 48 27 7 0 Number at risk: GC + PL GC + BV aData cutoff date: March 30, 2012. Median follow-up 41.9 months in PL arm and 42.3 months in BV arm, with 286 deaths (59.1% of patients) Proportion surviving Months Aghajanian et al. ESMO 2012. Asymptomatic relapse Single-agent farletuzumab Until progression Single-agent ORR Compare lengths of first and second remissions Farletuzumab - MORAb-003-002 Phase II: Design Epithelial Ovarian Cancer First platinum-sensitive relapse First remission of 6-18 months Evaluable disease by CA125 Symptomatic relapse Original Carbo/Taxane regimen Plus farletuzumab x 6 Farletuzumab maintenance Rx For responders Combination ORR White AJ et al. J Clin Oncol. 2010;28(15s):Abstract 5001. MorAb-003-002: Study Conclusions Overall response rate 70% Response rate similar in early (6-12 month) and late (12+ months) recurrent patients High rates of CA-125 normalization (89%) 1/5 patients had a PFI2 ≥ PFI1 Phase III studies Platinum-sensitive: fully enrolled Platinum-resistant (weekly paclitaxel): met futility endpoint White AJ et al. J Clin Oncol. 2010;28(15s):Abstract 5001. n=66 Randomized, Open-label, Phase II Study in Patients With Platinum-sensitive, Advanced Serous Ovarian Cancer Paclitaxel 175 mg/m2 (iv, d1) + carboplatin AUC6 (iv d1) Randomization (1:1) All patients followed for objective radiologic progression and survival Maintenance phase Olaparib 400 mg bid continuously Completion of 4–6 x 21-day cycles of chemotherapy Arm B Arm A n=81 n=81 n=55 Multinational study; 43 sites in 12 countries * Capsule formulation Patients with: Platinum-sensitive advanced ovarian cancer A serous histology or serous component Measurable disease ≤3 previous platinum-containing regimens Progression free for ≥6 months following completion of last platinum-containing regimen Maintenance phase No further study treatment Olaparib 200 mg bid* (d1–10 every 21 days) + paclitaxel 175 mg/m2 (iv, d1) + carboplatin AUC4 (iv, d1) Oza A. ASCO 2012; Abstract 5001. Paclitaxel Carboplatin (P/C) vs P/C Plus Olaparib (O/P/C) In Platinum Sensitive Recurrent Ovarian Cancer: PFS Time from randomization (months) 0 Proportion of patients progression free 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 2 4 6 8 10 12 16 20 Number of patients at risk Olaparib + P + C (AUC4) P + C (AUC6) 14 18 81 80 76 71 55 37 34 3 0 20 0 81 68 65 57 40 18 15 2 0 8 1 O/P/C P/C Oza A. ASCO 2012; Abstract 5001. GOG 9927: Phase I Combination Platinum sensitive recurrent EOC Chemotherapy based on CALYPSO Primary endpoint: 1st or 2nd cycle DLT Secondary endpoints: RR, PFS, Toxicity TR: PARPi in PBMCs, BRCA status PLD 30 mg/m2 Carboplatin AUC 5 Arm I Veliparib PO daily continuously Cycles: 28 days Planned administration: 6 cycles Arm II Veliparib PO daily D1-7 Cycles: 28 days Planned administration: 6 cycles www.clinicaltrials.gov/ct2/show/NCT01459380. Summary for Platinum-sensitive Recurrent Ovarian Cancer Consider Secondary Debulking Platinum retreatment is standard Treatment with a platinum-based doublet improves response rate, progression-free survival, and possibly overall survival Options: Taxane Carboplatin: Paclitaxel, Docetaxel (?), Weekly Paclitaxel (?) Gemcitabine Carboplatin +/- Bevacizumab PLD Carboplatin Case 3: Platinum Resistant Ovarian Cancer 60-year-old woman with extensive pelvic and peritoneal implants, ascites and large volume disease at the root of the mesentery Diagnosis of ovarian cancer made by paracentesis Deemed unresectable by a gynecologic oncologist Treated with neoadjuvant paclitaxel and carboplatin x 3 without response Then treated with topotecan (daily x 5 regimen) x 3 without response Required paracentesis weekly for palliation CA-125=6916 What treatment would you recommend? Case 3 Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) Weekly paclitaxel Gemcitabine Bevacizumab Weekly paclitaxel and bevacizumab Gemcitabine, carboplatin and bevacizumab Case 3 Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) (PLD is a reasonable choice but expected response rate is 6-16% in a less heavily pretreated population) Weekly paclitaxel (Weekly paclitaxel is also a reasonable option. In GOG protocol 126-N weekly paclitaxel had a response rate of 21% although eligibility limited to one prior treatment regimen) Gemcitabine (although single agent gemcitabine is not FDA approved for treatment of ovarian cancer, the combination of gemcitabine and carboplatin is approved for platinum sensitive patients thus gemcitabine alone is frequently used. Response rates in this population are expected to be less than 10%) Bevacizumab (Bevacizumab is a reasonable choice. In GOG protocol 170D bevacizumab showed a response rate of 21% in this population) Weekly paclitaxel and bevacizumab (Based on Aurelia, the combination of weekly paclitaxel and bevacizumab would be expected to have a higher response rate than weekly paclitaxel alone. Survival data is not yet available. It is not yet clear whether sequential chemotherapy and bevacizumab or the combination is preferable) Gemcitabine, carboplatin and bevacizumab (platinum-based therapy is not indicated in this patient with platinum-refractory disease.) Assume You Will Be Using Treatment With Bevacizumab: Which of the Following Are True Statements About Bevacizumab for Her 1. She will be at increased risk for bowel perforation 2. There is an increased risk of thrombo-embolic phenomena with bevacizumab 3. The response rate of ovarian cancer to single-agent bevacizumab is greater than for any other solid tumors tested to date 4. Hypertension and proteinuria are common side effects of bevacizumab 5. All of the above All the above are true statements in this case. Annals of Oncology 22 (Supplement 8): viii61–viii64, 2011. Active Agents in Ovarian Cancer Platinum-resistant Ovarian Cancer Cytotoxic Therapy Thresholds: 10%, 25% *Median of 3 prior lines *1 prior line Vergote IB et al. J Clin Oncol 2010;28:15s(suppl; abstr 5013). Bevacizumab in Relapsed Ovarian Cancer *Burger RA et al. J Clin Oncol 2007; 25: 5165–5171. **Garcia AA et al. J Clin Oncol 2008; 26: 76–82. ***Cannistra SA et al. J Clin Oncol 2007; 25: 5180–5186.
Slide 68 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R A N D O M I Z E n = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Placebo BEV 15 mg/kg II Stratification variables: GOG performance status (PS) Stage/debulking status RANDOM I Z E 1:1:1 15 months Paclitaxel (P) 175 mg/m2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 III Maintenance (16 cycles) BEV 15 mg/kg Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218: Investigator-assessed PFS + BEV (Arm II) CP (Arm I) *P-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 CA-125 to Determine Progression Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 Interim Survival Analysis Proportion Alive Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 48 aStratified analysis 625/625/623 442/432/437 173/162/171 46/39/40 No. at risk Burger RA et al. N Engl J Med. 2011;365:2473-2483. ICON7: Study Design Stratification variables: Stage/surgery Time since surgery GCIG group *Might vary based on GCIG group **Omit cycle 1 bevacizumab if <4 weeks from surgery Paclitaxel 175 mg/m2 Carboplatin AUC 6* AVASTIN Carboplatin AUC 6* Paclitaxel 175 mg/m2 Arm A Arm B 12 months Front-line EOC, PP or FT cancer Stage I-IIA (Gr 3 or CC) Stage IIB/C Stage III Stage IV n=1528 Bevacizumab 7.5 mg/kg ** Primary endpoints: PFS Secondary endpoints: OS, RR, safety, QOL, cost-effectiveness, translational No IRC present Perren T et al. N Engl J Med. 2011;365:2484-2496. Perren et al. ESMO 2010. ICON 7 Summary of Updated Results Kristensen G et al. J Clin Oncol. 2011;29: suppl; abstr LBA5006). Perren T et al. N Engl J Med. 2011;365:2484-2496. First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG 178—Investigating Paclitaxel as Consolidation Markman M et al. J Clin Oncol. 2003;21:2460-2465. 277 stage III/IV patients in complete clinical remission Paclitaxel 175 mg/m2 every 28 days × 3 months Paclitaxel 175 mg/m2 every 28 days × 12 months RANDOM I Z E CR = Complete response. Progression-free survival 0 20 40 60 80 100 0 12 24 36 48 Months after registration Paclitaxel 12 courses Paclitaxel 3 courses 110 At risk 112 Failed 20 34 Median, months 28 21 P = 0.0023 Percentage Markman M et al. J Clin Oncol. 2003;21:2460-2465. GOG 178 GOG-0212 Phase III Maintenance Therapy Trial Primary endpoint: survival Secondary endpoints: PFS, toxicity, QoL www.clinicaltrials.gov/ct2/show/NCT00108745. Macromolecular complex of paclitaxel poliglumex Patients with stage III/IV epithelial ovarian or primary peritoneal cancer, GOG PS ≤ 2, and complete response after surgery plus taxane and carboplatin (Planned n = 1400-1550) Paclitaxel Every 28 days for up to 12 courses No treatment Paclitaxel poliglumex Every 28 days for up to 12 courses Summary: Initial Treatment of Advanced Ovarian Cancer Surgery Attempt at maximal surgical cytoreduction Neoadjuvant chemo before surgery is an option for poor surgical candidates Chemotherapy 6-8 cycles taxane-platinum combination is standard IP admin benefits patients with low volume (optimal) disease but has increased toxicity NED patients treated with IP have a median survival of over 9 years Weekly (dose-dense) paclitaxel improves outcome in one study Confirmatory North American trials recently completed Bevacizumab during and after chemotherapy improves PFS but not OS Case Discussions Case 1: A Newly Diagnosed Patient With Ovarian Cancer 58 year old real estate broker with controlled hypertension presents with a pelvic mass, omental caking, and a CA125 of 2,056. She has no malnutrition or change in her weight. She is a PS=0. What would you recommend for this patient? Neoadjuvant chemotherapy Primary radical debulking surgery What Would You Recommend for This Patient? Neoadjuvant chemotherapy Primary radical debulking surgery Primary Cytoreduction Meta-analysis: 53 studies (1989–1998) 81 cohorts (Stage III/IV) n = 6885 patients Results Expert centers have high optimal rates Optimal vs not: 11 mos (50% increase) Each 10%  in cytoreduction = 5.5%  in survival Platinum intensity = NS Bristow. J Clin Oncol. 2002;20:1248. The Impact of Residual Tumor: What Is Optimal Debulking? % Progression-Free Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.52 (2.26; 2.81) >10 mm vs 1 mm – 10 mm: 1.36 (1.24; 1.50) log-rank: P<0.0001 % Overall Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.70 (2.37; 3.07) >10 mm vs 1 mm – 10 mm: 1.34 (1.21; 1.49) log-rank: P<0.0001 Generated from 3 prospective Phase III trials (OVAR 3,5, & 7) n = 3126 pts DuBois. Cancer. 2009;115:1234. Case 1 She has a TAH BSO, transverse colectomy, omentectomy and spends 7 days in the hospital (2 in the ICU). Except for an open wound with a wound-vac and getting 4 units of blood, she does well… The pathology shows a high-grade serous carcinoma. The surgeon noted small volume residual (5-9mm) disease throughout the abdomen. What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP Case 1 Question 2 What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP All the above answers are reasonable treatment choices. When would you start the bevacizumab? Cycle 1, 2 or 3? After the chemotherapy (maintenance)? Case 2: Platinum Sensitive Ovarian Cancer 52-year-old woman with high-grade serous carcinoma of the fallopian tube Optimally debulked in 2010 Treated with IV paclitaxel, IP cisplatin and IP paclitaxel completed June 2011 CA125 at presentation 5800 nadir post therapy 7 In 2012 : Increasing Ca125 (1200) Imaging: diffuse peritoneal carcinomatosis; pleural nodularity; mediastinal adenopathy Symptomatic: abdominal bloating, early satiety, and mild shortness of breath Disease free interval: 10-12 months Genetic testing: BRCA1/2 negative Case 2 Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin PLD, carboplatin and bevacizumab Gemcitabine and carboplatin Gemcitabine, carboplatin and bevacizumab Paclitaxel and carboplatin Weekly paclitaxel and carboplatin Paclitaxel, carboplatin and PARP inhibitor Case 2, Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin (PLD and carboplatin is a reasonable option based on results of the CALYPSO study showing superiority to paclitaxel and carboplatin) PLD, carboplatin and bevacizumab (PLD, carboplatin and bevacizumab has not been tested in a randomized phase III trial) Gemcitabine and carboplatin (Gemcitabine and carboplatin: this is reasonable based on a comparison with carboplatin alone (Pfisterer et.al. 2005) Gemcitabine, carboplatin and bevacizumab (Higher response rates and improved PFS are seen when bevacizumab is added to gem/carbo but OS is not improved (OCEANS trial) Paclitaxel and carboplatin (Paclitaxel and carboplatin can be used but based on prior taxane and results of CALYPSO, is used less) Weekly paclitaxel and carboplatin (Weekly paclitaxel has shown improved outcome when used with carboplatin for newly diagnosed patients but has not been rigorously tested in recurrent disease Paclitaxel, carboplatin and PARP inhibitor (PARP inhibitors are not yet FDA approved , so can only be obtained on a clinical trial. However, this is a very promising direction in ovarian cancer and a clinical trial of paclitaxel and carboplatin +/- olaparib showed improved PFS (Oza et.al. ASCO 2012) She Asks You Whether There Is Any Role for Surgery for Her Which of the following are true regarding secondary debulking? It is not considered for patients like her who relapse 10-12 months after completing initial chemotherapy The finding of carcinomatosis is a relatively strong contraindication to secondary debulking surgery Survival is improved for secondary debulking even if all disease can’t be removed at surgery Mediastinal and pleural disease are relatively strong contraindications to secondary debulking surgery 1 and 3 2 and 4 All of the above Secondary Debulking Candidate Selection Onda et al. J Cancer. 2005;92:1026. Pujade-Lauraine, Ann Oncol. 2011;22(Supplement 8):viii61–viii64. RANDOM I Z E GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: ≤ 0.5 cm > 0.5-2 cm PLD 30 mg/m2 Carboplatin AUC = 5 q 28 days x 6 Paclitaxel 175 mg/m2 Carboplatin AUC = 5 q 21 days x 6 GCIG = Gynecologic Cancer Intergroup PFS = progression-free survival PLD = pegylated liposomal doxorubicin Accrual 864 pts PFS primary endpoint Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. GCIG CALYPSO Trial Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. Selected Non-hematologic Toxicities During Treatment Alopecia *P< 0.001 Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. Targeted Agents in Ovarian Cancer Signaling/Angiogenesis Bevacizumab/Aflibercept RTKI’s: Pazopanib Cabozantinib Sorafenib, etc Cediranib Nintedanib Trebananib, MEDI-3617 PI3K/Akt/mTOR MEKi Folate: Vintafolide (EC-145) Farletuzumab NKTR-102 Taxanes/epothilones Immunotherapy – vaccines and inducers EP-100 PARPi ErbB3 CG + PL OCEANS: Study schema CG for 6 (up to 10) cycles Stratification variables: Platinum-free interval (6–12 vs >12 months) Cytoreductive surgery for recurrent disease (yes vs no) Platinum-sensitive recurrent OCa Measurable disease ECOG 0/1 No prior chemo for recurrent OC No prior BV (n=484) BV = bevacizumab; PL = placebo aEpithelial ovarian, primary peritoneal, or fallopian tube cancer G 1000 mg/m2, d1 & 8 C AUC 4 PL q3w until progression C AUC 4 BV 15 mg/kg q3w until progression G 1000 mg/m2, d1 & 8 CG + BV Aghajanian C et al. J Clin Oncol. 2012;30:2039-2045. 242 177 45 11 3 0 CG + PL OCEANS: Primary Analysis of PFS Months No. at risk 242 203 92 33 11 0 CG + BV 1.0 0.8 0.6 0.4 0.2 0 Proportion progression free 0 6 12 18 24 30 Aghajanian C et al. J Clin Oncol. 2012;30:2039-2045. 1.0 0.8 0.6 0.4 0.2 0 OCEANS: Third Interim OS Analysisa 0 6 12 18 24 30 36 42 48 54 60 242 235 221 190 159 117 77 44 23 7 0 242 239 226 201 171 127 78 48 27 7 0 Number at risk: GC + PL GC + BV aData cutoff date: March 30, 2012. Median follow-up 41.9 months in PL arm and 42.3 months in BV arm, with 286 deaths (59.1% of patients) Proportion surviving Months Aghajanian et al. ESMO 2012. Asymptomatic relapse Single-agent farletuzumab Until progression Single-agent ORR Compare lengths of first and second remissions Farletuzumab - MORAb-003-002 Phase II: Design Epithelial Ovarian Cancer First platinum-sensitive relapse First remission of 6-18 months Evaluable disease by CA125 Symptomatic relapse Original Carbo/Taxane regimen Plus farletuzumab x 6 Farletuzumab maintenance Rx For responders Combination ORR White AJ et al. J Clin Oncol. 2010;28(15s):Abstract 5001. MorAb-003-002: Study Conclusions Overall response rate 70% Response rate similar in early (6-12 month) and late (12+ months) recurrent patients High rates of CA-125 normalization (89%) 1/5 patients had a PFI2 ≥ PFI1 Phase III studies Platinum-sensitive: fully enrolled Platinum-resistant (weekly paclitaxel): met futility endpoint White AJ et al. J Clin Oncol. 2010;28(15s):Abstract 5001. n=66 Randomized, Open-label, Phase II Study in Patients With Platinum-sensitive, Advanced Serous Ovarian Cancer Paclitaxel 175 mg/m2 (iv, d1) + carboplatin AUC6 (iv d1) Randomization (1:1) All patients followed for objective radiologic progression and survival Maintenance phase Olaparib 400 mg bid continuously Completion of 4–6 x 21-day cycles of chemotherapy Arm B Arm A n=81 n=81 n=55 Multinational study; 43 sites in 12 countries * Capsule formulation Patients with: Platinum-sensitive advanced ovarian cancer A serous histology or serous component Measurable disease ≤3 previous platinum-containing regimens Progression free for ≥6 months following completion of last platinum-containing regimen Maintenance phase No further study treatment Olaparib 200 mg bid* (d1–10 every 21 days) + paclitaxel 175 mg/m2 (iv, d1) + carboplatin AUC4 (iv, d1) Oza A. ASCO 2012; Abstract 5001. Paclitaxel Carboplatin (P/C) vs P/C Plus Olaparib (O/P/C) In Platinum Sensitive Recurrent Ovarian Cancer: PFS Time from randomization (months) 0 Proportion of patients progression free 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 2 4 6 8 10 12 16 20 Number of patients at risk Olaparib + P + C (AUC4) P + C (AUC6) 14 18 81 80 76 71 55 37 34 3 0 20 0 81 68 65 57 40 18 15 2 0 8 1 O/P/C P/C Oza A. ASCO 2012; Abstract 5001. GOG 9927: Phase I Combination Platinum sensitive recurrent EOC Chemotherapy based on CALYPSO Primary endpoint: 1st or 2nd cycle DLT Secondary endpoints: RR, PFS, Toxicity TR: PARPi in PBMCs, BRCA status PLD 30 mg/m2 Carboplatin AUC 5 Arm I Veliparib PO daily continuously Cycles: 28 days Planned administration: 6 cycles Arm II Veliparib PO daily D1-7 Cycles: 28 days Planned administration: 6 cycles www.clinicaltrials.gov/ct2/show/NCT01459380. Summary for Platinum-sensitive Recurrent Ovarian Cancer Consider Secondary Debulking Platinum retreatment is standard Treatment with a platinum-based doublet improves response rate, progression-free survival, and possibly overall survival Options: Taxane Carboplatin: Paclitaxel, Docetaxel (?), Weekly Paclitaxel (?) Gemcitabine Carboplatin +/- Bevacizumab PLD Carboplatin Case 3: Platinum Resistant Ovarian Cancer 60-year-old woman with extensive pelvic and peritoneal implants, ascites and large volume disease at the root of the mesentery Diagnosis of ovarian cancer made by paracentesis Deemed unresectable by a gynecologic oncologist Treated with neoadjuvant paclitaxel and carboplatin x 3 without response Then treated with topotecan (daily x 5 regimen) x 3 without response Required paracentesis weekly for palliation CA-125=6916 What treatment would you recommend? Case 3 Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) Weekly paclitaxel Gemcitabine Bevacizumab Weekly paclitaxel and bevacizumab Gemcitabine, carboplatin and bevacizumab Case 3 Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) (PLD is a reasonable choice but expected response rate is 6-16% in a less heavily pretreated population) Weekly paclitaxel (Weekly paclitaxel is also a reasonable option. In GOG protocol 126-N weekly paclitaxel had a response rate of 21% although eligibility limited to one prior treatment regimen) Gemcitabine (although single agent gemcitabine is not FDA approved for treatment of ovarian cancer, the combination of gemcitabine and carboplatin is approved for platinum sensitive patients thus gemcitabine alone is frequently used. Response rates in this population are expected to be less than 10%) Bevacizumab (Bevacizumab is a reasonable choice. In GOG protocol 170D bevacizumab showed a response rate of 21% in this population) Weekly paclitaxel and bevacizumab (Based on Aurelia, the combination of weekly paclitaxel and bevacizumab would be expected to have a higher response rate than weekly paclitaxel alone. Survival data is not yet available. It is not yet clear whether sequential chemotherapy and bevacizumab or the combination is preferable) Gemcitabine, carboplatin and bevacizumab (platinum-based therapy is not indicated in this patient with platinum-refractory disease.) Assume You Will Be Using Treatment With Bevacizumab: Which of the Following Are True Statements About Bevacizumab for Her 1. She will be at increased risk for bowel perforation 2. There is an increased risk of thrombo-embolic phenomena with bevacizumab 3. The response rate of ovarian cancer to single-agent bevacizumab is greater than for any other solid tumors tested to date 4. Hypertension and proteinuria are common side effects of bevacizumab 5. All of the above All the above are true statements in this case. Annals of Oncology 22 (Supplement 8): viii61–viii64, 2011. Active Agents in Ovarian Cancer Platinum-resistant Ovarian Cancer Cytotoxic Therapy Thresholds: 10%, 25% *Median of 3 prior lines *1 prior line Vergote IB et al. J Clin Oncol 2010;28:15s(suppl; abstr 5013). Bevacizumab in Relapsed Ovarian Cancer *Burger RA et al. J Clin Oncol 2007; 25: 5165–5171. **Garcia AA et al. J Clin Oncol 2008; 26: 76–82. ***Cannistra SA et al. J Clin Oncol 2007; 25: 5180–5186. Ovarian Cancer: Targeted Therapy 1Tew et al. J Clin Oncol 2007;25:(suppl; abstr 5508). 2Biagi et al. Ann Oncol. 2011;22:335-340. 3Matulonis UA et al. J Clin Oncol. 2009;27:5601-5606. 4Buckanovich et al. J Clin Oncol. 2011;29(suppl; abstr 5008). 5Friedlander et.al. Gyn Oncol. 2010,. 6Ledermann et al. J Clin Oncol. 2011;29:3798.
Slide 69 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R A N D O M I Z E n = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Placebo BEV 15 mg/kg II Stratification variables: GOG performance status (PS) Stage/debulking status RANDOM I Z E 1:1:1 15 months Paclitaxel (P) 175 mg/m2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 III Maintenance (16 cycles) BEV 15 mg/kg Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218: Investigator-assessed PFS + BEV (Arm II) CP (Arm I) *P-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 CA-125 to Determine Progression Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 Interim Survival Analysis Proportion Alive Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 48 aStratified analysis 625/625/623 442/432/437 173/162/171 46/39/40 No. at risk Burger RA et al. N Engl J Med. 2011;365:2473-2483. ICON7: Study Design Stratification variables: Stage/surgery Time since surgery GCIG group *Might vary based on GCIG group **Omit cycle 1 bevacizumab if <4 weeks from surgery Paclitaxel 175 mg/m2 Carboplatin AUC 6* AVASTIN Carboplatin AUC 6* Paclitaxel 175 mg/m2 Arm A Arm B 12 months Front-line EOC, PP or FT cancer Stage I-IIA (Gr 3 or CC) Stage IIB/C Stage III Stage IV n=1528 Bevacizumab 7.5 mg/kg ** Primary endpoints: PFS Secondary endpoints: OS, RR, safety, QOL, cost-effectiveness, translational No IRC present Perren T et al. N Engl J Med. 2011;365:2484-2496. Perren et al. ESMO 2010. ICON 7 Summary of Updated Results Kristensen G et al. J Clin Oncol. 2011;29: suppl; abstr LBA5006). Perren T et al. N Engl J Med. 2011;365:2484-2496. First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG 178—Investigating Paclitaxel as Consolidation Markman M et al. J Clin Oncol. 2003;21:2460-2465. 277 stage III/IV patients in complete clinical remission Paclitaxel 175 mg/m2 every 28 days × 3 months Paclitaxel 175 mg/m2 every 28 days × 12 months RANDOM I Z E CR = Complete response. Progression-free survival 0 20 40 60 80 100 0 12 24 36 48 Months after registration Paclitaxel 12 courses Paclitaxel 3 courses 110 At risk 112 Failed 20 34 Median, months 28 21 P = 0.0023 Percentage Markman M et al. J Clin Oncol. 2003;21:2460-2465. GOG 178 GOG-0212 Phase III Maintenance Therapy Trial Primary endpoint: survival Secondary endpoints: PFS, toxicity, QoL www.clinicaltrials.gov/ct2/show/NCT00108745. Macromolecular complex of paclitaxel poliglumex Patients with stage III/IV epithelial ovarian or primary peritoneal cancer, GOG PS ≤ 2, and complete response after surgery plus taxane and carboplatin (Planned n = 1400-1550) Paclitaxel Every 28 days for up to 12 courses No treatment Paclitaxel poliglumex Every 28 days for up to 12 courses Summary: Initial Treatment of Advanced Ovarian Cancer Surgery Attempt at maximal surgical cytoreduction Neoadjuvant chemo before surgery is an option for poor surgical candidates Chemotherapy 6-8 cycles taxane-platinum combination is standard IP admin benefits patients with low volume (optimal) disease but has increased toxicity NED patients treated with IP have a median survival of over 9 years Weekly (dose-dense) paclitaxel improves outcome in one study Confirmatory North American trials recently completed Bevacizumab during and after chemotherapy improves PFS but not OS Case Discussions Case 1: A Newly Diagnosed Patient With Ovarian Cancer 58 year old real estate broker with controlled hypertension presents with a pelvic mass, omental caking, and a CA125 of 2,056. She has no malnutrition or change in her weight. She is a PS=0. What would you recommend for this patient? Neoadjuvant chemotherapy Primary radical debulking surgery What Would You Recommend for This Patient? Neoadjuvant chemotherapy Primary radical debulking surgery Primary Cytoreduction Meta-analysis: 53 studies (1989–1998) 81 cohorts (Stage III/IV) n = 6885 patients Results Expert centers have high optimal rates Optimal vs not: 11 mos (50% increase) Each 10%  in cytoreduction = 5.5%  in survival Platinum intensity = NS Bristow. J Clin Oncol. 2002;20:1248. The Impact of Residual Tumor: What Is Optimal Debulking? % Progression-Free Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.52 (2.26; 2.81) >10 mm vs 1 mm – 10 mm: 1.36 (1.24; 1.50) log-rank: P<0.0001 % Overall Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.70 (2.37; 3.07) >10 mm vs 1 mm – 10 mm: 1.34 (1.21; 1.49) log-rank: P<0.0001 Generated from 3 prospective Phase III trials (OVAR 3,5, & 7) n = 3126 pts DuBois. Cancer. 2009;115:1234. Case 1 She has a TAH BSO, transverse colectomy, omentectomy and spends 7 days in the hospital (2 in the ICU). Except for an open wound with a wound-vac and getting 4 units of blood, she does well… The pathology shows a high-grade serous carcinoma. The surgeon noted small volume residual (5-9mm) disease throughout the abdomen. What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP Case 1 Question 2 What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP All the above answers are reasonable treatment choices. When would you start the bevacizumab? Cycle 1, 2 or 3? After the chemotherapy (maintenance)? Case 2: Platinum Sensitive Ovarian Cancer 52-year-old woman with high-grade serous carcinoma of the fallopian tube Optimally debulked in 2010 Treated with IV paclitaxel, IP cisplatin and IP paclitaxel completed June 2011 CA125 at presentation 5800 nadir post therapy 7 In 2012 : Increasing Ca125 (1200) Imaging: diffuse peritoneal carcinomatosis; pleural nodularity; mediastinal adenopathy Symptomatic: abdominal bloating, early satiety, and mild shortness of breath Disease free interval: 10-12 months Genetic testing: BRCA1/2 negative Case 2 Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin PLD, carboplatin and bevacizumab Gemcitabine and carboplatin Gemcitabine, carboplatin and bevacizumab Paclitaxel and carboplatin Weekly paclitaxel and carboplatin Paclitaxel, carboplatin and PARP inhibitor Case 2, Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin (PLD and carboplatin is a reasonable option based on results of the CALYPSO study showing superiority to paclitaxel and carboplatin) PLD, carboplatin and bevacizumab (PLD, carboplatin and bevacizumab has not been tested in a randomized phase III trial) Gemcitabine and carboplatin (Gemcitabine and carboplatin: this is reasonable based on a comparison with carboplatin alone (Pfisterer et.al. 2005) Gemcitabine, carboplatin and bevacizumab (Higher response rates and improved PFS are seen when bevacizumab is added to gem/carbo but OS is not improved (OCEANS trial) Paclitaxel and carboplatin (Paclitaxel and carboplatin can be used but based on prior taxane and results of CALYPSO, is used less) Weekly paclitaxel and carboplatin (Weekly paclitaxel has shown improved outcome when used with carboplatin for newly diagnosed patients but has not been rigorously tested in recurrent disease Paclitaxel, carboplatin and PARP inhibitor (PARP inhibitors are not yet FDA approved , so can only be obtained on a clinical trial. However, this is a very promising direction in ovarian cancer and a clinical trial of paclitaxel and carboplatin +/- olaparib showed improved PFS (Oza et.al. ASCO 2012) She Asks You Whether There Is Any Role for Surgery for Her Which of the following are true regarding secondary debulking? It is not considered for patients like her who relapse 10-12 months after completing initial chemotherapy The finding of carcinomatosis is a relatively strong contraindication to secondary debulking surgery Survival is improved for secondary debulking even if all disease can’t be removed at surgery Mediastinal and pleural disease are relatively strong contraindications to secondary debulking surgery 1 and 3 2 and 4 All of the above Secondary Debulking Candidate Selection Onda et al. J Cancer. 2005;92:1026. Pujade-Lauraine, Ann Oncol. 2011;22(Supplement 8):viii61–viii64. RANDOM I Z E GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: ≤ 0.5 cm > 0.5-2 cm PLD 30 mg/m2 Carboplatin AUC = 5 q 28 days x 6 Paclitaxel 175 mg/m2 Carboplatin AUC = 5 q 21 days x 6 GCIG = Gynecologic Cancer Intergroup PFS = progression-free survival PLD = pegylated liposomal doxorubicin Accrual 864 pts PFS primary endpoint Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. GCIG CALYPSO Trial Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. Selected Non-hematologic Toxicities During Treatment Alopecia *P< 0.001 Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. Targeted Agents in Ovarian Cancer Signaling/Angiogenesis Bevacizumab/Aflibercept RTKI’s: Pazopanib Cabozantinib Sorafenib, etc Cediranib Nintedanib Trebananib, MEDI-3617 PI3K/Akt/mTOR MEKi Folate: Vintafolide (EC-145) Farletuzumab NKTR-102 Taxanes/epothilones Immunotherapy – vaccines and inducers EP-100 PARPi ErbB3 CG + PL OCEANS: Study schema CG for 6 (up to 10) cycles Stratification variables: Platinum-free interval (6–12 vs >12 months) Cytoreductive surgery for recurrent disease (yes vs no) Platinum-sensitive recurrent OCa Measurable disease ECOG 0/1 No prior chemo for recurrent OC No prior BV (n=484) BV = bevacizumab; PL = placebo aEpithelial ovarian, primary peritoneal, or fallopian tube cancer G 1000 mg/m2, d1 & 8 C AUC 4 PL q3w until progression C AUC 4 BV 15 mg/kg q3w until progression G 1000 mg/m2, d1 & 8 CG + BV Aghajanian C et al. J Clin Oncol. 2012;30:2039-2045. 242 177 45 11 3 0 CG + PL OCEANS: Primary Analysis of PFS Months No. at risk 242 203 92 33 11 0 CG + BV 1.0 0.8 0.6 0.4 0.2 0 Proportion progression free 0 6 12 18 24 30 Aghajanian C et al. J Clin Oncol. 2012;30:2039-2045. 1.0 0.8 0.6 0.4 0.2 0 OCEANS: Third Interim OS Analysisa 0 6 12 18 24 30 36 42 48 54 60 242 235 221 190 159 117 77 44 23 7 0 242 239 226 201 171 127 78 48 27 7 0 Number at risk: GC + PL GC + BV aData cutoff date: March 30, 2012. Median follow-up 41.9 months in PL arm and 42.3 months in BV arm, with 286 deaths (59.1% of patients) Proportion surviving Months Aghajanian et al. ESMO 2012. Asymptomatic relapse Single-agent farletuzumab Until progression Single-agent ORR Compare lengths of first and second remissions Farletuzumab - MORAb-003-002 Phase II: Design Epithelial Ovarian Cancer First platinum-sensitive relapse First remission of 6-18 months Evaluable disease by CA125 Symptomatic relapse Original Carbo/Taxane regimen Plus farletuzumab x 6 Farletuzumab maintenance Rx For responders Combination ORR White AJ et al. J Clin Oncol. 2010;28(15s):Abstract 5001. MorAb-003-002: Study Conclusions Overall response rate 70% Response rate similar in early (6-12 month) and late (12+ months) recurrent patients High rates of CA-125 normalization (89%) 1/5 patients had a PFI2 ≥ PFI1 Phase III studies Platinum-sensitive: fully enrolled Platinum-resistant (weekly paclitaxel): met futility endpoint White AJ et al. J Clin Oncol. 2010;28(15s):Abstract 5001. n=66 Randomized, Open-label, Phase II Study in Patients With Platinum-sensitive, Advanced Serous Ovarian Cancer Paclitaxel 175 mg/m2 (iv, d1) + carboplatin AUC6 (iv d1) Randomization (1:1) All patients followed for objective radiologic progression and survival Maintenance phase Olaparib 400 mg bid continuously Completion of 4–6 x 21-day cycles of chemotherapy Arm B Arm A n=81 n=81 n=55 Multinational study; 43 sites in 12 countries * Capsule formulation Patients with: Platinum-sensitive advanced ovarian cancer A serous histology or serous component Measurable disease ≤3 previous platinum-containing regimens Progression free for ≥6 months following completion of last platinum-containing regimen Maintenance phase No further study treatment Olaparib 200 mg bid* (d1–10 every 21 days) + paclitaxel 175 mg/m2 (iv, d1) + carboplatin AUC4 (iv, d1) Oza A. ASCO 2012; Abstract 5001. Paclitaxel Carboplatin (P/C) vs P/C Plus Olaparib (O/P/C) In Platinum Sensitive Recurrent Ovarian Cancer: PFS Time from randomization (months) 0 Proportion of patients progression free 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 2 4 6 8 10 12 16 20 Number of patients at risk Olaparib + P + C (AUC4) P + C (AUC6) 14 18 81 80 76 71 55 37 34 3 0 20 0 81 68 65 57 40 18 15 2 0 8 1 O/P/C P/C Oza A. ASCO 2012; Abstract 5001. GOG 9927: Phase I Combination Platinum sensitive recurrent EOC Chemotherapy based on CALYPSO Primary endpoint: 1st or 2nd cycle DLT Secondary endpoints: RR, PFS, Toxicity TR: PARPi in PBMCs, BRCA status PLD 30 mg/m2 Carboplatin AUC 5 Arm I Veliparib PO daily continuously Cycles: 28 days Planned administration: 6 cycles Arm II Veliparib PO daily D1-7 Cycles: 28 days Planned administration: 6 cycles www.clinicaltrials.gov/ct2/show/NCT01459380. Summary for Platinum-sensitive Recurrent Ovarian Cancer Consider Secondary Debulking Platinum retreatment is standard Treatment with a platinum-based doublet improves response rate, progression-free survival, and possibly overall survival Options: Taxane Carboplatin: Paclitaxel, Docetaxel (?), Weekly Paclitaxel (?) Gemcitabine Carboplatin +/- Bevacizumab PLD Carboplatin Case 3: Platinum Resistant Ovarian Cancer 60-year-old woman with extensive pelvic and peritoneal implants, ascites and large volume disease at the root of the mesentery Diagnosis of ovarian cancer made by paracentesis Deemed unresectable by a gynecologic oncologist Treated with neoadjuvant paclitaxel and carboplatin x 3 without response Then treated with topotecan (daily x 5 regimen) x 3 without response Required paracentesis weekly for palliation CA-125=6916 What treatment would you recommend? Case 3 Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) Weekly paclitaxel Gemcitabine Bevacizumab Weekly paclitaxel and bevacizumab Gemcitabine, carboplatin and bevacizumab Case 3 Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) (PLD is a reasonable choice but expected response rate is 6-16% in a less heavily pretreated population) Weekly paclitaxel (Weekly paclitaxel is also a reasonable option. In GOG protocol 126-N weekly paclitaxel had a response rate of 21% although eligibility limited to one prior treatment regimen) Gemcitabine (although single agent gemcitabine is not FDA approved for treatment of ovarian cancer, the combination of gemcitabine and carboplatin is approved for platinum sensitive patients thus gemcitabine alone is frequently used. Response rates in this population are expected to be less than 10%) Bevacizumab (Bevacizumab is a reasonable choice. In GOG protocol 170D bevacizumab showed a response rate of 21% in this population) Weekly paclitaxel and bevacizumab (Based on Aurelia, the combination of weekly paclitaxel and bevacizumab would be expected to have a higher response rate than weekly paclitaxel alone. Survival data is not yet available. It is not yet clear whether sequential chemotherapy and bevacizumab or the combination is preferable) Gemcitabine, carboplatin and bevacizumab (platinum-based therapy is not indicated in this patient with platinum-refractory disease.) Assume You Will Be Using Treatment With Bevacizumab: Which of the Following Are True Statements About Bevacizumab for Her 1. She will be at increased risk for bowel perforation 2. There is an increased risk of thrombo-embolic phenomena with bevacizumab 3. The response rate of ovarian cancer to single-agent bevacizumab is greater than for any other solid tumors tested to date 4. Hypertension and proteinuria are common side effects of bevacizumab 5. All of the above All the above are true statements in this case. Annals of Oncology 22 (Supplement 8): viii61–viii64, 2011. Active Agents in Ovarian Cancer Platinum-resistant Ovarian Cancer Cytotoxic Therapy Thresholds: 10%, 25% *Median of 3 prior lines *1 prior line Vergote IB et al. J Clin Oncol 2010;28:15s(suppl; abstr 5013). Bevacizumab in Relapsed Ovarian Cancer *Burger RA et al. J Clin Oncol 2007; 25: 5165–5171. **Garcia AA et al. J Clin Oncol 2008; 26: 76–82. ***Cannistra SA et al. J Clin Oncol 2007; 25: 5180–5186. Ovarian Cancer: Targeted Therapy 1Tew et al. J Clin Oncol 2007;25:(suppl; abstr 5508). 2Biagi et al. Ann Oncol. 2011;22:335-340. 3Matulonis UA et al. J Clin Oncol. 2009;27:5601-5606. 4Buckanovich et al. J Clin Oncol. 2011;29(suppl; abstr 5008). 5Friedlander et.al. Gyn Oncol. 2010,. 6Ledermann et al. J Clin Oncol. 2011;29:3798. PD Recurrent Ovarian Cancer Randomized Phase II Studies Weekly Paclitaxel AMG-386 10 mg/kg IV weekly n=53 Weekly Paclitaxel AMG-386 3 mg/kg IV weekly n=53 Weekly Paclitaxel Placebo n=55 Paclitaxel 80 mg/m2 IV weekly, 3 weeks on/1 week off AMG-386 10 mg/kg IV weekly RANDOM I Z E Ovarian, primary peritoneal, or fallopian tube cancer n=161 1-3 prior lines Karlan BY et al. J Clin Oncol. 2010;28:15s(suppl; abstr 5000).
Slide 70 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Role of IP Chemotherapy for Optimally Debulked Advanced-Stage Ovarian Cancer CP =Cyclophosphamide and cisplatin; IP = Intraperitoneal; TP = Paclitaxel and cisplatin. 1. Alberts DS, et al. N Engl J Med. 1996;335:1950-1955. 2. Markman M, et al. J Clin Oncol. 2001;19:1001-1007. 3. Armstrong DK et al. N Engl J Med. 2006;354:34-43. Reprinted with permission from Memorial Sloan-Kettering Cancer Web site. Available at: www.mskcc.org/patient_education/html/ 41495.cfm. Accessed March 9, 2006. GOG Protocol 172 IV = Intravenous; IP = Intraperitoneal Armstrong DK,et al. N Engl J Med. 2006;354:34-43. IV median overall survival = 49.7 months IP median overall survival = 65.6 months Relative risk of death = 0.75 (95% CI: 0.58, 0.97) P = .03 Rx Group Lost to Alive Dead Total Follow-up IV 5 78 127 210 IP 11 93 101 205 IP Compared to IV Chemotherapy Phase III Trials GOG 104 GOG 114 GOG 172 OS GOG 172 IP c/w OS GOG 158 PC Armstrong DK, Brady MF. J Clin Oncol. 2006;24(28):4531-4533. Long-term Outcomes in Patients with No Residual Disease Treated with IP Therapy Months 60.4 41.1 127.6 Landrum L et.al. GOG Symposium, July 2012. GOG 252 Stage II/III Disease: Small Volume Residual Cisplatin 75 mg/m2 (IP d2) Paclitaxel 135 mg/m2 (d1, 3h) Paclitaxel 60 mg/m2 (d8, IP) Bevacizumab (C2+ C22) x 21 days Epithelial Ovarian Cancer Optimal Stage III No prior therapy Phase III PFS primary endpoint Open: 27 Jul 2009 Closed: 30 Nov 2011 Accrual: 1100 Study Chair: J Walker III II Carboplatin AUC=6 (IP) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days ClinicalTrials.gov Identifier: NCT00951496 I Carboplatin AUC=6 (IV) Paclitaxel 80 mg/m2 (d1, 8, 15 3h) Bevacizumab (C2+ C22) x 21 days First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission JGOG: Dose-dense Weekly Paclitaxel Paclitaxel 180 mg/m2 Carbolatin AUC = 6 Carbolatin AUC = 6 Paclitaxel 80 mg/m2/w x3 Epithelial Ovarian or Peritoneal Stage II - IV No prior therapy Stratfied: residual disease, stage, and histology Primary endpoint: PFS Secondary endpoint: OS Accrual: 637 pts (intent-to-treat) I II Isonishi S et al. J Clin Oncol. 2008;26:A5506. x6-9 x6-9 Dose-dense paclitaxel associated with greater hematologic toxicity, and fewer patients completed all protocol therapy Improved PFS with dose-dense weekly paclitaxel JGOG: Dose-dense Weekly Paclitaxel Katsumata N et al Lancet. 2009;374:1331-1338. GOG 262 Stage III/IV Disease: Large Volume Residual Paclitaxel 80 mg/m2 IV every week + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression R A N D O M I Z E n = 625 Primary Endpoint = Progression free survival Activated: Sep 27 2010 Study Chair: J Chan Paclitaxel 175 mg/m2 IV + Carboplatin AUC 6 IV every 3 weeks x 6 cycles with optional Bevacizumab 15 mg/kg IV starting with cycle 2 until disease progression ClinicalTrials.gov Identifier: NCT01167712 First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG-0218: Schema Front-line: Epithelial OV, PP or FT cancer Stage III optimal (macroscopic) Stage III suboptimal Stage IV n=1800 (planned) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 Placebo BEV 15 mg/kg II Stratification variables: GOG performance status (PS) Stage/debulking status RANDOM I Z E 1:1:1 15 months Paclitaxel (P) 175 mg/m2 Carboplatin (C) AUC 6 Placebo I Arm Cytotoxic (6 cycles) Carboplatin (C) AUC 6 Paclitaxel (P) 175 mg/m2 III Maintenance (16 cycles) BEV 15 mg/kg Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218: Investigator-assessed PFS + BEV (Arm II) CP (Arm I) *P-value boundary = 0.0116 + BEV → BEV maintenance (Arm III) Proportion surviving progression free Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 CA-125 to Determine Progression Burger RA et al. N Engl J Med. 2011;365:2473-2483. GOG-0218 Interim Survival Analysis Proportion Alive Months since randomization 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 12 24 36 48 aStratified analysis 625/625/623 442/432/437 173/162/171 46/39/40 No. at risk Burger RA et al. N Engl J Med. 2011;365:2473-2483. ICON7: Study Design Stratification variables: Stage/surgery Time since surgery GCIG group *Might vary based on GCIG group **Omit cycle 1 bevacizumab if <4 weeks from surgery Paclitaxel 175 mg/m2 Carboplatin AUC 6* AVASTIN Carboplatin AUC 6* Paclitaxel 175 mg/m2 Arm A Arm B 12 months Front-line EOC, PP or FT cancer Stage I-IIA (Gr 3 or CC) Stage IIB/C Stage III Stage IV n=1528 Bevacizumab 7.5 mg/kg ** Primary endpoints: PFS Secondary endpoints: OS, RR, safety, QOL, cost-effectiveness, translational No IRC present Perren T et al. N Engl J Med. 2011;365:2484-2496. Perren et al. ESMO 2010. ICON 7 Summary of Updated Results Kristensen G et al. J Clin Oncol. 2011;29: suppl; abstr LBA5006). Perren T et al. N Engl J Med. 2011;365:2484-2496. First-line Therapy: Acceptable Approaches Docetaxel instead of paclitaxel Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission GOG 178—Investigating Paclitaxel as Consolidation Markman M et al. J Clin Oncol. 2003;21:2460-2465. 277 stage III/IV patients in complete clinical remission Paclitaxel 175 mg/m2 every 28 days × 3 months Paclitaxel 175 mg/m2 every 28 days × 12 months RANDOM I Z E CR = Complete response. Progression-free survival 0 20 40 60 80 100 0 12 24 36 48 Months after registration Paclitaxel 12 courses Paclitaxel 3 courses 110 At risk 112 Failed 20 34 Median, months 28 21 P = 0.0023 Percentage Markman M et al. J Clin Oncol. 2003;21:2460-2465. GOG 178 GOG-0212 Phase III Maintenance Therapy Trial Primary endpoint: survival Secondary endpoints: PFS, toxicity, QoL www.clinicaltrials.gov/ct2/show/NCT00108745. Macromolecular complex of paclitaxel poliglumex Patients with stage III/IV epithelial ovarian or primary peritoneal cancer, GOG PS ≤ 2, and complete response after surgery plus taxane and carboplatin (Planned n = 1400-1550) Paclitaxel Every 28 days for up to 12 courses No treatment Paclitaxel poliglumex Every 28 days for up to 12 courses Summary: Initial Treatment of Advanced Ovarian Cancer Surgery Attempt at maximal surgical cytoreduction Neoadjuvant chemo before surgery is an option for poor surgical candidates Chemotherapy 6-8 cycles taxane-platinum combination is standard IP admin benefits patients with low volume (optimal) disease but has increased toxicity NED patients treated with IP have a median survival of over 9 years Weekly (dose-dense) paclitaxel improves outcome in one study Confirmatory North American trials recently completed Bevacizumab during and after chemotherapy improves PFS but not OS Case Discussions Case 1: A Newly Diagnosed Patient With Ovarian Cancer 58 year old real estate broker with controlled hypertension presents with a pelvic mass, omental caking, and a CA125 of 2,056. She has no malnutrition or change in her weight. She is a PS=0. What would you recommend for this patient? Neoadjuvant chemotherapy Primary radical debulking surgery What Would You Recommend for This Patient? Neoadjuvant chemotherapy Primary radical debulking surgery Primary Cytoreduction Meta-analysis: 53 studies (1989–1998) 81 cohorts (Stage III/IV) n = 6885 patients Results Expert centers have high optimal rates Optimal vs not: 11 mos (50% increase) Each 10%  in cytoreduction = 5.5%  in survival Platinum intensity = NS Bristow. J Clin Oncol. 2002;20:1248. The Impact of Residual Tumor: What Is Optimal Debulking? % Progression-Free Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.52 (2.26; 2.81) >10 mm vs 1 mm – 10 mm: 1.36 (1.24; 1.50) log-rank: P<0.0001 % Overall Survival 0 mm 1 mm – 10 mm >10 mm HR (95% CI) 1 mm – 10 mm vs. 0 mm: 2.70 (2.37; 3.07) >10 mm vs 1 mm – 10 mm: 1.34 (1.21; 1.49) log-rank: P<0.0001 Generated from 3 prospective Phase III trials (OVAR 3,5, & 7) n = 3126 pts DuBois. Cancer. 2009;115:1234. Case 1 She has a TAH BSO, transverse colectomy, omentectomy and spends 7 days in the hospital (2 in the ICU). Except for an open wound with a wound-vac and getting 4 units of blood, she does well… The pathology shows a high-grade serous carcinoma. The surgeon noted small volume residual (5-9mm) disease throughout the abdomen. What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP Case 1 Question 2 What would you recommend for this patient at this point? IP chemotherapy IV chemotherapy Adding bevacizumab to either IV or IP All the above answers are reasonable treatment choices. When would you start the bevacizumab? Cycle 1, 2 or 3? After the chemotherapy (maintenance)? Case 2: Platinum Sensitive Ovarian Cancer 52-year-old woman with high-grade serous carcinoma of the fallopian tube Optimally debulked in 2010 Treated with IV paclitaxel, IP cisplatin and IP paclitaxel completed June 2011 CA125 at presentation 5800 nadir post therapy 7 In 2012 : Increasing Ca125 (1200) Imaging: diffuse peritoneal carcinomatosis; pleural nodularity; mediastinal adenopathy Symptomatic: abdominal bloating, early satiety, and mild shortness of breath Disease free interval: 10-12 months Genetic testing: BRCA1/2 negative Case 2 Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin PLD, carboplatin and bevacizumab Gemcitabine and carboplatin Gemcitabine, carboplatin and bevacizumab Paclitaxel and carboplatin Weekly paclitaxel and carboplatin Paclitaxel, carboplatin and PARP inhibitor Case 2, Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) and carboplatin (PLD and carboplatin is a reasonable option based on results of the CALYPSO study showing superiority to paclitaxel and carboplatin) PLD, carboplatin and bevacizumab (PLD, carboplatin and bevacizumab has not been tested in a randomized phase III trial) Gemcitabine and carboplatin (Gemcitabine and carboplatin: this is reasonable based on a comparison with carboplatin alone (Pfisterer et.al. 2005) Gemcitabine, carboplatin and bevacizumab (Higher response rates and improved PFS are seen when bevacizumab is added to gem/carbo but OS is not improved (OCEANS trial) Paclitaxel and carboplatin (Paclitaxel and carboplatin can be used but based on prior taxane and results of CALYPSO, is used less) Weekly paclitaxel and carboplatin (Weekly paclitaxel has shown improved outcome when used with carboplatin for newly diagnosed patients but has not been rigorously tested in recurrent disease Paclitaxel, carboplatin and PARP inhibitor (PARP inhibitors are not yet FDA approved , so can only be obtained on a clinical trial. However, this is a very promising direction in ovarian cancer and a clinical trial of paclitaxel and carboplatin +/- olaparib showed improved PFS (Oza et.al. ASCO 2012) She Asks You Whether There Is Any Role for Surgery for Her Which of the following are true regarding secondary debulking? It is not considered for patients like her who relapse 10-12 months after completing initial chemotherapy The finding of carcinomatosis is a relatively strong contraindication to secondary debulking surgery Survival is improved for secondary debulking even if all disease can’t be removed at surgery Mediastinal and pleural disease are relatively strong contraindications to secondary debulking surgery 1 and 3 2 and 4 All of the above Secondary Debulking Candidate Selection Onda et al. J Cancer. 2005;92:1026. Pujade-Lauraine, Ann Oncol. 2011;22(Supplement 8):viii61–viii64. RANDOM I Z E GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: ≤ 0.5 cm > 0.5-2 cm PLD 30 mg/m2 Carboplatin AUC = 5 q 28 days x 6 Paclitaxel 175 mg/m2 Carboplatin AUC = 5 q 21 days x 6 GCIG = Gynecologic Cancer Intergroup PFS = progression-free survival PLD = pegylated liposomal doxorubicin Accrual 864 pts PFS primary endpoint Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. GCIG CALYPSO Trial Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. Selected Non-hematologic Toxicities During Treatment Alopecia *P< 0.001 Pujade-Lauraine E et al. J Clin Oncol. 2010;28:3323-3329. Targeted Agents in Ovarian Cancer Signaling/Angiogenesis Bevacizumab/Aflibercept RTKI’s: Pazopanib Cabozantinib Sorafenib, etc Cediranib Nintedanib Trebananib, MEDI-3617 PI3K/Akt/mTOR MEKi Folate: Vintafolide (EC-145) Farletuzumab NKTR-102 Taxanes/epothilones Immunotherapy – vaccines and inducers EP-100 PARPi ErbB3 CG + PL OCEANS: Study schema CG for 6 (up to 10) cycles Stratification variables: Platinum-free interval (6–12 vs >12 months) Cytoreductive surgery for recurrent disease (yes vs no) Platinum-sensitive recurrent OCa Measurable disease ECOG 0/1 No prior chemo for recurrent OC No prior BV (n=484) BV = bevacizumab; PL = placebo aEpithelial ovarian, primary peritoneal, or fallopian tube cancer G 1000 mg/m2, d1 & 8 C AUC 4 PL q3w until progression C AUC 4 BV 15 mg/kg q3w until progression G 1000 mg/m2, d1 & 8 CG + BV Aghajanian C et al. J Clin Oncol. 2012;30:2039-2045. 242 177 45 11 3 0 CG + PL OCEANS: Primary Analysis of PFS Months No. at risk 242 203 92 33 11 0 CG + BV 1.0 0.8 0.6 0.4 0.2 0 Proportion progression free 0 6 12 18 24 30 Aghajanian C et al. J Clin Oncol. 2012;30:2039-2045. 1.0 0.8 0.6 0.4 0.2 0 OCEANS: Third Interim OS Analysisa 0 6 12 18 24 30 36 42 48 54 60 242 235 221 190 159 117 77 44 23 7 0 242 239 226 201 171 127 78 48 27 7 0 Number at risk: GC + PL GC + BV aData cutoff date: March 30, 2012. Median follow-up 41.9 months in PL arm and 42.3 months in BV arm, with 286 deaths (59.1% of patients) Proportion surviving Months Aghajanian et al. ESMO 2012. Asymptomatic relapse Single-agent farletuzumab Until progression Single-agent ORR Compare lengths of first and second remissions Farletuzumab - MORAb-003-002 Phase II: Design Epithelial Ovarian Cancer First platinum-sensitive relapse First remission of 6-18 months Evaluable disease by CA125 Symptomatic relapse Original Carbo/Taxane regimen Plus farletuzumab x 6 Farletuzumab maintenance Rx For responders Combination ORR White AJ et al. J Clin Oncol. 2010;28(15s):Abstract 5001. MorAb-003-002: Study Conclusions Overall response rate 70% Response rate similar in early (6-12 month) and late (12+ months) recurrent patients High rates of CA-125 normalization (89%) 1/5 patients had a PFI2 ≥ PFI1 Phase III studies Platinum-sensitive: fully enrolled Platinum-resistant (weekly paclitaxel): met futility endpoint White AJ et al. J Clin Oncol. 2010;28(15s):Abstract 5001. n=66 Randomized, Open-label, Phase II Study in Patients With Platinum-sensitive, Advanced Serous Ovarian Cancer Paclitaxel 175 mg/m2 (iv, d1) + carboplatin AUC6 (iv d1) Randomization (1:1) All patients followed for objective radiologic progression and survival Maintenance phase Olaparib 400 mg bid continuously Completion of 4–6 x 21-day cycles of chemotherapy Arm B Arm A n=81 n=81 n=55 Multinational study; 43 sites in 12 countries * Capsule formulation Patients with: Platinum-sensitive advanced ovarian cancer A serous histology or serous component Measurable disease ≤3 previous platinum-containing regimens Progression free for ≥6 months following completion of last platinum-containing regimen Maintenance phase No further study treatment Olaparib 200 mg bid* (d1–10 every 21 days) + paclitaxel 175 mg/m2 (iv, d1) + carboplatin AUC4 (iv, d1) Oza A. ASCO 2012; Abstract 5001. Paclitaxel Carboplatin (P/C) vs P/C Plus Olaparib (O/P/C) In Platinum Sensitive Recurrent Ovarian Cancer: PFS Time from randomization (months) 0 Proportion of patients progression free 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 2 4 6 8 10 12 16 20 Number of patients at risk Olaparib + P + C (AUC4) P + C (AUC6) 14 18 81 80 76 71 55 37 34 3 0 20 0 81 68 65 57 40 18 15 2 0 8 1 O/P/C P/C Oza A. ASCO 2012; Abstract 5001. GOG 9927: Phase I Combination Platinum sensitive recurrent EOC Chemotherapy based on CALYPSO Primary endpoint: 1st or 2nd cycle DLT Secondary endpoints: RR, PFS, Toxicity TR: PARPi in PBMCs, BRCA status PLD 30 mg/m2 Carboplatin AUC 5 Arm I Veliparib PO daily continuously Cycles: 28 days Planned administration: 6 cycles Arm II Veliparib PO daily D1-7 Cycles: 28 days Planned administration: 6 cycles www.clinicaltrials.gov/ct2/show/NCT01459380. Summary for Platinum-sensitive Recurrent Ovarian Cancer Consider Secondary Debulking Platinum retreatment is standard Treatment with a platinum-based doublet improves response rate, progression-free survival, and possibly overall survival Options: Taxane Carboplatin: Paclitaxel, Docetaxel (?), Weekly Paclitaxel (?) Gemcitabine Carboplatin +/- Bevacizumab PLD Carboplatin Case 3: Platinum Resistant Ovarian Cancer 60-year-old woman with extensive pelvic and peritoneal implants, ascites and large volume disease at the root of the mesentery Diagnosis of ovarian cancer made by paracentesis Deemed unresectable by a gynecologic oncologist Treated with neoadjuvant paclitaxel and carboplatin x 3 without response Then treated with topotecan (daily x 5 regimen) x 3 without response Required paracentesis weekly for palliation CA-125=6916 What treatment would you recommend? Case 3 Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) Weekly paclitaxel Gemcitabine Bevacizumab Weekly paclitaxel and bevacizumab Gemcitabine, carboplatin and bevacizumab Case 3 Question 1 What treatment would you recommend for this patient? Pegylated liposomal doxorubicin (PLD, doxil, lipodox) (PLD is a reasonable choice but expected response rate is 6-16% in a less heavily pretreated population) Weekly paclitaxel (Weekly paclitaxel is also a reasonable option. In GOG protocol 126-N weekly paclitaxel had a response rate of 21% although eligibility limited to one prior treatment regimen) Gemcitabine (although single agent gemcitabine is not FDA approved for treatment of ovarian cancer, the combination of gemcitabine and carboplatin is approved for platinum sensitive patients thus gemcitabine alone is frequently used. Response rates in this population are expected to be less than 10%) Bevacizumab (Bevacizumab is a reasonable choice. In GOG protocol 170D bevacizumab showed a response rate of 21% in this population) Weekly paclitaxel and bevacizumab (Based on Aurelia, the combination of weekly paclitaxel and bevacizumab would be expected to have a higher response rate than weekly paclitaxel alone. Survival data is not yet available. It is not yet clear whether sequential chemotherapy and bevacizumab or the combination is preferable) Gemcitabine, carboplatin and bevacizumab (platinum-based therapy is not indicated in this patient with platinum-refractory disease.) Assume You Will Be Using Treatment With Bevacizumab: Which of the Following Are True Statements About Bevacizumab for Her 1. She will be at increased risk for bowel perforation 2. There is an increased risk of thrombo-embolic phenomena with bevacizumab 3. The response rate of ovarian cancer to single-agent bevacizumab is greater than for any other solid tumors tested to date 4. Hypertension and proteinuria are common side effects of bevacizumab 5. All of the above All the above are true statements in this case. Annals of Oncology 22 (Supplement 8): viii61–viii64, 2011. Active Agents in Ovarian Cancer Platinum-resistant Ovarian Cancer Cytotoxic Therapy Thresholds: 10%, 25% *Median of 3 prior lines *1 prior line Vergote IB et al. J Clin Oncol 2010;28:15s(suppl; abstr 5013). Bevacizumab in Relapsed Ovarian Cancer *Burger RA et al. J Clin Oncol 2007; 25: 5165–5171. **Garcia AA et al. J Clin Oncol 2008; 26: 76–82. ***Cannistra SA et al. J Clin Oncol 2007; 25: 5180–5186. Ovarian Cancer: Targeted Therapy 1Tew et al. J Clin Oncol 2007;25:(suppl; abstr 5508). 2Biagi et al. Ann Oncol. 2011;22:335-340. 3Matulonis UA et al. J Clin Oncol. 2009;27:5601-5606. 4Buckanovich et al. J Clin Oncol. 2011;29(suppl; abstr 5008). 5Friedlander et.al. Gyn Oncol. 2010,. 6Ledermann et al. J Clin Oncol. 2011;29:3798. PD Recurrent Ovarian Cancer Randomized Phase II Studies Weekly Paclitaxel AMG-386 10 mg/kg IV weekly n=53 Weekly Paclitaxel AMG-386 3 mg/kg IV weekly n=53 Weekly Paclitaxel Placebo n=55 Paclitaxel 80 mg/m2 IV weekly, 3 weeks on/1 week off AMG-386 10 mg/kg IV weekly RANDOM I Z E Ovarian, primary peritoneal, or fallopian tube cancer n=161 1-3 prior lines Karlan BY et al. J Clin Oncol. 2010;28:15s(suppl; abstr 5000). Recurrent Ovarian Cancer Randomized Phase II Studies Primary endpoint: PFS *1-3 prior lines www.clinicaltrials.gov
Slide 71 - Welcome! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Presenter, MD: Research: Pharma Company; Consultant: Pharma Company TO BE FILLED IN BY PRESENTING PHYSICIAN(S) Off-label discussion disclosure:   This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Deborah K. Armstrong, MD: Advisory Board: Genentech; Clinical Trials: Genentech, Medimmune, Morphotek; Clinical Development Advisory Panel (CDAp): California Institute for Regenerative Medicine (CIRM); Data Safety Monitoring Board: Merrimack, Quintiles; Drugs Advisory Committee: Oncology Drugs Advisory Committee (ODAC) to the US FDA; Independent Safety Officer: Astellas; Member: Integration Panel (IP) for Department of Defense (DOD) Ovarian Cancer Research Program (OCRP); Dr. Armstrong’s spouse’s institution also receives funding from: Eisai, Exelixis Bradley J. Monk, MD, FACOG, FACS: Consultant: Array, Astellas, Boehringer Ingelheim, GlaxoSmithKline, Morphotek, Nektar, Roche/Genentech; Researcher: Amgen, Genentech, Merck, Novartis; Speaker: Johnson & Johnson, Roche/Genentech Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand; Jay Katz, CCMEP; CME Peer Review: Nothing to Disclose Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review the recently updated clinical practice guidelines for advanced ovarian cancer Compare the available treatment regimens and platinum-sensitive or platinum-resistant recurrent settings and choose the optimal treatment based on patient characteristics and recently presented clinical trial data Identify key investigational regimens in currently ongoing clinical studies for advanced ovarian cancer and counsel patients accordingly Basis for Basic Current Standard Systemic Therapy Studies showing paclitaxel/cisplatin superior to cyclophosphamide/cisplatin GOG Protocol 111[1] EORTC-NCIC OV 10[2] Studies showing paclitaxel/carboplatin at least equivalent to paclitaxel/cisplatin in efficacy AGO Trial[3] GOG Protocol 158[4] 1. McGuire WP et al. N Eng J Med .1996;334:1-6. 2. Piccart MJ et al. J Natl Cancer Inst. 2000;92:699-708. 3. DuBois A et al. J Natl Cancer Inst. 2003;95:1320-1329. 4. Ozols RF et al. J Clin Oncol. 2003;21:3194-3200. First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission First-line Therapy: Acceptable Approaches Neoadjuvant chemotherapy Intraperitoneal chemotherapy Weekly dosing Adding a targeted agent (e.g. bevacizumab) Maintenance or consolidation chemotherapy after complete remission Randomization Randomised EORTC-GCG/NCIC-CTG trial on NACT + IDS versus PDS Ovarian, tubal or peritonal cancer FIGO stage IIIc-IV (n = 718) 3 x Platinum based CT 3 x Platinum based CT ≥ 3 x Platinum based CT Primary Debulking Surgery Neoadjuvant chemotherapy Interval debulking (not obligatory) Interval debulking if no PD ≥ 3 x Platinum based CT Primary Endpoint: Overall survival Secondary endpoints: Progression Free Survival, Quality of Life, Complications IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. NACT + IDS versus PDS: ITT Median survial PDS: 29 months IDS: 30 months HR for IDS:0.98 (0.85, 1.14) IGCS Meeting October 25, 2009; N Engl J Med. 2010;363:943-953. First-line