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Slide 1 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology
Slide 2 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007.
Slide 3 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases
Slide 4 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics
Slide 5 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy
Slide 6 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease
Slide 7 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie
Slide 8 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001
Slide 9 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk
Slide 10 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks
Slide 11 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer
Slide 12 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin
Slide 13 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate
Slide 14 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan
Slide 15 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan
Slide 16 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life
Slide 17 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy
Slide 18 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days
Slide 19 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days GC vs TC Induction Regimens Followed by T Consolidation: Response Rates Gordon A, et al. ASCO 2008. Abstract 5536. *CR required a normalized CA-125.
Slide 20 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days GC vs TC Induction Regimens Followed by T Consolidation: Response Rates Gordon A, et al. ASCO 2008. Abstract 5536. *CR required a normalized CA-125. GC vs TC Induction Regimens Followed by T Consolidation: Pt-Based Toxicity Gordon A, et al. ASCO 2008. Abstract 5536.
Slide 21 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days GC vs TC Induction Regimens Followed by T Consolidation: Response Rates Gordon A, et al. ASCO 2008. Abstract 5536. *CR required a normalized CA-125. GC vs TC Induction Regimens Followed by T Consolidation: Pt-Based Toxicity Gordon A, et al. ASCO 2008. Abstract 5536. Conventional vs Dose-Dense TC (NOVEL): Study Design Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO 2008. Abstract 5506.
Slide 22 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days GC vs TC Induction Regimens Followed by T Consolidation: Response Rates Gordon A, et al. ASCO 2008. Abstract 5536. *CR required a normalized CA-125. GC vs TC Induction Regimens Followed by T Consolidation: Pt-Based Toxicity Gordon A, et al. ASCO 2008. Abstract 5536. Conventional vs Dose-Dense TC (NOVEL): Study Design Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO 2008. Abstract 5506. P = .72 Evaluated by WHO criteria Conventional vs Dose-Dense TC (NOVEL): Clinical Responses Isonishi S, et al. ASCO 2008. Abstract 5506.
Slide 23 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days GC vs TC Induction Regimens Followed by T Consolidation: Response Rates Gordon A, et al. ASCO 2008. Abstract 5536. *CR required a normalized CA-125. GC vs TC Induction Regimens Followed by T Consolidation: Pt-Based Toxicity Gordon A, et al. ASCO 2008. Abstract 5536. Conventional vs Dose-Dense TC (NOVEL): Study Design Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO 2008. Abstract 5506. P = .72 Evaluated by WHO criteria Conventional vs Dose-Dense TC (NOVEL): Clinical Responses Isonishi S, et al. ASCO 2008. Abstract 5506. Conventional vs Dose-Dense TC (NOVEL): PFS 0.0 0.2 0.4 0.6 0.8 1.0 0 12 30 54 Mos From Randomization Proportion Surviving Progression Free 0.1 0.3 0.5 0.7 0.9 6 18 42 24 48 36 Isonishi S, et al. ASCO 2008. Abstract 5506. dd-TC c-TC
Slide 24 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days GC vs TC Induction Regimens Followed by T Consolidation: Response Rates Gordon A, et al. ASCO 2008. Abstract 5536. *CR required a normalized CA-125. GC vs TC Induction Regimens Followed by T Consolidation: Pt-Based Toxicity Gordon A, et al. ASCO 2008. Abstract 5536. Conventional vs Dose-Dense TC (NOVEL): Study Design Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO 2008. Abstract 5506. P = .72 Evaluated by WHO criteria Conventional vs Dose-Dense TC (NOVEL): Clinical Responses Isonishi S, et al. ASCO 2008. Abstract 5506. Conventional vs Dose-Dense TC (NOVEL): PFS 0.0 0.2 0.4 0.6 0.8 1.0 0 12 30 54 Mos From Randomization Proportion Surviving Progression Free 0.1 0.3 0.5 0.7 0.9 6 18 42 24 48 36 Isonishi S, et al. ASCO 2008. Abstract 5506. dd-TC c-TC Ovarian Carcinoma: Clinical Course Symptoms Diagnosis Chemotherapy #1 Staging Primary cytoreduction Interval Cytoreduction Progression Chemo #2 Chemo #3+ Supportive Care Death Consolidation/ Maintenance Cure Secondary Cytoreduction Second-Look
Slide 25 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days GC vs TC Induction Regimens Followed by T Consolidation: Response Rates Gordon A, et al. ASCO 2008. Abstract 5536. *CR required a normalized CA-125. GC vs TC Induction Regimens Followed by T Consolidation: Pt-Based Toxicity Gordon A, et al. ASCO 2008. Abstract 5536. Conventional vs Dose-Dense TC (NOVEL): Study Design Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO 2008. Abstract 5506. P = .72 Evaluated by WHO criteria Conventional vs Dose-Dense TC (NOVEL): Clinical Responses Isonishi S, et al. ASCO 2008. Abstract 5506. Conventional vs Dose-Dense TC (NOVEL): PFS 0.0 0.2 0.4 0.6 0.8 1.0 0 12 30 54 Mos From Randomization Proportion Surviving Progression Free 0.1 0.3 0.5 0.7 0.9 6 18 42 24 48 36 Isonishi S, et al. ASCO 2008. Abstract 5506. dd-TC c-TC Ovarian Carcinoma: Clinical Course Symptoms Diagnosis Chemotherapy #1 Staging Primary cytoreduction Interval Cytoreduction Progression Chemo #2 Chemo #3+ Supportive Care Death Consolidation/ Maintenance Cure Secondary Cytoreduction Second-Look Goals of Treatment: Relapsed Ovarian Cancer Prolong Survival Delay Time to Progression Control Disease-Related Symptoms Minimize Treatment-Related Symptoms Maintain or Improve Quality of Life
Slide 26 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days GC vs TC Induction Regimens Followed by T Consolidation: Response Rates Gordon A, et al. ASCO 2008. Abstract 5536. *CR required a normalized CA-125. GC vs TC Induction Regimens Followed by T Consolidation: Pt-Based Toxicity Gordon A, et al. ASCO 2008. Abstract 5536. Conventional vs Dose-Dense TC (NOVEL): Study Design Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO 2008. Abstract 5506. P = .72 Evaluated by WHO criteria Conventional vs Dose-Dense TC (NOVEL): Clinical Responses Isonishi S, et al. ASCO 2008. Abstract 5506. Conventional vs Dose-Dense TC (NOVEL): PFS 0.0 0.2 0.4 0.6 0.8 1.0 0 12 30 54 Mos From Randomization Proportion Surviving Progression Free 0.1 0.3 0.5 0.7 0.9 6 18 42 24 48 36 Isonishi S, et al. ASCO 2008. Abstract 5506. dd-TC c-TC Ovarian Carcinoma: Clinical Course Symptoms Diagnosis Chemotherapy #1 Staging Primary cytoreduction Interval Cytoreduction Progression Chemo #2 Chemo #3+ Supportive Care Death Consolidation/ Maintenance Cure Secondary Cytoreduction Second-Look Goals of Treatment: Relapsed Ovarian Cancer Prolong Survival Delay Time to Progression Control Disease-Related Symptoms Minimize Treatment-Related Symptoms Maintain or Improve Quality of Life Issues Impacting Therapy for Recurrent Ovarian Cancer Treatment-free interval Impact of consolidation/maintenance therapy Number of prior regimens Response to prior therapy Toxicity from prior therapy Prior use of growth factors Transfusion requirements Neuropathy Volume and site(s) of disease Ascites/GI symptoms Performance status
Slide 27 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days GC vs TC Induction Regimens Followed by T Consolidation: Response Rates Gordon A, et al. ASCO 2008. Abstract 5536. *CR required a normalized CA-125. GC vs TC Induction Regimens Followed by T Consolidation: Pt-Based Toxicity Gordon A, et al. ASCO 2008. Abstract 5536. Conventional vs Dose-Dense TC (NOVEL): Study Design Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO 2008. Abstract 5506. P = .72 Evaluated by WHO criteria Conventional vs Dose-Dense TC (NOVEL): Clinical Responses Isonishi S, et al. ASCO 2008. Abstract 5506. Conventional vs Dose-Dense TC (NOVEL): PFS 0.0 0.2 0.4 0.6 0.8 1.0 0 12 30 54 Mos From Randomization Proportion Surviving Progression Free 0.1 0.3 0.5 0.7 0.9 6 18 42 24 48 36 Isonishi S, et al. ASCO 2008. Abstract 5506. dd-TC c-TC Ovarian Carcinoma: Clinical Course Symptoms Diagnosis Chemotherapy #1 Staging Primary cytoreduction Interval Cytoreduction Progression Chemo #2 Chemo #3+ Supportive Care Death Consolidation/ Maintenance Cure Secondary Cytoreduction Second-Look Goals of Treatment: Relapsed Ovarian Cancer Prolong Survival Delay Time to Progression Control Disease-Related Symptoms Minimize Treatment-Related Symptoms Maintain or Improve Quality of Life Issues Impacting Therapy for Recurrent Ovarian Cancer Treatment-free interval Impact of consolidation/maintenance therapy Number of prior regimens Response to prior therapy Toxicity from prior therapy Prior use of growth factors Transfusion requirements Neuropathy Volume and site(s) of disease Ascites/GI symptoms Performance status Surveillance Options for Ovarian Cancer Patients in Remission Second-look laparotomy Physical examination Include pelvic examination CA-125 Imaging CT scan MRI? PET scan? CT = computed tomography MRI = magnetic resonance imaging PET = positron emission tomography
Slide 28 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days GC vs TC Induction Regimens Followed by T Consolidation: Response Rates Gordon A, et al. ASCO 2008. Abstract 5536. *CR required a normalized CA-125. GC vs TC Induction Regimens Followed by T Consolidation: Pt-Based Toxicity Gordon A, et al. ASCO 2008. Abstract 5536. Conventional vs Dose-Dense TC (NOVEL): Study Design Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO 2008. Abstract 5506. P = .72 Evaluated by WHO criteria Conventional vs Dose-Dense TC (NOVEL): Clinical Responses Isonishi S, et al. ASCO 2008. Abstract 5506. Conventional vs Dose-Dense TC (NOVEL): PFS 0.0 0.2 0.4 0.6 0.8 1.0 0 12 30 54 Mos From Randomization Proportion Surviving Progression Free 0.1 0.3 0.5 0.7 0.9 6 18 42 24 48 36 Isonishi S, et al. ASCO 2008. Abstract 5506. dd-TC c-TC Ovarian Carcinoma: Clinical Course Symptoms Diagnosis Chemotherapy #1 Staging Primary cytoreduction Interval Cytoreduction Progression Chemo #2 Chemo #3+ Supportive Care Death Consolidation/ Maintenance Cure Secondary Cytoreduction Second-Look Goals of Treatment: Relapsed Ovarian Cancer Prolong Survival Delay Time to Progression Control Disease-Related Symptoms Minimize Treatment-Related Symptoms Maintain or Improve Quality of Life Issues Impacting Therapy for Recurrent Ovarian Cancer Treatment-free interval Impact of consolidation/maintenance therapy Number of prior regimens Response to prior therapy Toxicity from prior therapy Prior use of growth factors Transfusion requirements Neuropathy Volume and site(s) of disease Ascites/GI symptoms Performance status Surveillance Options for Ovarian Cancer Patients in Remission Second-look laparotomy Physical examination Include pelvic examination CA-125 Imaging CT scan MRI? PET scan? CT = computed tomography MRI = magnetic resonance imaging PET = positron emission tomography Ovarian Cancer: How is Relapse Defined? Continuous rise in CA-125 CA-125 above 100 Radiographic recurrence Symptomatic recurrence Physical examination findings Combination of above
Slide 29 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days GC vs TC Induction Regimens Followed by T Consolidation: Response Rates Gordon A, et al. ASCO 2008. Abstract 5536. *CR required a normalized CA-125. GC vs TC Induction Regimens Followed by T Consolidation: Pt-Based Toxicity Gordon A, et al. ASCO 2008. Abstract 5536. Conventional vs Dose-Dense TC (NOVEL): Study Design Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO 2008. Abstract 5506. P = .72 Evaluated by WHO criteria Conventional vs Dose-Dense TC (NOVEL): Clinical Responses Isonishi S, et al. ASCO 2008. Abstract 5506. Conventional vs Dose-Dense TC (NOVEL): PFS 0.0 0.2 0.4 0.6 0.8 1.0 0 12 30 54 Mos From Randomization Proportion Surviving Progression Free 0.1 0.3 0.5 0.7 0.9 6 18 42 24 48 36 Isonishi S, et al. ASCO 2008. Abstract 5506. dd-TC c-TC Ovarian Carcinoma: Clinical Course Symptoms Diagnosis Chemotherapy #1 Staging Primary cytoreduction Interval Cytoreduction Progression Chemo #2 Chemo #3+ Supportive Care Death Consolidation/ Maintenance Cure Secondary Cytoreduction Second-Look Goals of Treatment: Relapsed Ovarian Cancer Prolong Survival Delay Time to Progression Control Disease-Related Symptoms Minimize Treatment-Related Symptoms Maintain or Improve Quality of Life Issues Impacting Therapy for Recurrent Ovarian Cancer Treatment-free interval Impact of consolidation/maintenance therapy Number of prior regimens Response to prior therapy Toxicity from prior therapy Prior use of growth factors Transfusion requirements Neuropathy Volume and site(s) of disease Ascites/GI symptoms Performance status Surveillance Options for Ovarian Cancer Patients in Remission Second-look laparotomy Physical examination Include pelvic examination CA-125 Imaging CT scan MRI? PET scan? CT = computed tomography MRI = magnetic resonance imaging PET = positron emission tomography Ovarian Cancer: How is Relapse Defined? Continuous rise in CA-125 CA-125 above 100 Radiographic recurrence Symptomatic recurrence Physical examination findings Combination of above When Does Ovarian Cancer Recur? Carb = carboplatin; Cis = cisplatin; Doc = docetaxel; pac = paclitaxel; GOG = Gynecologic Oncology Group; IP = intraperitoneal; Pac = paclitaxel
Slide 30 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days GC vs TC Induction Regimens Followed by T Consolidation: Response Rates Gordon A, et al. ASCO 2008. Abstract 5536. *CR required a normalized CA-125. GC vs TC Induction Regimens Followed by T Consolidation: Pt-Based Toxicity Gordon A, et al. ASCO 2008. Abstract 5536. Conventional vs Dose-Dense TC (NOVEL): Study Design Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO 2008. Abstract 5506. P = .72 Evaluated by WHO criteria Conventional vs Dose-Dense TC (NOVEL): Clinical Responses Isonishi S, et al. ASCO 2008. Abstract 5506. Conventional vs Dose-Dense TC (NOVEL): PFS 0.0 0.2 0.4 0.6 0.8 1.0 0 12 30 54 Mos From Randomization Proportion Surviving Progression Free 0.1 0.3 0.5 0.7 0.9 6 18 42 24 48 36 Isonishi S, et al. ASCO 2008. Abstract 5506. dd-TC c-TC Ovarian Carcinoma: Clinical Course Symptoms Diagnosis Chemotherapy #1 Staging Primary cytoreduction Interval Cytoreduction Progression Chemo #2 Chemo #3+ Supportive Care Death Consolidation/ Maintenance Cure Secondary Cytoreduction Second-Look Goals of Treatment: Relapsed Ovarian Cancer Prolong Survival Delay Time to Progression Control Disease-Related Symptoms Minimize Treatment-Related Symptoms Maintain or Improve Quality of Life Issues Impacting Therapy for Recurrent Ovarian Cancer Treatment-free interval Impact of consolidation/maintenance therapy Number of prior regimens Response to prior therapy Toxicity from prior therapy Prior use of growth factors Transfusion requirements Neuropathy Volume and site(s) of disease Ascites/GI symptoms Performance status Surveillance Options for Ovarian Cancer Patients in Remission Second-look laparotomy Physical examination Include pelvic examination CA-125 Imaging CT scan MRI? PET scan? CT = computed tomography MRI = magnetic resonance imaging PET = positron emission tomography Ovarian Cancer: How is Relapse Defined? Continuous rise in CA-125 CA-125 above 100 Radiographic recurrence Symptomatic recurrence Physical examination findings Combination of above When Does Ovarian Cancer Recur? Carb = carboplatin; Cis = cisplatin; Doc = docetaxel; pac = paclitaxel; GOG = Gynecologic Oncology Group; IP = intraperitoneal; Pac = paclitaxel Active Agents in Ovarian Cancer
Slide 31 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days GC vs TC Induction Regimens Followed by T Consolidation: Response Rates Gordon A, et al. ASCO 2008. Abstract 5536. *CR required a normalized CA-125. GC vs TC Induction Regimens Followed by T Consolidation: Pt-Based Toxicity Gordon A, et al. ASCO 2008. Abstract 5536. Conventional vs Dose-Dense TC (NOVEL): Study Design Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO 2008. Abstract 5506. P = .72 Evaluated by WHO criteria Conventional vs Dose-Dense TC (NOVEL): Clinical Responses Isonishi S, et al. ASCO 2008. Abstract 5506. Conventional vs Dose-Dense TC (NOVEL): PFS 0.0 0.2 0.4 0.6 0.8 1.0 0 12 30 54 Mos From Randomization Proportion Surviving Progression Free 0.1 0.3 0.5 0.7 0.9 6 18 42 24 48 36 Isonishi S, et al. ASCO 2008. Abstract 5506. dd-TC c-TC Ovarian Carcinoma: Clinical Course Symptoms Diagnosis Chemotherapy #1 Staging Primary cytoreduction Interval Cytoreduction Progression Chemo #2 Chemo #3+ Supportive Care Death Consolidation/ Maintenance Cure Secondary Cytoreduction Second-Look Goals of Treatment: Relapsed Ovarian Cancer Prolong Survival Delay Time to Progression Control Disease-Related Symptoms Minimize Treatment-Related Symptoms Maintain or Improve Quality of Life Issues Impacting Therapy for Recurrent Ovarian Cancer Treatment-free interval Impact of consolidation/maintenance therapy Number of prior regimens Response to prior therapy Toxicity from prior therapy Prior use of growth factors Transfusion requirements Neuropathy Volume and site(s) of disease Ascites/GI symptoms Performance status Surveillance Options for Ovarian Cancer Patients in Remission Second-look laparotomy Physical examination Include pelvic examination CA-125 Imaging CT scan MRI? PET scan? CT = computed tomography MRI = magnetic resonance imaging PET = positron emission tomography Ovarian Cancer: How is Relapse Defined? Continuous rise in CA-125 CA-125 above 100 Radiographic recurrence Symptomatic recurrence Physical examination findings Combination of above When Does Ovarian Cancer Recur? Carb = carboplatin; Cis = cisplatin; Doc = docetaxel; pac = paclitaxel; GOG = Gynecologic Oncology Group; IP = intraperitoneal; Pac = paclitaxel Active Agents in Ovarian Cancer Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653.
Slide 32 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days GC vs TC Induction Regimens Followed by T Consolidation: Response Rates Gordon A, et al. ASCO 2008. Abstract 5536. *CR required a normalized CA-125. GC vs TC Induction Regimens Followed by T Consolidation: Pt-Based Toxicity Gordon A, et al. ASCO 2008. Abstract 5536. Conventional vs Dose-Dense TC (NOVEL): Study Design Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO 2008. Abstract 5506. P = .72 Evaluated by WHO criteria Conventional vs Dose-Dense TC (NOVEL): Clinical Responses Isonishi S, et al. ASCO 2008. Abstract 5506. Conventional vs Dose-Dense TC (NOVEL): PFS 0.0 0.2 0.4 0.6 0.8 1.0 0 12 30 54 Mos From Randomization Proportion Surviving Progression Free 0.1 0.3 0.5 0.7 0.9 6 18 42 24 48 36 Isonishi S, et al. ASCO 2008. Abstract 5506. dd-TC c-TC Ovarian Carcinoma: Clinical Course Symptoms Diagnosis Chemotherapy #1 Staging Primary cytoreduction Interval Cytoreduction Progression Chemo #2 Chemo #3+ Supportive Care Death Consolidation/ Maintenance Cure Secondary Cytoreduction Second-Look Goals of Treatment: Relapsed Ovarian Cancer Prolong Survival Delay Time to Progression Control Disease-Related Symptoms Minimize Treatment-Related Symptoms Maintain or Improve Quality of Life Issues Impacting Therapy for Recurrent Ovarian Cancer Treatment-free interval Impact of consolidation/maintenance therapy Number of prior regimens Response to prior therapy Toxicity from prior therapy Prior use of growth factors Transfusion requirements Neuropathy Volume and site(s) of disease Ascites/GI symptoms Performance status Surveillance Options for Ovarian Cancer Patients in Remission Second-look laparotomy Physical examination Include pelvic examination CA-125 Imaging CT scan MRI? PET scan? CT = computed tomography MRI = magnetic resonance imaging PET = positron emission tomography Ovarian Cancer: How is Relapse Defined? Continuous rise in CA-125 CA-125 above 100 Radiographic recurrence Symptomatic recurrence Physical examination findings Combination of above When Does Ovarian Cancer Recur? Carb = carboplatin; Cis = cisplatin; Doc = docetaxel; pac = paclitaxel; GOG = Gynecologic Oncology Group; IP = intraperitoneal; Pac = paclitaxel Active Agents in Ovarian Cancer Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Refractory P R I M A R Y T R E A T M E N T Resistant Sensitive 0 3 6 12 18 24 Months “Very Sensitive” Ovarian Cancer at First Relapse Definition of Sensitivity Defined as measurable recurrence, not biochemical (CA-125) recurrence
Slide 33 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days GC vs TC Induction Regimens Followed by T Consolidation: Response Rates Gordon A, et al. ASCO 2008. Abstract 5536. *CR required a normalized CA-125. GC vs TC Induction Regimens Followed by T Consolidation: Pt-Based Toxicity Gordon A, et al. ASCO 2008. Abstract 5536. Conventional vs Dose-Dense TC (NOVEL): Study Design Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO 2008. Abstract 5506. P = .72 Evaluated by WHO criteria Conventional vs Dose-Dense TC (NOVEL): Clinical Responses Isonishi S, et al. ASCO 2008. Abstract 5506. Conventional vs Dose-Dense TC (NOVEL): PFS 0.0 0.2 0.4 0.6 0.8 1.0 0 12 30 54 Mos From Randomization Proportion Surviving Progression Free 0.1 0.3 0.5 0.7 0.9 6 18 42 24 48 36 Isonishi S, et al. ASCO 2008. Abstract 5506. dd-TC c-TC Ovarian Carcinoma: Clinical Course Symptoms Diagnosis Chemotherapy #1 Staging Primary cytoreduction Interval Cytoreduction Progression Chemo #2 Chemo #3+ Supportive Care Death Consolidation/ Maintenance Cure Secondary Cytoreduction Second-Look Goals of Treatment: Relapsed Ovarian Cancer Prolong Survival Delay Time to Progression Control Disease-Related Symptoms Minimize Treatment-Related Symptoms Maintain or Improve Quality of Life Issues Impacting Therapy for Recurrent Ovarian Cancer Treatment-free interval Impact of consolidation/maintenance therapy Number of prior regimens Response to prior therapy Toxicity from prior therapy Prior use of growth factors Transfusion requirements Neuropathy Volume and site(s) of disease Ascites/GI symptoms Performance status Surveillance Options for Ovarian Cancer Patients in Remission Second-look laparotomy Physical examination Include pelvic examination CA-125 Imaging CT scan MRI? PET scan? CT = computed tomography MRI = magnetic resonance imaging PET = positron emission tomography Ovarian Cancer: How is Relapse Defined? Continuous rise in CA-125 CA-125 above 100 Radiographic recurrence Symptomatic recurrence Physical examination findings Combination of above When Does Ovarian Cancer Recur? Carb = carboplatin; Cis = cisplatin; Doc = docetaxel; pac = paclitaxel; GOG = Gynecologic Oncology Group; IP = intraperitoneal; Pac = paclitaxel Active Agents in Ovarian Cancer Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Refractory P R I M A R Y T R E A T M E N T Resistant Sensitive 0 3 6 12 18 24 Months “Very Sensitive” Ovarian Cancer at First Relapse Definition of Sensitivity Defined as measurable recurrence, not biochemical (CA-125) recurrence ICON 4 Schema Relapsed ovarian or primary Peritoneal requiring chemotherapy Previous platinum-based chemotherapy Conventional platinum-based chemotherapy Paclitaxel plus platinum chemotherapy R A N D O M I Z E Prior chemotherapy Carboplatin (31%) Paclitaxel/platinum (40%) Other (30%) TFI > 12 months for 75% Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group TFI = treatment-free interval
Slide 34 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days GC vs TC Induction Regimens Followed by T Consolidation: Response Rates Gordon A, et al. ASCO 2008. Abstract 5536. *CR required a normalized CA-125. GC vs TC Induction Regimens Followed by T Consolidation: Pt-Based Toxicity Gordon A, et al. ASCO 2008. Abstract 5536. Conventional vs Dose-Dense TC (NOVEL): Study Design Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO 2008. Abstract 5506. P = .72 Evaluated by WHO criteria Conventional vs Dose-Dense TC (NOVEL): Clinical Responses Isonishi S, et al. ASCO 2008. Abstract 5506. Conventional vs Dose-Dense TC (NOVEL): PFS 0.0 0.2 0.4 0.6 0.8 1.0 0 12 30 54 Mos From Randomization Proportion Surviving Progression Free 0.1 0.3 0.5 0.7 0.9 6 18 42 24 48 36 Isonishi S, et al. ASCO 2008. Abstract 5506. dd-TC c-TC Ovarian Carcinoma: Clinical Course Symptoms Diagnosis Chemotherapy #1 Staging Primary cytoreduction Interval Cytoreduction Progression Chemo #2 Chemo #3+ Supportive Care Death Consolidation/ Maintenance Cure Secondary Cytoreduction Second-Look Goals of Treatment: Relapsed Ovarian Cancer Prolong Survival Delay Time to Progression Control Disease-Related Symptoms Minimize Treatment-Related Symptoms Maintain or Improve Quality of Life Issues Impacting Therapy for Recurrent Ovarian Cancer Treatment-free interval Impact of consolidation/maintenance therapy Number of prior regimens Response to prior therapy Toxicity from prior therapy Prior use of growth factors Transfusion requirements Neuropathy Volume and site(s) of disease Ascites/GI symptoms Performance status Surveillance Options for Ovarian Cancer Patients in Remission Second-look laparotomy Physical examination Include pelvic examination CA-125 Imaging CT scan MRI? PET scan? CT = computed tomography MRI = magnetic resonance imaging PET = positron emission tomography Ovarian Cancer: How is Relapse Defined? Continuous rise in CA-125 CA-125 above 100 Radiographic recurrence Symptomatic recurrence Physical examination findings Combination of above When Does Ovarian Cancer Recur? Carb = carboplatin; Cis = cisplatin; Doc = docetaxel; pac = paclitaxel; GOG = Gynecologic Oncology Group; IP = intraperitoneal; Pac = paclitaxel Active Agents in Ovarian Cancer Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Refractory P R I M A R Y T R E A T M E N T Resistant Sensitive 0 3 6 12 18 24 Months “Very Sensitive” Ovarian Cancer at First Relapse Definition of Sensitivity Defined as measurable recurrence, not biochemical (CA-125) recurrence ICON 4 Schema Relapsed ovarian or primary Peritoneal requiring chemotherapy Previous platinum-based chemotherapy Conventional platinum-based chemotherapy Paclitaxel plus platinum chemotherapy R A N D O M I Z E Prior chemotherapy Carboplatin (31%) Paclitaxel/platinum (40%) Other (30%) TFI > 12 months for 75% Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group TFI = treatment-free interval ICON 4 Response (Difference of 12%; 95% CI -0.1% to 24%; p=0.06) CR = complete response; ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum; PR = partial response; Parmar MK, et al. Lancet. 2003;361:2099-2106.
Slide 35 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days GC vs TC Induction Regimens Followed by T Consolidation: Response Rates Gordon A, et al. ASCO 2008. Abstract 5536. *CR required a normalized CA-125. GC vs TC Induction Regimens Followed by T Consolidation: Pt-Based Toxicity Gordon A, et al. ASCO 2008. Abstract 5536. Conventional vs Dose-Dense TC (NOVEL): Study Design Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO 2008. Abstract 5506. P = .72 Evaluated by WHO criteria Conventional vs Dose-Dense TC (NOVEL): Clinical Responses Isonishi S, et al. ASCO 2008. Abstract 5506. Conventional vs Dose-Dense TC (NOVEL): PFS 0.0 0.2 0.4 0.6 0.8 1.0 0 12 30 54 Mos From Randomization Proportion Surviving Progression Free 0.1 0.3 0.5 0.7 0.9 6 18 42 24 48 36 Isonishi S, et al. ASCO 2008. Abstract 5506. dd-TC c-TC Ovarian Carcinoma: Clinical Course Symptoms Diagnosis Chemotherapy #1 Staging Primary cytoreduction Interval Cytoreduction Progression Chemo #2 Chemo #3+ Supportive Care Death Consolidation/ Maintenance Cure Secondary Cytoreduction Second-Look Goals of Treatment: Relapsed Ovarian Cancer Prolong Survival Delay Time to Progression Control Disease-Related Symptoms Minimize Treatment-Related Symptoms Maintain or Improve Quality of Life Issues Impacting Therapy for Recurrent Ovarian Cancer Treatment-free interval Impact of consolidation/maintenance therapy Number of prior regimens Response to prior therapy Toxicity from prior therapy Prior use of growth factors Transfusion requirements Neuropathy Volume and site(s) of disease Ascites/GI symptoms Performance status Surveillance Options for Ovarian Cancer Patients in Remission Second-look laparotomy Physical examination Include pelvic examination CA-125 Imaging CT scan MRI? PET scan? CT = computed tomography MRI = magnetic resonance imaging PET = positron emission tomography Ovarian Cancer: How is Relapse Defined? Continuous rise in CA-125 CA-125 above 100 Radiographic recurrence Symptomatic recurrence Physical examination findings Combination of above When Does Ovarian Cancer Recur? Carb = carboplatin; Cis = cisplatin; Doc = docetaxel; pac = paclitaxel; GOG = Gynecologic Oncology Group; IP = intraperitoneal; Pac = paclitaxel Active Agents in Ovarian Cancer Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Refractory P R I M A R Y T R E A T M E N T Resistant Sensitive 0 3 6 12 18 24 Months “Very Sensitive” Ovarian Cancer at First Relapse Definition of Sensitivity Defined as measurable recurrence, not biochemical (CA-125) recurrence ICON 4 Schema Relapsed ovarian or primary Peritoneal requiring chemotherapy Previous platinum-based chemotherapy Conventional platinum-based chemotherapy Paclitaxel plus platinum chemotherapy R A N D O M I Z E Prior chemotherapy Carboplatin (31%) Paclitaxel/platinum (40%) Other (30%) TFI > 12 months for 75% Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group TFI = treatment-free interval ICON 4 Response (Difference of 12%; 95% CI -0.1% to 24%; p=0.06) CR = complete response; ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum; PR = partial response; Parmar MK, et al. Lancet. 2003;361:2099-2106. Proportion alive and progression-free 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Patients at risk Pac-Plat 392 179 52 25 17 Plat 410 157 45 17 7 Years from randomization Hazard ratio = 0.76 (95% CI 0.66 - 0.89; p < 0.001) Absolute difference at 1 year = 10% (40% to 50%; 95% CI 4% to 15%) Ovarian Carcinoma: ICON 4 Progression-Free Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum
Slide 36 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days GC vs TC Induction Regimens Followed by T Consolidation: Response Rates Gordon A, et al. ASCO 2008. Abstract 5536. *CR required a normalized CA-125. GC vs TC Induction Regimens Followed by T Consolidation: Pt-Based Toxicity Gordon A, et al. ASCO 2008. Abstract 5536. Conventional vs Dose-Dense TC (NOVEL): Study Design Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO 2008. Abstract 5506. P = .72 Evaluated by WHO criteria Conventional vs Dose-Dense TC (NOVEL): Clinical Responses Isonishi S, et al. ASCO 2008. Abstract 5506. Conventional vs Dose-Dense TC (NOVEL): PFS 0.0 0.2 0.4 0.6 0.8 1.0 0 12 30 54 Mos From Randomization Proportion Surviving Progression Free 0.1 0.3 0.5 0.7 0.9 6 18 42 24 48 36 Isonishi S, et al. ASCO 2008. Abstract 5506. dd-TC c-TC Ovarian Carcinoma: Clinical Course Symptoms Diagnosis Chemotherapy #1 Staging Primary cytoreduction Interval Cytoreduction Progression Chemo #2 Chemo #3+ Supportive Care Death Consolidation/ Maintenance Cure Secondary Cytoreduction Second-Look Goals of Treatment: Relapsed Ovarian Cancer Prolong Survival Delay Time to Progression Control Disease-Related Symptoms Minimize Treatment-Related Symptoms Maintain or Improve Quality of Life Issues Impacting Therapy for Recurrent Ovarian Cancer Treatment-free interval Impact of consolidation/maintenance therapy Number of prior regimens Response to prior therapy Toxicity from prior therapy Prior use of growth factors Transfusion requirements Neuropathy Volume and site(s) of disease Ascites/GI symptoms Performance status Surveillance Options for Ovarian Cancer Patients in Remission Second-look laparotomy Physical examination Include pelvic examination CA-125 Imaging CT scan MRI? PET scan? CT = computed tomography MRI = magnetic resonance imaging PET = positron emission tomography Ovarian Cancer: How is Relapse Defined? Continuous rise in CA-125 CA-125 above 100 Radiographic recurrence Symptomatic recurrence Physical examination findings Combination of above When Does Ovarian Cancer Recur? Carb = carboplatin; Cis = cisplatin; Doc = docetaxel; pac = paclitaxel; GOG = Gynecologic Oncology Group; IP = intraperitoneal; Pac = paclitaxel Active Agents in Ovarian Cancer Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Refractory P R I M A R Y T R E A T M E N T Resistant Sensitive 0 3 6 12 18 24 Months “Very Sensitive” Ovarian Cancer at First Relapse Definition of Sensitivity Defined as measurable recurrence, not biochemical (CA-125) recurrence ICON 4 Schema Relapsed ovarian or primary Peritoneal requiring chemotherapy Previous platinum-based chemotherapy Conventional platinum-based chemotherapy Paclitaxel plus platinum chemotherapy R A N D O M I Z E Prior chemotherapy Carboplatin (31%) Paclitaxel/platinum (40%) Other (30%) TFI > 12 months for 75% Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group TFI = treatment-free interval ICON 4 Response (Difference of 12%; 95% CI -0.1% to 24%; p=0.06) CR = complete response; ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum; PR = partial response; Parmar MK, et al. Lancet. 2003;361:2099-2106. Proportion alive and progression-free 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Patients at risk Pac-Plat 392 179 52 25 17 Plat 410 157 45 17 7 Years from randomization Hazard ratio = 0.76 (95% CI 0.66 - 0.89; p < 0.001) Absolute difference at 1 year = 10% (40% to 50%; 95% CI 4% to 15%) Ovarian Carcinoma: ICON 4 Progression-Free Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum Hazard ratio = 0.82 (95% CI 0.69 - 0.97; p = 0.023) Absolute difference 2 years = 7% (50% to 57%; 95% CI 1% to 12%) Patients at risk Pac-Plat 392 306 167 96 43 Plat 410 295 150 68 33 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Years from randomization Proportion alive ICON 4: Overall Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum
Slide 37 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days GC vs TC Induction Regimens Followed by T Consolidation: Response Rates Gordon A, et al. ASCO 2008. Abstract 5536. *CR required a normalized CA-125. GC vs TC Induction Regimens Followed by T Consolidation: Pt-Based Toxicity Gordon A, et al. ASCO 2008. Abstract 5536. Conventional vs Dose-Dense TC (NOVEL): Study Design Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO 2008. Abstract 5506. P = .72 Evaluated by WHO criteria Conventional vs Dose-Dense TC (NOVEL): Clinical Responses Isonishi S, et al. ASCO 2008. Abstract 5506. Conventional vs Dose-Dense TC (NOVEL): PFS 0.0 0.2 0.4 0.6 0.8 1.0 0 12 30 54 Mos From Randomization Proportion Surviving Progression Free 0.1 0.3 0.5 0.7 0.9 6 18 42 24 48 36 Isonishi S, et al. ASCO 2008. Abstract 5506. dd-TC c-TC Ovarian Carcinoma: Clinical Course Symptoms Diagnosis Chemotherapy #1 Staging Primary cytoreduction Interval Cytoreduction Progression Chemo #2 Chemo #3+ Supportive Care Death Consolidation/ Maintenance Cure Secondary Cytoreduction Second-Look Goals of Treatment: Relapsed Ovarian Cancer Prolong Survival Delay Time to Progression Control Disease-Related Symptoms Minimize Treatment-Related Symptoms Maintain or Improve Quality of Life Issues Impacting Therapy for Recurrent Ovarian Cancer Treatment-free interval Impact of consolidation/maintenance therapy Number of prior regimens Response to prior therapy Toxicity from prior therapy Prior use of growth factors Transfusion requirements Neuropathy Volume and site(s) of disease Ascites/GI symptoms Performance status Surveillance Options for Ovarian Cancer Patients in Remission Second-look laparotomy Physical examination Include pelvic examination CA-125 Imaging CT scan MRI? PET scan? CT = computed tomography MRI = magnetic resonance imaging PET = positron emission tomography Ovarian Cancer: How is Relapse Defined? Continuous rise in CA-125 CA-125 above 100 Radiographic recurrence Symptomatic recurrence Physical examination findings Combination of above When Does Ovarian Cancer Recur? Carb = carboplatin; Cis = cisplatin; Doc = docetaxel; pac = paclitaxel; GOG = Gynecologic Oncology Group; IP = intraperitoneal; Pac = paclitaxel Active Agents in Ovarian Cancer Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Refractory P R I M A R Y T R E A T M E N T Resistant Sensitive 0 3 6 12 18 24 Months “Very Sensitive” Ovarian Cancer at First Relapse Definition of Sensitivity Defined as measurable recurrence, not biochemical (CA-125) recurrence ICON 4 Schema Relapsed ovarian or primary Peritoneal requiring chemotherapy Previous platinum-based chemotherapy Conventional platinum-based chemotherapy Paclitaxel plus platinum chemotherapy R A N D O M I Z E Prior chemotherapy Carboplatin (31%) Paclitaxel/platinum (40%) Other (30%) TFI > 12 months for 75% Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group TFI = treatment-free interval ICON 4 Response (Difference of 12%; 95% CI -0.1% to 24%; p=0.06) CR = complete response; ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum; PR = partial response; Parmar MK, et al. Lancet. 2003;361:2099-2106. Proportion alive and progression-free 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Patients at risk Pac-Plat 392 179 52 25 17 Plat 410 157 45 17 7 Years from randomization Hazard ratio = 0.76 (95% CI 0.66 - 0.89; p < 0.001) Absolute difference at 1 year = 10% (40% to 50%; 95% CI 4% to 15%) Ovarian Carcinoma: ICON 4 Progression-Free Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum Hazard ratio = 0.82 (95% CI 0.69 - 0.97; p = 0.023) Absolute difference 2 years = 7% (50% to 57%; 95% CI 1% to 12%) Patients at risk Pac-Plat 392 306 167 96 43 Plat 410 295 150 68 33 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Years from randomization Proportion alive ICON 4: Overall Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum R A N D O M I Z E Gemcitabine 1,000 mg/m2 days 1 + 8 Plus Carboplatin AUC 4 day 1 every 21 days × 6 Recurrent ovarian cancer 6+ months after platinum Strata PFI (6 - 12, >12 months) 1st-line therapy (platinum ± paclitaxel) Measurable vs evaluable Primary endpoint = PFS Gem/Carbo vs Carbo: Design Carboplatin AUC 5 day 1 every 21 days × 6 Carbo = carboplatin Gem = gemcitabine PFI = progression-free interval PFS = progression-free survival Pfisterer J, et al. J Clin Oncol. 2006; 24:4699-4707.
Slide 38 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days GC vs TC Induction Regimens Followed by T Consolidation: Response Rates Gordon A, et al. ASCO 2008. Abstract 5536. *CR required a normalized CA-125. GC vs TC Induction Regimens Followed by T Consolidation: Pt-Based Toxicity Gordon A, et al. ASCO 2008. Abstract 5536. Conventional vs Dose-Dense TC (NOVEL): Study Design Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO 2008. Abstract 5506. P = .72 Evaluated by WHO criteria Conventional vs Dose-Dense TC (NOVEL): Clinical Responses Isonishi S, et al. ASCO 2008. Abstract 5506. Conventional vs Dose-Dense TC (NOVEL): PFS 0.0 0.2 0.4 0.6 0.8 1.0 0 12 30 54 Mos From Randomization Proportion Surviving Progression Free 0.1 0.3 0.5 0.7 0.9 6 18 42 24 48 36 Isonishi S, et al. ASCO 2008. Abstract 5506. dd-TC c-TC Ovarian Carcinoma: Clinical Course Symptoms Diagnosis Chemotherapy #1 Staging Primary cytoreduction Interval Cytoreduction Progression Chemo #2 Chemo #3+ Supportive Care Death Consolidation/ Maintenance Cure Secondary Cytoreduction Second-Look Goals of Treatment: Relapsed Ovarian Cancer Prolong Survival Delay Time to Progression Control Disease-Related Symptoms Minimize Treatment-Related Symptoms Maintain or Improve Quality of Life Issues Impacting Therapy for Recurrent Ovarian Cancer Treatment-free interval Impact of consolidation/maintenance therapy Number of prior regimens Response to prior therapy Toxicity from prior therapy Prior use of growth factors Transfusion requirements Neuropathy Volume and site(s) of disease Ascites/GI symptoms Performance status Surveillance Options for Ovarian Cancer Patients in Remission Second-look laparotomy Physical examination Include pelvic examination CA-125 Imaging CT scan MRI? PET scan? CT = computed tomography MRI = magnetic resonance imaging PET = positron emission tomography Ovarian Cancer: How is Relapse Defined? Continuous rise in CA-125 CA-125 above 100 Radiographic recurrence Symptomatic recurrence Physical examination findings Combination of above When Does Ovarian Cancer Recur? Carb = carboplatin; Cis = cisplatin; Doc = docetaxel; pac = paclitaxel; GOG = Gynecologic Oncology Group; IP = intraperitoneal; Pac = paclitaxel Active Agents in Ovarian Cancer Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Refractory P R I M A R Y T R E A T M E N T Resistant Sensitive 0 3 6 12 18 24 Months “Very Sensitive” Ovarian Cancer at First Relapse Definition of Sensitivity Defined as measurable recurrence, not biochemical (CA-125) recurrence ICON 4 Schema Relapsed ovarian or primary Peritoneal requiring chemotherapy Previous platinum-based chemotherapy Conventional platinum-based chemotherapy Paclitaxel plus platinum chemotherapy R A N D O M I Z E Prior chemotherapy Carboplatin (31%) Paclitaxel/platinum (40%) Other (30%) TFI > 12 months for 75% Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group TFI = treatment-free interval ICON 4 Response (Difference of 12%; 95% CI -0.1% to 24%; p=0.06) CR = complete response; ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum; PR = partial response; Parmar MK, et al. Lancet. 2003;361:2099-2106. Proportion alive and progression-free 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Patients at risk Pac-Plat 392 179 52 25 17 Plat 410 157 45 17 7 Years from randomization Hazard ratio = 0.76 (95% CI 0.66 - 0.89; p < 0.001) Absolute difference at 1 year = 10% (40% to 50%; 95% CI 4% to 15%) Ovarian Carcinoma: ICON 4 Progression-Free Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum Hazard ratio = 0.82 (95% CI 0.69 - 0.97; p = 0.023) Absolute difference 2 years = 7% (50% to 57%; 95% CI 1% to 12%) Patients at risk Pac-Plat 392 306 167 96 43 Plat 410 295 150 68 33 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Years from randomization Proportion alive ICON 4: Overall Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum R A N D O M I Z E Gemcitabine 1,000 mg/m2 days 1 + 8 Plus Carboplatin AUC 4 day 1 every 21 days × 6 Recurrent ovarian cancer 6+ months after platinum Strata PFI (6 - 12, >12 months) 1st-line therapy (platinum ± paclitaxel) Measurable vs evaluable Primary endpoint = PFS Gem/Carbo vs Carbo: Design Carboplatin AUC 5 day 1 every 21 days × 6 Carbo = carboplatin Gem = gemcitabine PFI = progression-free interval PFS = progression-free survival Pfisterer J, et al. J Clin Oncol. 2006; 24:4699-4707. AGO OVAR 2.5 Primary Endpoint: Progression-Free Survival GCb: median = 8.6 mo Censoring: 12.4% Cb: median = 5.8 mo Censoring: 12.9% Cb Arm (N=178) GCb Arm (N=178) Log-rank p-value = 0.0038 Unadjusted HR = 0.72 (0.57 to 0.90) Adjusted HR* = 0.71 (0.57 to 0.89) * Adjusted for PFI, Tumor size Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin
Slide 39 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days GC vs TC Induction Regimens Followed by T Consolidation: Response Rates Gordon A, et al. ASCO 2008. Abstract 5536. *CR required a normalized CA-125. GC vs TC Induction Regimens Followed by T Consolidation: Pt-Based Toxicity Gordon A, et al. ASCO 2008. Abstract 5536. Conventional vs Dose-Dense TC (NOVEL): Study Design Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO 2008. Abstract 5506. P = .72 Evaluated by WHO criteria Conventional vs Dose-Dense TC (NOVEL): Clinical Responses Isonishi S, et al. ASCO 2008. Abstract 5506. Conventional vs Dose-Dense TC (NOVEL): PFS 0.0 0.2 0.4 0.6 0.8 1.0 0 12 30 54 Mos From Randomization Proportion Surviving Progression Free 0.1 0.3 0.5 0.7 0.9 6 18 42 24 48 36 Isonishi S, et al. ASCO 2008. Abstract 5506. dd-TC c-TC Ovarian Carcinoma: Clinical Course Symptoms Diagnosis Chemotherapy #1 Staging Primary cytoreduction Interval Cytoreduction Progression Chemo #2 Chemo #3+ Supportive Care Death Consolidation/ Maintenance Cure Secondary Cytoreduction Second-Look Goals of Treatment: Relapsed Ovarian Cancer Prolong Survival Delay Time to Progression Control Disease-Related Symptoms Minimize Treatment-Related Symptoms Maintain or Improve Quality of Life Issues Impacting Therapy for Recurrent Ovarian Cancer Treatment-free interval Impact of consolidation/maintenance therapy Number of prior regimens Response to prior therapy Toxicity from prior therapy Prior use of growth factors Transfusion requirements Neuropathy Volume and site(s) of disease Ascites/GI symptoms Performance status Surveillance Options for Ovarian Cancer Patients in Remission Second-look laparotomy Physical examination Include pelvic examination CA-125 Imaging CT scan MRI? PET scan? CT = computed tomography MRI = magnetic resonance imaging PET = positron emission tomography Ovarian Cancer: How is Relapse Defined? Continuous rise in CA-125 CA-125 above 100 Radiographic recurrence Symptomatic recurrence Physical examination findings Combination of above When Does Ovarian Cancer Recur? Carb = carboplatin; Cis = cisplatin; Doc = docetaxel; pac = paclitaxel; GOG = Gynecologic Oncology Group; IP = intraperitoneal; Pac = paclitaxel Active Agents in Ovarian Cancer Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Refractory P R I M A R Y T R E A T M E N T Resistant Sensitive 0 3 6 12 18 24 Months “Very Sensitive” Ovarian Cancer at First Relapse Definition of Sensitivity Defined as measurable recurrence, not biochemical (CA-125) recurrence ICON 4 Schema Relapsed ovarian or primary Peritoneal requiring chemotherapy Previous platinum-based chemotherapy Conventional platinum-based chemotherapy Paclitaxel plus platinum chemotherapy R A N D O M I Z E Prior chemotherapy Carboplatin (31%) Paclitaxel/platinum (40%) Other (30%) TFI > 12 months for 75% Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group TFI = treatment-free interval ICON 4 Response (Difference of 12%; 95% CI -0.1% to 24%; p=0.06) CR = complete response; ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum; PR = partial response; Parmar MK, et al. Lancet. 2003;361:2099-2106. Proportion alive and progression-free 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Patients at risk Pac-Plat 392 179 52 25 17 Plat 410 157 45 17 7 Years from randomization Hazard ratio = 0.76 (95% CI 0.66 - 0.89; p < 0.001) Absolute difference at 1 year = 10% (40% to 50%; 95% CI 4% to 15%) Ovarian Carcinoma: ICON 4 Progression-Free Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum Hazard ratio = 0.82 (95% CI 0.69 - 0.97; p = 0.023) Absolute difference 2 years = 7% (50% to 57%; 95% CI 1% to 12%) Patients at risk Pac-Plat 392 306 167 96 43 Plat 410 295 150 68 33 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Years from randomization Proportion alive ICON 4: Overall Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum R A N D O M I Z E Gemcitabine 1,000 mg/m2 days 1 + 8 Plus Carboplatin AUC 4 day 1 every 21 days × 6 Recurrent ovarian cancer 6+ months after platinum Strata PFI (6 - 12, >12 months) 1st-line therapy (platinum ± paclitaxel) Measurable vs evaluable Primary endpoint = PFS Gem/Carbo vs Carbo: Design Carboplatin AUC 5 day 1 every 21 days × 6 Carbo = carboplatin Gem = gemcitabine PFI = progression-free interval PFS = progression-free survival Pfisterer J, et al. J Clin Oncol. 2006; 24:4699-4707. AGO OVAR 2.5 Primary Endpoint: Progression-Free Survival GCb: median = 8.6 mo Censoring: 12.4% Cb: median = 5.8 mo Censoring: 12.9% Cb Arm (N=178) GCb Arm (N=178) Log-rank p-value = 0.0038 Unadjusted HR = 0.72 (0.57 to 0.90) Adjusted HR* = 0.71 (0.57 to 0.89) * Adjusted for PFI, Tumor size Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin AGO OVAR 2.5 Efficacy Results: Overall Survival 0.0 0.8 0.2 0.3 0.4 0.5 0.6 0.7 0.9 1.0 0.1 0 6 12 18 60 54 48 42 36 30 24 Proportion Surviving Months Median = 18.0 mo Censoring: 18.5% Median = 17.3 mo Censoring: 22.5% Cb Arm (N=178) GCb Arm (N=178) * Adjusted for PFI, Tumor size and performance status Log-rank p-value = 0.7349 Unadjusted HR = 0.96 (0.75 to 1.23) Adjusted* HR = 0.92 (0.72 to 1.16) Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin
Slide 40 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days GC vs TC Induction Regimens Followed by T Consolidation: Response Rates Gordon A, et al. ASCO 2008. Abstract 5536. *CR required a normalized CA-125. GC vs TC Induction Regimens Followed by T Consolidation: Pt-Based Toxicity Gordon A, et al. ASCO 2008. Abstract 5536. Conventional vs Dose-Dense TC (NOVEL): Study Design Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO 2008. Abstract 5506. P = .72 Evaluated by WHO criteria Conventional vs Dose-Dense TC (NOVEL): Clinical Responses Isonishi S, et al. ASCO 2008. Abstract 5506. Conventional vs Dose-Dense TC (NOVEL): PFS 0.0 0.2 0.4 0.6 0.8 1.0 0 12 30 54 Mos From Randomization Proportion Surviving Progression Free 0.1 0.3 0.5 0.7 0.9 6 18 42 24 48 36 Isonishi S, et al. ASCO 2008. Abstract 5506. dd-TC c-TC Ovarian Carcinoma: Clinical Course Symptoms Diagnosis Chemotherapy #1 Staging Primary cytoreduction Interval Cytoreduction Progression Chemo #2 Chemo #3+ Supportive Care Death Consolidation/ Maintenance Cure Secondary Cytoreduction Second-Look Goals of Treatment: Relapsed Ovarian Cancer Prolong Survival Delay Time to Progression Control Disease-Related Symptoms Minimize Treatment-Related Symptoms Maintain or Improve Quality of Life Issues Impacting Therapy for Recurrent Ovarian Cancer Treatment-free interval Impact of consolidation/maintenance therapy Number of prior regimens Response to prior therapy Toxicity from prior therapy Prior use of growth factors Transfusion requirements Neuropathy Volume and site(s) of disease Ascites/GI symptoms Performance status Surveillance Options for Ovarian Cancer Patients in Remission Second-look laparotomy Physical examination Include pelvic examination CA-125 Imaging CT scan MRI? PET scan? CT = computed tomography MRI = magnetic resonance imaging PET = positron emission tomography Ovarian Cancer: How is Relapse Defined? Continuous rise in CA-125 CA-125 above 100 Radiographic recurrence Symptomatic recurrence Physical examination findings Combination of above When Does Ovarian Cancer Recur? Carb = carboplatin; Cis = cisplatin; Doc = docetaxel; pac = paclitaxel; GOG = Gynecologic Oncology Group; IP = intraperitoneal; Pac = paclitaxel Active Agents in Ovarian Cancer Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Refractory P R I M A R Y T R E A T M E N T Resistant Sensitive 0 3 6 12 18 24 Months “Very Sensitive” Ovarian Cancer at First Relapse Definition of Sensitivity Defined as measurable recurrence, not biochemical (CA-125) recurrence ICON 4 Schema Relapsed ovarian or primary Peritoneal requiring chemotherapy Previous platinum-based chemotherapy Conventional platinum-based chemotherapy Paclitaxel plus platinum chemotherapy R A N D O M I Z E Prior chemotherapy Carboplatin (31%) Paclitaxel/platinum (40%) Other (30%) TFI > 12 months for 75% Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group TFI = treatment-free interval ICON 4 Response (Difference of 12%; 95% CI -0.1% to 24%; p=0.06) CR = complete response; ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum; PR = partial response; Parmar MK, et al. Lancet. 2003;361:2099-2106. Proportion alive and progression-free 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Patients at risk Pac-Plat 392 179 52 25 17 Plat 410 157 45 17 7 Years from randomization Hazard ratio = 0.76 (95% CI 0.66 - 0.89; p < 0.001) Absolute difference at 1 year = 10% (40% to 50%; 95% CI 4% to 15%) Ovarian Carcinoma: ICON 4 Progression-Free Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum Hazard ratio = 0.82 (95% CI 0.69 - 0.97; p = 0.023) Absolute difference 2 years = 7% (50% to 57%; 95% CI 1% to 12%) Patients at risk Pac-Plat 392 306 167 96 43 Plat 410 295 150 68 33 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Years from randomization Proportion alive ICON 4: Overall Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum R A N D O M I Z E Gemcitabine 1,000 mg/m2 days 1 + 8 Plus Carboplatin AUC 4 day 1 every 21 days × 6 Recurrent ovarian cancer 6+ months after platinum Strata PFI (6 - 12, >12 months) 1st-line therapy (platinum ± paclitaxel) Measurable vs evaluable Primary endpoint = PFS Gem/Carbo vs Carbo: Design Carboplatin AUC 5 day 1 every 21 days × 6 Carbo = carboplatin Gem = gemcitabine PFI = progression-free interval PFS = progression-free survival Pfisterer J, et al. J Clin Oncol. 2006; 24:4699-4707. AGO OVAR 2.5 Primary Endpoint: Progression-Free Survival GCb: median = 8.6 mo Censoring: 12.4% Cb: median = 5.8 mo Censoring: 12.9% Cb Arm (N=178) GCb Arm (N=178) Log-rank p-value = 0.0038 Unadjusted HR = 0.72 (0.57 to 0.90) Adjusted HR* = 0.71 (0.57 to 0.89) * Adjusted for PFI, Tumor size Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin AGO OVAR 2.5 Efficacy Results: Overall Survival 0.0 0.8 0.2 0.3 0.4 0.5 0.6 0.7 0.9 1.0 0.1 0 6 12 18 60 54 48 42 36 30 24 Proportion Surviving Months Median = 18.0 mo Censoring: 18.5% Median = 17.3 mo Censoring: 22.5% Cb Arm (N=178) GCb Arm (N=178) * Adjusted for PFI, Tumor size and performance status Log-rank p-value = 0.7349 Unadjusted HR = 0.96 (0.75 to 1.23) Adjusted* HR = 0.92 (0.72 to 1.16) Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: < 0.5 cm > 0.5-2 cm R A N D O M I Z E 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 Completed (Target accrual 864 pts) PFS 1° endpoint
Slide 41 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days GC vs TC Induction Regimens Followed by T Consolidation: Response Rates Gordon A, et al. ASCO 2008. Abstract 5536. *CR required a normalized CA-125. GC vs TC Induction Regimens Followed by T Consolidation: Pt-Based Toxicity Gordon A, et al. ASCO 2008. Abstract 5536. Conventional vs Dose-Dense TC (NOVEL): Study Design Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO 2008. Abstract 5506. P = .72 Evaluated by WHO criteria Conventional vs Dose-Dense TC (NOVEL): Clinical Responses Isonishi S, et al. ASCO 2008. Abstract 5506. Conventional vs Dose-Dense TC (NOVEL): PFS 0.0 0.2 0.4 0.6 0.8 1.0 0 12 30 54 Mos From Randomization Proportion Surviving Progression Free 0.1 0.3 0.5 0.7 0.9 6 18 42 24 48 36 Isonishi S, et al. ASCO 2008. Abstract 5506. dd-TC c-TC Ovarian Carcinoma: Clinical Course Symptoms Diagnosis Chemotherapy #1 Staging Primary cytoreduction Interval Cytoreduction Progression Chemo #2 Chemo #3+ Supportive Care Death Consolidation/ Maintenance Cure Secondary Cytoreduction Second-Look Goals of Treatment: Relapsed Ovarian Cancer Prolong Survival Delay Time to Progression Control Disease-Related Symptoms Minimize Treatment-Related Symptoms Maintain or Improve Quality of Life Issues Impacting Therapy for Recurrent Ovarian Cancer Treatment-free interval Impact of consolidation/maintenance therapy Number of prior regimens Response to prior therapy Toxicity from prior therapy Prior use of growth factors Transfusion requirements Neuropathy Volume and site(s) of disease Ascites/GI symptoms Performance status Surveillance Options for Ovarian Cancer Patients in Remission Second-look laparotomy Physical examination Include pelvic examination CA-125 Imaging CT scan MRI? PET scan? CT = computed tomography MRI = magnetic resonance imaging PET = positron emission tomography Ovarian Cancer: How is Relapse Defined? Continuous rise in CA-125 CA-125 above 100 Radiographic recurrence Symptomatic recurrence Physical examination findings Combination of above When Does Ovarian Cancer Recur? Carb = carboplatin; Cis = cisplatin; Doc = docetaxel; pac = paclitaxel; GOG = Gynecologic Oncology Group; IP = intraperitoneal; Pac = paclitaxel Active Agents in Ovarian Cancer Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Refractory P R I M A R Y T R E A T M E N T Resistant Sensitive 0 3 6 12 18 24 Months “Very Sensitive” Ovarian Cancer at First Relapse Definition of Sensitivity Defined as measurable recurrence, not biochemical (CA-125) recurrence ICON 4 Schema Relapsed ovarian or primary Peritoneal requiring chemotherapy Previous platinum-based chemotherapy Conventional platinum-based chemotherapy Paclitaxel plus platinum chemotherapy R A N D O M I Z E Prior chemotherapy Carboplatin (31%) Paclitaxel/platinum (40%) Other (30%) TFI > 12 months for 75% Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group TFI = treatment-free interval ICON 4 Response (Difference of 12%; 95% CI -0.1% to 24%; p=0.06) CR = complete response; ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum; PR = partial response; Parmar MK, et al. Lancet. 2003;361:2099-2106. Proportion alive and progression-free 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Patients at risk Pac-Plat 392 179 52 25 17 Plat 410 157 45 17 7 Years from randomization Hazard ratio = 0.76 (95% CI 0.66 - 0.89; p < 0.001) Absolute difference at 1 year = 10% (40% to 50%; 95% CI 4% to 15%) Ovarian Carcinoma: ICON 4 Progression-Free Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum Hazard ratio = 0.82 (95% CI 0.69 - 0.97; p = 0.023) Absolute difference 2 years = 7% (50% to 57%; 95% CI 1% to 12%) Patients at risk Pac-Plat 392 306 167 96 43 Plat 410 295 150 68 33 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Years from randomization Proportion alive ICON 4: Overall Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum R A N D O M I Z E Gemcitabine 1,000 mg/m2 days 1 + 8 Plus Carboplatin AUC 4 day 1 every 21 days × 6 Recurrent ovarian cancer 6+ months after platinum Strata PFI (6 - 12, >12 months) 1st-line therapy (platinum ± paclitaxel) Measurable vs evaluable Primary endpoint = PFS Gem/Carbo vs Carbo: Design Carboplatin AUC 5 day 1 every 21 days × 6 Carbo = carboplatin Gem = gemcitabine PFI = progression-free interval PFS = progression-free survival Pfisterer J, et al. J Clin Oncol. 2006; 24:4699-4707. AGO OVAR 2.5 Primary Endpoint: Progression-Free Survival GCb: median = 8.6 mo Censoring: 12.4% Cb: median = 5.8 mo Censoring: 12.9% Cb Arm (N=178) GCb Arm (N=178) Log-rank p-value = 0.0038 Unadjusted HR = 0.72 (0.57 to 0.90) Adjusted HR* = 0.71 (0.57 to 0.89) * Adjusted for PFI, Tumor size Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin AGO OVAR 2.5 Efficacy Results: Overall Survival 0.0 0.8 0.2 0.3 0.4 0.5 0.6 0.7 0.9 1.0 0.1 0 6 12 18 60 54 48 42 36 30 24 Proportion Surviving Months Median = 18.0 mo Censoring: 18.5% Median = 17.3 mo Censoring: 22.5% Cb Arm (N=178) GCb Arm (N=178) * Adjusted for PFI, Tumor size and performance status Log-rank p-value = 0.7349 Unadjusted HR = 0.96 (0.75 to 1.23) Adjusted* HR = 0.92 (0.72 to 1.16) Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: < 0.5 cm > 0.5-2 cm R A N D O M I Z E 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 Completed (Target accrual 864 pts) PFS 1° endpoint Farletuzumab (MORAb-003) in Platinum-Sensitive EOC: Study Rationale FRA is overexpressed in most EOC; largely absent from normal tissue Binding of MORAb-003 to FRA blocks phosphorylation by Lyn kinase; mediates FRA-expressing tumor cell killing; suppresses tumor growth in xenograft models Phase I study of single agent MORAb-003 demonstrated no significant adverse effects and suggested efficacy in platinum-resistant EOC
Slide 42 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days GC vs TC Induction Regimens Followed by T Consolidation: Response Rates Gordon A, et al. ASCO 2008. Abstract 5536. *CR required a normalized CA-125. GC vs TC Induction Regimens Followed by T Consolidation: Pt-Based Toxicity Gordon A, et al. ASCO 2008. Abstract 5536. Conventional vs Dose-Dense TC (NOVEL): Study Design Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO 2008. Abstract 5506. P = .72 Evaluated by WHO criteria Conventional vs Dose-Dense TC (NOVEL): Clinical Responses Isonishi S, et al. ASCO 2008. Abstract 5506. Conventional vs Dose-Dense TC (NOVEL): PFS 0.0 0.2 0.4 0.6 0.8 1.0 0 12 30 54 Mos From Randomization Proportion Surviving Progression Free 0.1 0.3 0.5 0.7 0.9 6 18 42 24 48 36 Isonishi S, et al. ASCO 2008. Abstract 5506. dd-TC c-TC Ovarian Carcinoma: Clinical Course Symptoms Diagnosis Chemotherapy #1 Staging Primary cytoreduction Interval Cytoreduction Progression Chemo #2 Chemo #3+ Supportive Care Death Consolidation/ Maintenance Cure Secondary Cytoreduction Second-Look Goals of Treatment: Relapsed Ovarian Cancer Prolong Survival Delay Time to Progression Control Disease-Related Symptoms Minimize Treatment-Related Symptoms Maintain or Improve Quality of Life Issues Impacting Therapy for Recurrent Ovarian Cancer Treatment-free interval Impact of consolidation/maintenance therapy Number of prior regimens Response to prior therapy Toxicity from prior therapy Prior use of growth factors Transfusion requirements Neuropathy Volume and site(s) of disease Ascites/GI symptoms Performance status Surveillance Options for Ovarian Cancer Patients in Remission Second-look laparotomy Physical examination Include pelvic examination CA-125 Imaging CT scan MRI? PET scan? CT = computed tomography MRI = magnetic resonance imaging PET = positron emission tomography Ovarian Cancer: How is Relapse Defined? Continuous rise in CA-125 CA-125 above 100 Radiographic recurrence Symptomatic recurrence Physical examination findings Combination of above When Does Ovarian Cancer Recur? Carb = carboplatin; Cis = cisplatin; Doc = docetaxel; pac = paclitaxel; GOG = Gynecologic Oncology Group; IP = intraperitoneal; Pac = paclitaxel Active Agents in Ovarian Cancer Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Refractory P R I M A R Y T R E A T M E N T Resistant Sensitive 0 3 6 12 18 24 Months “Very Sensitive” Ovarian Cancer at First Relapse Definition of Sensitivity Defined as measurable recurrence, not biochemical (CA-125) recurrence ICON 4 Schema Relapsed ovarian or primary Peritoneal requiring chemotherapy Previous platinum-based chemotherapy Conventional platinum-based chemotherapy Paclitaxel plus platinum chemotherapy R A N D O M I Z E Prior chemotherapy Carboplatin (31%) Paclitaxel/platinum (40%) Other (30%) TFI > 12 months for 75% Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group TFI = treatment-free interval ICON 4 Response (Difference of 12%; 95% CI -0.1% to 24%; p=0.06) CR = complete response; ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum; PR = partial response; Parmar MK, et al. Lancet. 2003;361:2099-2106. Proportion alive and progression-free 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Patients at risk Pac-Plat 392 179 52 25 17 Plat 410 157 45 17 7 Years from randomization Hazard ratio = 0.76 (95% CI 0.66 - 0.89; p < 0.001) Absolute difference at 1 year = 10% (40% to 50%; 95% CI 4% to 15%) Ovarian Carcinoma: ICON 4 Progression-Free Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum Hazard ratio = 0.82 (95% CI 0.69 - 0.97; p = 0.023) Absolute difference 2 years = 7% (50% to 57%; 95% CI 1% to 12%) Patients at risk Pac-Plat 392 306 167 96 43 Plat 410 295 150 68 33 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Years from randomization Proportion alive ICON 4: Overall Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum R A N D O M I Z E Gemcitabine 1,000 mg/m2 days 1 + 8 Plus Carboplatin AUC 4 day 1 every 21 days × 6 Recurrent ovarian cancer 6+ months after platinum Strata PFI (6 - 12, >12 months) 1st-line therapy (platinum ± paclitaxel) Measurable vs evaluable Primary endpoint = PFS Gem/Carbo vs Carbo: Design Carboplatin AUC 5 day 1 every 21 days × 6 Carbo = carboplatin Gem = gemcitabine PFI = progression-free interval PFS = progression-free survival Pfisterer J, et al. J Clin Oncol. 2006; 24:4699-4707. AGO OVAR 2.5 Primary Endpoint: Progression-Free Survival GCb: median = 8.6 mo Censoring: 12.4% Cb: median = 5.8 mo Censoring: 12.9% Cb Arm (N=178) GCb Arm (N=178) Log-rank p-value = 0.0038 Unadjusted HR = 0.72 (0.57 to 0.90) Adjusted HR* = 0.71 (0.57 to 0.89) * Adjusted for PFI, Tumor size Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin AGO OVAR 2.5 Efficacy Results: Overall Survival 0.0 0.8 0.2 0.3 0.4 0.5 0.6 0.7 0.9 1.0 0.1 0 6 12 18 60 54 48 42 36 30 24 Proportion Surviving Months Median = 18.0 mo Censoring: 18.5% Median = 17.3 mo Censoring: 22.5% Cb Arm (N=178) GCb Arm (N=178) * Adjusted for PFI, Tumor size and performance status Log-rank p-value = 0.7349 Unadjusted HR = 0.96 (0.75 to 1.23) Adjusted* HR = 0.92 (0.72 to 1.16) Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: < 0.5 cm > 0.5-2 cm R A N D O M I Z E 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 Completed (Target accrual 864 pts) PFS 1° endpoint Farletuzumab (MORAb-003) in Platinum-Sensitive EOC: Study Rationale FRA is overexpressed in most EOC; largely absent from normal tissue Binding of MORAb-003 to FRA blocks phosphorylation by Lyn kinase; mediates FRA-expressing tumor cell killing; suppresses tumor growth in xenograft models Phase I study of single agent MORAb-003 demonstrated no significant adverse effects and suggested efficacy in platinum-resistant EOC MORAb-003 in Platinum-Sensitive EOC: Phase II Study Design Patients with platinum-sensitive EOC in first relapse after first remission of 6-18 months duration with evaluable disease by CA125 (Enrolled N = 58; eligible n = 54) Asymptomatic relapse Single-agent Farletuzumab until progression (n = 28) Original Carbo/Taxane regimen + Farletuzumab for 6 cycles (n = 26) Symptomatic relapse Compare lengths of first and second remissions Farletuzumab maintenance Rx for responders Single-agent ORR Combination ORR Armstrong DK, et al. ASCO 2008. Abstract 5500.
Slide 43 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days GC vs TC Induction Regimens Followed by T Consolidation: Response Rates Gordon A, et al. ASCO 2008. Abstract 5536. *CR required a normalized CA-125. GC vs TC Induction Regimens Followed by T Consolidation: Pt-Based Toxicity Gordon A, et al. ASCO 2008. Abstract 5536. Conventional vs Dose-Dense TC (NOVEL): Study Design Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO 2008. Abstract 5506. P = .72 Evaluated by WHO criteria Conventional vs Dose-Dense TC (NOVEL): Clinical Responses Isonishi S, et al. ASCO 2008. Abstract 5506. Conventional vs Dose-Dense TC (NOVEL): PFS 0.0 0.2 0.4 0.6 0.8 1.0 0 12 30 54 Mos From Randomization Proportion Surviving Progression Free 0.1 0.3 0.5 0.7 0.9 6 18 42 24 48 36 Isonishi S, et al. ASCO 2008. Abstract 5506. dd-TC c-TC Ovarian Carcinoma: Clinical Course Symptoms Diagnosis Chemotherapy #1 Staging Primary cytoreduction Interval Cytoreduction Progression Chemo #2 Chemo #3+ Supportive Care Death Consolidation/ Maintenance Cure Secondary Cytoreduction Second-Look Goals of Treatment: Relapsed Ovarian Cancer Prolong Survival Delay Time to Progression Control Disease-Related Symptoms Minimize Treatment-Related Symptoms Maintain or Improve Quality of Life Issues Impacting Therapy for Recurrent Ovarian Cancer Treatment-free interval Impact of consolidation/maintenance therapy Number of prior regimens Response to prior therapy Toxicity from prior therapy Prior use of growth factors Transfusion requirements Neuropathy Volume and site(s) of disease Ascites/GI symptoms Performance status Surveillance Options for Ovarian Cancer Patients in Remission Second-look laparotomy Physical examination Include pelvic examination CA-125 Imaging CT scan MRI? PET scan? CT = computed tomography MRI = magnetic resonance imaging PET = positron emission tomography Ovarian Cancer: How is Relapse Defined? Continuous rise in CA-125 CA-125 above 100 Radiographic recurrence Symptomatic recurrence Physical examination findings Combination of above When Does Ovarian Cancer Recur? Carb = carboplatin; Cis = cisplatin; Doc = docetaxel; pac = paclitaxel; GOG = Gynecologic Oncology Group; IP = intraperitoneal; Pac = paclitaxel Active Agents in Ovarian Cancer Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Refractory P R I M A R Y T R E A T M E N T Resistant Sensitive 0 3 6 12 18 24 Months “Very Sensitive” Ovarian Cancer at First Relapse Definition of Sensitivity Defined as measurable recurrence, not biochemical (CA-125) recurrence ICON 4 Schema Relapsed ovarian or primary Peritoneal requiring chemotherapy Previous platinum-based chemotherapy Conventional platinum-based chemotherapy Paclitaxel plus platinum chemotherapy R A N D O M I Z E Prior chemotherapy Carboplatin (31%) Paclitaxel/platinum (40%) Other (30%) TFI > 12 months for 75% Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group TFI = treatment-free interval ICON 4 Response (Difference of 12%; 95% CI -0.1% to 24%; p=0.06) CR = complete response; ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum; PR = partial response; Parmar MK, et al. Lancet. 2003;361:2099-2106. Proportion alive and progression-free 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Patients at risk Pac-Plat 392 179 52 25 17 Plat 410 157 45 17 7 Years from randomization Hazard ratio = 0.76 (95% CI 0.66 - 0.89; p < 0.001) Absolute difference at 1 year = 10% (40% to 50%; 95% CI 4% to 15%) Ovarian Carcinoma: ICON 4 Progression-Free Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum Hazard ratio = 0.82 (95% CI 0.69 - 0.97; p = 0.023) Absolute difference 2 years = 7% (50% to 57%; 95% CI 1% to 12%) Patients at risk Pac-Plat 392 306 167 96 43 Plat 410 295 150 68 33 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Years from randomization Proportion alive ICON 4: Overall Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum R A N D O M I Z E Gemcitabine 1,000 mg/m2 days 1 + 8 Plus Carboplatin AUC 4 day 1 every 21 days × 6 Recurrent ovarian cancer 6+ months after platinum Strata PFI (6 - 12, >12 months) 1st-line therapy (platinum ± paclitaxel) Measurable vs evaluable Primary endpoint = PFS Gem/Carbo vs Carbo: Design Carboplatin AUC 5 day 1 every 21 days × 6 Carbo = carboplatin Gem = gemcitabine PFI = progression-free interval PFS = progression-free survival Pfisterer J, et al. J Clin Oncol. 2006; 24:4699-4707. AGO OVAR 2.5 Primary Endpoint: Progression-Free Survival GCb: median = 8.6 mo Censoring: 12.4% Cb: median = 5.8 mo Censoring: 12.9% Cb Arm (N=178) GCb Arm (N=178) Log-rank p-value = 0.0038 Unadjusted HR = 0.72 (0.57 to 0.90) Adjusted HR* = 0.71 (0.57 to 0.89) * Adjusted for PFI, Tumor size Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin AGO OVAR 2.5 Efficacy Results: Overall Survival 0.0 0.8 0.2 0.3 0.4 0.5 0.6 0.7 0.9 1.0 0.1 0 6 12 18 60 54 48 42 36 30 24 Proportion Surviving Months Median = 18.0 mo Censoring: 18.5% Median = 17.3 mo Censoring: 22.5% Cb Arm (N=178) GCb Arm (N=178) * Adjusted for PFI, Tumor size and performance status Log-rank p-value = 0.7349 Unadjusted HR = 0.96 (0.75 to 1.23) Adjusted* HR = 0.92 (0.72 to 1.16) Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: < 0.5 cm > 0.5-2 cm R A N D O M I Z E 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 Completed (Target accrual 864 pts) PFS 1° endpoint Farletuzumab (MORAb-003) in Platinum-Sensitive EOC: Study Rationale FRA is overexpressed in most EOC; largely absent from normal tissue Binding of MORAb-003 to FRA blocks phosphorylation by Lyn kinase; mediates FRA-expressing tumor cell killing; suppresses tumor growth in xenograft models Phase I study of single agent MORAb-003 demonstrated no significant adverse effects and suggested efficacy in platinum-resistant EOC MORAb-003 in Platinum-Sensitive EOC: Phase II Study Design Patients with platinum-sensitive EOC in first relapse after first remission of 6-18 months duration with evaluable disease by CA125 (Enrolled N = 58; eligible n = 54) Asymptomatic relapse Single-agent Farletuzumab until progression (n = 28) Original Carbo/Taxane regimen + Farletuzumab for 6 cycles (n = 26) Symptomatic relapse Compare lengths of first and second remissions Farletuzumab maintenance Rx for responders Single-agent ORR Combination ORR Armstrong DK, et al. ASCO 2008. Abstract 5500. All arms MORAb-003: 100 mg/m2 weekly Run-in phase with 6 subjects at 37.5 and 6 at 62.5 mg/m2 Combination therapy arm every 21 days x 6 cycles Carboplatin: AUC 5-6 Taxane Paclitaxel 175 mg/m2 over 3 hours or Docetaxel 75 mg/m2 MORAb-003-002 Phase II: Treatment Arms Armstrong DK, et al. ASCO 2008. Abstract 5500.
Slide 44 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days GC vs TC Induction Regimens Followed by T Consolidation: Response Rates Gordon A, et al. ASCO 2008. Abstract 5536. *CR required a normalized CA-125. GC vs TC Induction Regimens Followed by T Consolidation: Pt-Based Toxicity Gordon A, et al. ASCO 2008. Abstract 5536. Conventional vs Dose-Dense TC (NOVEL): Study Design Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO 2008. Abstract 5506. P = .72 Evaluated by WHO criteria Conventional vs Dose-Dense TC (NOVEL): Clinical Responses Isonishi S, et al. ASCO 2008. Abstract 5506. Conventional vs Dose-Dense TC (NOVEL): PFS 0.0 0.2 0.4 0.6 0.8 1.0 0 12 30 54 Mos From Randomization Proportion Surviving Progression Free 0.1 0.3 0.5 0.7 0.9 6 18 42 24 48 36 Isonishi S, et al. ASCO 2008. Abstract 5506. dd-TC c-TC Ovarian Carcinoma: Clinical Course Symptoms Diagnosis Chemotherapy #1 Staging Primary cytoreduction Interval Cytoreduction Progression Chemo #2 Chemo #3+ Supportive Care Death Consolidation/ Maintenance Cure Secondary Cytoreduction Second-Look Goals of Treatment: Relapsed Ovarian Cancer Prolong Survival Delay Time to Progression Control Disease-Related Symptoms Minimize Treatment-Related Symptoms Maintain or Improve Quality of Life Issues Impacting Therapy for Recurrent Ovarian Cancer Treatment-free interval Impact of consolidation/maintenance therapy Number of prior regimens Response to prior therapy Toxicity from prior therapy Prior use of growth factors Transfusion requirements Neuropathy Volume and site(s) of disease Ascites/GI symptoms Performance status Surveillance Options for Ovarian Cancer Patients in Remission Second-look laparotomy Physical examination Include pelvic examination CA-125 Imaging CT scan MRI? PET scan? CT = computed tomography MRI = magnetic resonance imaging PET = positron emission tomography Ovarian Cancer: How is Relapse Defined? Continuous rise in CA-125 CA-125 above 100 Radiographic recurrence Symptomatic recurrence Physical examination findings Combination of above When Does Ovarian Cancer Recur? Carb = carboplatin; Cis = cisplatin; Doc = docetaxel; pac = paclitaxel; GOG = Gynecologic Oncology Group; IP = intraperitoneal; Pac = paclitaxel Active Agents in Ovarian Cancer Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Refractory P R I M A R Y T R E A T M E N T Resistant Sensitive 0 3 6 12 18 24 Months “Very Sensitive” Ovarian Cancer at First Relapse Definition of Sensitivity Defined as measurable recurrence, not biochemical (CA-125) recurrence ICON 4 Schema Relapsed ovarian or primary Peritoneal requiring chemotherapy Previous platinum-based chemotherapy Conventional platinum-based chemotherapy Paclitaxel plus platinum chemotherapy R A N D O M I Z E Prior chemotherapy Carboplatin (31%) Paclitaxel/platinum (40%) Other (30%) TFI > 12 months for 75% Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group TFI = treatment-free interval ICON 4 Response (Difference of 12%; 95% CI -0.1% to 24%; p=0.06) CR = complete response; ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum; PR = partial response; Parmar MK, et al. Lancet. 2003;361:2099-2106. Proportion alive and progression-free 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Patients at risk Pac-Plat 392 179 52 25 17 Plat 410 157 45 17 7 Years from randomization Hazard ratio = 0.76 (95% CI 0.66 - 0.89; p < 0.001) Absolute difference at 1 year = 10% (40% to 50%; 95% CI 4% to 15%) Ovarian Carcinoma: ICON 4 Progression-Free Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum Hazard ratio = 0.82 (95% CI 0.69 - 0.97; p = 0.023) Absolute difference 2 years = 7% (50% to 57%; 95% CI 1% to 12%) Patients at risk Pac-Plat 392 306 167 96 43 Plat 410 295 150 68 33 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Years from randomization Proportion alive ICON 4: Overall Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum R A N D O M I Z E Gemcitabine 1,000 mg/m2 days 1 + 8 Plus Carboplatin AUC 4 day 1 every 21 days × 6 Recurrent ovarian cancer 6+ months after platinum Strata PFI (6 - 12, >12 months) 1st-line therapy (platinum ± paclitaxel) Measurable vs evaluable Primary endpoint = PFS Gem/Carbo vs Carbo: Design Carboplatin AUC 5 day 1 every 21 days × 6 Carbo = carboplatin Gem = gemcitabine PFI = progression-free interval PFS = progression-free survival Pfisterer J, et al. J Clin Oncol. 2006; 24:4699-4707. AGO OVAR 2.5 Primary Endpoint: Progression-Free Survival GCb: median = 8.6 mo Censoring: 12.4% Cb: median = 5.8 mo Censoring: 12.9% Cb Arm (N=178) GCb Arm (N=178) Log-rank p-value = 0.0038 Unadjusted HR = 0.72 (0.57 to 0.90) Adjusted HR* = 0.71 (0.57 to 0.89) * Adjusted for PFI, Tumor size Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin AGO OVAR 2.5 Efficacy Results: Overall Survival 0.0 0.8 0.2 0.3 0.4 0.5 0.6 0.7 0.9 1.0 0.1 0 6 12 18 60 54 48 42 36 30 24 Proportion Surviving Months Median = 18.0 mo Censoring: 18.5% Median = 17.3 mo Censoring: 22.5% Cb Arm (N=178) GCb Arm (N=178) * Adjusted for PFI, Tumor size and performance status Log-rank p-value = 0.7349 Unadjusted HR = 0.96 (0.75 to 1.23) Adjusted* HR = 0.92 (0.72 to 1.16) Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: < 0.5 cm > 0.5-2 cm R A N D O M I Z E 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 Completed (Target accrual 864 pts) PFS 1° endpoint Farletuzumab (MORAb-003) in Platinum-Sensitive EOC: Study Rationale FRA is overexpressed in most EOC; largely absent from normal tissue Binding of MORAb-003 to FRA blocks phosphorylation by Lyn kinase; mediates FRA-expressing tumor cell killing; suppresses tumor growth in xenograft models Phase I study of single agent MORAb-003 demonstrated no significant adverse effects and suggested efficacy in platinum-resistant EOC MORAb-003 in Platinum-Sensitive EOC: Phase II Study Design Patients with platinum-sensitive EOC in first relapse after first remission of 6-18 months duration with evaluable disease by CA125 (Enrolled N = 58; eligible n = 54) Asymptomatic relapse Single-agent Farletuzumab until progression (n = 28) Original Carbo/Taxane regimen + Farletuzumab for 6 cycles (n = 26) Symptomatic relapse Compare lengths of first and second remissions Farletuzumab maintenance Rx for responders Single-agent ORR Combination ORR Armstrong DK, et al. ASCO 2008. Abstract 5500. All arms MORAb-003: 100 mg/m2 weekly Run-in phase with 6 subjects at 37.5 and 6 at 62.5 mg/m2 Combination therapy arm every 21 days x 6 cycles Carboplatin: AUC 5-6 Taxane Paclitaxel 175 mg/m2 over 3 hours or Docetaxel 75 mg/m2 MORAb-003-002 Phase II: Treatment Arms Armstrong DK, et al. ASCO 2008. Abstract 5500. Comparison of First vs Second Remission Length: n = 6 Data as of May 5, 2008. Armstrong DK, et al. ASCO 2008. Abstract 5500.
Slide 45 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days GC vs TC Induction Regimens Followed by T Consolidation: Response Rates Gordon A, et al. ASCO 2008. Abstract 5536. *CR required a normalized CA-125. GC vs TC Induction Regimens Followed by T Consolidation: Pt-Based Toxicity Gordon A, et al. ASCO 2008. Abstract 5536. Conventional vs Dose-Dense TC (NOVEL): Study Design Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO 2008. Abstract 5506. P = .72 Evaluated by WHO criteria Conventional vs Dose-Dense TC (NOVEL): Clinical Responses Isonishi S, et al. ASCO 2008. Abstract 5506. Conventional vs Dose-Dense TC (NOVEL): PFS 0.0 0.2 0.4 0.6 0.8 1.0 0 12 30 54 Mos From Randomization Proportion Surviving Progression Free 0.1 0.3 0.5 0.7 0.9 6 18 42 24 48 36 Isonishi S, et al. ASCO 2008. Abstract 5506. dd-TC c-TC Ovarian Carcinoma: Clinical Course Symptoms Diagnosis Chemotherapy #1 Staging Primary cytoreduction Interval Cytoreduction Progression Chemo #2 Chemo #3+ Supportive Care Death Consolidation/ Maintenance Cure Secondary Cytoreduction Second-Look Goals of Treatment: Relapsed Ovarian Cancer Prolong Survival Delay Time to Progression Control Disease-Related Symptoms Minimize Treatment-Related Symptoms Maintain or Improve Quality of Life Issues Impacting Therapy for Recurrent Ovarian Cancer Treatment-free interval Impact of consolidation/maintenance therapy Number of prior regimens Response to prior therapy Toxicity from prior therapy Prior use of growth factors Transfusion requirements Neuropathy Volume and site(s) of disease Ascites/GI symptoms Performance status Surveillance Options for Ovarian Cancer Patients in Remission Second-look laparotomy Physical examination Include pelvic examination CA-125 Imaging CT scan MRI? PET scan? CT = computed tomography MRI = magnetic resonance imaging PET = positron emission tomography Ovarian Cancer: How is Relapse Defined? Continuous rise in CA-125 CA-125 above 100 Radiographic recurrence Symptomatic recurrence Physical examination findings Combination of above When Does Ovarian Cancer Recur? Carb = carboplatin; Cis = cisplatin; Doc = docetaxel; pac = paclitaxel; GOG = Gynecologic Oncology Group; IP = intraperitoneal; Pac = paclitaxel Active Agents in Ovarian Cancer Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Refractory P R I M A R Y T R E A T M E N T Resistant Sensitive 0 3 6 12 18 24 Months “Very Sensitive” Ovarian Cancer at First Relapse Definition of Sensitivity Defined as measurable recurrence, not biochemical (CA-125) recurrence ICON 4 Schema Relapsed ovarian or primary Peritoneal requiring chemotherapy Previous platinum-based chemotherapy Conventional platinum-based chemotherapy Paclitaxel plus platinum chemotherapy R A N D O M I Z E Prior chemotherapy Carboplatin (31%) Paclitaxel/platinum (40%) Other (30%) TFI > 12 months for 75% Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group TFI = treatment-free interval ICON 4 Response (Difference of 12%; 95% CI -0.1% to 24%; p=0.06) CR = complete response; ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum; PR = partial response; Parmar MK, et al. Lancet. 2003;361:2099-2106. Proportion alive and progression-free 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Patients at risk Pac-Plat 392 179 52 25 17 Plat 410 157 45 17 7 Years from randomization Hazard ratio = 0.76 (95% CI 0.66 - 0.89; p < 0.001) Absolute difference at 1 year = 10% (40% to 50%; 95% CI 4% to 15%) Ovarian Carcinoma: ICON 4 Progression-Free Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum Hazard ratio = 0.82 (95% CI 0.69 - 0.97; p = 0.023) Absolute difference 2 years = 7% (50% to 57%; 95% CI 1% to 12%) Patients at risk Pac-Plat 392 306 167 96 43 Plat 410 295 150 68 33 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Years from randomization Proportion alive ICON 4: Overall Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum R A N D O M I Z E Gemcitabine 1,000 mg/m2 days 1 + 8 Plus Carboplatin AUC 4 day 1 every 21 days × 6 Recurrent ovarian cancer 6+ months after platinum Strata PFI (6 - 12, >12 months) 1st-line therapy (platinum ± paclitaxel) Measurable vs evaluable Primary endpoint = PFS Gem/Carbo vs Carbo: Design Carboplatin AUC 5 day 1 every 21 days × 6 Carbo = carboplatin Gem = gemcitabine PFI = progression-free interval PFS = progression-free survival Pfisterer J, et al. J Clin Oncol. 2006; 24:4699-4707. AGO OVAR 2.5 Primary Endpoint: Progression-Free Survival GCb: median = 8.6 mo Censoring: 12.4% Cb: median = 5.8 mo Censoring: 12.9% Cb Arm (N=178) GCb Arm (N=178) Log-rank p-value = 0.0038 Unadjusted HR = 0.72 (0.57 to 0.90) Adjusted HR* = 0.71 (0.57 to 0.89) * Adjusted for PFI, Tumor size Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin AGO OVAR 2.5 Efficacy Results: Overall Survival 0.0 0.8 0.2 0.3 0.4 0.5 0.6 0.7 0.9 1.0 0.1 0 6 12 18 60 54 48 42 36 30 24 Proportion Surviving Months Median = 18.0 mo Censoring: 18.5% Median = 17.3 mo Censoring: 22.5% Cb Arm (N=178) GCb Arm (N=178) * Adjusted for PFI, Tumor size and performance status Log-rank p-value = 0.7349 Unadjusted HR = 0.96 (0.75 to 1.23) Adjusted* HR = 0.92 (0.72 to 1.16) Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: < 0.5 cm > 0.5-2 cm R A N D O M I Z E 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 Completed (Target accrual 864 pts) PFS 1° endpoint Farletuzumab (MORAb-003) in Platinum-Sensitive EOC: Study Rationale FRA is overexpressed in most EOC; largely absent from normal tissue Binding of MORAb-003 to FRA blocks phosphorylation by Lyn kinase; mediates FRA-expressing tumor cell killing; suppresses tumor growth in xenograft models Phase I study of single agent MORAb-003 demonstrated no significant adverse effects and suggested efficacy in platinum-resistant EOC MORAb-003 in Platinum-Sensitive EOC: Phase II Study Design Patients with platinum-sensitive EOC in first relapse after first remission of 6-18 months duration with evaluable disease by CA125 (Enrolled N = 58; eligible n = 54) Asymptomatic relapse Single-agent Farletuzumab until progression (n = 28) Original Carbo/Taxane regimen + Farletuzumab for 6 cycles (n = 26) Symptomatic relapse Compare lengths of first and second remissions Farletuzumab maintenance Rx for responders Single-agent ORR Combination ORR Armstrong DK, et al. ASCO 2008. Abstract 5500. All arms MORAb-003: 100 mg/m2 weekly Run-in phase with 6 subjects at 37.5 and 6 at 62.5 mg/m2 Combination therapy arm every 21 days x 6 cycles Carboplatin: AUC 5-6 Taxane Paclitaxel 175 mg/m2 over 3 hours or Docetaxel 75 mg/m2 MORAb-003-002 Phase II: Treatment Arms Armstrong DK, et al. ASCO 2008. Abstract 5500. Comparison of First vs Second Remission Length: n = 6 Data as of May 5, 2008. Armstrong DK, et al. ASCO 2008. Abstract 5500. MORAb-003-002 Clinical Responses by RECIST (Combination Therapy) Best response CR: 7.4% PR: 62.9% SD: 25.9% PD: 3.7% Based on all scans submitted as of December 3, 2007 (~ 30%) By independent central reader MORAb-003 well tolerated; no increase observed in toxicity profile in combination arm ORR: 70.3% Patient benefit: 96.3% Armstrong DK, et al. ASCO 2008. Abstract 5500.
Slide 46 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days GC vs TC Induction Regimens Followed by T Consolidation: Response Rates Gordon A, et al. ASCO 2008. Abstract 5536. *CR required a normalized CA-125. GC vs TC Induction Regimens Followed by T Consolidation: Pt-Based Toxicity Gordon A, et al. ASCO 2008. Abstract 5536. Conventional vs Dose-Dense TC (NOVEL): Study Design Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO 2008. Abstract 5506. P = .72 Evaluated by WHO criteria Conventional vs Dose-Dense TC (NOVEL): Clinical Responses Isonishi S, et al. ASCO 2008. Abstract 5506. Conventional vs Dose-Dense TC (NOVEL): PFS 0.0 0.2 0.4 0.6 0.8 1.0 0 12 30 54 Mos From Randomization Proportion Surviving Progression Free 0.1 0.3 0.5 0.7 0.9 6 18 42 24 48 36 Isonishi S, et al. ASCO 2008. Abstract 5506. dd-TC c-TC Ovarian Carcinoma: Clinical Course Symptoms Diagnosis Chemotherapy #1 Staging Primary cytoreduction Interval Cytoreduction Progression Chemo #2 Chemo #3+ Supportive Care Death Consolidation/ Maintenance Cure Secondary Cytoreduction Second-Look Goals of Treatment: Relapsed Ovarian Cancer Prolong Survival Delay Time to Progression Control Disease-Related Symptoms Minimize Treatment-Related Symptoms Maintain or Improve Quality of Life Issues Impacting Therapy for Recurrent Ovarian Cancer Treatment-free interval Impact of consolidation/maintenance therapy Number of prior regimens Response to prior therapy Toxicity from prior therapy Prior use of growth factors Transfusion requirements Neuropathy Volume and site(s) of disease Ascites/GI symptoms Performance status Surveillance Options for Ovarian Cancer Patients in Remission Second-look laparotomy Physical examination Include pelvic examination CA-125 Imaging CT scan MRI? PET scan? CT = computed tomography MRI = magnetic resonance imaging PET = positron emission tomography Ovarian Cancer: How is Relapse Defined? Continuous rise in CA-125 CA-125 above 100 Radiographic recurrence Symptomatic recurrence Physical examination findings Combination of above When Does Ovarian Cancer Recur? Carb = carboplatin; Cis = cisplatin; Doc = docetaxel; pac = paclitaxel; GOG = Gynecologic Oncology Group; IP = intraperitoneal; Pac = paclitaxel Active Agents in Ovarian Cancer Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Refractory P R I M A R Y T R E A T M E N T Resistant Sensitive 0 3 6 12 18 24 Months “Very Sensitive” Ovarian Cancer at First Relapse Definition of Sensitivity Defined as measurable recurrence, not biochemical (CA-125) recurrence ICON 4 Schema Relapsed ovarian or primary Peritoneal requiring chemotherapy Previous platinum-based chemotherapy Conventional platinum-based chemotherapy Paclitaxel plus platinum chemotherapy R A N D O M I Z E Prior chemotherapy Carboplatin (31%) Paclitaxel/platinum (40%) Other (30%) TFI > 12 months for 75% Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group TFI = treatment-free interval ICON 4 Response (Difference of 12%; 95% CI -0.1% to 24%; p=0.06) CR = complete response; ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum; PR = partial response; Parmar MK, et al. Lancet. 2003;361:2099-2106. Proportion alive and progression-free 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Patients at risk Pac-Plat 392 179 52 25 17 Plat 410 157 45 17 7 Years from randomization Hazard ratio = 0.76 (95% CI 0.66 - 0.89; p < 0.001) Absolute difference at 1 year = 10% (40% to 50%; 95% CI 4% to 15%) Ovarian Carcinoma: ICON 4 Progression-Free Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum Hazard ratio = 0.82 (95% CI 0.69 - 0.97; p = 0.023) Absolute difference 2 years = 7% (50% to 57%; 95% CI 1% to 12%) Patients at risk Pac-Plat 392 306 167 96 43 Plat 410 295 150 68 33 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Years from randomization Proportion alive ICON 4: Overall Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum R A N D O M I Z E Gemcitabine 1,000 mg/m2 days 1 + 8 Plus Carboplatin AUC 4 day 1 every 21 days × 6 Recurrent ovarian cancer 6+ months after platinum Strata PFI (6 - 12, >12 months) 1st-line therapy (platinum ± paclitaxel) Measurable vs evaluable Primary endpoint = PFS Gem/Carbo vs Carbo: Design Carboplatin AUC 5 day 1 every 21 days × 6 Carbo = carboplatin Gem = gemcitabine PFI = progression-free interval PFS = progression-free survival Pfisterer J, et al. J Clin Oncol. 2006; 24:4699-4707. AGO OVAR 2.5 Primary Endpoint: Progression-Free Survival GCb: median = 8.6 mo Censoring: 12.4% Cb: median = 5.8 mo Censoring: 12.9% Cb Arm (N=178) GCb Arm (N=178) Log-rank p-value = 0.0038 Unadjusted HR = 0.72 (0.57 to 0.90) Adjusted HR* = 0.71 (0.57 to 0.89) * Adjusted for PFI, Tumor size Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin AGO OVAR 2.5 Efficacy Results: Overall Survival 0.0 0.8 0.2 0.3 0.4 0.5 0.6 0.7 0.9 1.0 0.1 0 6 12 18 60 54 48 42 36 30 24 Proportion Surviving Months Median = 18.0 mo Censoring: 18.5% Median = 17.3 mo Censoring: 22.5% Cb Arm (N=178) GCb Arm (N=178) * Adjusted for PFI, Tumor size and performance status Log-rank p-value = 0.7349 Unadjusted HR = 0.96 (0.75 to 1.23) Adjusted* HR = 0.92 (0.72 to 1.16) Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: < 0.5 cm > 0.5-2 cm R A N D O M I Z E 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 Completed (Target accrual 864 pts) PFS 1° endpoint Farletuzumab (MORAb-003) in Platinum-Sensitive EOC: Study Rationale FRA is overexpressed in most EOC; largely absent from normal tissue Binding of MORAb-003 to FRA blocks phosphorylation by Lyn kinase; mediates FRA-expressing tumor cell killing; suppresses tumor growth in xenograft models Phase I study of single agent MORAb-003 demonstrated no significant adverse effects and suggested efficacy in platinum-resistant EOC MORAb-003 in Platinum-Sensitive EOC: Phase II Study Design Patients with platinum-sensitive EOC in first relapse after first remission of 6-18 months duration with evaluable disease by CA125 (Enrolled N = 58; eligible n = 54) Asymptomatic relapse Single-agent Farletuzumab until progression (n = 28) Original Carbo/Taxane regimen + Farletuzumab for 6 cycles (n = 26) Symptomatic relapse Compare lengths of first and second remissions Farletuzumab maintenance Rx for responders Single-agent ORR Combination ORR Armstrong DK, et al. ASCO 2008. Abstract 5500. All arms MORAb-003: 100 mg/m2 weekly Run-in phase with 6 subjects at 37.5 and 6 at 62.5 mg/m2 Combination therapy arm every 21 days x 6 cycles Carboplatin: AUC 5-6 Taxane Paclitaxel 175 mg/m2 over 3 hours or Docetaxel 75 mg/m2 MORAb-003-002 Phase II: Treatment Arms Armstrong DK, et al. ASCO 2008. Abstract 5500. Comparison of First vs Second Remission Length: n = 6 Data as of May 5, 2008. Armstrong DK, et al. ASCO 2008. Abstract 5500. MORAb-003-002 Clinical Responses by RECIST (Combination Therapy) Best response CR: 7.4% PR: 62.9% SD: 25.9% PD: 3.7% Based on all scans submitted as of December 3, 2007 (~ 30%) By independent central reader MORAb-003 well tolerated; no increase observed in toxicity profile in combination arm ORR: 70.3% Patient benefit: 96.3% Armstrong DK, et al. ASCO 2008. Abstract 5500. Secondary Cytoreduction Controversial Inconsistent definitions Benefit appears confined to patients likely to respond to additional chemo: >12 month PFI Isolated site of recurrence Disease completely resectable Kidney Resected Liver Diaphragm Kidney Vena Cava Tumor Mass Renal Vein PFI = progression-free interval
Slide 47 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days GC vs TC Induction Regimens Followed by T Consolidation: Response Rates Gordon A, et al. ASCO 2008. Abstract 5536. *CR required a normalized CA-125. GC vs TC Induction Regimens Followed by T Consolidation: Pt-Based Toxicity Gordon A, et al. ASCO 2008. Abstract 5536. Conventional vs Dose-Dense TC (NOVEL): Study Design Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO 2008. Abstract 5506. P = .72 Evaluated by WHO criteria Conventional vs Dose-Dense TC (NOVEL): Clinical Responses Isonishi S, et al. ASCO 2008. Abstract 5506. Conventional vs Dose-Dense TC (NOVEL): PFS 0.0 0.2 0.4 0.6 0.8 1.0 0 12 30 54 Mos From Randomization Proportion Surviving Progression Free 0.1 0.3 0.5 0.7 0.9 6 18 42 24 48 36 Isonishi S, et al. ASCO 2008. Abstract 5506. dd-TC c-TC Ovarian Carcinoma: Clinical Course Symptoms Diagnosis Chemotherapy #1 Staging Primary cytoreduction Interval Cytoreduction Progression Chemo #2 Chemo #3+ Supportive Care Death Consolidation/ Maintenance Cure Secondary Cytoreduction Second-Look Goals of Treatment: Relapsed Ovarian Cancer Prolong Survival Delay Time to Progression Control Disease-Related Symptoms Minimize Treatment-Related Symptoms Maintain or Improve Quality of Life Issues Impacting Therapy for Recurrent Ovarian Cancer Treatment-free interval Impact of consolidation/maintenance therapy Number of prior regimens Response to prior therapy Toxicity from prior therapy Prior use of growth factors Transfusion requirements Neuropathy Volume and site(s) of disease Ascites/GI symptoms Performance status Surveillance Options for Ovarian Cancer Patients in Remission Second-look laparotomy Physical examination Include pelvic examination CA-125 Imaging CT scan MRI? PET scan? CT = computed tomography MRI = magnetic resonance imaging PET = positron emission tomography Ovarian Cancer: How is Relapse Defined? Continuous rise in CA-125 CA-125 above 100 Radiographic recurrence Symptomatic recurrence Physical examination findings Combination of above When Does Ovarian Cancer Recur? Carb = carboplatin; Cis = cisplatin; Doc = docetaxel; pac = paclitaxel; GOG = Gynecologic Oncology Group; IP = intraperitoneal; Pac = paclitaxel Active Agents in Ovarian Cancer Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Refractory P R I M A R Y T R E A T M E N T Resistant Sensitive 0 3 6 12 18 24 Months “Very Sensitive” Ovarian Cancer at First Relapse Definition of Sensitivity Defined as measurable recurrence, not biochemical (CA-125) recurrence ICON 4 Schema Relapsed ovarian or primary Peritoneal requiring chemotherapy Previous platinum-based chemotherapy Conventional platinum-based chemotherapy Paclitaxel plus platinum chemotherapy R A N D O M I Z E Prior chemotherapy Carboplatin (31%) Paclitaxel/platinum (40%) Other (30%) TFI > 12 months for 75% Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group TFI = treatment-free interval ICON 4 Response (Difference of 12%; 95% CI -0.1% to 24%; p=0.06) CR = complete response; ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum; PR = partial response; Parmar MK, et al. Lancet. 2003;361:2099-2106. Proportion alive and progression-free 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Patients at risk Pac-Plat 392 179 52 25 17 Plat 410 157 45 17 7 Years from randomization Hazard ratio = 0.76 (95% CI 0.66 - 0.89; p < 0.001) Absolute difference at 1 year = 10% (40% to 50%; 95% CI 4% to 15%) Ovarian Carcinoma: ICON 4 Progression-Free Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum Hazard ratio = 0.82 (95% CI 0.69 - 0.97; p = 0.023) Absolute difference 2 years = 7% (50% to 57%; 95% CI 1% to 12%) Patients at risk Pac-Plat 392 306 167 96 43 Plat 410 295 150 68 33 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Years from randomization Proportion alive ICON 4: Overall Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum R A N D O M I Z E Gemcitabine 1,000 mg/m2 days 1 + 8 Plus Carboplatin AUC 4 day 1 every 21 days × 6 Recurrent ovarian cancer 6+ months after platinum Strata PFI (6 - 12, >12 months) 1st-line therapy (platinum ± paclitaxel) Measurable vs evaluable Primary endpoint = PFS Gem/Carbo vs Carbo: Design Carboplatin AUC 5 day 1 every 21 days × 6 Carbo = carboplatin Gem = gemcitabine PFI = progression-free interval PFS = progression-free survival Pfisterer J, et al. J Clin Oncol. 2006; 24:4699-4707. AGO OVAR 2.5 Primary Endpoint: Progression-Free Survival GCb: median = 8.6 mo Censoring: 12.4% Cb: median = 5.8 mo Censoring: 12.9% Cb Arm (N=178) GCb Arm (N=178) Log-rank p-value = 0.0038 Unadjusted HR = 0.72 (0.57 to 0.90) Adjusted HR* = 0.71 (0.57 to 0.89) * Adjusted for PFI, Tumor size Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin AGO OVAR 2.5 Efficacy Results: Overall Survival 0.0 0.8 0.2 0.3 0.4 0.5 0.6 0.7 0.9 1.0 0.1 0 6 12 18 60 54 48 42 36 30 24 Proportion Surviving Months Median = 18.0 mo Censoring: 18.5% Median = 17.3 mo Censoring: 22.5% Cb Arm (N=178) GCb Arm (N=178) * Adjusted for PFI, Tumor size and performance status Log-rank p-value = 0.7349 Unadjusted HR = 0.96 (0.75 to 1.23) Adjusted* HR = 0.92 (0.72 to 1.16) Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: < 0.5 cm > 0.5-2 cm R A N D O M I Z E 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 Completed (Target accrual 864 pts) PFS 1° endpoint Farletuzumab (MORAb-003) in Platinum-Sensitive EOC: Study Rationale FRA is overexpressed in most EOC; largely absent from normal tissue Binding of MORAb-003 to FRA blocks phosphorylation by Lyn kinase; mediates FRA-expressing tumor cell killing; suppresses tumor growth in xenograft models Phase I study of single agent MORAb-003 demonstrated no significant adverse effects and suggested efficacy in platinum-resistant EOC MORAb-003 in Platinum-Sensitive EOC: Phase II Study Design Patients with platinum-sensitive EOC in first relapse after first remission of 6-18 months duration with evaluable disease by CA125 (Enrolled N = 58; eligible n = 54) Asymptomatic relapse Single-agent Farletuzumab until progression (n = 28) Original Carbo/Taxane regimen + Farletuzumab for 6 cycles (n = 26) Symptomatic relapse Compare lengths of first and second remissions Farletuzumab maintenance Rx for responders Single-agent ORR Combination ORR Armstrong DK, et al. ASCO 2008. Abstract 5500. All arms MORAb-003: 100 mg/m2 weekly Run-in phase with 6 subjects at 37.5 and 6 at 62.5 mg/m2 Combination therapy arm every 21 days x 6 cycles Carboplatin: AUC 5-6 Taxane Paclitaxel 175 mg/m2 over 3 hours or Docetaxel 75 mg/m2 MORAb-003-002 Phase II: Treatment Arms Armstrong DK, et al. ASCO 2008. Abstract 5500. Comparison of First vs Second Remission Length: n = 6 Data as of May 5, 2008. Armstrong DK, et al. ASCO 2008. Abstract 5500. MORAb-003-002 Clinical Responses by RECIST (Combination Therapy) Best response CR: 7.4% PR: 62.9% SD: 25.9% PD: 3.7% Based on all scans submitted as of December 3, 2007 (~ 30%) By independent central reader MORAb-003 well tolerated; no increase observed in toxicity profile in combination arm ORR: 70.3% Patient benefit: 96.3% Armstrong DK, et al. ASCO 2008. Abstract 5500. Secondary Cytoreduction Controversial Inconsistent definitions Benefit appears confined to patients likely to respond to additional chemo: >12 month PFI Isolated site of recurrence Disease completely resectable Kidney Resected Liver Diaphragm Kidney Vena Cava Tumor Mass Renal Vein PFI = progression-free interval TTP mos >12 >12 >12 >17.5 >36 >24 12-24 >24 Ovarian Cancer Secondary Cytoreduction: Post-Surgery Survival Author Janicke Segna Zang Gadducci Eisenkop Munkarah Scarabelli Tay Total/Range Year 1992 1993 2000 2000 2000 2001 2001 2002 N 30 100 60 30 114 25 148 46 553 Survival Median mos 16 16.6 13 21 16.8 26 13-26 TTP mos <12 <12 <12 <17.5 <12 <24 <12 <12 Survival Median mos 8 8.8 8 15 25 42 12 6 6-42 Survival Median mos (P) 29 (0.002) 22.9 (0.007) 12 (0.02) 25 (0.04) 56.8 (0.005) 57 (NS) 32 (0.001) 39 (0.001) 12-56 TTP = time to progression
Slide 48 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days GC vs TC Induction Regimens Followed by T Consolidation: Response Rates Gordon A, et al. ASCO 2008. Abstract 5536. *CR required a normalized CA-125. GC vs TC Induction Regimens Followed by T Consolidation: Pt-Based Toxicity Gordon A, et al. ASCO 2008. Abstract 5536. Conventional vs Dose-Dense TC (NOVEL): Study Design Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO 2008. Abstract 5506. P = .72 Evaluated by WHO criteria Conventional vs Dose-Dense TC (NOVEL): Clinical Responses Isonishi S, et al. ASCO 2008. Abstract 5506. Conventional vs Dose-Dense TC (NOVEL): PFS 0.0 0.2 0.4 0.6 0.8 1.0 0 12 30 54 Mos From Randomization Proportion Surviving Progression Free 0.1 0.3 0.5 0.7 0.9 6 18 42 24 48 36 Isonishi S, et al. ASCO 2008. Abstract 5506. dd-TC c-TC Ovarian Carcinoma: Clinical Course Symptoms Diagnosis Chemotherapy #1 Staging Primary cytoreduction Interval Cytoreduction Progression Chemo #2 Chemo #3+ Supportive Care Death Consolidation/ Maintenance Cure Secondary Cytoreduction Second-Look Goals of Treatment: Relapsed Ovarian Cancer Prolong Survival Delay Time to Progression Control Disease-Related Symptoms Minimize Treatment-Related Symptoms Maintain or Improve Quality of Life Issues Impacting Therapy for Recurrent Ovarian Cancer Treatment-free interval Impact of consolidation/maintenance therapy Number of prior regimens Response to prior therapy Toxicity from prior therapy Prior use of growth factors Transfusion requirements Neuropathy Volume and site(s) of disease Ascites/GI symptoms Performance status Surveillance Options for Ovarian Cancer Patients in Remission Second-look laparotomy Physical examination Include pelvic examination CA-125 Imaging CT scan MRI? PET scan? CT = computed tomography MRI = magnetic resonance imaging PET = positron emission tomography Ovarian Cancer: How is Relapse Defined? Continuous rise in CA-125 CA-125 above 100 Radiographic recurrence Symptomatic recurrence Physical examination findings Combination of above When Does Ovarian Cancer Recur? Carb = carboplatin; Cis = cisplatin; Doc = docetaxel; pac = paclitaxel; GOG = Gynecologic Oncology Group; IP = intraperitoneal; Pac = paclitaxel Active Agents in Ovarian Cancer Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Refractory P R I M A R Y T R E A T M E N T Resistant Sensitive 0 3 6 12 18 24 Months “Very Sensitive” Ovarian Cancer at First Relapse Definition of Sensitivity Defined as measurable recurrence, not biochemical (CA-125) recurrence ICON 4 Schema Relapsed ovarian or primary Peritoneal requiring chemotherapy Previous platinum-based chemotherapy Conventional platinum-based chemotherapy Paclitaxel plus platinum chemotherapy R A N D O M I Z E Prior chemotherapy Carboplatin (31%) Paclitaxel/platinum (40%) Other (30%) TFI > 12 months for 75% Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group TFI = treatment-free interval ICON 4 Response (Difference of 12%; 95% CI -0.1% to 24%; p=0.06) CR = complete response; ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum; PR = partial response; Parmar MK, et al. Lancet. 2003;361:2099-2106. Proportion alive and progression-free 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Patients at risk Pac-Plat 392 179 52 25 17 Plat 410 157 45 17 7 Years from randomization Hazard ratio = 0.76 (95% CI 0.66 - 0.89; p < 0.001) Absolute difference at 1 year = 10% (40% to 50%; 95% CI 4% to 15%) Ovarian Carcinoma: ICON 4 Progression-Free Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum Hazard ratio = 0.82 (95% CI 0.69 - 0.97; p = 0.023) Absolute difference 2 years = 7% (50% to 57%; 95% CI 1% to 12%) Patients at risk Pac-Plat 392 306 167 96 43 Plat 410 295 150 68 33 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Years from randomization Proportion alive ICON 4: Overall Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum R A N D O M I Z E Gemcitabine 1,000 mg/m2 days 1 + 8 Plus Carboplatin AUC 4 day 1 every 21 days × 6 Recurrent ovarian cancer 6+ months after platinum Strata PFI (6 - 12, >12 months) 1st-line therapy (platinum ± paclitaxel) Measurable vs evaluable Primary endpoint = PFS Gem/Carbo vs Carbo: Design Carboplatin AUC 5 day 1 every 21 days × 6 Carbo = carboplatin Gem = gemcitabine PFI = progression-free interval PFS = progression-free survival Pfisterer J, et al. J Clin Oncol. 2006; 24:4699-4707. AGO OVAR 2.5 Primary Endpoint: Progression-Free Survival GCb: median = 8.6 mo Censoring: 12.4% Cb: median = 5.8 mo Censoring: 12.9% Cb Arm (N=178) GCb Arm (N=178) Log-rank p-value = 0.0038 Unadjusted HR = 0.72 (0.57 to 0.90) Adjusted HR* = 0.71 (0.57 to 0.89) * Adjusted for PFI, Tumor size Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin AGO OVAR 2.5 Efficacy Results: Overall Survival 0.0 0.8 0.2 0.3 0.4 0.5 0.6 0.7 0.9 1.0 0.1 0 6 12 18 60 54 48 42 36 30 24 Proportion Surviving Months Median = 18.0 mo Censoring: 18.5% Median = 17.3 mo Censoring: 22.5% Cb Arm (N=178) GCb Arm (N=178) * Adjusted for PFI, Tumor size and performance status Log-rank p-value = 0.7349 Unadjusted HR = 0.96 (0.75 to 1.23) Adjusted* HR = 0.92 (0.72 to 1.16) Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: < 0.5 cm > 0.5-2 cm R A N D O M I Z E 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 Completed (Target accrual 864 pts) PFS 1° endpoint Farletuzumab (MORAb-003) in Platinum-Sensitive EOC: Study Rationale FRA is overexpressed in most EOC; largely absent from normal tissue Binding of MORAb-003 to FRA blocks phosphorylation by Lyn kinase; mediates FRA-expressing tumor cell killing; suppresses tumor growth in xenograft models Phase I study of single agent MORAb-003 demonstrated no significant adverse effects and suggested efficacy in platinum-resistant EOC MORAb-003 in Platinum-Sensitive EOC: Phase II Study Design Patients with platinum-sensitive EOC in first relapse after first remission of 6-18 months duration with evaluable disease by CA125 (Enrolled N = 58; eligible n = 54) Asymptomatic relapse Single-agent Farletuzumab until progression (n = 28) Original Carbo/Taxane regimen + Farletuzumab for 6 cycles (n = 26) Symptomatic relapse Compare lengths of first and second remissions Farletuzumab maintenance Rx for responders Single-agent ORR Combination ORR Armstrong DK, et al. ASCO 2008. Abstract 5500. All arms MORAb-003: 100 mg/m2 weekly Run-in phase with 6 subjects at 37.5 and 6 at 62.5 mg/m2 Combination therapy arm every 21 days x 6 cycles Carboplatin: AUC 5-6 Taxane Paclitaxel 175 mg/m2 over 3 hours or Docetaxel 75 mg/m2 MORAb-003-002 Phase II: Treatment Arms Armstrong DK, et al. ASCO 2008. Abstract 5500. Comparison of First vs Second Remission Length: n = 6 Data as of May 5, 2008. Armstrong DK, et al. ASCO 2008. Abstract 5500. MORAb-003-002 Clinical Responses by RECIST (Combination Therapy) Best response CR: 7.4% PR: 62.9% SD: 25.9% PD: 3.7% Based on all scans submitted as of December 3, 2007 (~ 30%) By independent central reader MORAb-003 well tolerated; no increase observed in toxicity profile in combination arm ORR: 70.3% Patient benefit: 96.3% Armstrong DK, et al. ASCO 2008. Abstract 5500. Secondary Cytoreduction Controversial Inconsistent definitions Benefit appears confined to patients likely to respond to additional chemo: >12 month PFI Isolated site of recurrence Disease completely resectable Kidney Resected Liver Diaphragm Kidney Vena Cava Tumor Mass Renal Vein PFI = progression-free interval TTP mos >12 >12 >12 >17.5 >36 >24 12-24 >24 Ovarian Cancer Secondary Cytoreduction: Post-Surgery Survival Author Janicke Segna Zang Gadducci Eisenkop Munkarah Scarabelli Tay Total/Range Year 1992 1993 2000 2000 2000 2001 2001 2002 N 30 100 60 30 114 25 148 46 553 Survival Median mos 16 16.6 13 21 16.8 26 13-26 TTP mos <12 <12 <12 <17.5 <12 <24 <12 <12 Survival Median mos 8 8.8 8 15 25 42 12 6 6-42 Survival Median mos (P) 29 (0.002) 22.9 (0.007) 12 (0.02) 25 (0.04) 56.8 (0.005) 57 (NS) 32 (0.001) 39 (0.001) 12-56 TTP = time to progression GOG 213- PI Robert Coleman Surgical Candidate? Recurrent ovarian or peritoneal cancer TFI >6 mos YES NO Surgery No surgery Carboplatin + Paclitaxel Carboplatin + Paclitaxel + Bevacizumab + Bevacizumab Maintenance Randomize to Chemotherapy GOG = Gynecologic Oncology Group TFI = treatment-free interval
Slide 49 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days GC vs TC Induction Regimens Followed by T Consolidation: Response Rates Gordon A, et al. ASCO 2008. Abstract 5536. *CR required a normalized CA-125. GC vs TC Induction Regimens Followed by T Consolidation: Pt-Based Toxicity Gordon A, et al. ASCO 2008. Abstract 5536. Conventional vs Dose-Dense TC (NOVEL): Study Design Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO 2008. Abstract 5506. P = .72 Evaluated by WHO criteria Conventional vs Dose-Dense TC (NOVEL): Clinical Responses Isonishi S, et al. ASCO 2008. Abstract 5506. Conventional vs Dose-Dense TC (NOVEL): PFS 0.0 0.2 0.4 0.6 0.8 1.0 0 12 30 54 Mos From Randomization Proportion Surviving Progression Free 0.1 0.3 0.5 0.7 0.9 6 18 42 24 48 36 Isonishi S, et al. ASCO 2008. Abstract 5506. dd-TC c-TC Ovarian Carcinoma: Clinical Course Symptoms Diagnosis Chemotherapy #1 Staging Primary cytoreduction Interval Cytoreduction Progression Chemo #2 Chemo #3+ Supportive Care Death Consolidation/ Maintenance Cure Secondary Cytoreduction Second-Look Goals of Treatment: Relapsed Ovarian Cancer Prolong Survival Delay Time to Progression Control Disease-Related Symptoms Minimize Treatment-Related Symptoms Maintain or Improve Quality of Life Issues Impacting Therapy for Recurrent Ovarian Cancer Treatment-free interval Impact of consolidation/maintenance therapy Number of prior regimens Response to prior therapy Toxicity from prior therapy Prior use of growth factors Transfusion requirements Neuropathy Volume and site(s) of disease Ascites/GI symptoms Performance status Surveillance Options for Ovarian Cancer Patients in Remission Second-look laparotomy Physical examination Include pelvic examination CA-125 Imaging CT scan MRI? PET scan? CT = computed tomography MRI = magnetic resonance imaging PET = positron emission tomography Ovarian Cancer: How is Relapse Defined? Continuous rise in CA-125 CA-125 above 100 Radiographic recurrence Symptomatic recurrence Physical examination findings Combination of above When Does Ovarian Cancer Recur? Carb = carboplatin; Cis = cisplatin; Doc = docetaxel; pac = paclitaxel; GOG = Gynecologic Oncology Group; IP = intraperitoneal; Pac = paclitaxel Active Agents in Ovarian Cancer Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Refractory P R I M A R Y T R E A T M E N T Resistant Sensitive 0 3 6 12 18 24 Months “Very Sensitive” Ovarian Cancer at First Relapse Definition of Sensitivity Defined as measurable recurrence, not biochemical (CA-125) recurrence ICON 4 Schema Relapsed ovarian or primary Peritoneal requiring chemotherapy Previous platinum-based chemotherapy Conventional platinum-based chemotherapy Paclitaxel plus platinum chemotherapy R A N D O M I Z E Prior chemotherapy Carboplatin (31%) Paclitaxel/platinum (40%) Other (30%) TFI > 12 months for 75% Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group TFI = treatment-free interval ICON 4 Response (Difference of 12%; 95% CI -0.1% to 24%; p=0.06) CR = complete response; ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum; PR = partial response; Parmar MK, et al. Lancet. 2003;361:2099-2106. Proportion alive and progression-free 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Patients at risk Pac-Plat 392 179 52 25 17 Plat 410 157 45 17 7 Years from randomization Hazard ratio = 0.76 (95% CI 0.66 - 0.89; p < 0.001) Absolute difference at 1 year = 10% (40% to 50%; 95% CI 4% to 15%) Ovarian Carcinoma: ICON 4 Progression-Free Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum Hazard ratio = 0.82 (95% CI 0.69 - 0.97; p = 0.023) Absolute difference 2 years = 7% (50% to 57%; 95% CI 1% to 12%) Patients at risk Pac-Plat 392 306 167 96 43 Plat 410 295 150 68 33 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Years from randomization Proportion alive ICON 4: Overall Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum R A N D O M I Z E Gemcitabine 1,000 mg/m2 days 1 + 8 Plus Carboplatin AUC 4 day 1 every 21 days × 6 Recurrent ovarian cancer 6+ months after platinum Strata PFI (6 - 12, >12 months) 1st-line therapy (platinum ± paclitaxel) Measurable vs evaluable Primary endpoint = PFS Gem/Carbo vs Carbo: Design Carboplatin AUC 5 day 1 every 21 days × 6 Carbo = carboplatin Gem = gemcitabine PFI = progression-free interval PFS = progression-free survival Pfisterer J, et al. J Clin Oncol. 2006; 24:4699-4707. AGO OVAR 2.5 Primary Endpoint: Progression-Free Survival GCb: median = 8.6 mo Censoring: 12.4% Cb: median = 5.8 mo Censoring: 12.9% Cb Arm (N=178) GCb Arm (N=178) Log-rank p-value = 0.0038 Unadjusted HR = 0.72 (0.57 to 0.90) Adjusted HR* = 0.71 (0.57 to 0.89) * Adjusted for PFI, Tumor size Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin AGO OVAR 2.5 Efficacy Results: Overall Survival 0.0 0.8 0.2 0.3 0.4 0.5 0.6 0.7 0.9 1.0 0.1 0 6 12 18 60 54 48 42 36 30 24 Proportion Surviving Months Median = 18.0 mo Censoring: 18.5% Median = 17.3 mo Censoring: 22.5% Cb Arm (N=178) GCb Arm (N=178) * Adjusted for PFI, Tumor size and performance status Log-rank p-value = 0.7349 Unadjusted HR = 0.96 (0.75 to 1.23) Adjusted* HR = 0.92 (0.72 to 1.16) Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: < 0.5 cm > 0.5-2 cm R A N D O M I Z E 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 Completed (Target accrual 864 pts) PFS 1° endpoint Farletuzumab (MORAb-003) in Platinum-Sensitive EOC: Study Rationale FRA is overexpressed in most EOC; largely absent from normal tissue Binding of MORAb-003 to FRA blocks phosphorylation by Lyn kinase; mediates FRA-expressing tumor cell killing; suppresses tumor growth in xenograft models Phase I study of single agent MORAb-003 demonstrated no significant adverse effects and suggested efficacy in platinum-resistant EOC MORAb-003 in Platinum-Sensitive EOC: Phase II Study Design Patients with platinum-sensitive EOC in first relapse after first remission of 6-18 months duration with evaluable disease by CA125 (Enrolled N = 58; eligible n = 54) Asymptomatic relapse Single-agent Farletuzumab until progression (n = 28) Original Carbo/Taxane regimen + Farletuzumab for 6 cycles (n = 26) Symptomatic relapse Compare lengths of first and second remissions Farletuzumab maintenance Rx for responders Single-agent ORR Combination ORR Armstrong DK, et al. ASCO 2008. Abstract 5500. All arms MORAb-003: 100 mg/m2 weekly Run-in phase with 6 subjects at 37.5 and 6 at 62.5 mg/m2 Combination therapy arm every 21 days x 6 cycles Carboplatin: AUC 5-6 Taxane Paclitaxel 175 mg/m2 over 3 hours or Docetaxel 75 mg/m2 MORAb-003-002 Phase II: Treatment Arms Armstrong DK, et al. ASCO 2008. Abstract 5500. Comparison of First vs Second Remission Length: n = 6 Data as of May 5, 2008. Armstrong DK, et al. ASCO 2008. Abstract 5500. MORAb-003-002 Clinical Responses by RECIST (Combination Therapy) Best response CR: 7.4% PR: 62.9% SD: 25.9% PD: 3.7% Based on all scans submitted as of December 3, 2007 (~ 30%) By independent central reader MORAb-003 well tolerated; no increase observed in toxicity profile in combination arm ORR: 70.3% Patient benefit: 96.3% Armstrong DK, et al. ASCO 2008. Abstract 5500. Secondary Cytoreduction Controversial Inconsistent definitions Benefit appears confined to patients likely to respond to additional chemo: >12 month PFI Isolated site of recurrence Disease completely resectable Kidney Resected Liver Diaphragm Kidney Vena Cava Tumor Mass Renal Vein PFI = progression-free interval TTP mos >12 >12 >12 >17.5 >36 >24 12-24 >24 Ovarian Cancer Secondary Cytoreduction: Post-Surgery Survival Author Janicke Segna Zang Gadducci Eisenkop Munkarah Scarabelli Tay Total/Range Year 1992 1993 2000 2000 2000 2001 2001 2002 N 30 100 60 30 114 25 148 46 553 Survival Median mos 16 16.6 13 21 16.8 26 13-26 TTP mos <12 <12 <12 <17.5 <12 <24 <12 <12 Survival Median mos 8 8.8 8 15 25 42 12 6 6-42 Survival Median mos (P) 29 (0.002) 22.9 (0.007) 12 (0.02) 25 (0.04) 56.8 (0.005) 57 (NS) 32 (0.001) 39 (0.001) 12-56 TTP = time to progression GOG 213- PI Robert Coleman Surgical Candidate? Recurrent ovarian or peritoneal cancer TFI >6 mos YES NO Surgery No surgery Carboplatin + Paclitaxel Carboplatin + Paclitaxel + Bevacizumab + Bevacizumab Maintenance Randomize to Chemotherapy GOG = Gynecologic Oncology Group TFI = treatment-free interval Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653.
Slide 50 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days GC vs TC Induction Regimens Followed by T Consolidation: Response Rates Gordon A, et al. ASCO 2008. Abstract 5536. *CR required a normalized CA-125. GC vs TC Induction Regimens Followed by T Consolidation: Pt-Based Toxicity Gordon A, et al. ASCO 2008. Abstract 5536. Conventional vs Dose-Dense TC (NOVEL): Study Design Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO 2008. Abstract 5506. P = .72 Evaluated by WHO criteria Conventional vs Dose-Dense TC (NOVEL): Clinical Responses Isonishi S, et al. ASCO 2008. Abstract 5506. Conventional vs Dose-Dense TC (NOVEL): PFS 0.0 0.2 0.4 0.6 0.8 1.0 0 12 30 54 Mos From Randomization Proportion Surviving Progression Free 0.1 0.3 0.5 0.7 0.9 6 18 42 24 48 36 Isonishi S, et al. ASCO 2008. Abstract 5506. dd-TC c-TC Ovarian Carcinoma: Clinical Course Symptoms Diagnosis Chemotherapy #1 Staging Primary cytoreduction Interval Cytoreduction Progression Chemo #2 Chemo #3+ Supportive Care Death Consolidation/ Maintenance Cure Secondary Cytoreduction Second-Look Goals of Treatment: Relapsed Ovarian Cancer Prolong Survival Delay Time to Progression Control Disease-Related Symptoms Minimize Treatment-Related Symptoms Maintain or Improve Quality of Life Issues Impacting Therapy for Recurrent Ovarian Cancer Treatment-free interval Impact of consolidation/maintenance therapy Number of prior regimens Response to prior therapy Toxicity from prior therapy Prior use of growth factors Transfusion requirements Neuropathy Volume and site(s) of disease Ascites/GI symptoms Performance status Surveillance Options for Ovarian Cancer Patients in Remission Second-look laparotomy Physical examination Include pelvic examination CA-125 Imaging CT scan MRI? PET scan? CT = computed tomography MRI = magnetic resonance imaging PET = positron emission tomography Ovarian Cancer: How is Relapse Defined? Continuous rise in CA-125 CA-125 above 100 Radiographic recurrence Symptomatic recurrence Physical examination findings Combination of above When Does Ovarian Cancer Recur? Carb = carboplatin; Cis = cisplatin; Doc = docetaxel; pac = paclitaxel; GOG = Gynecologic Oncology Group; IP = intraperitoneal; Pac = paclitaxel Active Agents in Ovarian Cancer Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Refractory P R I M A R Y T R E A T M E N T Resistant Sensitive 0 3 6 12 18 24 Months “Very Sensitive” Ovarian Cancer at First Relapse Definition of Sensitivity Defined as measurable recurrence, not biochemical (CA-125) recurrence ICON 4 Schema Relapsed ovarian or primary Peritoneal requiring chemotherapy Previous platinum-based chemotherapy Conventional platinum-based chemotherapy Paclitaxel plus platinum chemotherapy R A N D O M I Z E Prior chemotherapy Carboplatin (31%) Paclitaxel/platinum (40%) Other (30%) TFI > 12 months for 75% Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group TFI = treatment-free interval ICON 4 Response (Difference of 12%; 95% CI -0.1% to 24%; p=0.06) CR = complete response; ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum; PR = partial response; Parmar MK, et al. Lancet. 2003;361:2099-2106. Proportion alive and progression-free 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Patients at risk Pac-Plat 392 179 52 25 17 Plat 410 157 45 17 7 Years from randomization Hazard ratio = 0.76 (95% CI 0.66 - 0.89; p < 0.001) Absolute difference at 1 year = 10% (40% to 50%; 95% CI 4% to 15%) Ovarian Carcinoma: ICON 4 Progression-Free Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum Hazard ratio = 0.82 (95% CI 0.69 - 0.97; p = 0.023) Absolute difference 2 years = 7% (50% to 57%; 95% CI 1% to 12%) Patients at risk Pac-Plat 392 306 167 96 43 Plat 410 295 150 68 33 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Years from randomization Proportion alive ICON 4: Overall Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum R A N D O M I Z E Gemcitabine 1,000 mg/m2 days 1 + 8 Plus Carboplatin AUC 4 day 1 every 21 days × 6 Recurrent ovarian cancer 6+ months after platinum Strata PFI (6 - 12, >12 months) 1st-line therapy (platinum ± paclitaxel) Measurable vs evaluable Primary endpoint = PFS Gem/Carbo vs Carbo: Design Carboplatin AUC 5 day 1 every 21 days × 6 Carbo = carboplatin Gem = gemcitabine PFI = progression-free interval PFS = progression-free survival Pfisterer J, et al. J Clin Oncol. 2006; 24:4699-4707. AGO OVAR 2.5 Primary Endpoint: Progression-Free Survival GCb: median = 8.6 mo Censoring: 12.4% Cb: median = 5.8 mo Censoring: 12.9% Cb Arm (N=178) GCb Arm (N=178) Log-rank p-value = 0.0038 Unadjusted HR = 0.72 (0.57 to 0.90) Adjusted HR* = 0.71 (0.57 to 0.89) * Adjusted for PFI, Tumor size Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin AGO OVAR 2.5 Efficacy Results: Overall Survival 0.0 0.8 0.2 0.3 0.4 0.5 0.6 0.7 0.9 1.0 0.1 0 6 12 18 60 54 48 42 36 30 24 Proportion Surviving Months Median = 18.0 mo Censoring: 18.5% Median = 17.3 mo Censoring: 22.5% Cb Arm (N=178) GCb Arm (N=178) * Adjusted for PFI, Tumor size and performance status Log-rank p-value = 0.7349 Unadjusted HR = 0.96 (0.75 to 1.23) Adjusted* HR = 0.92 (0.72 to 1.16) Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: < 0.5 cm > 0.5-2 cm R A N D O M I Z E 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 Completed (Target accrual 864 pts) PFS 1° endpoint Farletuzumab (MORAb-003) in Platinum-Sensitive EOC: Study Rationale FRA is overexpressed in most EOC; largely absent from normal tissue Binding of MORAb-003 to FRA blocks phosphorylation by Lyn kinase; mediates FRA-expressing tumor cell killing; suppresses tumor growth in xenograft models Phase I study of single agent MORAb-003 demonstrated no significant adverse effects and suggested efficacy in platinum-resistant EOC MORAb-003 in Platinum-Sensitive EOC: Phase II Study Design Patients with platinum-sensitive EOC in first relapse after first remission of 6-18 months duration with evaluable disease by CA125 (Enrolled N = 58; eligible n = 54) Asymptomatic relapse Single-agent Farletuzumab until progression (n = 28) Original Carbo/Taxane regimen + Farletuzumab for 6 cycles (n = 26) Symptomatic relapse Compare lengths of first and second remissions Farletuzumab maintenance Rx for responders Single-agent ORR Combination ORR Armstrong DK, et al. ASCO 2008. Abstract 5500. All arms MORAb-003: 100 mg/m2 weekly Run-in phase with 6 subjects at 37.5 and 6 at 62.5 mg/m2 Combination therapy arm every 21 days x 6 cycles Carboplatin: AUC 5-6 Taxane Paclitaxel 175 mg/m2 over 3 hours or Docetaxel 75 mg/m2 MORAb-003-002 Phase II: Treatment Arms Armstrong DK, et al. ASCO 2008. Abstract 5500. Comparison of First vs Second Remission Length: n = 6 Data as of May 5, 2008. Armstrong DK, et al. ASCO 2008. Abstract 5500. MORAb-003-002 Clinical Responses by RECIST (Combination Therapy) Best response CR: 7.4% PR: 62.9% SD: 25.9% PD: 3.7% Based on all scans submitted as of December 3, 2007 (~ 30%) By independent central reader MORAb-003 well tolerated; no increase observed in toxicity profile in combination arm ORR: 70.3% Patient benefit: 96.3% Armstrong DK, et al. ASCO 2008. Abstract 5500. Secondary Cytoreduction Controversial Inconsistent definitions Benefit appears confined to patients likely to respond to additional chemo: >12 month PFI Isolated site of recurrence Disease completely resectable Kidney Resected Liver Diaphragm Kidney Vena Cava Tumor Mass Renal Vein PFI = progression-free interval TTP mos >12 >12 >12 >17.5 >36 >24 12-24 >24 Ovarian Cancer Secondary Cytoreduction: Post-Surgery Survival Author Janicke Segna Zang Gadducci Eisenkop Munkarah Scarabelli Tay Total/Range Year 1992 1993 2000 2000 2000 2001 2001 2002 N 30 100 60 30 114 25 148 46 553 Survival Median mos 16 16.6 13 21 16.8 26 13-26 TTP mos <12 <12 <12 <17.5 <12 <24 <12 <12 Survival Median mos 8 8.8 8 15 25 42 12 6 6-42 Survival Median mos (P) 29 (0.002) 22.9 (0.007) 12 (0.02) 25 (0.04) 56.8 (0.005) 57 (NS) 32 (0.001) 39 (0.001) 12-56 TTP = time to progression GOG 213- PI Robert Coleman Surgical Candidate? Recurrent ovarian or peritoneal cancer TFI >6 mos YES NO Surgery No surgery Carboplatin + Paclitaxel Carboplatin + Paclitaxel + Bevacizumab + Bevacizumab Maintenance Randomize to Chemotherapy GOG = Gynecologic Oncology Group TFI = treatment-free interval Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Recent Phase II GOG Studies in Platinum-Resistant Ovarian Cancer Study Agents Response/comm 126-B CDDP & Cyclosporine-A 3/23 (13%) Inactive 126-C Hexamethylmelamine 3/30 (10%) Inactive 126-D Pyrazoloacridine 2/24 (8.4%) Inactive 126-E PSC833 + paclitaxel 1/16 (6%) Inactive 126-G CI-958 1/25 (4%) Inactive 126-H Topotecan (24 h) 1/25 (4%) Inactive 126-I 9-amino-camptothecin 8/58 (14%) Moderate 126-J Docetaxel 13/58 (22%) Active (post-paclitaxel) Bookman MA. Semin Oncol 2002;29(suppl 1):20-31. CDDP = c/s-diamminedichloroplatinum (cisplatin) GOG = gynecologic oncology group
Slide 51 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days GC vs TC Induction Regimens Followed by T Consolidation: Response Rates Gordon A, et al. ASCO 2008. Abstract 5536. *CR required a normalized CA-125. GC vs TC Induction Regimens Followed by T Consolidation: Pt-Based Toxicity Gordon A, et al. ASCO 2008. Abstract 5536. Conventional vs Dose-Dense TC (NOVEL): Study Design Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO 2008. Abstract 5506. P = .72 Evaluated by WHO criteria Conventional vs Dose-Dense TC (NOVEL): Clinical Responses Isonishi S, et al. ASCO 2008. Abstract 5506. Conventional vs Dose-Dense TC (NOVEL): PFS 0.0 0.2 0.4 0.6 0.8 1.0 0 12 30 54 Mos From Randomization Proportion Surviving Progression Free 0.1 0.3 0.5 0.7 0.9 6 18 42 24 48 36 Isonishi S, et al. ASCO 2008. Abstract 5506. dd-TC c-TC Ovarian Carcinoma: Clinical Course Symptoms Diagnosis Chemotherapy #1 Staging Primary cytoreduction Interval Cytoreduction Progression Chemo #2 Chemo #3+ Supportive Care Death Consolidation/ Maintenance Cure Secondary Cytoreduction Second-Look Goals of Treatment: Relapsed Ovarian Cancer Prolong Survival Delay Time to Progression Control Disease-Related Symptoms Minimize Treatment-Related Symptoms Maintain or Improve Quality of Life Issues Impacting Therapy for Recurrent Ovarian Cancer Treatment-free interval Impact of consolidation/maintenance therapy Number of prior regimens Response to prior therapy Toxicity from prior therapy Prior use of growth factors Transfusion requirements Neuropathy Volume and site(s) of disease Ascites/GI symptoms Performance status Surveillance Options for Ovarian Cancer Patients in Remission Second-look laparotomy Physical examination Include pelvic examination CA-125 Imaging CT scan MRI? PET scan? CT = computed tomography MRI = magnetic resonance imaging PET = positron emission tomography Ovarian Cancer: How is Relapse Defined? Continuous rise in CA-125 CA-125 above 100 Radiographic recurrence Symptomatic recurrence Physical examination findings Combination of above When Does Ovarian Cancer Recur? Carb = carboplatin; Cis = cisplatin; Doc = docetaxel; pac = paclitaxel; GOG = Gynecologic Oncology Group; IP = intraperitoneal; Pac = paclitaxel Active Agents in Ovarian Cancer Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Refractory P R I M A R Y T R E A T M E N T Resistant Sensitive 0 3 6 12 18 24 Months “Very Sensitive” Ovarian Cancer at First Relapse Definition of Sensitivity Defined as measurable recurrence, not biochemical (CA-125) recurrence ICON 4 Schema Relapsed ovarian or primary Peritoneal requiring chemotherapy Previous platinum-based chemotherapy Conventional platinum-based chemotherapy Paclitaxel plus platinum chemotherapy R A N D O M I Z E Prior chemotherapy Carboplatin (31%) Paclitaxel/platinum (40%) Other (30%) TFI > 12 months for 75% Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group TFI = treatment-free interval ICON 4 Response (Difference of 12%; 95% CI -0.1% to 24%; p=0.06) CR = complete response; ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum; PR = partial response; Parmar MK, et al. Lancet. 2003;361:2099-2106. Proportion alive and progression-free 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Patients at risk Pac-Plat 392 179 52 25 17 Plat 410 157 45 17 7 Years from randomization Hazard ratio = 0.76 (95% CI 0.66 - 0.89; p < 0.001) Absolute difference at 1 year = 10% (40% to 50%; 95% CI 4% to 15%) Ovarian Carcinoma: ICON 4 Progression-Free Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum Hazard ratio = 0.82 (95% CI 0.69 - 0.97; p = 0.023) Absolute difference 2 years = 7% (50% to 57%; 95% CI 1% to 12%) Patients at risk Pac-Plat 392 306 167 96 43 Plat 410 295 150 68 33 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Years from randomization Proportion alive ICON 4: Overall Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum R A N D O M I Z E Gemcitabine 1,000 mg/m2 days 1 + 8 Plus Carboplatin AUC 4 day 1 every 21 days × 6 Recurrent ovarian cancer 6+ months after platinum Strata PFI (6 - 12, >12 months) 1st-line therapy (platinum ± paclitaxel) Measurable vs evaluable Primary endpoint = PFS Gem/Carbo vs Carbo: Design Carboplatin AUC 5 day 1 every 21 days × 6 Carbo = carboplatin Gem = gemcitabine PFI = progression-free interval PFS = progression-free survival Pfisterer J, et al. J Clin Oncol. 2006; 24:4699-4707. AGO OVAR 2.5 Primary Endpoint: Progression-Free Survival GCb: median = 8.6 mo Censoring: 12.4% Cb: median = 5.8 mo Censoring: 12.9% Cb Arm (N=178) GCb Arm (N=178) Log-rank p-value = 0.0038 Unadjusted HR = 0.72 (0.57 to 0.90) Adjusted HR* = 0.71 (0.57 to 0.89) * Adjusted for PFI, Tumor size Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin AGO OVAR 2.5 Efficacy Results: Overall Survival 0.0 0.8 0.2 0.3 0.4 0.5 0.6 0.7 0.9 1.0 0.1 0 6 12 18 60 54 48 42 36 30 24 Proportion Surviving Months Median = 18.0 mo Censoring: 18.5% Median = 17.3 mo Censoring: 22.5% Cb Arm (N=178) GCb Arm (N=178) * Adjusted for PFI, Tumor size and performance status Log-rank p-value = 0.7349 Unadjusted HR = 0.96 (0.75 to 1.23) Adjusted* HR = 0.92 (0.72 to 1.16) Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: < 0.5 cm > 0.5-2 cm R A N D O M I Z E 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 Completed (Target accrual 864 pts) PFS 1° endpoint Farletuzumab (MORAb-003) in Platinum-Sensitive EOC: Study Rationale FRA is overexpressed in most EOC; largely absent from normal tissue Binding of MORAb-003 to FRA blocks phosphorylation by Lyn kinase; mediates FRA-expressing tumor cell killing; suppresses tumor growth in xenograft models Phase I study of single agent MORAb-003 demonstrated no significant adverse effects and suggested efficacy in platinum-resistant EOC MORAb-003 in Platinum-Sensitive EOC: Phase II Study Design Patients with platinum-sensitive EOC in first relapse after first remission of 6-18 months duration with evaluable disease by CA125 (Enrolled N = 58; eligible n = 54) Asymptomatic relapse Single-agent Farletuzumab until progression (n = 28) Original Carbo/Taxane regimen + Farletuzumab for 6 cycles (n = 26) Symptomatic relapse Compare lengths of first and second remissions Farletuzumab maintenance Rx for responders Single-agent ORR Combination ORR Armstrong DK, et al. ASCO 2008. Abstract 5500. All arms MORAb-003: 100 mg/m2 weekly Run-in phase with 6 subjects at 37.5 and 6 at 62.5 mg/m2 Combination therapy arm every 21 days x 6 cycles Carboplatin: AUC 5-6 Taxane Paclitaxel 175 mg/m2 over 3 hours or Docetaxel 75 mg/m2 MORAb-003-002 Phase II: Treatment Arms Armstrong DK, et al. ASCO 2008. Abstract 5500. Comparison of First vs Second Remission Length: n = 6 Data as of May 5, 2008. Armstrong DK, et al. ASCO 2008. Abstract 5500. MORAb-003-002 Clinical Responses by RECIST (Combination Therapy) Best response CR: 7.4% PR: 62.9% SD: 25.9% PD: 3.7% Based on all scans submitted as of December 3, 2007 (~ 30%) By independent central reader MORAb-003 well tolerated; no increase observed in toxicity profile in combination arm ORR: 70.3% Patient benefit: 96.3% Armstrong DK, et al. ASCO 2008. Abstract 5500. Secondary Cytoreduction Controversial Inconsistent definitions Benefit appears confined to patients likely to respond to additional chemo: >12 month PFI Isolated site of recurrence Disease completely resectable Kidney Resected Liver Diaphragm Kidney Vena Cava Tumor Mass Renal Vein PFI = progression-free interval TTP mos >12 >12 >12 >17.5 >36 >24 12-24 >24 Ovarian Cancer Secondary Cytoreduction: Post-Surgery Survival Author Janicke Segna Zang Gadducci Eisenkop Munkarah Scarabelli Tay Total/Range Year 1992 1993 2000 2000 2000 2001 2001 2002 N 30 100 60 30 114 25 148 46 553 Survival Median mos 16 16.6 13 21 16.8 26 13-26 TTP mos <12 <12 <12 <17.5 <12 <24 <12 <12 Survival Median mos 8 8.8 8 15 25 42 12 6 6-42 Survival Median mos (P) 29 (0.002) 22.9 (0.007) 12 (0.02) 25 (0.04) 56.8 (0.005) 57 (NS) 32 (0.001) 39 (0.001) 12-56 TTP = time to progression GOG 213- PI Robert Coleman Surgical Candidate? Recurrent ovarian or peritoneal cancer TFI >6 mos YES NO Surgery No surgery Carboplatin + Paclitaxel Carboplatin + Paclitaxel + Bevacizumab + Bevacizumab Maintenance Randomize to Chemotherapy GOG = Gynecologic Oncology Group TFI = treatment-free interval Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Recent Phase II GOG Studies in Platinum-Resistant Ovarian Cancer Study Agents Response/comm 126-B CDDP & Cyclosporine-A 3/23 (13%) Inactive 126-C Hexamethylmelamine 3/30 (10%) Inactive 126-D Pyrazoloacridine 2/24 (8.4%) Inactive 126-E PSC833 + paclitaxel 1/16 (6%) Inactive 126-G CI-958 1/25 (4%) Inactive 126-H Topotecan (24 h) 1/25 (4%) Inactive 126-I 9-amino-camptothecin 8/58 (14%) Moderate 126-J Docetaxel 13/58 (22%) Active (post-paclitaxel) Bookman MA. Semin Oncol 2002;29(suppl 1):20-31. CDDP = c/s-diamminedichloroplatinum (cisplatin) GOG = gynecologic oncology group Recent Phase II GOG Studies in Platinum-Resistant Ovarian Cancer Study Agents Response/comm 126-K Oxaliplatin 1/25 (4%) Inactive 126-L Gemcitabine/CDDP 9/57 (16%) Moderate 126-M Ixabepilone 7/50 (14%) Moderate 126-N Paclitaxel weekly 10/48 (21%) Active (post-paclitaxel) 126-O Triapine-CDDP Not Feasible 126-P Paclitaxel & Celecoxib Closed Early 126-Q Pemetrexed 10/48 (21%) Active 126-R Abraxane Accrual in Progress Bookman MA. Semin Oncol 2002;29(suppl 1):20-31. CDDP = c/s-diamminedichloroplatinum (cisplatin) GOG = gynecologic oncology group
Slide 52 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days GC vs TC Induction Regimens Followed by T Consolidation: Response Rates Gordon A, et al. ASCO 2008. Abstract 5536. *CR required a normalized CA-125. GC vs TC Induction Regimens Followed by T Consolidation: Pt-Based Toxicity Gordon A, et al. ASCO 2008. Abstract 5536. Conventional vs Dose-Dense TC (NOVEL): Study Design Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO 2008. Abstract 5506. P = .72 Evaluated by WHO criteria Conventional vs Dose-Dense TC (NOVEL): Clinical Responses Isonishi S, et al. ASCO 2008. Abstract 5506. Conventional vs Dose-Dense TC (NOVEL): PFS 0.0 0.2 0.4 0.6 0.8 1.0 0 12 30 54 Mos From Randomization Proportion Surviving Progression Free 0.1 0.3 0.5 0.7 0.9 6 18 42 24 48 36 Isonishi S, et al. ASCO 2008. Abstract 5506. dd-TC c-TC Ovarian Carcinoma: Clinical Course Symptoms Diagnosis Chemotherapy #1 Staging Primary cytoreduction Interval Cytoreduction Progression Chemo #2 Chemo #3+ Supportive Care Death Consolidation/ Maintenance Cure Secondary Cytoreduction Second-Look Goals of Treatment: Relapsed Ovarian Cancer Prolong Survival Delay Time to Progression Control Disease-Related Symptoms Minimize Treatment-Related Symptoms Maintain or Improve Quality of Life Issues Impacting Therapy for Recurrent Ovarian Cancer Treatment-free interval Impact of consolidation/maintenance therapy Number of prior regimens Response to prior therapy Toxicity from prior therapy Prior use of growth factors Transfusion requirements Neuropathy Volume and site(s) of disease Ascites/GI symptoms Performance status Surveillance Options for Ovarian Cancer Patients in Remission Second-look laparotomy Physical examination Include pelvic examination CA-125 Imaging CT scan MRI? PET scan? CT = computed tomography MRI = magnetic resonance imaging PET = positron emission tomography Ovarian Cancer: How is Relapse Defined? Continuous rise in CA-125 CA-125 above 100 Radiographic recurrence Symptomatic recurrence Physical examination findings Combination of above When Does Ovarian Cancer Recur? Carb = carboplatin; Cis = cisplatin; Doc = docetaxel; pac = paclitaxel; GOG = Gynecologic Oncology Group; IP = intraperitoneal; Pac = paclitaxel Active Agents in Ovarian Cancer Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Refractory P R I M A R Y T R E A T M E N T Resistant Sensitive 0 3 6 12 18 24 Months “Very Sensitive” Ovarian Cancer at First Relapse Definition of Sensitivity Defined as measurable recurrence, not biochemical (CA-125) recurrence ICON 4 Schema Relapsed ovarian or primary Peritoneal requiring chemotherapy Previous platinum-based chemotherapy Conventional platinum-based chemotherapy Paclitaxel plus platinum chemotherapy R A N D O M I Z E Prior chemotherapy Carboplatin (31%) Paclitaxel/platinum (40%) Other (30%) TFI > 12 months for 75% Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group TFI = treatment-free interval ICON 4 Response (Difference of 12%; 95% CI -0.1% to 24%; p=0.06) CR = complete response; ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum; PR = partial response; Parmar MK, et al. Lancet. 2003;361:2099-2106. Proportion alive and progression-free 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Patients at risk Pac-Plat 392 179 52 25 17 Plat 410 157 45 17 7 Years from randomization Hazard ratio = 0.76 (95% CI 0.66 - 0.89; p < 0.001) Absolute difference at 1 year = 10% (40% to 50%; 95% CI 4% to 15%) Ovarian Carcinoma: ICON 4 Progression-Free Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum Hazard ratio = 0.82 (95% CI 0.69 - 0.97; p = 0.023) Absolute difference 2 years = 7% (50% to 57%; 95% CI 1% to 12%) Patients at risk Pac-Plat 392 306 167 96 43 Plat 410 295 150 68 33 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Years from randomization Proportion alive ICON 4: Overall Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum R A N D O M I Z E Gemcitabine 1,000 mg/m2 days 1 + 8 Plus Carboplatin AUC 4 day 1 every 21 days × 6 Recurrent ovarian cancer 6+ months after platinum Strata PFI (6 - 12, >12 months) 1st-line therapy (platinum ± paclitaxel) Measurable vs evaluable Primary endpoint = PFS Gem/Carbo vs Carbo: Design Carboplatin AUC 5 day 1 every 21 days × 6 Carbo = carboplatin Gem = gemcitabine PFI = progression-free interval PFS = progression-free survival Pfisterer J, et al. J Clin Oncol. 2006; 24:4699-4707. AGO OVAR 2.5 Primary Endpoint: Progression-Free Survival GCb: median = 8.6 mo Censoring: 12.4% Cb: median = 5.8 mo Censoring: 12.9% Cb Arm (N=178) GCb Arm (N=178) Log-rank p-value = 0.0038 Unadjusted HR = 0.72 (0.57 to 0.90) Adjusted HR* = 0.71 (0.57 to 0.89) * Adjusted for PFI, Tumor size Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin AGO OVAR 2.5 Efficacy Results: Overall Survival 0.0 0.8 0.2 0.3 0.4 0.5 0.6 0.7 0.9 1.0 0.1 0 6 12 18 60 54 48 42 36 30 24 Proportion Surviving Months Median = 18.0 mo Censoring: 18.5% Median = 17.3 mo Censoring: 22.5% Cb Arm (N=178) GCb Arm (N=178) * Adjusted for PFI, Tumor size and performance status Log-rank p-value = 0.7349 Unadjusted HR = 0.96 (0.75 to 1.23) Adjusted* HR = 0.92 (0.72 to 1.16) Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: < 0.5 cm > 0.5-2 cm R A N D O M I Z E 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 Completed (Target accrual 864 pts) PFS 1° endpoint Farletuzumab (MORAb-003) in Platinum-Sensitive EOC: Study Rationale FRA is overexpressed in most EOC; largely absent from normal tissue Binding of MORAb-003 to FRA blocks phosphorylation by Lyn kinase; mediates FRA-expressing tumor cell killing; suppresses tumor growth in xenograft models Phase I study of single agent MORAb-003 demonstrated no significant adverse effects and suggested efficacy in platinum-resistant EOC MORAb-003 in Platinum-Sensitive EOC: Phase II Study Design Patients with platinum-sensitive EOC in first relapse after first remission of 6-18 months duration with evaluable disease by CA125 (Enrolled N = 58; eligible n = 54) Asymptomatic relapse Single-agent Farletuzumab until progression (n = 28) Original Carbo/Taxane regimen + Farletuzumab for 6 cycles (n = 26) Symptomatic relapse Compare lengths of first and second remissions Farletuzumab maintenance Rx for responders Single-agent ORR Combination ORR Armstrong DK, et al. ASCO 2008. Abstract 5500. All arms MORAb-003: 100 mg/m2 weekly Run-in phase with 6 subjects at 37.5 and 6 at 62.5 mg/m2 Combination therapy arm every 21 days x 6 cycles Carboplatin: AUC 5-6 Taxane Paclitaxel 175 mg/m2 over 3 hours or Docetaxel 75 mg/m2 MORAb-003-002 Phase II: Treatment Arms Armstrong DK, et al. ASCO 2008. Abstract 5500. Comparison of First vs Second Remission Length: n = 6 Data as of May 5, 2008. Armstrong DK, et al. ASCO 2008. Abstract 5500. MORAb-003-002 Clinical Responses by RECIST (Combination Therapy) Best response CR: 7.4% PR: 62.9% SD: 25.9% PD: 3.7% Based on all scans submitted as of December 3, 2007 (~ 30%) By independent central reader MORAb-003 well tolerated; no increase observed in toxicity profile in combination arm ORR: 70.3% Patient benefit: 96.3% Armstrong DK, et al. ASCO 2008. Abstract 5500. Secondary Cytoreduction Controversial Inconsistent definitions Benefit appears confined to patients likely to respond to additional chemo: >12 month PFI Isolated site of recurrence Disease completely resectable Kidney Resected Liver Diaphragm Kidney Vena Cava Tumor Mass Renal Vein PFI = progression-free interval TTP mos >12 >12 >12 >17.5 >36 >24 12-24 >24 Ovarian Cancer Secondary Cytoreduction: Post-Surgery Survival Author Janicke Segna Zang Gadducci Eisenkop Munkarah Scarabelli Tay Total/Range Year 1992 1993 2000 2000 2000 2001 2001 2002 N 30 100 60 30 114 25 148 46 553 Survival Median mos 16 16.6 13 21 16.8 26 13-26 TTP mos <12 <12 <12 <17.5 <12 <24 <12 <12 Survival Median mos 8 8.8 8 15 25 42 12 6 6-42 Survival Median mos (P) 29 (0.002) 22.9 (0.007) 12 (0.02) 25 (0.04) 56.8 (0.005) 57 (NS) 32 (0.001) 39 (0.001) 12-56 TTP = time to progression GOG 213- PI Robert Coleman Surgical Candidate? Recurrent ovarian or peritoneal cancer TFI >6 mos YES NO Surgery No surgery Carboplatin + Paclitaxel Carboplatin + Paclitaxel + Bevacizumab + Bevacizumab Maintenance Randomize to Chemotherapy GOG = Gynecologic Oncology Group TFI = treatment-free interval Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Recent Phase II GOG Studies in Platinum-Resistant Ovarian Cancer Study Agents Response/comm 126-B CDDP & Cyclosporine-A 3/23 (13%) Inactive 126-C Hexamethylmelamine 3/30 (10%) Inactive 126-D Pyrazoloacridine 2/24 (8.4%) Inactive 126-E PSC833 + paclitaxel 1/16 (6%) Inactive 126-G CI-958 1/25 (4%) Inactive 126-H Topotecan (24 h) 1/25 (4%) Inactive 126-I 9-amino-camptothecin 8/58 (14%) Moderate 126-J Docetaxel 13/58 (22%) Active (post-paclitaxel) Bookman MA. Semin Oncol 2002;29(suppl 1):20-31. CDDP = c/s-diamminedichloroplatinum (cisplatin) GOG = gynecologic oncology group Recent Phase II GOG Studies in Platinum-Resistant Ovarian Cancer Study Agents Response/comm 126-K Oxaliplatin 1/25 (4%) Inactive 126-L Gemcitabine/CDDP 9/57 (16%) Moderate 126-M Ixabepilone 7/50 (14%) Moderate 126-N Paclitaxel weekly 10/48 (21%) Active (post-paclitaxel) 126-O Triapine-CDDP Not Feasible 126-P Paclitaxel & Celecoxib Closed Early 126-Q Pemetrexed 10/48 (21%) Active 126-R Abraxane Accrual in Progress Bookman MA. Semin Oncol 2002;29(suppl 1):20-31. CDDP = c/s-diamminedichloroplatinum (cisplatin) GOG = gynecologic oncology group Pemetrexed in Platinum-Resistant EOC: Phase II GOG Study Schema Miller DS, et al. ASCO 2008. Abstract 5524. Patients with persistent or recurrent platinum-resistant EOC or primary peritoneal cancer who have failed on higher priority treatment protocols Pemetrexed 900 mg/m2 IV every 21 days for 1 cycle; patients who have received previous radiotherapy will initiate pemetrexed at level I reduction dose until disease progression or adverse effect prohibits further therapy
Slide 53 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days GC vs TC Induction Regimens Followed by T Consolidation: Response Rates Gordon A, et al. ASCO 2008. Abstract 5536. *CR required a normalized CA-125. GC vs TC Induction Regimens Followed by T Consolidation: Pt-Based Toxicity Gordon A, et al. ASCO 2008. Abstract 5536. Conventional vs Dose-Dense TC (NOVEL): Study Design Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO 2008. Abstract 5506. P = .72 Evaluated by WHO criteria Conventional vs Dose-Dense TC (NOVEL): Clinical Responses Isonishi S, et al. ASCO 2008. Abstract 5506. Conventional vs Dose-Dense TC (NOVEL): PFS 0.0 0.2 0.4 0.6 0.8 1.0 0 12 30 54 Mos From Randomization Proportion Surviving Progression Free 0.1 0.3 0.5 0.7 0.9 6 18 42 24 48 36 Isonishi S, et al. ASCO 2008. Abstract 5506. dd-TC c-TC Ovarian Carcinoma: Clinical Course Symptoms Diagnosis Chemotherapy #1 Staging Primary cytoreduction Interval Cytoreduction Progression Chemo #2 Chemo #3+ Supportive Care Death Consolidation/ Maintenance Cure Secondary Cytoreduction Second-Look Goals of Treatment: Relapsed Ovarian Cancer Prolong Survival Delay Time to Progression Control Disease-Related Symptoms Minimize Treatment-Related Symptoms Maintain or Improve Quality of Life Issues Impacting Therapy for Recurrent Ovarian Cancer Treatment-free interval Impact of consolidation/maintenance therapy Number of prior regimens Response to prior therapy Toxicity from prior therapy Prior use of growth factors Transfusion requirements Neuropathy Volume and site(s) of disease Ascites/GI symptoms Performance status Surveillance Options for Ovarian Cancer Patients in Remission Second-look laparotomy Physical examination Include pelvic examination CA-125 Imaging CT scan MRI? PET scan? CT = computed tomography MRI = magnetic resonance imaging PET = positron emission tomography Ovarian Cancer: How is Relapse Defined? Continuous rise in CA-125 CA-125 above 100 Radiographic recurrence Symptomatic recurrence Physical examination findings Combination of above When Does Ovarian Cancer Recur? Carb = carboplatin; Cis = cisplatin; Doc = docetaxel; pac = paclitaxel; GOG = Gynecologic Oncology Group; IP = intraperitoneal; Pac = paclitaxel Active Agents in Ovarian Cancer Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Refractory P R I M A R Y T R E A T M E N T Resistant Sensitive 0 3 6 12 18 24 Months “Very Sensitive” Ovarian Cancer at First Relapse Definition of Sensitivity Defined as measurable recurrence, not biochemical (CA-125) recurrence ICON 4 Schema Relapsed ovarian or primary Peritoneal requiring chemotherapy Previous platinum-based chemotherapy Conventional platinum-based chemotherapy Paclitaxel plus platinum chemotherapy R A N D O M I Z E Prior chemotherapy Carboplatin (31%) Paclitaxel/platinum (40%) Other (30%) TFI > 12 months for 75% Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group TFI = treatment-free interval ICON 4 Response (Difference of 12%; 95% CI -0.1% to 24%; p=0.06) CR = complete response; ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum; PR = partial response; Parmar MK, et al. Lancet. 2003;361:2099-2106. Proportion alive and progression-free 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Patients at risk Pac-Plat 392 179 52 25 17 Plat 410 157 45 17 7 Years from randomization Hazard ratio = 0.76 (95% CI 0.66 - 0.89; p < 0.001) Absolute difference at 1 year = 10% (40% to 50%; 95% CI 4% to 15%) Ovarian Carcinoma: ICON 4 Progression-Free Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum Hazard ratio = 0.82 (95% CI 0.69 - 0.97; p = 0.023) Absolute difference 2 years = 7% (50% to 57%; 95% CI 1% to 12%) Patients at risk Pac-Plat 392 306 167 96 43 Plat 410 295 150 68 33 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Years from randomization Proportion alive ICON 4: Overall Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum R A N D O M I Z E Gemcitabine 1,000 mg/m2 days 1 + 8 Plus Carboplatin AUC 4 day 1 every 21 days × 6 Recurrent ovarian cancer 6+ months after platinum Strata PFI (6 - 12, >12 months) 1st-line therapy (platinum ± paclitaxel) Measurable vs evaluable Primary endpoint = PFS Gem/Carbo vs Carbo: Design Carboplatin AUC 5 day 1 every 21 days × 6 Carbo = carboplatin Gem = gemcitabine PFI = progression-free interval PFS = progression-free survival Pfisterer J, et al. J Clin Oncol. 2006; 24:4699-4707. AGO OVAR 2.5 Primary Endpoint: Progression-Free Survival GCb: median = 8.6 mo Censoring: 12.4% Cb: median = 5.8 mo Censoring: 12.9% Cb Arm (N=178) GCb Arm (N=178) Log-rank p-value = 0.0038 Unadjusted HR = 0.72 (0.57 to 0.90) Adjusted HR* = 0.71 (0.57 to 0.89) * Adjusted for PFI, Tumor size Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin AGO OVAR 2.5 Efficacy Results: Overall Survival 0.0 0.8 0.2 0.3 0.4 0.5 0.6 0.7 0.9 1.0 0.1 0 6 12 18 60 54 48 42 36 30 24 Proportion Surviving Months Median = 18.0 mo Censoring: 18.5% Median = 17.3 mo Censoring: 22.5% Cb Arm (N=178) GCb Arm (N=178) * Adjusted for PFI, Tumor size and performance status Log-rank p-value = 0.7349 Unadjusted HR = 0.96 (0.75 to 1.23) Adjusted* HR = 0.92 (0.72 to 1.16) Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: < 0.5 cm > 0.5-2 cm R A N D O M I Z E 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 Completed (Target accrual 864 pts) PFS 1° endpoint Farletuzumab (MORAb-003) in Platinum-Sensitive EOC: Study Rationale FRA is overexpressed in most EOC; largely absent from normal tissue Binding of MORAb-003 to FRA blocks phosphorylation by Lyn kinase; mediates FRA-expressing tumor cell killing; suppresses tumor growth in xenograft models Phase I study of single agent MORAb-003 demonstrated no significant adverse effects and suggested efficacy in platinum-resistant EOC MORAb-003 in Platinum-Sensitive EOC: Phase II Study Design Patients with platinum-sensitive EOC in first relapse after first remission of 6-18 months duration with evaluable disease by CA125 (Enrolled N = 58; eligible n = 54) Asymptomatic relapse Single-agent Farletuzumab until progression (n = 28) Original Carbo/Taxane regimen + Farletuzumab for 6 cycles (n = 26) Symptomatic relapse Compare lengths of first and second remissions Farletuzumab maintenance Rx for responders Single-agent ORR Combination ORR Armstrong DK, et al. ASCO 2008. Abstract 5500. All arms MORAb-003: 100 mg/m2 weekly Run-in phase with 6 subjects at 37.5 and 6 at 62.5 mg/m2 Combination therapy arm every 21 days x 6 cycles Carboplatin: AUC 5-6 Taxane Paclitaxel 175 mg/m2 over 3 hours or Docetaxel 75 mg/m2 MORAb-003-002 Phase II: Treatment Arms Armstrong DK, et al. ASCO 2008. Abstract 5500. Comparison of First vs Second Remission Length: n = 6 Data as of May 5, 2008. Armstrong DK, et al. ASCO 2008. Abstract 5500. MORAb-003-002 Clinical Responses by RECIST (Combination Therapy) Best response CR: 7.4% PR: 62.9% SD: 25.9% PD: 3.7% Based on all scans submitted as of December 3, 2007 (~ 30%) By independent central reader MORAb-003 well tolerated; no increase observed in toxicity profile in combination arm ORR: 70.3% Patient benefit: 96.3% Armstrong DK, et al. ASCO 2008. Abstract 5500. Secondary Cytoreduction Controversial Inconsistent definitions Benefit appears confined to patients likely to respond to additional chemo: >12 month PFI Isolated site of recurrence Disease completely resectable Kidney Resected Liver Diaphragm Kidney Vena Cava Tumor Mass Renal Vein PFI = progression-free interval TTP mos >12 >12 >12 >17.5 >36 >24 12-24 >24 Ovarian Cancer Secondary Cytoreduction: Post-Surgery Survival Author Janicke Segna Zang Gadducci Eisenkop Munkarah Scarabelli Tay Total/Range Year 1992 1993 2000 2000 2000 2001 2001 2002 N 30 100 60 30 114 25 148 46 553 Survival Median mos 16 16.6 13 21 16.8 26 13-26 TTP mos <12 <12 <12 <17.5 <12 <24 <12 <12 Survival Median mos 8 8.8 8 15 25 42 12 6 6-42 Survival Median mos (P) 29 (0.002) 22.9 (0.007) 12 (0.02) 25 (0.04) 56.8 (0.005) 57 (NS) 32 (0.001) 39 (0.001) 12-56 TTP = time to progression GOG 213- PI Robert Coleman Surgical Candidate? Recurrent ovarian or peritoneal cancer TFI >6 mos YES NO Surgery No surgery Carboplatin + Paclitaxel Carboplatin + Paclitaxel + Bevacizumab + Bevacizumab Maintenance Randomize to Chemotherapy GOG = Gynecologic Oncology Group TFI = treatment-free interval Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Recent Phase II GOG Studies in Platinum-Resistant Ovarian Cancer Study Agents Response/comm 126-B CDDP & Cyclosporine-A 3/23 (13%) Inactive 126-C Hexamethylmelamine 3/30 (10%) Inactive 126-D Pyrazoloacridine 2/24 (8.4%) Inactive 126-E PSC833 + paclitaxel 1/16 (6%) Inactive 126-G CI-958 1/25 (4%) Inactive 126-H Topotecan (24 h) 1/25 (4%) Inactive 126-I 9-amino-camptothecin 8/58 (14%) Moderate 126-J Docetaxel 13/58 (22%) Active (post-paclitaxel) Bookman MA. Semin Oncol 2002;29(suppl 1):20-31. CDDP = c/s-diamminedichloroplatinum (cisplatin) GOG = gynecologic oncology group Recent Phase II GOG Studies in Platinum-Resistant Ovarian Cancer Study Agents Response/comm 126-K Oxaliplatin 1/25 (4%) Inactive 126-L Gemcitabine/CDDP 9/57 (16%) Moderate 126-M Ixabepilone 7/50 (14%) Moderate 126-N Paclitaxel weekly 10/48 (21%) Active (post-paclitaxel) 126-O Triapine-CDDP Not Feasible 126-P Paclitaxel & Celecoxib Closed Early 126-Q Pemetrexed 10/48 (21%) Active 126-R Abraxane Accrual in Progress Bookman MA. Semin Oncol 2002;29(suppl 1):20-31. CDDP = c/s-diamminedichloroplatinum (cisplatin) GOG = gynecologic oncology group Pemetrexed in Platinum-Resistant EOC: Phase II GOG Study Schema Miller DS, et al. ASCO 2008. Abstract 5524. Patients with persistent or recurrent platinum-resistant EOC or primary peritoneal cancer who have failed on higher priority treatment protocols Pemetrexed 900 mg/m2 IV every 21 days for 1 cycle; patients who have received previous radiotherapy will initiate pemetrexed at level I reduction dose until disease progression or adverse effect prohibits further therapy Phase II GOG Study Evaluation of Pemetrexed: Clinical Responses Miller DS, et al. ASCO 2008. Abstract 5524. *1 patient remains on therapy.
Slide 54 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days GC vs TC Induction Regimens Followed by T Consolidation: Response Rates Gordon A, et al. ASCO 2008. Abstract 5536. *CR required a normalized CA-125. GC vs TC Induction Regimens Followed by T Consolidation: Pt-Based Toxicity Gordon A, et al. ASCO 2008. Abstract 5536. Conventional vs Dose-Dense TC (NOVEL): Study Design Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO 2008. Abstract 5506. P = .72 Evaluated by WHO criteria Conventional vs Dose-Dense TC (NOVEL): Clinical Responses Isonishi S, et al. ASCO 2008. Abstract 5506. Conventional vs Dose-Dense TC (NOVEL): PFS 0.0 0.2 0.4 0.6 0.8 1.0 0 12 30 54 Mos From Randomization Proportion Surviving Progression Free 0.1 0.3 0.5 0.7 0.9 6 18 42 24 48 36 Isonishi S, et al. ASCO 2008. Abstract 5506. dd-TC c-TC Ovarian Carcinoma: Clinical Course Symptoms Diagnosis Chemotherapy #1 Staging Primary cytoreduction Interval Cytoreduction Progression Chemo #2 Chemo #3+ Supportive Care Death Consolidation/ Maintenance Cure Secondary Cytoreduction Second-Look Goals of Treatment: Relapsed Ovarian Cancer Prolong Survival Delay Time to Progression Control Disease-Related Symptoms Minimize Treatment-Related Symptoms Maintain or Improve Quality of Life Issues Impacting Therapy for Recurrent Ovarian Cancer Treatment-free interval Impact of consolidation/maintenance therapy Number of prior regimens Response to prior therapy Toxicity from prior therapy Prior use of growth factors Transfusion requirements Neuropathy Volume and site(s) of disease Ascites/GI symptoms Performance status Surveillance Options for Ovarian Cancer Patients in Remission Second-look laparotomy Physical examination Include pelvic examination CA-125 Imaging CT scan MRI? PET scan? CT = computed tomography MRI = magnetic resonance imaging PET = positron emission tomography Ovarian Cancer: How is Relapse Defined? Continuous rise in CA-125 CA-125 above 100 Radiographic recurrence Symptomatic recurrence Physical examination findings Combination of above When Does Ovarian Cancer Recur? Carb = carboplatin; Cis = cisplatin; Doc = docetaxel; pac = paclitaxel; GOG = Gynecologic Oncology Group; IP = intraperitoneal; Pac = paclitaxel Active Agents in Ovarian Cancer Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Refractory P R I M A R Y T R E A T M E N T Resistant Sensitive 0 3 6 12 18 24 Months “Very Sensitive” Ovarian Cancer at First Relapse Definition of Sensitivity Defined as measurable recurrence, not biochemical (CA-125) recurrence ICON 4 Schema Relapsed ovarian or primary Peritoneal requiring chemotherapy Previous platinum-based chemotherapy Conventional platinum-based chemotherapy Paclitaxel plus platinum chemotherapy R A N D O M I Z E Prior chemotherapy Carboplatin (31%) Paclitaxel/platinum (40%) Other (30%) TFI > 12 months for 75% Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group TFI = treatment-free interval ICON 4 Response (Difference of 12%; 95% CI -0.1% to 24%; p=0.06) CR = complete response; ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum; PR = partial response; Parmar MK, et al. Lancet. 2003;361:2099-2106. Proportion alive and progression-free 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Patients at risk Pac-Plat 392 179 52 25 17 Plat 410 157 45 17 7 Years from randomization Hazard ratio = 0.76 (95% CI 0.66 - 0.89; p < 0.001) Absolute difference at 1 year = 10% (40% to 50%; 95% CI 4% to 15%) Ovarian Carcinoma: ICON 4 Progression-Free Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum Hazard ratio = 0.82 (95% CI 0.69 - 0.97; p = 0.023) Absolute difference 2 years = 7% (50% to 57%; 95% CI 1% to 12%) Patients at risk Pac-Plat 392 306 167 96 43 Plat 410 295 150 68 33 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Years from randomization Proportion alive ICON 4: Overall Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum R A N D O M I Z E Gemcitabine 1,000 mg/m2 days 1 + 8 Plus Carboplatin AUC 4 day 1 every 21 days × 6 Recurrent ovarian cancer 6+ months after platinum Strata PFI (6 - 12, >12 months) 1st-line therapy (platinum ± paclitaxel) Measurable vs evaluable Primary endpoint = PFS Gem/Carbo vs Carbo: Design Carboplatin AUC 5 day 1 every 21 days × 6 Carbo = carboplatin Gem = gemcitabine PFI = progression-free interval PFS = progression-free survival Pfisterer J, et al. J Clin Oncol. 2006; 24:4699-4707. AGO OVAR 2.5 Primary Endpoint: Progression-Free Survival GCb: median = 8.6 mo Censoring: 12.4% Cb: median = 5.8 mo Censoring: 12.9% Cb Arm (N=178) GCb Arm (N=178) Log-rank p-value = 0.0038 Unadjusted HR = 0.72 (0.57 to 0.90) Adjusted HR* = 0.71 (0.57 to 0.89) * Adjusted for PFI, Tumor size Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin AGO OVAR 2.5 Efficacy Results: Overall Survival 0.0 0.8 0.2 0.3 0.4 0.5 0.6 0.7 0.9 1.0 0.1 0 6 12 18 60 54 48 42 36 30 24 Proportion Surviving Months Median = 18.0 mo Censoring: 18.5% Median = 17.3 mo Censoring: 22.5% Cb Arm (N=178) GCb Arm (N=178) * Adjusted for PFI, Tumor size and performance status Log-rank p-value = 0.7349 Unadjusted HR = 0.96 (0.75 to 1.23) Adjusted* HR = 0.92 (0.72 to 1.16) Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: < 0.5 cm > 0.5-2 cm R A N D O M I Z E 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 Completed (Target accrual 864 pts) PFS 1° endpoint Farletuzumab (MORAb-003) in Platinum-Sensitive EOC: Study Rationale FRA is overexpressed in most EOC; largely absent from normal tissue Binding of MORAb-003 to FRA blocks phosphorylation by Lyn kinase; mediates FRA-expressing tumor cell killing; suppresses tumor growth in xenograft models Phase I study of single agent MORAb-003 demonstrated no significant adverse effects and suggested efficacy in platinum-resistant EOC MORAb-003 in Platinum-Sensitive EOC: Phase II Study Design Patients with platinum-sensitive EOC in first relapse after first remission of 6-18 months duration with evaluable disease by CA125 (Enrolled N = 58; eligible n = 54) Asymptomatic relapse Single-agent Farletuzumab until progression (n = 28) Original Carbo/Taxane regimen + Farletuzumab for 6 cycles (n = 26) Symptomatic relapse Compare lengths of first and second remissions Farletuzumab maintenance Rx for responders Single-agent ORR Combination ORR Armstrong DK, et al. ASCO 2008. Abstract 5500. All arms MORAb-003: 100 mg/m2 weekly Run-in phase with 6 subjects at 37.5 and 6 at 62.5 mg/m2 Combination therapy arm every 21 days x 6 cycles Carboplatin: AUC 5-6 Taxane Paclitaxel 175 mg/m2 over 3 hours or Docetaxel 75 mg/m2 MORAb-003-002 Phase II: Treatment Arms Armstrong DK, et al. ASCO 2008. Abstract 5500. Comparison of First vs Second Remission Length: n = 6 Data as of May 5, 2008. Armstrong DK, et al. ASCO 2008. Abstract 5500. MORAb-003-002 Clinical Responses by RECIST (Combination Therapy) Best response CR: 7.4% PR: 62.9% SD: 25.9% PD: 3.7% Based on all scans submitted as of December 3, 2007 (~ 30%) By independent central reader MORAb-003 well tolerated; no increase observed in toxicity profile in combination arm ORR: 70.3% Patient benefit: 96.3% Armstrong DK, et al. ASCO 2008. Abstract 5500. Secondary Cytoreduction Controversial Inconsistent definitions Benefit appears confined to patients likely to respond to additional chemo: >12 month PFI Isolated site of recurrence Disease completely resectable Kidney Resected Liver Diaphragm Kidney Vena Cava Tumor Mass Renal Vein PFI = progression-free interval TTP mos >12 >12 >12 >17.5 >36 >24 12-24 >24 Ovarian Cancer Secondary Cytoreduction: Post-Surgery Survival Author Janicke Segna Zang Gadducci Eisenkop Munkarah Scarabelli Tay Total/Range Year 1992 1993 2000 2000 2000 2001 2001 2002 N 30 100 60 30 114 25 148 46 553 Survival Median mos 16 16.6 13 21 16.8 26 13-26 TTP mos <12 <12 <12 <17.5 <12 <24 <12 <12 Survival Median mos 8 8.8 8 15 25 42 12 6 6-42 Survival Median mos (P) 29 (0.002) 22.9 (0.007) 12 (0.02) 25 (0.04) 56.8 (0.005) 57 (NS) 32 (0.001) 39 (0.001) 12-56 TTP = time to progression GOG 213- PI Robert Coleman Surgical Candidate? Recurrent ovarian or peritoneal cancer TFI >6 mos YES NO Surgery No surgery Carboplatin + Paclitaxel Carboplatin + Paclitaxel + Bevacizumab + Bevacizumab Maintenance Randomize to Chemotherapy GOG = Gynecologic Oncology Group TFI = treatment-free interval Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Recent Phase II GOG Studies in Platinum-Resistant Ovarian Cancer Study Agents Response/comm 126-B CDDP & Cyclosporine-A 3/23 (13%) Inactive 126-C Hexamethylmelamine 3/30 (10%) Inactive 126-D Pyrazoloacridine 2/24 (8.4%) Inactive 126-E PSC833 + paclitaxel 1/16 (6%) Inactive 126-G CI-958 1/25 (4%) Inactive 126-H Topotecan (24 h) 1/25 (4%) Inactive 126-I 9-amino-camptothecin 8/58 (14%) Moderate 126-J Docetaxel 13/58 (22%) Active (post-paclitaxel) Bookman MA. Semin Oncol 2002;29(suppl 1):20-31. CDDP = c/s-diamminedichloroplatinum (cisplatin) GOG = gynecologic oncology group Recent Phase II GOG Studies in Platinum-Resistant Ovarian Cancer Study Agents Response/comm 126-K Oxaliplatin 1/25 (4%) Inactive 126-L Gemcitabine/CDDP 9/57 (16%) Moderate 126-M Ixabepilone 7/50 (14%) Moderate 126-N Paclitaxel weekly 10/48 (21%) Active (post-paclitaxel) 126-O Triapine-CDDP Not Feasible 126-P Paclitaxel & Celecoxib Closed Early 126-Q Pemetrexed 10/48 (21%) Active 126-R Abraxane Accrual in Progress Bookman MA. Semin Oncol 2002;29(suppl 1):20-31. CDDP = c/s-diamminedichloroplatinum (cisplatin) GOG = gynecologic oncology group Pemetrexed in Platinum-Resistant EOC: Phase II GOG Study Schema Miller DS, et al. ASCO 2008. Abstract 5524. Patients with persistent or recurrent platinum-resistant EOC or primary peritoneal cancer who have failed on higher priority treatment protocols Pemetrexed 900 mg/m2 IV every 21 days for 1 cycle; patients who have received previous radiotherapy will initiate pemetrexed at level I reduction dose until disease progression or adverse effect prohibits further therapy Phase II GOG Study Evaluation of Pemetrexed: Clinical Responses Miller DS, et al. ASCO 2008. Abstract 5524. *1 patient remains on therapy. Cochrane Review of Tamoxifen for Relapsed Ovarian Cancer 13 studies (11non-randomized series, 1 non-randomized phase II and 1 randomized trial) 59 of 568 women (10.4%) treated with tamoxifen achieved an objective response (RR) RR varied from 0% to 56% Stable disease, for variable periods of 4 weeks or more, in 109 of 356 (30.6%) from 8 studies Not enough data to assess duration of RR, survival, or the effect of tamoxifen on quality of life No reliable data from randomized controlled trials Williams CJ. Cochrane Database Syst Rev. 2000;(2):CD001034. RR = response rate
Slide 55 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days GC vs TC Induction Regimens Followed by T Consolidation: Response Rates Gordon A, et al. ASCO 2008. Abstract 5536. *CR required a normalized CA-125. GC vs TC Induction Regimens Followed by T Consolidation: Pt-Based Toxicity Gordon A, et al. ASCO 2008. Abstract 5536. Conventional vs Dose-Dense TC (NOVEL): Study Design Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO 2008. Abstract 5506. P = .72 Evaluated by WHO criteria Conventional vs Dose-Dense TC (NOVEL): Clinical Responses Isonishi S, et al. ASCO 2008. Abstract 5506. Conventional vs Dose-Dense TC (NOVEL): PFS 0.0 0.2 0.4 0.6 0.8 1.0 0 12 30 54 Mos From Randomization Proportion Surviving Progression Free 0.1 0.3 0.5 0.7 0.9 6 18 42 24 48 36 Isonishi S, et al. ASCO 2008. Abstract 5506. dd-TC c-TC Ovarian Carcinoma: Clinical Course Symptoms Diagnosis Chemotherapy #1 Staging Primary cytoreduction Interval Cytoreduction Progression Chemo #2 Chemo #3+ Supportive Care Death Consolidation/ Maintenance Cure Secondary Cytoreduction Second-Look Goals of Treatment: Relapsed Ovarian Cancer Prolong Survival Delay Time to Progression Control Disease-Related Symptoms Minimize Treatment-Related Symptoms Maintain or Improve Quality of Life Issues Impacting Therapy for Recurrent Ovarian Cancer Treatment-free interval Impact of consolidation/maintenance therapy Number of prior regimens Response to prior therapy Toxicity from prior therapy Prior use of growth factors Transfusion requirements Neuropathy Volume and site(s) of disease Ascites/GI symptoms Performance status Surveillance Options for Ovarian Cancer Patients in Remission Second-look laparotomy Physical examination Include pelvic examination CA-125 Imaging CT scan MRI? PET scan? CT = computed tomography MRI = magnetic resonance imaging PET = positron emission tomography Ovarian Cancer: How is Relapse Defined? Continuous rise in CA-125 CA-125 above 100 Radiographic recurrence Symptomatic recurrence Physical examination findings Combination of above When Does Ovarian Cancer Recur? Carb = carboplatin; Cis = cisplatin; Doc = docetaxel; pac = paclitaxel; GOG = Gynecologic Oncology Group; IP = intraperitoneal; Pac = paclitaxel Active Agents in Ovarian Cancer Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Refractory P R I M A R Y T R E A T M E N T Resistant Sensitive 0 3 6 12 18 24 Months “Very Sensitive” Ovarian Cancer at First Relapse Definition of Sensitivity Defined as measurable recurrence, not biochemical (CA-125) recurrence ICON 4 Schema Relapsed ovarian or primary Peritoneal requiring chemotherapy Previous platinum-based chemotherapy Conventional platinum-based chemotherapy Paclitaxel plus platinum chemotherapy R A N D O M I Z E Prior chemotherapy Carboplatin (31%) Paclitaxel/platinum (40%) Other (30%) TFI > 12 months for 75% Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group TFI = treatment-free interval ICON 4 Response (Difference of 12%; 95% CI -0.1% to 24%; p=0.06) CR = complete response; ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum; PR = partial response; Parmar MK, et al. Lancet. 2003;361:2099-2106. Proportion alive and progression-free 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Patients at risk Pac-Plat 392 179 52 25 17 Plat 410 157 45 17 7 Years from randomization Hazard ratio = 0.76 (95% CI 0.66 - 0.89; p < 0.001) Absolute difference at 1 year = 10% (40% to 50%; 95% CI 4% to 15%) Ovarian Carcinoma: ICON 4 Progression-Free Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum Hazard ratio = 0.82 (95% CI 0.69 - 0.97; p = 0.023) Absolute difference 2 years = 7% (50% to 57%; 95% CI 1% to 12%) Patients at risk Pac-Plat 392 306 167 96 43 Plat 410 295 150 68 33 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Years from randomization Proportion alive ICON 4: Overall Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum R A N D O M I Z E Gemcitabine 1,000 mg/m2 days 1 + 8 Plus Carboplatin AUC 4 day 1 every 21 days × 6 Recurrent ovarian cancer 6+ months after platinum Strata PFI (6 - 12, >12 months) 1st-line therapy (platinum ± paclitaxel) Measurable vs evaluable Primary endpoint = PFS Gem/Carbo vs Carbo: Design Carboplatin AUC 5 day 1 every 21 days × 6 Carbo = carboplatin Gem = gemcitabine PFI = progression-free interval PFS = progression-free survival Pfisterer J, et al. J Clin Oncol. 2006; 24:4699-4707. AGO OVAR 2.5 Primary Endpoint: Progression-Free Survival GCb: median = 8.6 mo Censoring: 12.4% Cb: median = 5.8 mo Censoring: 12.9% Cb Arm (N=178) GCb Arm (N=178) Log-rank p-value = 0.0038 Unadjusted HR = 0.72 (0.57 to 0.90) Adjusted HR* = 0.71 (0.57 to 0.89) * Adjusted for PFI, Tumor size Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin AGO OVAR 2.5 Efficacy Results: Overall Survival 0.0 0.8 0.2 0.3 0.4 0.5 0.6 0.7 0.9 1.0 0.1 0 6 12 18 60 54 48 42 36 30 24 Proportion Surviving Months Median = 18.0 mo Censoring: 18.5% Median = 17.3 mo Censoring: 22.5% Cb Arm (N=178) GCb Arm (N=178) * Adjusted for PFI, Tumor size and performance status Log-rank p-value = 0.7349 Unadjusted HR = 0.96 (0.75 to 1.23) Adjusted* HR = 0.92 (0.72 to 1.16) Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: < 0.5 cm > 0.5-2 cm R A N D O M I Z E 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 Completed (Target accrual 864 pts) PFS 1° endpoint Farletuzumab (MORAb-003) in Platinum-Sensitive EOC: Study Rationale FRA is overexpressed in most EOC; largely absent from normal tissue Binding of MORAb-003 to FRA blocks phosphorylation by Lyn kinase; mediates FRA-expressing tumor cell killing; suppresses tumor growth in xenograft models Phase I study of single agent MORAb-003 demonstrated no significant adverse effects and suggested efficacy in platinum-resistant EOC MORAb-003 in Platinum-Sensitive EOC: Phase II Study Design Patients with platinum-sensitive EOC in first relapse after first remission of 6-18 months duration with evaluable disease by CA125 (Enrolled N = 58; eligible n = 54) Asymptomatic relapse Single-agent Farletuzumab until progression (n = 28) Original Carbo/Taxane regimen + Farletuzumab for 6 cycles (n = 26) Symptomatic relapse Compare lengths of first and second remissions Farletuzumab maintenance Rx for responders Single-agent ORR Combination ORR Armstrong DK, et al. ASCO 2008. Abstract 5500. All arms MORAb-003: 100 mg/m2 weekly Run-in phase with 6 subjects at 37.5 and 6 at 62.5 mg/m2 Combination therapy arm every 21 days x 6 cycles Carboplatin: AUC 5-6 Taxane Paclitaxel 175 mg/m2 over 3 hours or Docetaxel 75 mg/m2 MORAb-003-002 Phase II: Treatment Arms Armstrong DK, et al. ASCO 2008. Abstract 5500. Comparison of First vs Second Remission Length: n = 6 Data as of May 5, 2008. Armstrong DK, et al. ASCO 2008. Abstract 5500. MORAb-003-002 Clinical Responses by RECIST (Combination Therapy) Best response CR: 7.4% PR: 62.9% SD: 25.9% PD: 3.7% Based on all scans submitted as of December 3, 2007 (~ 30%) By independent central reader MORAb-003 well tolerated; no increase observed in toxicity profile in combination arm ORR: 70.3% Patient benefit: 96.3% Armstrong DK, et al. ASCO 2008. Abstract 5500. Secondary Cytoreduction Controversial Inconsistent definitions Benefit appears confined to patients likely to respond to additional chemo: >12 month PFI Isolated site of recurrence Disease completely resectable Kidney Resected Liver Diaphragm Kidney Vena Cava Tumor Mass Renal Vein PFI = progression-free interval TTP mos >12 >12 >12 >17.5 >36 >24 12-24 >24 Ovarian Cancer Secondary Cytoreduction: Post-Surgery Survival Author Janicke Segna Zang Gadducci Eisenkop Munkarah Scarabelli Tay Total/Range Year 1992 1993 2000 2000 2000 2001 2001 2002 N 30 100 60 30 114 25 148 46 553 Survival Median mos 16 16.6 13 21 16.8 26 13-26 TTP mos <12 <12 <12 <17.5 <12 <24 <12 <12 Survival Median mos 8 8.8 8 15 25 42 12 6 6-42 Survival Median mos (P) 29 (0.002) 22.9 (0.007) 12 (0.02) 25 (0.04) 56.8 (0.005) 57 (NS) 32 (0.001) 39 (0.001) 12-56 TTP = time to progression GOG 213- PI Robert Coleman Surgical Candidate? Recurrent ovarian or peritoneal cancer TFI >6 mos YES NO Surgery No surgery Carboplatin + Paclitaxel Carboplatin + Paclitaxel + Bevacizumab + Bevacizumab Maintenance Randomize to Chemotherapy GOG = Gynecologic Oncology Group TFI = treatment-free interval Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Recent Phase II GOG Studies in Platinum-Resistant Ovarian Cancer Study Agents Response/comm 126-B CDDP & Cyclosporine-A 3/23 (13%) Inactive 126-C Hexamethylmelamine 3/30 (10%) Inactive 126-D Pyrazoloacridine 2/24 (8.4%) Inactive 126-E PSC833 + paclitaxel 1/16 (6%) Inactive 126-G CI-958 1/25 (4%) Inactive 126-H Topotecan (24 h) 1/25 (4%) Inactive 126-I 9-amino-camptothecin 8/58 (14%) Moderate 126-J Docetaxel 13/58 (22%) Active (post-paclitaxel) Bookman MA. Semin Oncol 2002;29(suppl 1):20-31. CDDP = c/s-diamminedichloroplatinum (cisplatin) GOG = gynecologic oncology group Recent Phase II GOG Studies in Platinum-Resistant Ovarian Cancer Study Agents Response/comm 126-K Oxaliplatin 1/25 (4%) Inactive 126-L Gemcitabine/CDDP 9/57 (16%) Moderate 126-M Ixabepilone 7/50 (14%) Moderate 126-N Paclitaxel weekly 10/48 (21%) Active (post-paclitaxel) 126-O Triapine-CDDP Not Feasible 126-P Paclitaxel & Celecoxib Closed Early 126-Q Pemetrexed 10/48 (21%) Active 126-R Abraxane Accrual in Progress Bookman MA. Semin Oncol 2002;29(suppl 1):20-31. CDDP = c/s-diamminedichloroplatinum (cisplatin) GOG = gynecologic oncology group Pemetrexed in Platinum-Resistant EOC: Phase II GOG Study Schema Miller DS, et al. ASCO 2008. Abstract 5524. Patients with persistent or recurrent platinum-resistant EOC or primary peritoneal cancer who have failed on higher priority treatment protocols Pemetrexed 900 mg/m2 IV every 21 days for 1 cycle; patients who have received previous radiotherapy will initiate pemetrexed at level I reduction dose until disease progression or adverse effect prohibits further therapy Phase II GOG Study Evaluation of Pemetrexed: Clinical Responses Miller DS, et al. ASCO 2008. Abstract 5524. *1 patient remains on therapy. Cochrane Review of Tamoxifen for Relapsed Ovarian Cancer 13 studies (11non-randomized series, 1 non-randomized phase II and 1 randomized trial) 59 of 568 women (10.4%) treated with tamoxifen achieved an objective response (RR) RR varied from 0% to 56% Stable disease, for variable periods of 4 weeks or more, in 109 of 356 (30.6%) from 8 studies Not enough data to assess duration of RR, survival, or the effect of tamoxifen on quality of life No reliable data from randomized controlled trials Williams CJ. Cochrane Database Syst Rev. 2000;(2):CD001034. RR = response rate GOG Experience GOG 160: Trastuzumab GOG 170 Human Interleukin-12 (170B) Lapatinib (170G) Gefitinib (170C) Vorinostat (170H) Bevacizumab (170D) Temsirolimus (170I) Imatinib (170E) Enzastaurin (170J) Bay 43-9006 (170F) Mifepristone (170K) Ongoing GOG Phase II Effort Insufficiently Active Too Early Active GOG = Gynecologic Oncology Group
Slide 56 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days GC vs TC Induction Regimens Followed by T Consolidation: Response Rates Gordon A, et al. ASCO 2008. Abstract 5536. *CR required a normalized CA-125. GC vs TC Induction Regimens Followed by T Consolidation: Pt-Based Toxicity Gordon A, et al. ASCO 2008. Abstract 5536. Conventional vs Dose-Dense TC (NOVEL): Study Design Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO 2008. Abstract 5506. P = .72 Evaluated by WHO criteria Conventional vs Dose-Dense TC (NOVEL): Clinical Responses Isonishi S, et al. ASCO 2008. Abstract 5506. Conventional vs Dose-Dense TC (NOVEL): PFS 0.0 0.2 0.4 0.6 0.8 1.0 0 12 30 54 Mos From Randomization Proportion Surviving Progression Free 0.1 0.3 0.5 0.7 0.9 6 18 42 24 48 36 Isonishi S, et al. ASCO 2008. Abstract 5506. dd-TC c-TC Ovarian Carcinoma: Clinical Course Symptoms Diagnosis Chemotherapy #1 Staging Primary cytoreduction Interval Cytoreduction Progression Chemo #2 Chemo #3+ Supportive Care Death Consolidation/ Maintenance Cure Secondary Cytoreduction Second-Look Goals of Treatment: Relapsed Ovarian Cancer Prolong Survival Delay Time to Progression Control Disease-Related Symptoms Minimize Treatment-Related Symptoms Maintain or Improve Quality of Life Issues Impacting Therapy for Recurrent Ovarian Cancer Treatment-free interval Impact of consolidation/maintenance therapy Number of prior regimens Response to prior therapy Toxicity from prior therapy Prior use of growth factors Transfusion requirements Neuropathy Volume and site(s) of disease Ascites/GI symptoms Performance status Surveillance Options for Ovarian Cancer Patients in Remission Second-look laparotomy Physical examination Include pelvic examination CA-125 Imaging CT scan MRI? PET scan? CT = computed tomography MRI = magnetic resonance imaging PET = positron emission tomography Ovarian Cancer: How is Relapse Defined? Continuous rise in CA-125 CA-125 above 100 Radiographic recurrence Symptomatic recurrence Physical examination findings Combination of above When Does Ovarian Cancer Recur? Carb = carboplatin; Cis = cisplatin; Doc = docetaxel; pac = paclitaxel; GOG = Gynecologic Oncology Group; IP = intraperitoneal; Pac = paclitaxel Active Agents in Ovarian Cancer Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Refractory P R I M A R Y T R E A T M E N T Resistant Sensitive 0 3 6 12 18 24 Months “Very Sensitive” Ovarian Cancer at First Relapse Definition of Sensitivity Defined as measurable recurrence, not biochemical (CA-125) recurrence ICON 4 Schema Relapsed ovarian or primary Peritoneal requiring chemotherapy Previous platinum-based chemotherapy Conventional platinum-based chemotherapy Paclitaxel plus platinum chemotherapy R A N D O M I Z E Prior chemotherapy Carboplatin (31%) Paclitaxel/platinum (40%) Other (30%) TFI > 12 months for 75% Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group TFI = treatment-free interval ICON 4 Response (Difference of 12%; 95% CI -0.1% to 24%; p=0.06) CR = complete response; ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum; PR = partial response; Parmar MK, et al. Lancet. 2003;361:2099-2106. Proportion alive and progression-free 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Patients at risk Pac-Plat 392 179 52 25 17 Plat 410 157 45 17 7 Years from randomization Hazard ratio = 0.76 (95% CI 0.66 - 0.89; p < 0.001) Absolute difference at 1 year = 10% (40% to 50%; 95% CI 4% to 15%) Ovarian Carcinoma: ICON 4 Progression-Free Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum Hazard ratio = 0.82 (95% CI 0.69 - 0.97; p = 0.023) Absolute difference 2 years = 7% (50% to 57%; 95% CI 1% to 12%) Patients at risk Pac-Plat 392 306 167 96 43 Plat 410 295 150 68 33 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Years from randomization Proportion alive ICON 4: Overall Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum R A N D O M I Z E Gemcitabine 1,000 mg/m2 days 1 + 8 Plus Carboplatin AUC 4 day 1 every 21 days × 6 Recurrent ovarian cancer 6+ months after platinum Strata PFI (6 - 12, >12 months) 1st-line therapy (platinum ± paclitaxel) Measurable vs evaluable Primary endpoint = PFS Gem/Carbo vs Carbo: Design Carboplatin AUC 5 day 1 every 21 days × 6 Carbo = carboplatin Gem = gemcitabine PFI = progression-free interval PFS = progression-free survival Pfisterer J, et al. J Clin Oncol. 2006; 24:4699-4707. AGO OVAR 2.5 Primary Endpoint: Progression-Free Survival GCb: median = 8.6 mo Censoring: 12.4% Cb: median = 5.8 mo Censoring: 12.9% Cb Arm (N=178) GCb Arm (N=178) Log-rank p-value = 0.0038 Unadjusted HR = 0.72 (0.57 to 0.90) Adjusted HR* = 0.71 (0.57 to 0.89) * Adjusted for PFI, Tumor size Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin AGO OVAR 2.5 Efficacy Results: Overall Survival 0.0 0.8 0.2 0.3 0.4 0.5 0.6 0.7 0.9 1.0 0.1 0 6 12 18 60 54 48 42 36 30 24 Proportion Surviving Months Median = 18.0 mo Censoring: 18.5% Median = 17.3 mo Censoring: 22.5% Cb Arm (N=178) GCb Arm (N=178) * Adjusted for PFI, Tumor size and performance status Log-rank p-value = 0.7349 Unadjusted HR = 0.96 (0.75 to 1.23) Adjusted* HR = 0.92 (0.72 to 1.16) Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: < 0.5 cm > 0.5-2 cm R A N D O M I Z E 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 Completed (Target accrual 864 pts) PFS 1° endpoint Farletuzumab (MORAb-003) in Platinum-Sensitive EOC: Study Rationale FRA is overexpressed in most EOC; largely absent from normal tissue Binding of MORAb-003 to FRA blocks phosphorylation by Lyn kinase; mediates FRA-expressing tumor cell killing; suppresses tumor growth in xenograft models Phase I study of single agent MORAb-003 demonstrated no significant adverse effects and suggested efficacy in platinum-resistant EOC MORAb-003 in Platinum-Sensitive EOC: Phase II Study Design Patients with platinum-sensitive EOC in first relapse after first remission of 6-18 months duration with evaluable disease by CA125 (Enrolled N = 58; eligible n = 54) Asymptomatic relapse Single-agent Farletuzumab until progression (n = 28) Original Carbo/Taxane regimen + Farletuzumab for 6 cycles (n = 26) Symptomatic relapse Compare lengths of first and second remissions Farletuzumab maintenance Rx for responders Single-agent ORR Combination ORR Armstrong DK, et al. ASCO 2008. Abstract 5500. All arms MORAb-003: 100 mg/m2 weekly Run-in phase with 6 subjects at 37.5 and 6 at 62.5 mg/m2 Combination therapy arm every 21 days x 6 cycles Carboplatin: AUC 5-6 Taxane Paclitaxel 175 mg/m2 over 3 hours or Docetaxel 75 mg/m2 MORAb-003-002 Phase II: Treatment Arms Armstrong DK, et al. ASCO 2008. Abstract 5500. Comparison of First vs Second Remission Length: n = 6 Data as of May 5, 2008. Armstrong DK, et al. ASCO 2008. Abstract 5500. MORAb-003-002 Clinical Responses by RECIST (Combination Therapy) Best response CR: 7.4% PR: 62.9% SD: 25.9% PD: 3.7% Based on all scans submitted as of December 3, 2007 (~ 30%) By independent central reader MORAb-003 well tolerated; no increase observed in toxicity profile in combination arm ORR: 70.3% Patient benefit: 96.3% Armstrong DK, et al. ASCO 2008. Abstract 5500. Secondary Cytoreduction Controversial Inconsistent definitions Benefit appears confined to patients likely to respond to additional chemo: >12 month PFI Isolated site of recurrence Disease completely resectable Kidney Resected Liver Diaphragm Kidney Vena Cava Tumor Mass Renal Vein PFI = progression-free interval TTP mos >12 >12 >12 >17.5 >36 >24 12-24 >24 Ovarian Cancer Secondary Cytoreduction: Post-Surgery Survival Author Janicke Segna Zang Gadducci Eisenkop Munkarah Scarabelli Tay Total/Range Year 1992 1993 2000 2000 2000 2001 2001 2002 N 30 100 60 30 114 25 148 46 553 Survival Median mos 16 16.6 13 21 16.8 26 13-26 TTP mos <12 <12 <12 <17.5 <12 <24 <12 <12 Survival Median mos 8 8.8 8 15 25 42 12 6 6-42 Survival Median mos (P) 29 (0.002) 22.9 (0.007) 12 (0.02) 25 (0.04) 56.8 (0.005) 57 (NS) 32 (0.001) 39 (0.001) 12-56 TTP = time to progression GOG 213- PI Robert Coleman Surgical Candidate? Recurrent ovarian or peritoneal cancer TFI >6 mos YES NO Surgery No surgery Carboplatin + Paclitaxel Carboplatin + Paclitaxel + Bevacizumab + Bevacizumab Maintenance Randomize to Chemotherapy GOG = Gynecologic Oncology Group TFI = treatment-free interval Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Recent Phase II GOG Studies in Platinum-Resistant Ovarian Cancer Study Agents Response/comm 126-B CDDP & Cyclosporine-A 3/23 (13%) Inactive 126-C Hexamethylmelamine 3/30 (10%) Inactive 126-D Pyrazoloacridine 2/24 (8.4%) Inactive 126-E PSC833 + paclitaxel 1/16 (6%) Inactive 126-G CI-958 1/25 (4%) Inactive 126-H Topotecan (24 h) 1/25 (4%) Inactive 126-I 9-amino-camptothecin 8/58 (14%) Moderate 126-J Docetaxel 13/58 (22%) Active (post-paclitaxel) Bookman MA. Semin Oncol 2002;29(suppl 1):20-31. CDDP = c/s-diamminedichloroplatinum (cisplatin) GOG = gynecologic oncology group Recent Phase II GOG Studies in Platinum-Resistant Ovarian Cancer Study Agents Response/comm 126-K Oxaliplatin 1/25 (4%) Inactive 126-L Gemcitabine/CDDP 9/57 (16%) Moderate 126-M Ixabepilone 7/50 (14%) Moderate 126-N Paclitaxel weekly 10/48 (21%) Active (post-paclitaxel) 126-O Triapine-CDDP Not Feasible 126-P Paclitaxel & Celecoxib Closed Early 126-Q Pemetrexed 10/48 (21%) Active 126-R Abraxane Accrual in Progress Bookman MA. Semin Oncol 2002;29(suppl 1):20-31. CDDP = c/s-diamminedichloroplatinum (cisplatin) GOG = gynecologic oncology group Pemetrexed in Platinum-Resistant EOC: Phase II GOG Study Schema Miller DS, et al. ASCO 2008. Abstract 5524. Patients with persistent or recurrent platinum-resistant EOC or primary peritoneal cancer who have failed on higher priority treatment protocols Pemetrexed 900 mg/m2 IV every 21 days for 1 cycle; patients who have received previous radiotherapy will initiate pemetrexed at level I reduction dose until disease progression or adverse effect prohibits further therapy Phase II GOG Study Evaluation of Pemetrexed: Clinical Responses Miller DS, et al. ASCO 2008. Abstract 5524. *1 patient remains on therapy. Cochrane Review of Tamoxifen for Relapsed Ovarian Cancer 13 studies (11non-randomized series, 1 non-randomized phase II and 1 randomized trial) 59 of 568 women (10.4%) treated with tamoxifen achieved an objective response (RR) RR varied from 0% to 56% Stable disease, for variable periods of 4 weeks or more, in 109 of 356 (30.6%) from 8 studies Not enough data to assess duration of RR, survival, or the effect of tamoxifen on quality of life No reliable data from randomized controlled trials Williams CJ. Cochrane Database Syst Rev. 2000;(2):CD001034. RR = response rate GOG Experience GOG 160: Trastuzumab GOG 170 Human Interleukin-12 (170B) Lapatinib (170G) Gefitinib (170C) Vorinostat (170H) Bevacizumab (170D) Temsirolimus (170I) Imatinib (170E) Enzastaurin (170J) Bay 43-9006 (170F) Mifepristone (170K) Ongoing GOG Phase II Effort Insufficiently Active Too Early Active GOG = Gynecologic Oncology Group Antiangiogenic Agents in Testing for Treatment of Ovarian Cancer Agent Targets Ligand binding: Bevacizumab VEGF-A VEGF-Trap VEGF-A, -B, -C, -D, -E, PIGF-1 and -2 Receptor binding: Volociximab 51 integrin IMC-1121B VEGFR-2 Receptor tyrosine kinase inhibition: Valatanib VEGFR-1, -2, -3, PDGFR, and c-kit Sunitinib PDGFR, VEGFR-1, -2, -3, c-kit, Flt-3 AMG-706 VEGFR-1, -2, -3, PDGFR, and c-kit Sorafenib Raf, VEGFR-2, -3, Flt-3, c-kit, PDGFR-  Non-receptor kinase inhibition: Temsirolimus, everolimus mTOR Enzastaurin PKC-  Dasatinib Src kinase EGFR = epidermal growth factor receptor; Mab = monoclonal antibody; mTOR = mammalian target of rapamycin; PDGF-R = platelet derived growth factor receptor; PKC-b = protein kinase C-beta; VEGF = vascular endothelial growth factor
Slide 57 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days GC vs TC Induction Regimens Followed by T Consolidation: Response Rates Gordon A, et al. ASCO 2008. Abstract 5536. *CR required a normalized CA-125. GC vs TC Induction Regimens Followed by T Consolidation: Pt-Based Toxicity Gordon A, et al. ASCO 2008. Abstract 5536. Conventional vs Dose-Dense TC (NOVEL): Study Design Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO 2008. Abstract 5506. P = .72 Evaluated by WHO criteria Conventional vs Dose-Dense TC (NOVEL): Clinical Responses Isonishi S, et al. ASCO 2008. Abstract 5506. Conventional vs Dose-Dense TC (NOVEL): PFS 0.0 0.2 0.4 0.6 0.8 1.0 0 12 30 54 Mos From Randomization Proportion Surviving Progression Free 0.1 0.3 0.5 0.7 0.9 6 18 42 24 48 36 Isonishi S, et al. ASCO 2008. Abstract 5506. dd-TC c-TC Ovarian Carcinoma: Clinical Course Symptoms Diagnosis Chemotherapy #1 Staging Primary cytoreduction Interval Cytoreduction Progression Chemo #2 Chemo #3+ Supportive Care Death Consolidation/ Maintenance Cure Secondary Cytoreduction Second-Look Goals of Treatment: Relapsed Ovarian Cancer Prolong Survival Delay Time to Progression Control Disease-Related Symptoms Minimize Treatment-Related Symptoms Maintain or Improve Quality of Life Issues Impacting Therapy for Recurrent Ovarian Cancer Treatment-free interval Impact of consolidation/maintenance therapy Number of prior regimens Response to prior therapy Toxicity from prior therapy Prior use of growth factors Transfusion requirements Neuropathy Volume and site(s) of disease Ascites/GI symptoms Performance status Surveillance Options for Ovarian Cancer Patients in Remission Second-look laparotomy Physical examination Include pelvic examination CA-125 Imaging CT scan MRI? PET scan? CT = computed tomography MRI = magnetic resonance imaging PET = positron emission tomography Ovarian Cancer: How is Relapse Defined? Continuous rise in CA-125 CA-125 above 100 Radiographic recurrence Symptomatic recurrence Physical examination findings Combination of above When Does Ovarian Cancer Recur? Carb = carboplatin; Cis = cisplatin; Doc = docetaxel; pac = paclitaxel; GOG = Gynecologic Oncology Group; IP = intraperitoneal; Pac = paclitaxel Active Agents in Ovarian Cancer Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Refractory P R I M A R Y T R E A T M E N T Resistant Sensitive 0 3 6 12 18 24 Months “Very Sensitive” Ovarian Cancer at First Relapse Definition of Sensitivity Defined as measurable recurrence, not biochemical (CA-125) recurrence ICON 4 Schema Relapsed ovarian or primary Peritoneal requiring chemotherapy Previous platinum-based chemotherapy Conventional platinum-based chemotherapy Paclitaxel plus platinum chemotherapy R A N D O M I Z E Prior chemotherapy Carboplatin (31%) Paclitaxel/platinum (40%) Other (30%) TFI > 12 months for 75% Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group TFI = treatment-free interval ICON 4 Response (Difference of 12%; 95% CI -0.1% to 24%; p=0.06) CR = complete response; ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum; PR = partial response; Parmar MK, et al. Lancet. 2003;361:2099-2106. Proportion alive and progression-free 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Patients at risk Pac-Plat 392 179 52 25 17 Plat 410 157 45 17 7 Years from randomization Hazard ratio = 0.76 (95% CI 0.66 - 0.89; p < 0.001) Absolute difference at 1 year = 10% (40% to 50%; 95% CI 4% to 15%) Ovarian Carcinoma: ICON 4 Progression-Free Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum Hazard ratio = 0.82 (95% CI 0.69 - 0.97; p = 0.023) Absolute difference 2 years = 7% (50% to 57%; 95% CI 1% to 12%) Patients at risk Pac-Plat 392 306 167 96 43 Plat 410 295 150 68 33 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Years from randomization Proportion alive ICON 4: Overall Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum R A N D O M I Z E Gemcitabine 1,000 mg/m2 days 1 + 8 Plus Carboplatin AUC 4 day 1 every 21 days × 6 Recurrent ovarian cancer 6+ months after platinum Strata PFI (6 - 12, >12 months) 1st-line therapy (platinum ± paclitaxel) Measurable vs evaluable Primary endpoint = PFS Gem/Carbo vs Carbo: Design Carboplatin AUC 5 day 1 every 21 days × 6 Carbo = carboplatin Gem = gemcitabine PFI = progression-free interval PFS = progression-free survival Pfisterer J, et al. J Clin Oncol. 2006; 24:4699-4707. AGO OVAR 2.5 Primary Endpoint: Progression-Free Survival GCb: median = 8.6 mo Censoring: 12.4% Cb: median = 5.8 mo Censoring: 12.9% Cb Arm (N=178) GCb Arm (N=178) Log-rank p-value = 0.0038 Unadjusted HR = 0.72 (0.57 to 0.90) Adjusted HR* = 0.71 (0.57 to 0.89) * Adjusted for PFI, Tumor size Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin AGO OVAR 2.5 Efficacy Results: Overall Survival 0.0 0.8 0.2 0.3 0.4 0.5 0.6 0.7 0.9 1.0 0.1 0 6 12 18 60 54 48 42 36 30 24 Proportion Surviving Months Median = 18.0 mo Censoring: 18.5% Median = 17.3 mo Censoring: 22.5% Cb Arm (N=178) GCb Arm (N=178) * Adjusted for PFI, Tumor size and performance status Log-rank p-value = 0.7349 Unadjusted HR = 0.96 (0.75 to 1.23) Adjusted* HR = 0.92 (0.72 to 1.16) Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: < 0.5 cm > 0.5-2 cm R A N D O M I Z E 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 Completed (Target accrual 864 pts) PFS 1° endpoint Farletuzumab (MORAb-003) in Platinum-Sensitive EOC: Study Rationale FRA is overexpressed in most EOC; largely absent from normal tissue Binding of MORAb-003 to FRA blocks phosphorylation by Lyn kinase; mediates FRA-expressing tumor cell killing; suppresses tumor growth in xenograft models Phase I study of single agent MORAb-003 demonstrated no significant adverse effects and suggested efficacy in platinum-resistant EOC MORAb-003 in Platinum-Sensitive EOC: Phase II Study Design Patients with platinum-sensitive EOC in first relapse after first remission of 6-18 months duration with evaluable disease by CA125 (Enrolled N = 58; eligible n = 54) Asymptomatic relapse Single-agent Farletuzumab until progression (n = 28) Original Carbo/Taxane regimen + Farletuzumab for 6 cycles (n = 26) Symptomatic relapse Compare lengths of first and second remissions Farletuzumab maintenance Rx for responders Single-agent ORR Combination ORR Armstrong DK, et al. ASCO 2008. Abstract 5500. All arms MORAb-003: 100 mg/m2 weekly Run-in phase with 6 subjects at 37.5 and 6 at 62.5 mg/m2 Combination therapy arm every 21 days x 6 cycles Carboplatin: AUC 5-6 Taxane Paclitaxel 175 mg/m2 over 3 hours or Docetaxel 75 mg/m2 MORAb-003-002 Phase II: Treatment Arms Armstrong DK, et al. ASCO 2008. Abstract 5500. Comparison of First vs Second Remission Length: n = 6 Data as of May 5, 2008. Armstrong DK, et al. ASCO 2008. Abstract 5500. MORAb-003-002 Clinical Responses by RECIST (Combination Therapy) Best response CR: 7.4% PR: 62.9% SD: 25.9% PD: 3.7% Based on all scans submitted as of December 3, 2007 (~ 30%) By independent central reader MORAb-003 well tolerated; no increase observed in toxicity profile in combination arm ORR: 70.3% Patient benefit: 96.3% Armstrong DK, et al. ASCO 2008. Abstract 5500. Secondary Cytoreduction Controversial Inconsistent definitions Benefit appears confined to patients likely to respond to additional chemo: >12 month PFI Isolated site of recurrence Disease completely resectable Kidney Resected Liver Diaphragm Kidney Vena Cava Tumor Mass Renal Vein PFI = progression-free interval TTP mos >12 >12 >12 >17.5 >36 >24 12-24 >24 Ovarian Cancer Secondary Cytoreduction: Post-Surgery Survival Author Janicke Segna Zang Gadducci Eisenkop Munkarah Scarabelli Tay Total/Range Year 1992 1993 2000 2000 2000 2001 2001 2002 N 30 100 60 30 114 25 148 46 553 Survival Median mos 16 16.6 13 21 16.8 26 13-26 TTP mos <12 <12 <12 <17.5 <12 <24 <12 <12 Survival Median mos 8 8.8 8 15 25 42 12 6 6-42 Survival Median mos (P) 29 (0.002) 22.9 (0.007) 12 (0.02) 25 (0.04) 56.8 (0.005) 57 (NS) 32 (0.001) 39 (0.001) 12-56 TTP = time to progression GOG 213- PI Robert Coleman Surgical Candidate? Recurrent ovarian or peritoneal cancer TFI >6 mos YES NO Surgery No surgery Carboplatin + Paclitaxel Carboplatin + Paclitaxel + Bevacizumab + Bevacizumab Maintenance Randomize to Chemotherapy GOG = Gynecologic Oncology Group TFI = treatment-free interval Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Recent Phase II GOG Studies in Platinum-Resistant Ovarian Cancer Study Agents Response/comm 126-B CDDP & Cyclosporine-A 3/23 (13%) Inactive 126-C Hexamethylmelamine 3/30 (10%) Inactive 126-D Pyrazoloacridine 2/24 (8.4%) Inactive 126-E PSC833 + paclitaxel 1/16 (6%) Inactive 126-G CI-958 1/25 (4%) Inactive 126-H Topotecan (24 h) 1/25 (4%) Inactive 126-I 9-amino-camptothecin 8/58 (14%) Moderate 126-J Docetaxel 13/58 (22%) Active (post-paclitaxel) Bookman MA. Semin Oncol 2002;29(suppl 1):20-31. CDDP = c/s-diamminedichloroplatinum (cisplatin) GOG = gynecologic oncology group Recent Phase II GOG Studies in Platinum-Resistant Ovarian Cancer Study Agents Response/comm 126-K Oxaliplatin 1/25 (4%) Inactive 126-L Gemcitabine/CDDP 9/57 (16%) Moderate 126-M Ixabepilone 7/50 (14%) Moderate 126-N Paclitaxel weekly 10/48 (21%) Active (post-paclitaxel) 126-O Triapine-CDDP Not Feasible 126-P Paclitaxel & Celecoxib Closed Early 126-Q Pemetrexed 10/48 (21%) Active 126-R Abraxane Accrual in Progress Bookman MA. Semin Oncol 2002;29(suppl 1):20-31. CDDP = c/s-diamminedichloroplatinum (cisplatin) GOG = gynecologic oncology group Pemetrexed in Platinum-Resistant EOC: Phase II GOG Study Schema Miller DS, et al. ASCO 2008. Abstract 5524. Patients with persistent or recurrent platinum-resistant EOC or primary peritoneal cancer who have failed on higher priority treatment protocols Pemetrexed 900 mg/m2 IV every 21 days for 1 cycle; patients who have received previous radiotherapy will initiate pemetrexed at level I reduction dose until disease progression or adverse effect prohibits further therapy Phase II GOG Study Evaluation of Pemetrexed: Clinical Responses Miller DS, et al. ASCO 2008. Abstract 5524. *1 patient remains on therapy. Cochrane Review of Tamoxifen for Relapsed Ovarian Cancer 13 studies (11non-randomized series, 1 non-randomized phase II and 1 randomized trial) 59 of 568 women (10.4%) treated with tamoxifen achieved an objective response (RR) RR varied from 0% to 56% Stable disease, for variable periods of 4 weeks or more, in 109 of 356 (30.6%) from 8 studies Not enough data to assess duration of RR, survival, or the effect of tamoxifen on quality of life No reliable data from randomized controlled trials Williams CJ. Cochrane Database Syst Rev. 2000;(2):CD001034. RR = response rate GOG Experience GOG 160: Trastuzumab GOG 170 Human Interleukin-12 (170B) Lapatinib (170G) Gefitinib (170C) Vorinostat (170H) Bevacizumab (170D) Temsirolimus (170I) Imatinib (170E) Enzastaurin (170J) Bay 43-9006 (170F) Mifepristone (170K) Ongoing GOG Phase II Effort Insufficiently Active Too Early Active GOG = Gynecologic Oncology Group Antiangiogenic Agents in Testing for Treatment of Ovarian Cancer Agent Targets Ligand binding: Bevacizumab VEGF-A VEGF-Trap VEGF-A, -B, -C, -D, -E, PIGF-1 and -2 Receptor binding: Volociximab 51 integrin IMC-1121B VEGFR-2 Receptor tyrosine kinase inhibition: Valatanib VEGFR-1, -2, -3, PDGFR, and c-kit Sunitinib PDGFR, VEGFR-1, -2, -3, c-kit, Flt-3 AMG-706 VEGFR-1, -2, -3, PDGFR, and c-kit Sorafenib Raf, VEGFR-2, -3, Flt-3, c-kit, PDGFR-  Non-receptor kinase inhibition: Temsirolimus, everolimus mTOR Enzastaurin PKC-  Dasatinib Src kinase EGFR = epidermal growth factor receptor; Mab = monoclonal antibody; mTOR = mammalian target of rapamycin; PDGF-R = platelet derived growth factor receptor; PKC-b = protein kinase C-beta; VEGF = vascular endothelial growth factor Rationale for Targeting VEGF in Treatment of Epithelial Ovarian Cancer Human tumors VEGF over-expressed in epithelial ovarian cancers, associated with Ascites formation Malignant progression Poor prognosis Preclinical models of solid tumors Anti-VEGF therapy: Slowing of tumor progression Resolution of malignant effusions Synergy with cytotoxic agents Han ES, et al. Expert Rev Anticancer Ther. 2007;7(10):1339-1345. Burger RA. J Clin Oncol. 2007;25(20):2902-2908. VEGF = vascular endothelial growth factor
Slide 58 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days GC vs TC Induction Regimens Followed by T Consolidation: Response Rates Gordon A, et al. ASCO 2008. Abstract 5536. *CR required a normalized CA-125. GC vs TC Induction Regimens Followed by T Consolidation: Pt-Based Toxicity Gordon A, et al. ASCO 2008. Abstract 5536. Conventional vs Dose-Dense TC (NOVEL): Study Design Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO 2008. Abstract 5506. P = .72 Evaluated by WHO criteria Conventional vs Dose-Dense TC (NOVEL): Clinical Responses Isonishi S, et al. ASCO 2008. Abstract 5506. Conventional vs Dose-Dense TC (NOVEL): PFS 0.0 0.2 0.4 0.6 0.8 1.0 0 12 30 54 Mos From Randomization Proportion Surviving Progression Free 0.1 0.3 0.5 0.7 0.9 6 18 42 24 48 36 Isonishi S, et al. ASCO 2008. Abstract 5506. dd-TC c-TC Ovarian Carcinoma: Clinical Course Symptoms Diagnosis Chemotherapy #1 Staging Primary cytoreduction Interval Cytoreduction Progression Chemo #2 Chemo #3+ Supportive Care Death Consolidation/ Maintenance Cure Secondary Cytoreduction Second-Look Goals of Treatment: Relapsed Ovarian Cancer Prolong Survival Delay Time to Progression Control Disease-Related Symptoms Minimize Treatment-Related Symptoms Maintain or Improve Quality of Life Issues Impacting Therapy for Recurrent Ovarian Cancer Treatment-free interval Impact of consolidation/maintenance therapy Number of prior regimens Response to prior therapy Toxicity from prior therapy Prior use of growth factors Transfusion requirements Neuropathy Volume and site(s) of disease Ascites/GI symptoms Performance status Surveillance Options for Ovarian Cancer Patients in Remission Second-look laparotomy Physical examination Include pelvic examination CA-125 Imaging CT scan MRI? PET scan? CT = computed tomography MRI = magnetic resonance imaging PET = positron emission tomography Ovarian Cancer: How is Relapse Defined? Continuous rise in CA-125 CA-125 above 100 Radiographic recurrence Symptomatic recurrence Physical examination findings Combination of above When Does Ovarian Cancer Recur? Carb = carboplatin; Cis = cisplatin; Doc = docetaxel; pac = paclitaxel; GOG = Gynecologic Oncology Group; IP = intraperitoneal; Pac = paclitaxel Active Agents in Ovarian Cancer Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Refractory P R I M A R Y T R E A T M E N T Resistant Sensitive 0 3 6 12 18 24 Months “Very Sensitive” Ovarian Cancer at First Relapse Definition of Sensitivity Defined as measurable recurrence, not biochemical (CA-125) recurrence ICON 4 Schema Relapsed ovarian or primary Peritoneal requiring chemotherapy Previous platinum-based chemotherapy Conventional platinum-based chemotherapy Paclitaxel plus platinum chemotherapy R A N D O M I Z E Prior chemotherapy Carboplatin (31%) Paclitaxel/platinum (40%) Other (30%) TFI > 12 months for 75% Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group TFI = treatment-free interval ICON 4 Response (Difference of 12%; 95% CI -0.1% to 24%; p=0.06) CR = complete response; ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum; PR = partial response; Parmar MK, et al. Lancet. 2003;361:2099-2106. Proportion alive and progression-free 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Patients at risk Pac-Plat 392 179 52 25 17 Plat 410 157 45 17 7 Years from randomization Hazard ratio = 0.76 (95% CI 0.66 - 0.89; p < 0.001) Absolute difference at 1 year = 10% (40% to 50%; 95% CI 4% to 15%) Ovarian Carcinoma: ICON 4 Progression-Free Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum Hazard ratio = 0.82 (95% CI 0.69 - 0.97; p = 0.023) Absolute difference 2 years = 7% (50% to 57%; 95% CI 1% to 12%) Patients at risk Pac-Plat 392 306 167 96 43 Plat 410 295 150 68 33 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Years from randomization Proportion alive ICON 4: Overall Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum R A N D O M I Z E Gemcitabine 1,000 mg/m2 days 1 + 8 Plus Carboplatin AUC 4 day 1 every 21 days × 6 Recurrent ovarian cancer 6+ months after platinum Strata PFI (6 - 12, >12 months) 1st-line therapy (platinum ± paclitaxel) Measurable vs evaluable Primary endpoint = PFS Gem/Carbo vs Carbo: Design Carboplatin AUC 5 day 1 every 21 days × 6 Carbo = carboplatin Gem = gemcitabine PFI = progression-free interval PFS = progression-free survival Pfisterer J, et al. J Clin Oncol. 2006; 24:4699-4707. AGO OVAR 2.5 Primary Endpoint: Progression-Free Survival GCb: median = 8.6 mo Censoring: 12.4% Cb: median = 5.8 mo Censoring: 12.9% Cb Arm (N=178) GCb Arm (N=178) Log-rank p-value = 0.0038 Unadjusted HR = 0.72 (0.57 to 0.90) Adjusted HR* = 0.71 (0.57 to 0.89) * Adjusted for PFI, Tumor size Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin AGO OVAR 2.5 Efficacy Results: Overall Survival 0.0 0.8 0.2 0.3 0.4 0.5 0.6 0.7 0.9 1.0 0.1 0 6 12 18 60 54 48 42 36 30 24 Proportion Surviving Months Median = 18.0 mo Censoring: 18.5% Median = 17.3 mo Censoring: 22.5% Cb Arm (N=178) GCb Arm (N=178) * Adjusted for PFI, Tumor size and performance status Log-rank p-value = 0.7349 Unadjusted HR = 0.96 (0.75 to 1.23) Adjusted* HR = 0.92 (0.72 to 1.16) Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: < 0.5 cm > 0.5-2 cm R A N D O M I Z E 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 Completed (Target accrual 864 pts) PFS 1° endpoint Farletuzumab (MORAb-003) in Platinum-Sensitive EOC: Study Rationale FRA is overexpressed in most EOC; largely absent from normal tissue Binding of MORAb-003 to FRA blocks phosphorylation by Lyn kinase; mediates FRA-expressing tumor cell killing; suppresses tumor growth in xenograft models Phase I study of single agent MORAb-003 demonstrated no significant adverse effects and suggested efficacy in platinum-resistant EOC MORAb-003 in Platinum-Sensitive EOC: Phase II Study Design Patients with platinum-sensitive EOC in first relapse after first remission of 6-18 months duration with evaluable disease by CA125 (Enrolled N = 58; eligible n = 54) Asymptomatic relapse Single-agent Farletuzumab until progression (n = 28) Original Carbo/Taxane regimen + Farletuzumab for 6 cycles (n = 26) Symptomatic relapse Compare lengths of first and second remissions Farletuzumab maintenance Rx for responders Single-agent ORR Combination ORR Armstrong DK, et al. ASCO 2008. Abstract 5500. All arms MORAb-003: 100 mg/m2 weekly Run-in phase with 6 subjects at 37.5 and 6 at 62.5 mg/m2 Combination therapy arm every 21 days x 6 cycles Carboplatin: AUC 5-6 Taxane Paclitaxel 175 mg/m2 over 3 hours or Docetaxel 75 mg/m2 MORAb-003-002 Phase II: Treatment Arms Armstrong DK, et al. ASCO 2008. Abstract 5500. Comparison of First vs Second Remission Length: n = 6 Data as of May 5, 2008. Armstrong DK, et al. ASCO 2008. Abstract 5500. MORAb-003-002 Clinical Responses by RECIST (Combination Therapy) Best response CR: 7.4% PR: 62.9% SD: 25.9% PD: 3.7% Based on all scans submitted as of December 3, 2007 (~ 30%) By independent central reader MORAb-003 well tolerated; no increase observed in toxicity profile in combination arm ORR: 70.3% Patient benefit: 96.3% Armstrong DK, et al. ASCO 2008. Abstract 5500. Secondary Cytoreduction Controversial Inconsistent definitions Benefit appears confined to patients likely to respond to additional chemo: >12 month PFI Isolated site of recurrence Disease completely resectable Kidney Resected Liver Diaphragm Kidney Vena Cava Tumor Mass Renal Vein PFI = progression-free interval TTP mos >12 >12 >12 >17.5 >36 >24 12-24 >24 Ovarian Cancer Secondary Cytoreduction: Post-Surgery Survival Author Janicke Segna Zang Gadducci Eisenkop Munkarah Scarabelli Tay Total/Range Year 1992 1993 2000 2000 2000 2001 2001 2002 N 30 100 60 30 114 25 148 46 553 Survival Median mos 16 16.6 13 21 16.8 26 13-26 TTP mos <12 <12 <12 <17.5 <12 <24 <12 <12 Survival Median mos 8 8.8 8 15 25 42 12 6 6-42 Survival Median mos (P) 29 (0.002) 22.9 (0.007) 12 (0.02) 25 (0.04) 56.8 (0.005) 57 (NS) 32 (0.001) 39 (0.001) 12-56 TTP = time to progression GOG 213- PI Robert Coleman Surgical Candidate? Recurrent ovarian or peritoneal cancer TFI >6 mos YES NO Surgery No surgery Carboplatin + Paclitaxel Carboplatin + Paclitaxel + Bevacizumab + Bevacizumab Maintenance Randomize to Chemotherapy GOG = Gynecologic Oncology Group TFI = treatment-free interval Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Recent Phase II GOG Studies in Platinum-Resistant Ovarian Cancer Study Agents Response/comm 126-B CDDP & Cyclosporine-A 3/23 (13%) Inactive 126-C Hexamethylmelamine 3/30 (10%) Inactive 126-D Pyrazoloacridine 2/24 (8.4%) Inactive 126-E PSC833 + paclitaxel 1/16 (6%) Inactive 126-G CI-958 1/25 (4%) Inactive 126-H Topotecan (24 h) 1/25 (4%) Inactive 126-I 9-amino-camptothecin 8/58 (14%) Moderate 126-J Docetaxel 13/58 (22%) Active (post-paclitaxel) Bookman MA. Semin Oncol 2002;29(suppl 1):20-31. CDDP = c/s-diamminedichloroplatinum (cisplatin) GOG = gynecologic oncology group Recent Phase II GOG Studies in Platinum-Resistant Ovarian Cancer Study Agents Response/comm 126-K Oxaliplatin 1/25 (4%) Inactive 126-L Gemcitabine/CDDP 9/57 (16%) Moderate 126-M Ixabepilone 7/50 (14%) Moderate 126-N Paclitaxel weekly 10/48 (21%) Active (post-paclitaxel) 126-O Triapine-CDDP Not Feasible 126-P Paclitaxel & Celecoxib Closed Early 126-Q Pemetrexed 10/48 (21%) Active 126-R Abraxane Accrual in Progress Bookman MA. Semin Oncol 2002;29(suppl 1):20-31. CDDP = c/s-diamminedichloroplatinum (cisplatin) GOG = gynecologic oncology group Pemetrexed in Platinum-Resistant EOC: Phase II GOG Study Schema Miller DS, et al. ASCO 2008. Abstract 5524. Patients with persistent or recurrent platinum-resistant EOC or primary peritoneal cancer who have failed on higher priority treatment protocols Pemetrexed 900 mg/m2 IV every 21 days for 1 cycle; patients who have received previous radiotherapy will initiate pemetrexed at level I reduction dose until disease progression or adverse effect prohibits further therapy Phase II GOG Study Evaluation of Pemetrexed: Clinical Responses Miller DS, et al. ASCO 2008. Abstract 5524. *1 patient remains on therapy. Cochrane Review of Tamoxifen for Relapsed Ovarian Cancer 13 studies (11non-randomized series, 1 non-randomized phase II and 1 randomized trial) 59 of 568 women (10.4%) treated with tamoxifen achieved an objective response (RR) RR varied from 0% to 56% Stable disease, for variable periods of 4 weeks or more, in 109 of 356 (30.6%) from 8 studies Not enough data to assess duration of RR, survival, or the effect of tamoxifen on quality of life No reliable data from randomized controlled trials Williams CJ. Cochrane Database Syst Rev. 2000;(2):CD001034. RR = response rate GOG Experience GOG 160: Trastuzumab GOG 170 Human Interleukin-12 (170B) Lapatinib (170G) Gefitinib (170C) Vorinostat (170H) Bevacizumab (170D) Temsirolimus (170I) Imatinib (170E) Enzastaurin (170J) Bay 43-9006 (170F) Mifepristone (170K) Ongoing GOG Phase II Effort Insufficiently Active Too Early Active GOG = Gynecologic Oncology Group Antiangiogenic Agents in Testing for Treatment of Ovarian Cancer Agent Targets Ligand binding: Bevacizumab VEGF-A VEGF-Trap VEGF-A, -B, -C, -D, -E, PIGF-1 and -2 Receptor binding: Volociximab 51 integrin IMC-1121B VEGFR-2 Receptor tyrosine kinase inhibition: Valatanib VEGFR-1, -2, -3, PDGFR, and c-kit Sunitinib PDGFR, VEGFR-1, -2, -3, c-kit, Flt-3 AMG-706 VEGFR-1, -2, -3, PDGFR, and c-kit Sorafenib Raf, VEGFR-2, -3, Flt-3, c-kit, PDGFR-  Non-receptor kinase inhibition: Temsirolimus, everolimus mTOR Enzastaurin PKC-  Dasatinib Src kinase EGFR = epidermal growth factor receptor; Mab = monoclonal antibody; mTOR = mammalian target of rapamycin; PDGF-R = platelet derived growth factor receptor; PKC-b = protein kinase C-beta; VEGF = vascular endothelial growth factor Rationale for Targeting VEGF in Treatment of Epithelial Ovarian Cancer Human tumors VEGF over-expressed in epithelial ovarian cancers, associated with Ascites formation Malignant progression Poor prognosis Preclinical models of solid tumors Anti-VEGF therapy: Slowing of tumor progression Resolution of malignant effusions Synergy with cytotoxic agents Han ES, et al. Expert Rev Anticancer Ther. 2007;7(10):1339-1345. Burger RA. J Clin Oncol. 2007;25(20):2902-2908. VEGF = vascular endothelial growth factor Agents Targeting the VEGF Pathway VEGFR-2 VEGFR-1 Endothelial Cell Small-Molecule Inhibitors VEGF Soluble VEGFRs (VEGF-TRAP) Podar K, et al. Blood. 2005;105(4):1383-1395. VEGF = vascular endothelial growth factor VEGFR = VEGF receptor
Slide 59 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days GC vs TC Induction Regimens Followed by T Consolidation: Response Rates Gordon A, et al. ASCO 2008. Abstract 5536. *CR required a normalized CA-125. GC vs TC Induction Regimens Followed by T Consolidation: Pt-Based Toxicity Gordon A, et al. ASCO 2008. Abstract 5536. Conventional vs Dose-Dense TC (NOVEL): Study Design Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO 2008. Abstract 5506. P = .72 Evaluated by WHO criteria Conventional vs Dose-Dense TC (NOVEL): Clinical Responses Isonishi S, et al. ASCO 2008. Abstract 5506. Conventional vs Dose-Dense TC (NOVEL): PFS 0.0 0.2 0.4 0.6 0.8 1.0 0 12 30 54 Mos From Randomization Proportion Surviving Progression Free 0.1 0.3 0.5 0.7 0.9 6 18 42 24 48 36 Isonishi S, et al. ASCO 2008. Abstract 5506. dd-TC c-TC Ovarian Carcinoma: Clinical Course Symptoms Diagnosis Chemotherapy #1 Staging Primary cytoreduction Interval Cytoreduction Progression Chemo #2 Chemo #3+ Supportive Care Death Consolidation/ Maintenance Cure Secondary Cytoreduction Second-Look Goals of Treatment: Relapsed Ovarian Cancer Prolong Survival Delay Time to Progression Control Disease-Related Symptoms Minimize Treatment-Related Symptoms Maintain or Improve Quality of Life Issues Impacting Therapy for Recurrent Ovarian Cancer Treatment-free interval Impact of consolidation/maintenance therapy Number of prior regimens Response to prior therapy Toxicity from prior therapy Prior use of growth factors Transfusion requirements Neuropathy Volume and site(s) of disease Ascites/GI symptoms Performance status Surveillance Options for Ovarian Cancer Patients in Remission Second-look laparotomy Physical examination Include pelvic examination CA-125 Imaging CT scan MRI? PET scan? CT = computed tomography MRI = magnetic resonance imaging PET = positron emission tomography Ovarian Cancer: How is Relapse Defined? Continuous rise in CA-125 CA-125 above 100 Radiographic recurrence Symptomatic recurrence Physical examination findings Combination of above When Does Ovarian Cancer Recur? Carb = carboplatin; Cis = cisplatin; Doc = docetaxel; pac = paclitaxel; GOG = Gynecologic Oncology Group; IP = intraperitoneal; Pac = paclitaxel Active Agents in Ovarian Cancer Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Refractory P R I M A R Y T R E A T M E N T Resistant Sensitive 0 3 6 12 18 24 Months “Very Sensitive” Ovarian Cancer at First Relapse Definition of Sensitivity Defined as measurable recurrence, not biochemical (CA-125) recurrence ICON 4 Schema Relapsed ovarian or primary Peritoneal requiring chemotherapy Previous platinum-based chemotherapy Conventional platinum-based chemotherapy Paclitaxel plus platinum chemotherapy R A N D O M I Z E Prior chemotherapy Carboplatin (31%) Paclitaxel/platinum (40%) Other (30%) TFI > 12 months for 75% Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group TFI = treatment-free interval ICON 4 Response (Difference of 12%; 95% CI -0.1% to 24%; p=0.06) CR = complete response; ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum; PR = partial response; Parmar MK, et al. Lancet. 2003;361:2099-2106. Proportion alive and progression-free 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Patients at risk Pac-Plat 392 179 52 25 17 Plat 410 157 45 17 7 Years from randomization Hazard ratio = 0.76 (95% CI 0.66 - 0.89; p < 0.001) Absolute difference at 1 year = 10% (40% to 50%; 95% CI 4% to 15%) Ovarian Carcinoma: ICON 4 Progression-Free Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum Hazard ratio = 0.82 (95% CI 0.69 - 0.97; p = 0.023) Absolute difference 2 years = 7% (50% to 57%; 95% CI 1% to 12%) Patients at risk Pac-Plat 392 306 167 96 43 Plat 410 295 150 68 33 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Years from randomization Proportion alive ICON 4: Overall Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum R A N D O M I Z E Gemcitabine 1,000 mg/m2 days 1 + 8 Plus Carboplatin AUC 4 day 1 every 21 days × 6 Recurrent ovarian cancer 6+ months after platinum Strata PFI (6 - 12, >12 months) 1st-line therapy (platinum ± paclitaxel) Measurable vs evaluable Primary endpoint = PFS Gem/Carbo vs Carbo: Design Carboplatin AUC 5 day 1 every 21 days × 6 Carbo = carboplatin Gem = gemcitabine PFI = progression-free interval PFS = progression-free survival Pfisterer J, et al. J Clin Oncol. 2006; 24:4699-4707. AGO OVAR 2.5 Primary Endpoint: Progression-Free Survival GCb: median = 8.6 mo Censoring: 12.4% Cb: median = 5.8 mo Censoring: 12.9% Cb Arm (N=178) GCb Arm (N=178) Log-rank p-value = 0.0038 Unadjusted HR = 0.72 (0.57 to 0.90) Adjusted HR* = 0.71 (0.57 to 0.89) * Adjusted for PFI, Tumor size Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin AGO OVAR 2.5 Efficacy Results: Overall Survival 0.0 0.8 0.2 0.3 0.4 0.5 0.6 0.7 0.9 1.0 0.1 0 6 12 18 60 54 48 42 36 30 24 Proportion Surviving Months Median = 18.0 mo Censoring: 18.5% Median = 17.3 mo Censoring: 22.5% Cb Arm (N=178) GCb Arm (N=178) * Adjusted for PFI, Tumor size and performance status Log-rank p-value = 0.7349 Unadjusted HR = 0.96 (0.75 to 1.23) Adjusted* HR = 0.92 (0.72 to 1.16) Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: < 0.5 cm > 0.5-2 cm R A N D O M I Z E 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 Completed (Target accrual 864 pts) PFS 1° endpoint Farletuzumab (MORAb-003) in Platinum-Sensitive EOC: Study Rationale FRA is overexpressed in most EOC; largely absent from normal tissue Binding of MORAb-003 to FRA blocks phosphorylation by Lyn kinase; mediates FRA-expressing tumor cell killing; suppresses tumor growth in xenograft models Phase I study of single agent MORAb-003 demonstrated no significant adverse effects and suggested efficacy in platinum-resistant EOC MORAb-003 in Platinum-Sensitive EOC: Phase II Study Design Patients with platinum-sensitive EOC in first relapse after first remission of 6-18 months duration with evaluable disease by CA125 (Enrolled N = 58; eligible n = 54) Asymptomatic relapse Single-agent Farletuzumab until progression (n = 28) Original Carbo/Taxane regimen + Farletuzumab for 6 cycles (n = 26) Symptomatic relapse Compare lengths of first and second remissions Farletuzumab maintenance Rx for responders Single-agent ORR Combination ORR Armstrong DK, et al. ASCO 2008. Abstract 5500. All arms MORAb-003: 100 mg/m2 weekly Run-in phase with 6 subjects at 37.5 and 6 at 62.5 mg/m2 Combination therapy arm every 21 days x 6 cycles Carboplatin: AUC 5-6 Taxane Paclitaxel 175 mg/m2 over 3 hours or Docetaxel 75 mg/m2 MORAb-003-002 Phase II: Treatment Arms Armstrong DK, et al. ASCO 2008. Abstract 5500. Comparison of First vs Second Remission Length: n = 6 Data as of May 5, 2008. Armstrong DK, et al. ASCO 2008. Abstract 5500. MORAb-003-002 Clinical Responses by RECIST (Combination Therapy) Best response CR: 7.4% PR: 62.9% SD: 25.9% PD: 3.7% Based on all scans submitted as of December 3, 2007 (~ 30%) By independent central reader MORAb-003 well tolerated; no increase observed in toxicity profile in combination arm ORR: 70.3% Patient benefit: 96.3% Armstrong DK, et al. ASCO 2008. Abstract 5500. Secondary Cytoreduction Controversial Inconsistent definitions Benefit appears confined to patients likely to respond to additional chemo: >12 month PFI Isolated site of recurrence Disease completely resectable Kidney Resected Liver Diaphragm Kidney Vena Cava Tumor Mass Renal Vein PFI = progression-free interval TTP mos >12 >12 >12 >17.5 >36 >24 12-24 >24 Ovarian Cancer Secondary Cytoreduction: Post-Surgery Survival Author Janicke Segna Zang Gadducci Eisenkop Munkarah Scarabelli Tay Total/Range Year 1992 1993 2000 2000 2000 2001 2001 2002 N 30 100 60 30 114 25 148 46 553 Survival Median mos 16 16.6 13 21 16.8 26 13-26 TTP mos <12 <12 <12 <17.5 <12 <24 <12 <12 Survival Median mos 8 8.8 8 15 25 42 12 6 6-42 Survival Median mos (P) 29 (0.002) 22.9 (0.007) 12 (0.02) 25 (0.04) 56.8 (0.005) 57 (NS) 32 (0.001) 39 (0.001) 12-56 TTP = time to progression GOG 213- PI Robert Coleman Surgical Candidate? Recurrent ovarian or peritoneal cancer TFI >6 mos YES NO Surgery No surgery Carboplatin + Paclitaxel Carboplatin + Paclitaxel + Bevacizumab + Bevacizumab Maintenance Randomize to Chemotherapy GOG = Gynecologic Oncology Group TFI = treatment-free interval Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Recent Phase II GOG Studies in Platinum-Resistant Ovarian Cancer Study Agents Response/comm 126-B CDDP & Cyclosporine-A 3/23 (13%) Inactive 126-C Hexamethylmelamine 3/30 (10%) Inactive 126-D Pyrazoloacridine 2/24 (8.4%) Inactive 126-E PSC833 + paclitaxel 1/16 (6%) Inactive 126-G CI-958 1/25 (4%) Inactive 126-H Topotecan (24 h) 1/25 (4%) Inactive 126-I 9-amino-camptothecin 8/58 (14%) Moderate 126-J Docetaxel 13/58 (22%) Active (post-paclitaxel) Bookman MA. Semin Oncol 2002;29(suppl 1):20-31. CDDP = c/s-diamminedichloroplatinum (cisplatin) GOG = gynecologic oncology group Recent Phase II GOG Studies in Platinum-Resistant Ovarian Cancer Study Agents Response/comm 126-K Oxaliplatin 1/25 (4%) Inactive 126-L Gemcitabine/CDDP 9/57 (16%) Moderate 126-M Ixabepilone 7/50 (14%) Moderate 126-N Paclitaxel weekly 10/48 (21%) Active (post-paclitaxel) 126-O Triapine-CDDP Not Feasible 126-P Paclitaxel & Celecoxib Closed Early 126-Q Pemetrexed 10/48 (21%) Active 126-R Abraxane Accrual in Progress Bookman MA. Semin Oncol 2002;29(suppl 1):20-31. CDDP = c/s-diamminedichloroplatinum (cisplatin) GOG = gynecologic oncology group Pemetrexed in Platinum-Resistant EOC: Phase II GOG Study Schema Miller DS, et al. ASCO 2008. Abstract 5524. Patients with persistent or recurrent platinum-resistant EOC or primary peritoneal cancer who have failed on higher priority treatment protocols Pemetrexed 900 mg/m2 IV every 21 days for 1 cycle; patients who have received previous radiotherapy will initiate pemetrexed at level I reduction dose until disease progression or adverse effect prohibits further therapy Phase II GOG Study Evaluation of Pemetrexed: Clinical Responses Miller DS, et al. ASCO 2008. Abstract 5524. *1 patient remains on therapy. Cochrane Review of Tamoxifen for Relapsed Ovarian Cancer 13 studies (11non-randomized series, 1 non-randomized phase II and 1 randomized trial) 59 of 568 women (10.4%) treated with tamoxifen achieved an objective response (RR) RR varied from 0% to 56% Stable disease, for variable periods of 4 weeks or more, in 109 of 356 (30.6%) from 8 studies Not enough data to assess duration of RR, survival, or the effect of tamoxifen on quality of life No reliable data from randomized controlled trials Williams CJ. Cochrane Database Syst Rev. 2000;(2):CD001034. RR = response rate GOG Experience GOG 160: Trastuzumab GOG 170 Human Interleukin-12 (170B) Lapatinib (170G) Gefitinib (170C) Vorinostat (170H) Bevacizumab (170D) Temsirolimus (170I) Imatinib (170E) Enzastaurin (170J) Bay 43-9006 (170F) Mifepristone (170K) Ongoing GOG Phase II Effort Insufficiently Active Too Early Active GOG = Gynecologic Oncology Group Antiangiogenic Agents in Testing for Treatment of Ovarian Cancer Agent Targets Ligand binding: Bevacizumab VEGF-A VEGF-Trap VEGF-A, -B, -C, -D, -E, PIGF-1 and -2 Receptor binding: Volociximab 51 integrin IMC-1121B VEGFR-2 Receptor tyrosine kinase inhibition: Valatanib VEGFR-1, -2, -3, PDGFR, and c-kit Sunitinib PDGFR, VEGFR-1, -2, -3, c-kit, Flt-3 AMG-706 VEGFR-1, -2, -3, PDGFR, and c-kit Sorafenib Raf, VEGFR-2, -3, Flt-3, c-kit, PDGFR-  Non-receptor kinase inhibition: Temsirolimus, everolimus mTOR Enzastaurin PKC-  Dasatinib Src kinase EGFR = epidermal growth factor receptor; Mab = monoclonal antibody; mTOR = mammalian target of rapamycin; PDGF-R = platelet derived growth factor receptor; PKC-b = protein kinase C-beta; VEGF = vascular endothelial growth factor Rationale for Targeting VEGF in Treatment of Epithelial Ovarian Cancer Human tumors VEGF over-expressed in epithelial ovarian cancers, associated with Ascites formation Malignant progression Poor prognosis Preclinical models of solid tumors Anti-VEGF therapy: Slowing of tumor progression Resolution of malignant effusions Synergy with cytotoxic agents Han ES, et al. Expert Rev Anticancer Ther. 2007;7(10):1339-1345. Burger RA. J Clin Oncol. 2007;25(20):2902-2908. VEGF = vascular endothelial growth factor Agents Targeting the VEGF Pathway VEGFR-2 VEGFR-1 Endothelial Cell Small-Molecule Inhibitors VEGF Soluble VEGFRs (VEGF-TRAP) Podar K, et al. Blood. 2005;105(4):1383-1395. VEGF = vascular endothelial growth factor VEGFR = VEGF receptor Bevacizumab - Toxicity Proteinuria (usually G1 – G2) Muco-cutaneous hemorrhage Common – G1 epistaxis Rare (possibly life-threatening) G2-G4 tumor site hemorrhage (primarily lung cancer trials) Arterial thromboembolism Uncommon (3% - 5%) Risk factors: age > 65, prior arterial TE Risk of venous thromboembolism not increased GI perforation – wound healing Perforation uncommon (2% - 4% in solid tumor population) Wound dehiscence rate 1% Han ES, et al. Expert Rev Anticancer Ther. 2007;7(10):1339-1345. Burger RA. J Clin Oncol. 2007;25(20):2902-2908. G1, G2 = immunoglobulins GI = gastrointestinal TE = thromboembolism
Slide 60 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days GC vs TC Induction Regimens Followed by T Consolidation: Response Rates Gordon A, et al. ASCO 2008. Abstract 5536. *CR required a normalized CA-125. GC vs TC Induction Regimens Followed by T Consolidation: Pt-Based Toxicity Gordon A, et al. ASCO 2008. Abstract 5536. Conventional vs Dose-Dense TC (NOVEL): Study Design Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO 2008. Abstract 5506. P = .72 Evaluated by WHO criteria Conventional vs Dose-Dense TC (NOVEL): Clinical Responses Isonishi S, et al. ASCO 2008. Abstract 5506. Conventional vs Dose-Dense TC (NOVEL): PFS 0.0 0.2 0.4 0.6 0.8 1.0 0 12 30 54 Mos From Randomization Proportion Surviving Progression Free 0.1 0.3 0.5 0.7 0.9 6 18 42 24 48 36 Isonishi S, et al. ASCO 2008. Abstract 5506. dd-TC c-TC Ovarian Carcinoma: Clinical Course Symptoms Diagnosis Chemotherapy #1 Staging Primary cytoreduction Interval Cytoreduction Progression Chemo #2 Chemo #3+ Supportive Care Death Consolidation/ Maintenance Cure Secondary Cytoreduction Second-Look Goals of Treatment: Relapsed Ovarian Cancer Prolong Survival Delay Time to Progression Control Disease-Related Symptoms Minimize Treatment-Related Symptoms Maintain or Improve Quality of Life Issues Impacting Therapy for Recurrent Ovarian Cancer Treatment-free interval Impact of consolidation/maintenance therapy Number of prior regimens Response to prior therapy Toxicity from prior therapy Prior use of growth factors Transfusion requirements Neuropathy Volume and site(s) of disease Ascites/GI symptoms Performance status Surveillance Options for Ovarian Cancer Patients in Remission Second-look laparotomy Physical examination Include pelvic examination CA-125 Imaging CT scan MRI? PET scan? CT = computed tomography MRI = magnetic resonance imaging PET = positron emission tomography Ovarian Cancer: How is Relapse Defined? Continuous rise in CA-125 CA-125 above 100 Radiographic recurrence Symptomatic recurrence Physical examination findings Combination of above When Does Ovarian Cancer Recur? Carb = carboplatin; Cis = cisplatin; Doc = docetaxel; pac = paclitaxel; GOG = Gynecologic Oncology Group; IP = intraperitoneal; Pac = paclitaxel Active Agents in Ovarian Cancer Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Refractory P R I M A R Y T R E A T M E N T Resistant Sensitive 0 3 6 12 18 24 Months “Very Sensitive” Ovarian Cancer at First Relapse Definition of Sensitivity Defined as measurable recurrence, not biochemical (CA-125) recurrence ICON 4 Schema Relapsed ovarian or primary Peritoneal requiring chemotherapy Previous platinum-based chemotherapy Conventional platinum-based chemotherapy Paclitaxel plus platinum chemotherapy R A N D O M I Z E Prior chemotherapy Carboplatin (31%) Paclitaxel/platinum (40%) Other (30%) TFI > 12 months for 75% Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group TFI = treatment-free interval ICON 4 Response (Difference of 12%; 95% CI -0.1% to 24%; p=0.06) CR = complete response; ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum; PR = partial response; Parmar MK, et al. Lancet. 2003;361:2099-2106. Proportion alive and progression-free 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Patients at risk Pac-Plat 392 179 52 25 17 Plat 410 157 45 17 7 Years from randomization Hazard ratio = 0.76 (95% CI 0.66 - 0.89; p < 0.001) Absolute difference at 1 year = 10% (40% to 50%; 95% CI 4% to 15%) Ovarian Carcinoma: ICON 4 Progression-Free Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum Hazard ratio = 0.82 (95% CI 0.69 - 0.97; p = 0.023) Absolute difference 2 years = 7% (50% to 57%; 95% CI 1% to 12%) Patients at risk Pac-Plat 392 306 167 96 43 Plat 410 295 150 68 33 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Years from randomization Proportion alive ICON 4: Overall Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum R A N D O M I Z E Gemcitabine 1,000 mg/m2 days 1 + 8 Plus Carboplatin AUC 4 day 1 every 21 days × 6 Recurrent ovarian cancer 6+ months after platinum Strata PFI (6 - 12, >12 months) 1st-line therapy (platinum ± paclitaxel) Measurable vs evaluable Primary endpoint = PFS Gem/Carbo vs Carbo: Design Carboplatin AUC 5 day 1 every 21 days × 6 Carbo = carboplatin Gem = gemcitabine PFI = progression-free interval PFS = progression-free survival Pfisterer J, et al. J Clin Oncol. 2006; 24:4699-4707. AGO OVAR 2.5 Primary Endpoint: Progression-Free Survival GCb: median = 8.6 mo Censoring: 12.4% Cb: median = 5.8 mo Censoring: 12.9% Cb Arm (N=178) GCb Arm (N=178) Log-rank p-value = 0.0038 Unadjusted HR = 0.72 (0.57 to 0.90) Adjusted HR* = 0.71 (0.57 to 0.89) * Adjusted for PFI, Tumor size Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin AGO OVAR 2.5 Efficacy Results: Overall Survival 0.0 0.8 0.2 0.3 0.4 0.5 0.6 0.7 0.9 1.0 0.1 0 6 12 18 60 54 48 42 36 30 24 Proportion Surviving Months Median = 18.0 mo Censoring: 18.5% Median = 17.3 mo Censoring: 22.5% Cb Arm (N=178) GCb Arm (N=178) * Adjusted for PFI, Tumor size and performance status Log-rank p-value = 0.7349 Unadjusted HR = 0.96 (0.75 to 1.23) Adjusted* HR = 0.92 (0.72 to 1.16) Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: < 0.5 cm > 0.5-2 cm R A N D O M I Z E 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 Completed (Target accrual 864 pts) PFS 1° endpoint Farletuzumab (MORAb-003) in Platinum-Sensitive EOC: Study Rationale FRA is overexpressed in most EOC; largely absent from normal tissue Binding of MORAb-003 to FRA blocks phosphorylation by Lyn kinase; mediates FRA-expressing tumor cell killing; suppresses tumor growth in xenograft models Phase I study of single agent MORAb-003 demonstrated no significant adverse effects and suggested efficacy in platinum-resistant EOC MORAb-003 in Platinum-Sensitive EOC: Phase II Study Design Patients with platinum-sensitive EOC in first relapse after first remission of 6-18 months duration with evaluable disease by CA125 (Enrolled N = 58; eligible n = 54) Asymptomatic relapse Single-agent Farletuzumab until progression (n = 28) Original Carbo/Taxane regimen + Farletuzumab for 6 cycles (n = 26) Symptomatic relapse Compare lengths of first and second remissions Farletuzumab maintenance Rx for responders Single-agent ORR Combination ORR Armstrong DK, et al. ASCO 2008. Abstract 5500. All arms MORAb-003: 100 mg/m2 weekly Run-in phase with 6 subjects at 37.5 and 6 at 62.5 mg/m2 Combination therapy arm every 21 days x 6 cycles Carboplatin: AUC 5-6 Taxane Paclitaxel 175 mg/m2 over 3 hours or Docetaxel 75 mg/m2 MORAb-003-002 Phase II: Treatment Arms Armstrong DK, et al. ASCO 2008. Abstract 5500. Comparison of First vs Second Remission Length: n = 6 Data as of May 5, 2008. Armstrong DK, et al. ASCO 2008. Abstract 5500. MORAb-003-002 Clinical Responses by RECIST (Combination Therapy) Best response CR: 7.4% PR: 62.9% SD: 25.9% PD: 3.7% Based on all scans submitted as of December 3, 2007 (~ 30%) By independent central reader MORAb-003 well tolerated; no increase observed in toxicity profile in combination arm ORR: 70.3% Patient benefit: 96.3% Armstrong DK, et al. ASCO 2008. Abstract 5500. Secondary Cytoreduction Controversial Inconsistent definitions Benefit appears confined to patients likely to respond to additional chemo: >12 month PFI Isolated site of recurrence Disease completely resectable Kidney Resected Liver Diaphragm Kidney Vena Cava Tumor Mass Renal Vein PFI = progression-free interval TTP mos >12 >12 >12 >17.5 >36 >24 12-24 >24 Ovarian Cancer Secondary Cytoreduction: Post-Surgery Survival Author Janicke Segna Zang Gadducci Eisenkop Munkarah Scarabelli Tay Total/Range Year 1992 1993 2000 2000 2000 2001 2001 2002 N 30 100 60 30 114 25 148 46 553 Survival Median mos 16 16.6 13 21 16.8 26 13-26 TTP mos <12 <12 <12 <17.5 <12 <24 <12 <12 Survival Median mos 8 8.8 8 15 25 42 12 6 6-42 Survival Median mos (P) 29 (0.002) 22.9 (0.007) 12 (0.02) 25 (0.04) 56.8 (0.005) 57 (NS) 32 (0.001) 39 (0.001) 12-56 TTP = time to progression GOG 213- PI Robert Coleman Surgical Candidate? Recurrent ovarian or peritoneal cancer TFI >6 mos YES NO Surgery No surgery Carboplatin + Paclitaxel Carboplatin + Paclitaxel + Bevacizumab + Bevacizumab Maintenance Randomize to Chemotherapy GOG = Gynecologic Oncology Group TFI = treatment-free interval Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Recent Phase II GOG Studies in Platinum-Resistant Ovarian Cancer Study Agents Response/comm 126-B CDDP & Cyclosporine-A 3/23 (13%) Inactive 126-C Hexamethylmelamine 3/30 (10%) Inactive 126-D Pyrazoloacridine 2/24 (8.4%) Inactive 126-E PSC833 + paclitaxel 1/16 (6%) Inactive 126-G CI-958 1/25 (4%) Inactive 126-H Topotecan (24 h) 1/25 (4%) Inactive 126-I 9-amino-camptothecin 8/58 (14%) Moderate 126-J Docetaxel 13/58 (22%) Active (post-paclitaxel) Bookman MA. Semin Oncol 2002;29(suppl 1):20-31. CDDP = c/s-diamminedichloroplatinum (cisplatin) GOG = gynecologic oncology group Recent Phase II GOG Studies in Platinum-Resistant Ovarian Cancer Study Agents Response/comm 126-K Oxaliplatin 1/25 (4%) Inactive 126-L Gemcitabine/CDDP 9/57 (16%) Moderate 126-M Ixabepilone 7/50 (14%) Moderate 126-N Paclitaxel weekly 10/48 (21%) Active (post-paclitaxel) 126-O Triapine-CDDP Not Feasible 126-P Paclitaxel & Celecoxib Closed Early 126-Q Pemetrexed 10/48 (21%) Active 126-R Abraxane Accrual in Progress Bookman MA. Semin Oncol 2002;29(suppl 1):20-31. CDDP = c/s-diamminedichloroplatinum (cisplatin) GOG = gynecologic oncology group Pemetrexed in Platinum-Resistant EOC: Phase II GOG Study Schema Miller DS, et al. ASCO 2008. Abstract 5524. Patients with persistent or recurrent platinum-resistant EOC or primary peritoneal cancer who have failed on higher priority treatment protocols Pemetrexed 900 mg/m2 IV every 21 days for 1 cycle; patients who have received previous radiotherapy will initiate pemetrexed at level I reduction dose until disease progression or adverse effect prohibits further therapy Phase II GOG Study Evaluation of Pemetrexed: Clinical Responses Miller DS, et al. ASCO 2008. Abstract 5524. *1 patient remains on therapy. Cochrane Review of Tamoxifen for Relapsed Ovarian Cancer 13 studies (11non-randomized series, 1 non-randomized phase II and 1 randomized trial) 59 of 568 women (10.4%) treated with tamoxifen achieved an objective response (RR) RR varied from 0% to 56% Stable disease, for variable periods of 4 weeks or more, in 109 of 356 (30.6%) from 8 studies Not enough data to assess duration of RR, survival, or the effect of tamoxifen on quality of life No reliable data from randomized controlled trials Williams CJ. Cochrane Database Syst Rev. 2000;(2):CD001034. RR = response rate GOG Experience GOG 160: Trastuzumab GOG 170 Human Interleukin-12 (170B) Lapatinib (170G) Gefitinib (170C) Vorinostat (170H) Bevacizumab (170D) Temsirolimus (170I) Imatinib (170E) Enzastaurin (170J) Bay 43-9006 (170F) Mifepristone (170K) Ongoing GOG Phase II Effort Insufficiently Active Too Early Active GOG = Gynecologic Oncology Group Antiangiogenic Agents in Testing for Treatment of Ovarian Cancer Agent Targets Ligand binding: Bevacizumab VEGF-A VEGF-Trap VEGF-A, -B, -C, -D, -E, PIGF-1 and -2 Receptor binding: Volociximab 51 integrin IMC-1121B VEGFR-2 Receptor tyrosine kinase inhibition: Valatanib VEGFR-1, -2, -3, PDGFR, and c-kit Sunitinib PDGFR, VEGFR-1, -2, -3, c-kit, Flt-3 AMG-706 VEGFR-1, -2, -3, PDGFR, and c-kit Sorafenib Raf, VEGFR-2, -3, Flt-3, c-kit, PDGFR-  Non-receptor kinase inhibition: Temsirolimus, everolimus mTOR Enzastaurin PKC-  Dasatinib Src kinase EGFR = epidermal growth factor receptor; Mab = monoclonal antibody; mTOR = mammalian target of rapamycin; PDGF-R = platelet derived growth factor receptor; PKC-b = protein kinase C-beta; VEGF = vascular endothelial growth factor Rationale for Targeting VEGF in Treatment of Epithelial Ovarian Cancer Human tumors VEGF over-expressed in epithelial ovarian cancers, associated with Ascites formation Malignant progression Poor prognosis Preclinical models of solid tumors Anti-VEGF therapy: Slowing of tumor progression Resolution of malignant effusions Synergy with cytotoxic agents Han ES, et al. Expert Rev Anticancer Ther. 2007;7(10):1339-1345. Burger RA. J Clin Oncol. 2007;25(20):2902-2908. VEGF = vascular endothelial growth factor Agents Targeting the VEGF Pathway VEGFR-2 VEGFR-1 Endothelial Cell Small-Molecule Inhibitors VEGF Soluble VEGFRs (VEGF-TRAP) Podar K, et al. Blood. 2005;105(4):1383-1395. VEGF = vascular endothelial growth factor VEGFR = VEGF receptor Bevacizumab - Toxicity Proteinuria (usually G1 – G2) Muco-cutaneous hemorrhage Common – G1 epistaxis Rare (possibly life-threatening) G2-G4 tumor site hemorrhage (primarily lung cancer trials) Arterial thromboembolism Uncommon (3% - 5%) Risk factors: age > 65, prior arterial TE Risk of venous thromboembolism not increased GI perforation – wound healing Perforation uncommon (2% - 4% in solid tumor population) Wound dehiscence rate 1% Han ES, et al. Expert Rev Anticancer Ther. 2007;7(10):1339-1345. Burger RA. J Clin Oncol. 2007;25(20):2902-2908. G1, G2 = immunoglobulins GI = gastrointestinal TE = thromboembolism Phase II Studies of Bevacizumab in Ovarian Cancer Cannistra SA, et al. J Clin Oncol. 2007;25(33):5180-5186. Burger RA, et al. J Clin Oncol. 2007;25(33):5165-5171. Garcia AA, et al. J Clin Oncol. 2008;26(1):76-82. CR = complete response GI = gastrointestinal PR = partial response
Slide 61 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days GC vs TC Induction Regimens Followed by T Consolidation: Response Rates Gordon A, et al. ASCO 2008. Abstract 5536. *CR required a normalized CA-125. GC vs TC Induction Regimens Followed by T Consolidation: Pt-Based Toxicity Gordon A, et al. ASCO 2008. Abstract 5536. Conventional vs Dose-Dense TC (NOVEL): Study Design Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO 2008. Abstract 5506. P = .72 Evaluated by WHO criteria Conventional vs Dose-Dense TC (NOVEL): Clinical Responses Isonishi S, et al. ASCO 2008. Abstract 5506. Conventional vs Dose-Dense TC (NOVEL): PFS 0.0 0.2 0.4 0.6 0.8 1.0 0 12 30 54 Mos From Randomization Proportion Surviving Progression Free 0.1 0.3 0.5 0.7 0.9 6 18 42 24 48 36 Isonishi S, et al. ASCO 2008. Abstract 5506. dd-TC c-TC Ovarian Carcinoma: Clinical Course Symptoms Diagnosis Chemotherapy #1 Staging Primary cytoreduction Interval Cytoreduction Progression Chemo #2 Chemo #3+ Supportive Care Death Consolidation/ Maintenance Cure Secondary Cytoreduction Second-Look Goals of Treatment: Relapsed Ovarian Cancer Prolong Survival Delay Time to Progression Control Disease-Related Symptoms Minimize Treatment-Related Symptoms Maintain or Improve Quality of Life Issues Impacting Therapy for Recurrent Ovarian Cancer Treatment-free interval Impact of consolidation/maintenance therapy Number of prior regimens Response to prior therapy Toxicity from prior therapy Prior use of growth factors Transfusion requirements Neuropathy Volume and site(s) of disease Ascites/GI symptoms Performance status Surveillance Options for Ovarian Cancer Patients in Remission Second-look laparotomy Physical examination Include pelvic examination CA-125 Imaging CT scan MRI? PET scan? CT = computed tomography MRI = magnetic resonance imaging PET = positron emission tomography Ovarian Cancer: How is Relapse Defined? Continuous rise in CA-125 CA-125 above 100 Radiographic recurrence Symptomatic recurrence Physical examination findings Combination of above When Does Ovarian Cancer Recur? Carb = carboplatin; Cis = cisplatin; Doc = docetaxel; pac = paclitaxel; GOG = Gynecologic Oncology Group; IP = intraperitoneal; Pac = paclitaxel Active Agents in Ovarian Cancer Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Refractory P R I M A R Y T R E A T M E N T Resistant Sensitive 0 3 6 12 18 24 Months “Very Sensitive” Ovarian Cancer at First Relapse Definition of Sensitivity Defined as measurable recurrence, not biochemical (CA-125) recurrence ICON 4 Schema Relapsed ovarian or primary Peritoneal requiring chemotherapy Previous platinum-based chemotherapy Conventional platinum-based chemotherapy Paclitaxel plus platinum chemotherapy R A N D O M I Z E Prior chemotherapy Carboplatin (31%) Paclitaxel/platinum (40%) Other (30%) TFI > 12 months for 75% Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group TFI = treatment-free interval ICON 4 Response (Difference of 12%; 95% CI -0.1% to 24%; p=0.06) CR = complete response; ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum; PR = partial response; Parmar MK, et al. Lancet. 2003;361:2099-2106. Proportion alive and progression-free 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Patients at risk Pac-Plat 392 179 52 25 17 Plat 410 157 45 17 7 Years from randomization Hazard ratio = 0.76 (95% CI 0.66 - 0.89; p < 0.001) Absolute difference at 1 year = 10% (40% to 50%; 95% CI 4% to 15%) Ovarian Carcinoma: ICON 4 Progression-Free Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum Hazard ratio = 0.82 (95% CI 0.69 - 0.97; p = 0.023) Absolute difference 2 years = 7% (50% to 57%; 95% CI 1% to 12%) Patients at risk Pac-Plat 392 306 167 96 43 Plat 410 295 150 68 33 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Years from randomization Proportion alive ICON 4: Overall Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum R A N D O M I Z E Gemcitabine 1,000 mg/m2 days 1 + 8 Plus Carboplatin AUC 4 day 1 every 21 days × 6 Recurrent ovarian cancer 6+ months after platinum Strata PFI (6 - 12, >12 months) 1st-line therapy (platinum ± paclitaxel) Measurable vs evaluable Primary endpoint = PFS Gem/Carbo vs Carbo: Design Carboplatin AUC 5 day 1 every 21 days × 6 Carbo = carboplatin Gem = gemcitabine PFI = progression-free interval PFS = progression-free survival Pfisterer J, et al. J Clin Oncol. 2006; 24:4699-4707. AGO OVAR 2.5 Primary Endpoint: Progression-Free Survival GCb: median = 8.6 mo Censoring: 12.4% Cb: median = 5.8 mo Censoring: 12.9% Cb Arm (N=178) GCb Arm (N=178) Log-rank p-value = 0.0038 Unadjusted HR = 0.72 (0.57 to 0.90) Adjusted HR* = 0.71 (0.57 to 0.89) * Adjusted for PFI, Tumor size Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin AGO OVAR 2.5 Efficacy Results: Overall Survival 0.0 0.8 0.2 0.3 0.4 0.5 0.6 0.7 0.9 1.0 0.1 0 6 12 18 60 54 48 42 36 30 24 Proportion Surviving Months Median = 18.0 mo Censoring: 18.5% Median = 17.3 mo Censoring: 22.5% Cb Arm (N=178) GCb Arm (N=178) * Adjusted for PFI, Tumor size and performance status Log-rank p-value = 0.7349 Unadjusted HR = 0.96 (0.75 to 1.23) Adjusted* HR = 0.92 (0.72 to 1.16) Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: < 0.5 cm > 0.5-2 cm R A N D O M I Z E 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 Completed (Target accrual 864 pts) PFS 1° endpoint Farletuzumab (MORAb-003) in Platinum-Sensitive EOC: Study Rationale FRA is overexpressed in most EOC; largely absent from normal tissue Binding of MORAb-003 to FRA blocks phosphorylation by Lyn kinase; mediates FRA-expressing tumor cell killing; suppresses tumor growth in xenograft models Phase I study of single agent MORAb-003 demonstrated no significant adverse effects and suggested efficacy in platinum-resistant EOC MORAb-003 in Platinum-Sensitive EOC: Phase II Study Design Patients with platinum-sensitive EOC in first relapse after first remission of 6-18 months duration with evaluable disease by CA125 (Enrolled N = 58; eligible n = 54) Asymptomatic relapse Single-agent Farletuzumab until progression (n = 28) Original Carbo/Taxane regimen + Farletuzumab for 6 cycles (n = 26) Symptomatic relapse Compare lengths of first and second remissions Farletuzumab maintenance Rx for responders Single-agent ORR Combination ORR Armstrong DK, et al. ASCO 2008. Abstract 5500. All arms MORAb-003: 100 mg/m2 weekly Run-in phase with 6 subjects at 37.5 and 6 at 62.5 mg/m2 Combination therapy arm every 21 days x 6 cycles Carboplatin: AUC 5-6 Taxane Paclitaxel 175 mg/m2 over 3 hours or Docetaxel 75 mg/m2 MORAb-003-002 Phase II: Treatment Arms Armstrong DK, et al. ASCO 2008. Abstract 5500. Comparison of First vs Second Remission Length: n = 6 Data as of May 5, 2008. Armstrong DK, et al. ASCO 2008. Abstract 5500. MORAb-003-002 Clinical Responses by RECIST (Combination Therapy) Best response CR: 7.4% PR: 62.9% SD: 25.9% PD: 3.7% Based on all scans submitted as of December 3, 2007 (~ 30%) By independent central reader MORAb-003 well tolerated; no increase observed in toxicity profile in combination arm ORR: 70.3% Patient benefit: 96.3% Armstrong DK, et al. ASCO 2008. Abstract 5500. Secondary Cytoreduction Controversial Inconsistent definitions Benefit appears confined to patients likely to respond to additional chemo: >12 month PFI Isolated site of recurrence Disease completely resectable Kidney Resected Liver Diaphragm Kidney Vena Cava Tumor Mass Renal Vein PFI = progression-free interval TTP mos >12 >12 >12 >17.5 >36 >24 12-24 >24 Ovarian Cancer Secondary Cytoreduction: Post-Surgery Survival Author Janicke Segna Zang Gadducci Eisenkop Munkarah Scarabelli Tay Total/Range Year 1992 1993 2000 2000 2000 2001 2001 2002 N 30 100 60 30 114 25 148 46 553 Survival Median mos 16 16.6 13 21 16.8 26 13-26 TTP mos <12 <12 <12 <17.5 <12 <24 <12 <12 Survival Median mos 8 8.8 8 15 25 42 12 6 6-42 Survival Median mos (P) 29 (0.002) 22.9 (0.007) 12 (0.02) 25 (0.04) 56.8 (0.005) 57 (NS) 32 (0.001) 39 (0.001) 12-56 TTP = time to progression GOG 213- PI Robert Coleman Surgical Candidate? Recurrent ovarian or peritoneal cancer TFI >6 mos YES NO Surgery No surgery Carboplatin + Paclitaxel Carboplatin + Paclitaxel + Bevacizumab + Bevacizumab Maintenance Randomize to Chemotherapy GOG = Gynecologic Oncology Group TFI = treatment-free interval Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Recent Phase II GOG Studies in Platinum-Resistant Ovarian Cancer Study Agents Response/comm 126-B CDDP & Cyclosporine-A 3/23 (13%) Inactive 126-C Hexamethylmelamine 3/30 (10%) Inactive 126-D Pyrazoloacridine 2/24 (8.4%) Inactive 126-E PSC833 + paclitaxel 1/16 (6%) Inactive 126-G CI-958 1/25 (4%) Inactive 126-H Topotecan (24 h) 1/25 (4%) Inactive 126-I 9-amino-camptothecin 8/58 (14%) Moderate 126-J Docetaxel 13/58 (22%) Active (post-paclitaxel) Bookman MA. Semin Oncol 2002;29(suppl 1):20-31. CDDP = c/s-diamminedichloroplatinum (cisplatin) GOG = gynecologic oncology group Recent Phase II GOG Studies in Platinum-Resistant Ovarian Cancer Study Agents Response/comm 126-K Oxaliplatin 1/25 (4%) Inactive 126-L Gemcitabine/CDDP 9/57 (16%) Moderate 126-M Ixabepilone 7/50 (14%) Moderate 126-N Paclitaxel weekly 10/48 (21%) Active (post-paclitaxel) 126-O Triapine-CDDP Not Feasible 126-P Paclitaxel & Celecoxib Closed Early 126-Q Pemetrexed 10/48 (21%) Active 126-R Abraxane Accrual in Progress Bookman MA. Semin Oncol 2002;29(suppl 1):20-31. CDDP = c/s-diamminedichloroplatinum (cisplatin) GOG = gynecologic oncology group Pemetrexed in Platinum-Resistant EOC: Phase II GOG Study Schema Miller DS, et al. ASCO 2008. Abstract 5524. Patients with persistent or recurrent platinum-resistant EOC or primary peritoneal cancer who have failed on higher priority treatment protocols Pemetrexed 900 mg/m2 IV every 21 days for 1 cycle; patients who have received previous radiotherapy will initiate pemetrexed at level I reduction dose until disease progression or adverse effect prohibits further therapy Phase II GOG Study Evaluation of Pemetrexed: Clinical Responses Miller DS, et al. ASCO 2008. Abstract 5524. *1 patient remains on therapy. Cochrane Review of Tamoxifen for Relapsed Ovarian Cancer 13 studies (11non-randomized series, 1 non-randomized phase II and 1 randomized trial) 59 of 568 women (10.4%) treated with tamoxifen achieved an objective response (RR) RR varied from 0% to 56% Stable disease, for variable periods of 4 weeks or more, in 109 of 356 (30.6%) from 8 studies Not enough data to assess duration of RR, survival, or the effect of tamoxifen on quality of life No reliable data from randomized controlled trials Williams CJ. Cochrane Database Syst Rev. 2000;(2):CD001034. RR = response rate GOG Experience GOG 160: Trastuzumab GOG 170 Human Interleukin-12 (170B) Lapatinib (170G) Gefitinib (170C) Vorinostat (170H) Bevacizumab (170D) Temsirolimus (170I) Imatinib (170E) Enzastaurin (170J) Bay 43-9006 (170F) Mifepristone (170K) Ongoing GOG Phase II Effort Insufficiently Active Too Early Active GOG = Gynecologic Oncology Group Antiangiogenic Agents in Testing for Treatment of Ovarian Cancer Agent Targets Ligand binding: Bevacizumab VEGF-A VEGF-Trap VEGF-A, -B, -C, -D, -E, PIGF-1 and -2 Receptor binding: Volociximab 51 integrin IMC-1121B VEGFR-2 Receptor tyrosine kinase inhibition: Valatanib VEGFR-1, -2, -3, PDGFR, and c-kit Sunitinib PDGFR, VEGFR-1, -2, -3, c-kit, Flt-3 AMG-706 VEGFR-1, -2, -3, PDGFR, and c-kit Sorafenib Raf, VEGFR-2, -3, Flt-3, c-kit, PDGFR-  Non-receptor kinase inhibition: Temsirolimus, everolimus mTOR Enzastaurin PKC-  Dasatinib Src kinase EGFR = epidermal growth factor receptor; Mab = monoclonal antibody; mTOR = mammalian target of rapamycin; PDGF-R = platelet derived growth factor receptor; PKC-b = protein kinase C-beta; VEGF = vascular endothelial growth factor Rationale for Targeting VEGF in Treatment of Epithelial Ovarian Cancer Human tumors VEGF over-expressed in epithelial ovarian cancers, associated with Ascites formation Malignant progression Poor prognosis Preclinical models of solid tumors Anti-VEGF therapy: Slowing of tumor progression Resolution of malignant effusions Synergy with cytotoxic agents Han ES, et al. Expert Rev Anticancer Ther. 2007;7(10):1339-1345. Burger RA. J Clin Oncol. 2007;25(20):2902-2908. VEGF = vascular endothelial growth factor Agents Targeting the VEGF Pathway VEGFR-2 VEGFR-1 Endothelial Cell Small-Molecule Inhibitors VEGF Soluble VEGFRs (VEGF-TRAP) Podar K, et al. Blood. 2005;105(4):1383-1395. VEGF = vascular endothelial growth factor VEGFR = VEGF receptor Bevacizumab - Toxicity Proteinuria (usually G1 – G2) Muco-cutaneous hemorrhage Common – G1 epistaxis Rare (possibly life-threatening) G2-G4 tumor site hemorrhage (primarily lung cancer trials) Arterial thromboembolism Uncommon (3% - 5%) Risk factors: age > 65, prior arterial TE Risk of venous thromboembolism not increased GI perforation – wound healing Perforation uncommon (2% - 4% in solid tumor population) Wound dehiscence rate 1% Han ES, et al. Expert Rev Anticancer Ther. 2007;7(10):1339-1345. Burger RA. J Clin Oncol. 2007;25(20):2902-2908. G1, G2 = immunoglobulins GI = gastrointestinal TE = thromboembolism Phase II Studies of Bevacizumab in Ovarian Cancer Cannistra SA, et al. J Clin Oncol. 2007;25(33):5180-5186. Burger RA, et al. J Clin Oncol. 2007;25(33):5165-5171. Garcia AA, et al. J Clin Oncol. 2008;26(1):76-82. CR = complete response GI = gastrointestinal PR = partial response GI Perforations with Bevacizumab in Ovarian Cancer Han E, et al. Gynecol Oncol. 2007;105(1):3-6. GI = gastrointestinal
Slide 62 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days GC vs TC Induction Regimens Followed by T Consolidation: Response Rates Gordon A, et al. ASCO 2008. Abstract 5536. *CR required a normalized CA-125. GC vs TC Induction Regimens Followed by T Consolidation: Pt-Based Toxicity Gordon A, et al. ASCO 2008. Abstract 5536. Conventional vs Dose-Dense TC (NOVEL): Study Design Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO 2008. Abstract 5506. P = .72 Evaluated by WHO criteria Conventional vs Dose-Dense TC (NOVEL): Clinical Responses Isonishi S, et al. ASCO 2008. Abstract 5506. Conventional vs Dose-Dense TC (NOVEL): PFS 0.0 0.2 0.4 0.6 0.8 1.0 0 12 30 54 Mos From Randomization Proportion Surviving Progression Free 0.1 0.3 0.5 0.7 0.9 6 18 42 24 48 36 Isonishi S, et al. ASCO 2008. Abstract 5506. dd-TC c-TC Ovarian Carcinoma: Clinical Course Symptoms Diagnosis Chemotherapy #1 Staging Primary cytoreduction Interval Cytoreduction Progression Chemo #2 Chemo #3+ Supportive Care Death Consolidation/ Maintenance Cure Secondary Cytoreduction Second-Look Goals of Treatment: Relapsed Ovarian Cancer Prolong Survival Delay Time to Progression Control Disease-Related Symptoms Minimize Treatment-Related Symptoms Maintain or Improve Quality of Life Issues Impacting Therapy for Recurrent Ovarian Cancer Treatment-free interval Impact of consolidation/maintenance therapy Number of prior regimens Response to prior therapy Toxicity from prior therapy Prior use of growth factors Transfusion requirements Neuropathy Volume and site(s) of disease Ascites/GI symptoms Performance status Surveillance Options for Ovarian Cancer Patients in Remission Second-look laparotomy Physical examination Include pelvic examination CA-125 Imaging CT scan MRI? PET scan? CT = computed tomography MRI = magnetic resonance imaging PET = positron emission tomography Ovarian Cancer: How is Relapse Defined? Continuous rise in CA-125 CA-125 above 100 Radiographic recurrence Symptomatic recurrence Physical examination findings Combination of above When Does Ovarian Cancer Recur? Carb = carboplatin; Cis = cisplatin; Doc = docetaxel; pac = paclitaxel; GOG = Gynecologic Oncology Group; IP = intraperitoneal; Pac = paclitaxel Active Agents in Ovarian Cancer Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Refractory P R I M A R Y T R E A T M E N T Resistant Sensitive 0 3 6 12 18 24 Months “Very Sensitive” Ovarian Cancer at First Relapse Definition of Sensitivity Defined as measurable recurrence, not biochemical (CA-125) recurrence ICON 4 Schema Relapsed ovarian or primary Peritoneal requiring chemotherapy Previous platinum-based chemotherapy Conventional platinum-based chemotherapy Paclitaxel plus platinum chemotherapy R A N D O M I Z E Prior chemotherapy Carboplatin (31%) Paclitaxel/platinum (40%) Other (30%) TFI > 12 months for 75% Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group TFI = treatment-free interval ICON 4 Response (Difference of 12%; 95% CI -0.1% to 24%; p=0.06) CR = complete response; ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum; PR = partial response; Parmar MK, et al. Lancet. 2003;361:2099-2106. Proportion alive and progression-free 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Patients at risk Pac-Plat 392 179 52 25 17 Plat 410 157 45 17 7 Years from randomization Hazard ratio = 0.76 (95% CI 0.66 - 0.89; p < 0.001) Absolute difference at 1 year = 10% (40% to 50%; 95% CI 4% to 15%) Ovarian Carcinoma: ICON 4 Progression-Free Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum Hazard ratio = 0.82 (95% CI 0.69 - 0.97; p = 0.023) Absolute difference 2 years = 7% (50% to 57%; 95% CI 1% to 12%) Patients at risk Pac-Plat 392 306 167 96 43 Plat 410 295 150 68 33 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Years from randomization Proportion alive ICON 4: Overall Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum R A N D O M I Z E Gemcitabine 1,000 mg/m2 days 1 + 8 Plus Carboplatin AUC 4 day 1 every 21 days × 6 Recurrent ovarian cancer 6+ months after platinum Strata PFI (6 - 12, >12 months) 1st-line therapy (platinum ± paclitaxel) Measurable vs evaluable Primary endpoint = PFS Gem/Carbo vs Carbo: Design Carboplatin AUC 5 day 1 every 21 days × 6 Carbo = carboplatin Gem = gemcitabine PFI = progression-free interval PFS = progression-free survival Pfisterer J, et al. J Clin Oncol. 2006; 24:4699-4707. AGO OVAR 2.5 Primary Endpoint: Progression-Free Survival GCb: median = 8.6 mo Censoring: 12.4% Cb: median = 5.8 mo Censoring: 12.9% Cb Arm (N=178) GCb Arm (N=178) Log-rank p-value = 0.0038 Unadjusted HR = 0.72 (0.57 to 0.90) Adjusted HR* = 0.71 (0.57 to 0.89) * Adjusted for PFI, Tumor size Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin AGO OVAR 2.5 Efficacy Results: Overall Survival 0.0 0.8 0.2 0.3 0.4 0.5 0.6 0.7 0.9 1.0 0.1 0 6 12 18 60 54 48 42 36 30 24 Proportion Surviving Months Median = 18.0 mo Censoring: 18.5% Median = 17.3 mo Censoring: 22.5% Cb Arm (N=178) GCb Arm (N=178) * Adjusted for PFI, Tumor size and performance status Log-rank p-value = 0.7349 Unadjusted HR = 0.96 (0.75 to 1.23) Adjusted* HR = 0.92 (0.72 to 1.16) Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: < 0.5 cm > 0.5-2 cm R A N D O M I Z E 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 Completed (Target accrual 864 pts) PFS 1° endpoint Farletuzumab (MORAb-003) in Platinum-Sensitive EOC: Study Rationale FRA is overexpressed in most EOC; largely absent from normal tissue Binding of MORAb-003 to FRA blocks phosphorylation by Lyn kinase; mediates FRA-expressing tumor cell killing; suppresses tumor growth in xenograft models Phase I study of single agent MORAb-003 demonstrated no significant adverse effects and suggested efficacy in platinum-resistant EOC MORAb-003 in Platinum-Sensitive EOC: Phase II Study Design Patients with platinum-sensitive EOC in first relapse after first remission of 6-18 months duration with evaluable disease by CA125 (Enrolled N = 58; eligible n = 54) Asymptomatic relapse Single-agent Farletuzumab until progression (n = 28) Original Carbo/Taxane regimen + Farletuzumab for 6 cycles (n = 26) Symptomatic relapse Compare lengths of first and second remissions Farletuzumab maintenance Rx for responders Single-agent ORR Combination ORR Armstrong DK, et al. ASCO 2008. Abstract 5500. All arms MORAb-003: 100 mg/m2 weekly Run-in phase with 6 subjects at 37.5 and 6 at 62.5 mg/m2 Combination therapy arm every 21 days x 6 cycles Carboplatin: AUC 5-6 Taxane Paclitaxel 175 mg/m2 over 3 hours or Docetaxel 75 mg/m2 MORAb-003-002 Phase II: Treatment Arms Armstrong DK, et al. ASCO 2008. Abstract 5500. Comparison of First vs Second Remission Length: n = 6 Data as of May 5, 2008. Armstrong DK, et al. ASCO 2008. Abstract 5500. MORAb-003-002 Clinical Responses by RECIST (Combination Therapy) Best response CR: 7.4% PR: 62.9% SD: 25.9% PD: 3.7% Based on all scans submitted as of December 3, 2007 (~ 30%) By independent central reader MORAb-003 well tolerated; no increase observed in toxicity profile in combination arm ORR: 70.3% Patient benefit: 96.3% Armstrong DK, et al. ASCO 2008. Abstract 5500. Secondary Cytoreduction Controversial Inconsistent definitions Benefit appears confined to patients likely to respond to additional chemo: >12 month PFI Isolated site of recurrence Disease completely resectable Kidney Resected Liver Diaphragm Kidney Vena Cava Tumor Mass Renal Vein PFI = progression-free interval TTP mos >12 >12 >12 >17.5 >36 >24 12-24 >24 Ovarian Cancer Secondary Cytoreduction: Post-Surgery Survival Author Janicke Segna Zang Gadducci Eisenkop Munkarah Scarabelli Tay Total/Range Year 1992 1993 2000 2000 2000 2001 2001 2002 N 30 100 60 30 114 25 148 46 553 Survival Median mos 16 16.6 13 21 16.8 26 13-26 TTP mos <12 <12 <12 <17.5 <12 <24 <12 <12 Survival Median mos 8 8.8 8 15 25 42 12 6 6-42 Survival Median mos (P) 29 (0.002) 22.9 (0.007) 12 (0.02) 25 (0.04) 56.8 (0.005) 57 (NS) 32 (0.001) 39 (0.001) 12-56 TTP = time to progression GOG 213- PI Robert Coleman Surgical Candidate? Recurrent ovarian or peritoneal cancer TFI >6 mos YES NO Surgery No surgery Carboplatin + Paclitaxel Carboplatin + Paclitaxel + Bevacizumab + Bevacizumab Maintenance Randomize to Chemotherapy GOG = Gynecologic Oncology Group TFI = treatment-free interval Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Recent Phase II GOG Studies in Platinum-Resistant Ovarian Cancer Study Agents Response/comm 126-B CDDP & Cyclosporine-A 3/23 (13%) Inactive 126-C Hexamethylmelamine 3/30 (10%) Inactive 126-D Pyrazoloacridine 2/24 (8.4%) Inactive 126-E PSC833 + paclitaxel 1/16 (6%) Inactive 126-G CI-958 1/25 (4%) Inactive 126-H Topotecan (24 h) 1/25 (4%) Inactive 126-I 9-amino-camptothecin 8/58 (14%) Moderate 126-J Docetaxel 13/58 (22%) Active (post-paclitaxel) Bookman MA. Semin Oncol 2002;29(suppl 1):20-31. CDDP = c/s-diamminedichloroplatinum (cisplatin) GOG = gynecologic oncology group Recent Phase II GOG Studies in Platinum-Resistant Ovarian Cancer Study Agents Response/comm 126-K Oxaliplatin 1/25 (4%) Inactive 126-L Gemcitabine/CDDP 9/57 (16%) Moderate 126-M Ixabepilone 7/50 (14%) Moderate 126-N Paclitaxel weekly 10/48 (21%) Active (post-paclitaxel) 126-O Triapine-CDDP Not Feasible 126-P Paclitaxel & Celecoxib Closed Early 126-Q Pemetrexed 10/48 (21%) Active 126-R Abraxane Accrual in Progress Bookman MA. Semin Oncol 2002;29(suppl 1):20-31. CDDP = c/s-diamminedichloroplatinum (cisplatin) GOG = gynecologic oncology group Pemetrexed in Platinum-Resistant EOC: Phase II GOG Study Schema Miller DS, et al. ASCO 2008. Abstract 5524. Patients with persistent or recurrent platinum-resistant EOC or primary peritoneal cancer who have failed on higher priority treatment protocols Pemetrexed 900 mg/m2 IV every 21 days for 1 cycle; patients who have received previous radiotherapy will initiate pemetrexed at level I reduction dose until disease progression or adverse effect prohibits further therapy Phase II GOG Study Evaluation of Pemetrexed: Clinical Responses Miller DS, et al. ASCO 2008. Abstract 5524. *1 patient remains on therapy. Cochrane Review of Tamoxifen for Relapsed Ovarian Cancer 13 studies (11non-randomized series, 1 non-randomized phase II and 1 randomized trial) 59 of 568 women (10.4%) treated with tamoxifen achieved an objective response (RR) RR varied from 0% to 56% Stable disease, for variable periods of 4 weeks or more, in 109 of 356 (30.6%) from 8 studies Not enough data to assess duration of RR, survival, or the effect of tamoxifen on quality of life No reliable data from randomized controlled trials Williams CJ. Cochrane Database Syst Rev. 2000;(2):CD001034. RR = response rate GOG Experience GOG 160: Trastuzumab GOG 170 Human Interleukin-12 (170B) Lapatinib (170G) Gefitinib (170C) Vorinostat (170H) Bevacizumab (170D) Temsirolimus (170I) Imatinib (170E) Enzastaurin (170J) Bay 43-9006 (170F) Mifepristone (170K) Ongoing GOG Phase II Effort Insufficiently Active Too Early Active GOG = Gynecologic Oncology Group Antiangiogenic Agents in Testing for Treatment of Ovarian Cancer Agent Targets Ligand binding: Bevacizumab VEGF-A VEGF-Trap VEGF-A, -B, -C, -D, -E, PIGF-1 and -2 Receptor binding: Volociximab 51 integrin IMC-1121B VEGFR-2 Receptor tyrosine kinase inhibition: Valatanib VEGFR-1, -2, -3, PDGFR, and c-kit Sunitinib PDGFR, VEGFR-1, -2, -3, c-kit, Flt-3 AMG-706 VEGFR-1, -2, -3, PDGFR, and c-kit Sorafenib Raf, VEGFR-2, -3, Flt-3, c-kit, PDGFR-  Non-receptor kinase inhibition: Temsirolimus, everolimus mTOR Enzastaurin PKC-  Dasatinib Src kinase EGFR = epidermal growth factor receptor; Mab = monoclonal antibody; mTOR = mammalian target of rapamycin; PDGF-R = platelet derived growth factor receptor; PKC-b = protein kinase C-beta; VEGF = vascular endothelial growth factor Rationale for Targeting VEGF in Treatment of Epithelial Ovarian Cancer Human tumors VEGF over-expressed in epithelial ovarian cancers, associated with Ascites formation Malignant progression Poor prognosis Preclinical models of solid tumors Anti-VEGF therapy: Slowing of tumor progression Resolution of malignant effusions Synergy with cytotoxic agents Han ES, et al. Expert Rev Anticancer Ther. 2007;7(10):1339-1345. Burger RA. J Clin Oncol. 2007;25(20):2902-2908. VEGF = vascular endothelial growth factor Agents Targeting the VEGF Pathway VEGFR-2 VEGFR-1 Endothelial Cell Small-Molecule Inhibitors VEGF Soluble VEGFRs (VEGF-TRAP) Podar K, et al. Blood. 2005;105(4):1383-1395. VEGF = vascular endothelial growth factor VEGFR = VEGF receptor Bevacizumab - Toxicity Proteinuria (usually G1 – G2) Muco-cutaneous hemorrhage Common – G1 epistaxis Rare (possibly life-threatening) G2-G4 tumor site hemorrhage (primarily lung cancer trials) Arterial thromboembolism Uncommon (3% - 5%) Risk factors: age > 65, prior arterial TE Risk of venous thromboembolism not increased GI perforation – wound healing Perforation uncommon (2% - 4% in solid tumor population) Wound dehiscence rate 1% Han ES, et al. Expert Rev Anticancer Ther. 2007;7(10):1339-1345. Burger RA. J Clin Oncol. 2007;25(20):2902-2908. G1, G2 = immunoglobulins GI = gastrointestinal TE = thromboembolism Phase II Studies of Bevacizumab in Ovarian Cancer Cannistra SA, et al. J Clin Oncol. 2007;25(33):5180-5186. Burger RA, et al. J Clin Oncol. 2007;25(33):5165-5171. Garcia AA, et al. J Clin Oncol. 2008;26(1):76-82. CR = complete response GI = gastrointestinal PR = partial response GI Perforations with Bevacizumab in Ovarian Cancer Han E, et al. Gynecol Oncol. 2007;105(1):3-6. GI = gastrointestinal NCI Registered Phase II Trials: Anti-VEGF + Cytotoxic * Front Line **Carboplatin and Paclitaxel Bev = bevacizumab; Carbo = carboplatin Gem = gemcitabine; IP = intraperitoneal Mab = monoclonal antibody; Ox = Oxaliplatin; VEGF = vascular endothelial growth factor
Slide 63 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days GC vs TC Induction Regimens Followed by T Consolidation: Response Rates Gordon A, et al. ASCO 2008. Abstract 5536. *CR required a normalized CA-125. GC vs TC Induction Regimens Followed by T Consolidation: Pt-Based Toxicity Gordon A, et al. ASCO 2008. Abstract 5536. Conventional vs Dose-Dense TC (NOVEL): Study Design Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO 2008. Abstract 5506. P = .72 Evaluated by WHO criteria Conventional vs Dose-Dense TC (NOVEL): Clinical Responses Isonishi S, et al. ASCO 2008. Abstract 5506. Conventional vs Dose-Dense TC (NOVEL): PFS 0.0 0.2 0.4 0.6 0.8 1.0 0 12 30 54 Mos From Randomization Proportion Surviving Progression Free 0.1 0.3 0.5 0.7 0.9 6 18 42 24 48 36 Isonishi S, et al. ASCO 2008. Abstract 5506. dd-TC c-TC Ovarian Carcinoma: Clinical Course Symptoms Diagnosis Chemotherapy #1 Staging Primary cytoreduction Interval Cytoreduction Progression Chemo #2 Chemo #3+ Supportive Care Death Consolidation/ Maintenance Cure Secondary Cytoreduction Second-Look Goals of Treatment: Relapsed Ovarian Cancer Prolong Survival Delay Time to Progression Control Disease-Related Symptoms Minimize Treatment-Related Symptoms Maintain or Improve Quality of Life Issues Impacting Therapy for Recurrent Ovarian Cancer Treatment-free interval Impact of consolidation/maintenance therapy Number of prior regimens Response to prior therapy Toxicity from prior therapy Prior use of growth factors Transfusion requirements Neuropathy Volume and site(s) of disease Ascites/GI symptoms Performance status Surveillance Options for Ovarian Cancer Patients in Remission Second-look laparotomy Physical examination Include pelvic examination CA-125 Imaging CT scan MRI? PET scan? CT = computed tomography MRI = magnetic resonance imaging PET = positron emission tomography Ovarian Cancer: How is Relapse Defined? Continuous rise in CA-125 CA-125 above 100 Radiographic recurrence Symptomatic recurrence Physical examination findings Combination of above When Does Ovarian Cancer Recur? Carb = carboplatin; Cis = cisplatin; Doc = docetaxel; pac = paclitaxel; GOG = Gynecologic Oncology Group; IP = intraperitoneal; Pac = paclitaxel Active Agents in Ovarian Cancer Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Refractory P R I M A R Y T R E A T M E N T Resistant Sensitive 0 3 6 12 18 24 Months “Very Sensitive” Ovarian Cancer at First Relapse Definition of Sensitivity Defined as measurable recurrence, not biochemical (CA-125) recurrence ICON 4 Schema Relapsed ovarian or primary Peritoneal requiring chemotherapy Previous platinum-based chemotherapy Conventional platinum-based chemotherapy Paclitaxel plus platinum chemotherapy R A N D O M I Z E Prior chemotherapy Carboplatin (31%) Paclitaxel/platinum (40%) Other (30%) TFI > 12 months for 75% Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group TFI = treatment-free interval ICON 4 Response (Difference of 12%; 95% CI -0.1% to 24%; p=0.06) CR = complete response; ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum; PR = partial response; Parmar MK, et al. Lancet. 2003;361:2099-2106. Proportion alive and progression-free 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Patients at risk Pac-Plat 392 179 52 25 17 Plat 410 157 45 17 7 Years from randomization Hazard ratio = 0.76 (95% CI 0.66 - 0.89; p < 0.001) Absolute difference at 1 year = 10% (40% to 50%; 95% CI 4% to 15%) Ovarian Carcinoma: ICON 4 Progression-Free Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum Hazard ratio = 0.82 (95% CI 0.69 - 0.97; p = 0.023) Absolute difference 2 years = 7% (50% to 57%; 95% CI 1% to 12%) Patients at risk Pac-Plat 392 306 167 96 43 Plat 410 295 150 68 33 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Years from randomization Proportion alive ICON 4: Overall Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum R A N D O M I Z E Gemcitabine 1,000 mg/m2 days 1 + 8 Plus Carboplatin AUC 4 day 1 every 21 days × 6 Recurrent ovarian cancer 6+ months after platinum Strata PFI (6 - 12, >12 months) 1st-line therapy (platinum ± paclitaxel) Measurable vs evaluable Primary endpoint = PFS Gem/Carbo vs Carbo: Design Carboplatin AUC 5 day 1 every 21 days × 6 Carbo = carboplatin Gem = gemcitabine PFI = progression-free interval PFS = progression-free survival Pfisterer J, et al. J Clin Oncol. 2006; 24:4699-4707. AGO OVAR 2.5 Primary Endpoint: Progression-Free Survival GCb: median = 8.6 mo Censoring: 12.4% Cb: median = 5.8 mo Censoring: 12.9% Cb Arm (N=178) GCb Arm (N=178) Log-rank p-value = 0.0038 Unadjusted HR = 0.72 (0.57 to 0.90) Adjusted HR* = 0.71 (0.57 to 0.89) * Adjusted for PFI, Tumor size Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin AGO OVAR 2.5 Efficacy Results: Overall Survival 0.0 0.8 0.2 0.3 0.4 0.5 0.6 0.7 0.9 1.0 0.1 0 6 12 18 60 54 48 42 36 30 24 Proportion Surviving Months Median = 18.0 mo Censoring: 18.5% Median = 17.3 mo Censoring: 22.5% Cb Arm (N=178) GCb Arm (N=178) * Adjusted for PFI, Tumor size and performance status Log-rank p-value = 0.7349 Unadjusted HR = 0.96 (0.75 to 1.23) Adjusted* HR = 0.92 (0.72 to 1.16) Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: < 0.5 cm > 0.5-2 cm R A N D O M I Z E 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 Completed (Target accrual 864 pts) PFS 1° endpoint Farletuzumab (MORAb-003) in Platinum-Sensitive EOC: Study Rationale FRA is overexpressed in most EOC; largely absent from normal tissue Binding of MORAb-003 to FRA blocks phosphorylation by Lyn kinase; mediates FRA-expressing tumor cell killing; suppresses tumor growth in xenograft models Phase I study of single agent MORAb-003 demonstrated no significant adverse effects and suggested efficacy in platinum-resistant EOC MORAb-003 in Platinum-Sensitive EOC: Phase II Study Design Patients with platinum-sensitive EOC in first relapse after first remission of 6-18 months duration with evaluable disease by CA125 (Enrolled N = 58; eligible n = 54) Asymptomatic relapse Single-agent Farletuzumab until progression (n = 28) Original Carbo/Taxane regimen + Farletuzumab for 6 cycles (n = 26) Symptomatic relapse Compare lengths of first and second remissions Farletuzumab maintenance Rx for responders Single-agent ORR Combination ORR Armstrong DK, et al. ASCO 2008. Abstract 5500. All arms MORAb-003: 100 mg/m2 weekly Run-in phase with 6 subjects at 37.5 and 6 at 62.5 mg/m2 Combination therapy arm every 21 days x 6 cycles Carboplatin: AUC 5-6 Taxane Paclitaxel 175 mg/m2 over 3 hours or Docetaxel 75 mg/m2 MORAb-003-002 Phase II: Treatment Arms Armstrong DK, et al. ASCO 2008. Abstract 5500. Comparison of First vs Second Remission Length: n = 6 Data as of May 5, 2008. Armstrong DK, et al. ASCO 2008. Abstract 5500. MORAb-003-002 Clinical Responses by RECIST (Combination Therapy) Best response CR: 7.4% PR: 62.9% SD: 25.9% PD: 3.7% Based on all scans submitted as of December 3, 2007 (~ 30%) By independent central reader MORAb-003 well tolerated; no increase observed in toxicity profile in combination arm ORR: 70.3% Patient benefit: 96.3% Armstrong DK, et al. ASCO 2008. Abstract 5500. Secondary Cytoreduction Controversial Inconsistent definitions Benefit appears confined to patients likely to respond to additional chemo: >12 month PFI Isolated site of recurrence Disease completely resectable Kidney Resected Liver Diaphragm Kidney Vena Cava Tumor Mass Renal Vein PFI = progression-free interval TTP mos >12 >12 >12 >17.5 >36 >24 12-24 >24 Ovarian Cancer Secondary Cytoreduction: Post-Surgery Survival Author Janicke Segna Zang Gadducci Eisenkop Munkarah Scarabelli Tay Total/Range Year 1992 1993 2000 2000 2000 2001 2001 2002 N 30 100 60 30 114 25 148 46 553 Survival Median mos 16 16.6 13 21 16.8 26 13-26 TTP mos <12 <12 <12 <17.5 <12 <24 <12 <12 Survival Median mos 8 8.8 8 15 25 42 12 6 6-42 Survival Median mos (P) 29 (0.002) 22.9 (0.007) 12 (0.02) 25 (0.04) 56.8 (0.005) 57 (NS) 32 (0.001) 39 (0.001) 12-56 TTP = time to progression GOG 213- PI Robert Coleman Surgical Candidate? Recurrent ovarian or peritoneal cancer TFI >6 mos YES NO Surgery No surgery Carboplatin + Paclitaxel Carboplatin + Paclitaxel + Bevacizumab + Bevacizumab Maintenance Randomize to Chemotherapy GOG = Gynecologic Oncology Group TFI = treatment-free interval Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Recent Phase II GOG Studies in Platinum-Resistant Ovarian Cancer Study Agents Response/comm 126-B CDDP & Cyclosporine-A 3/23 (13%) Inactive 126-C Hexamethylmelamine 3/30 (10%) Inactive 126-D Pyrazoloacridine 2/24 (8.4%) Inactive 126-E PSC833 + paclitaxel 1/16 (6%) Inactive 126-G CI-958 1/25 (4%) Inactive 126-H Topotecan (24 h) 1/25 (4%) Inactive 126-I 9-amino-camptothecin 8/58 (14%) Moderate 126-J Docetaxel 13/58 (22%) Active (post-paclitaxel) Bookman MA. Semin Oncol 2002;29(suppl 1):20-31. CDDP = c/s-diamminedichloroplatinum (cisplatin) GOG = gynecologic oncology group Recent Phase II GOG Studies in Platinum-Resistant Ovarian Cancer Study Agents Response/comm 126-K Oxaliplatin 1/25 (4%) Inactive 126-L Gemcitabine/CDDP 9/57 (16%) Moderate 126-M Ixabepilone 7/50 (14%) Moderate 126-N Paclitaxel weekly 10/48 (21%) Active (post-paclitaxel) 126-O Triapine-CDDP Not Feasible 126-P Paclitaxel & Celecoxib Closed Early 126-Q Pemetrexed 10/48 (21%) Active 126-R Abraxane Accrual in Progress Bookman MA. Semin Oncol 2002;29(suppl 1):20-31. CDDP = c/s-diamminedichloroplatinum (cisplatin) GOG = gynecologic oncology group Pemetrexed in Platinum-Resistant EOC: Phase II GOG Study Schema Miller DS, et al. ASCO 2008. Abstract 5524. Patients with persistent or recurrent platinum-resistant EOC or primary peritoneal cancer who have failed on higher priority treatment protocols Pemetrexed 900 mg/m2 IV every 21 days for 1 cycle; patients who have received previous radiotherapy will initiate pemetrexed at level I reduction dose until disease progression or adverse effect prohibits further therapy Phase II GOG Study Evaluation of Pemetrexed: Clinical Responses Miller DS, et al. ASCO 2008. Abstract 5524. *1 patient remains on therapy. Cochrane Review of Tamoxifen for Relapsed Ovarian Cancer 13 studies (11non-randomized series, 1 non-randomized phase II and 1 randomized trial) 59 of 568 women (10.4%) treated with tamoxifen achieved an objective response (RR) RR varied from 0% to 56% Stable disease, for variable periods of 4 weeks or more, in 109 of 356 (30.6%) from 8 studies Not enough data to assess duration of RR, survival, or the effect of tamoxifen on quality of life No reliable data from randomized controlled trials Williams CJ. Cochrane Database Syst Rev. 2000;(2):CD001034. RR = response rate GOG Experience GOG 160: Trastuzumab GOG 170 Human Interleukin-12 (170B) Lapatinib (170G) Gefitinib (170C) Vorinostat (170H) Bevacizumab (170D) Temsirolimus (170I) Imatinib (170E) Enzastaurin (170J) Bay 43-9006 (170F) Mifepristone (170K) Ongoing GOG Phase II Effort Insufficiently Active Too Early Active GOG = Gynecologic Oncology Group Antiangiogenic Agents in Testing for Treatment of Ovarian Cancer Agent Targets Ligand binding: Bevacizumab VEGF-A VEGF-Trap VEGF-A, -B, -C, -D, -E, PIGF-1 and -2 Receptor binding: Volociximab 51 integrin IMC-1121B VEGFR-2 Receptor tyrosine kinase inhibition: Valatanib VEGFR-1, -2, -3, PDGFR, and c-kit Sunitinib PDGFR, VEGFR-1, -2, -3, c-kit, Flt-3 AMG-706 VEGFR-1, -2, -3, PDGFR, and c-kit Sorafenib Raf, VEGFR-2, -3, Flt-3, c-kit, PDGFR-  Non-receptor kinase inhibition: Temsirolimus, everolimus mTOR Enzastaurin PKC-  Dasatinib Src kinase EGFR = epidermal growth factor receptor; Mab = monoclonal antibody; mTOR = mammalian target of rapamycin; PDGF-R = platelet derived growth factor receptor; PKC-b = protein kinase C-beta; VEGF = vascular endothelial growth factor Rationale for Targeting VEGF in Treatment of Epithelial Ovarian Cancer Human tumors VEGF over-expressed in epithelial ovarian cancers, associated with Ascites formation Malignant progression Poor prognosis Preclinical models of solid tumors Anti-VEGF therapy: Slowing of tumor progression Resolution of malignant effusions Synergy with cytotoxic agents Han ES, et al. Expert Rev Anticancer Ther. 2007;7(10):1339-1345. Burger RA. J Clin Oncol. 2007;25(20):2902-2908. VEGF = vascular endothelial growth factor Agents Targeting the VEGF Pathway VEGFR-2 VEGFR-1 Endothelial Cell Small-Molecule Inhibitors VEGF Soluble VEGFRs (VEGF-TRAP) Podar K, et al. Blood. 2005;105(4):1383-1395. VEGF = vascular endothelial growth factor VEGFR = VEGF receptor Bevacizumab - Toxicity Proteinuria (usually G1 – G2) Muco-cutaneous hemorrhage Common – G1 epistaxis Rare (possibly life-threatening) G2-G4 tumor site hemorrhage (primarily lung cancer trials) Arterial thromboembolism Uncommon (3% - 5%) Risk factors: age > 65, prior arterial TE Risk of venous thromboembolism not increased GI perforation – wound healing Perforation uncommon (2% - 4% in solid tumor population) Wound dehiscence rate 1% Han ES, et al. Expert Rev Anticancer Ther. 2007;7(10):1339-1345. Burger RA. J Clin Oncol. 2007;25(20):2902-2908. G1, G2 = immunoglobulins GI = gastrointestinal TE = thromboembolism Phase II Studies of Bevacizumab in Ovarian Cancer Cannistra SA, et al. J Clin Oncol. 2007;25(33):5180-5186. Burger RA, et al. J Clin Oncol. 2007;25(33):5165-5171. Garcia AA, et al. J Clin Oncol. 2008;26(1):76-82. CR = complete response GI = gastrointestinal PR = partial response GI Perforations with Bevacizumab in Ovarian Cancer Han E, et al. Gynecol Oncol. 2007;105(1):3-6. GI = gastrointestinal NCI Registered Phase II Trials: Anti-VEGF + Cytotoxic * Front Line **Carboplatin and Paclitaxel Bev = bevacizumab; Carbo = carboplatin Gem = gemcitabine; IP = intraperitoneal Mab = monoclonal antibody; Ox = Oxaliplatin; VEGF = vascular endothelial growth factor NCI Registered Phase II Trials: VEGF + EGFR Inhibitors Bev = bevacizumab EGFR = epidermal growth factor receptor Mab = monoclonal antibody VEGF = vascular endothelial growth factor
Slide 64 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days GC vs TC Induction Regimens Followed by T Consolidation: Response Rates Gordon A, et al. ASCO 2008. Abstract 5536. *CR required a normalized CA-125. GC vs TC Induction Regimens Followed by T Consolidation: Pt-Based Toxicity Gordon A, et al. ASCO 2008. Abstract 5536. Conventional vs Dose-Dense TC (NOVEL): Study Design Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO 2008. Abstract 5506. P = .72 Evaluated by WHO criteria Conventional vs Dose-Dense TC (NOVEL): Clinical Responses Isonishi S, et al. ASCO 2008. Abstract 5506. Conventional vs Dose-Dense TC (NOVEL): PFS 0.0 0.2 0.4 0.6 0.8 1.0 0 12 30 54 Mos From Randomization Proportion Surviving Progression Free 0.1 0.3 0.5 0.7 0.9 6 18 42 24 48 36 Isonishi S, et al. ASCO 2008. Abstract 5506. dd-TC c-TC Ovarian Carcinoma: Clinical Course Symptoms Diagnosis Chemotherapy #1 Staging Primary cytoreduction Interval Cytoreduction Progression Chemo #2 Chemo #3+ Supportive Care Death Consolidation/ Maintenance Cure Secondary Cytoreduction Second-Look Goals of Treatment: Relapsed Ovarian Cancer Prolong Survival Delay Time to Progression Control Disease-Related Symptoms Minimize Treatment-Related Symptoms Maintain or Improve Quality of Life Issues Impacting Therapy for Recurrent Ovarian Cancer Treatment-free interval Impact of consolidation/maintenance therapy Number of prior regimens Response to prior therapy Toxicity from prior therapy Prior use of growth factors Transfusion requirements Neuropathy Volume and site(s) of disease Ascites/GI symptoms Performance status Surveillance Options for Ovarian Cancer Patients in Remission Second-look laparotomy Physical examination Include pelvic examination CA-125 Imaging CT scan MRI? PET scan? CT = computed tomography MRI = magnetic resonance imaging PET = positron emission tomography Ovarian Cancer: How is Relapse Defined? Continuous rise in CA-125 CA-125 above 100 Radiographic recurrence Symptomatic recurrence Physical examination findings Combination of above When Does Ovarian Cancer Recur? Carb = carboplatin; Cis = cisplatin; Doc = docetaxel; pac = paclitaxel; GOG = Gynecologic Oncology Group; IP = intraperitoneal; Pac = paclitaxel Active Agents in Ovarian Cancer Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Refractory P R I M A R Y T R E A T M E N T Resistant Sensitive 0 3 6 12 18 24 Months “Very Sensitive” Ovarian Cancer at First Relapse Definition of Sensitivity Defined as measurable recurrence, not biochemical (CA-125) recurrence ICON 4 Schema Relapsed ovarian or primary Peritoneal requiring chemotherapy Previous platinum-based chemotherapy Conventional platinum-based chemotherapy Paclitaxel plus platinum chemotherapy R A N D O M I Z E Prior chemotherapy Carboplatin (31%) Paclitaxel/platinum (40%) Other (30%) TFI > 12 months for 75% Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group TFI = treatment-free interval ICON 4 Response (Difference of 12%; 95% CI -0.1% to 24%; p=0.06) CR = complete response; ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum; PR = partial response; Parmar MK, et al. Lancet. 2003;361:2099-2106. Proportion alive and progression-free 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Patients at risk Pac-Plat 392 179 52 25 17 Plat 410 157 45 17 7 Years from randomization Hazard ratio = 0.76 (95% CI 0.66 - 0.89; p < 0.001) Absolute difference at 1 year = 10% (40% to 50%; 95% CI 4% to 15%) Ovarian Carcinoma: ICON 4 Progression-Free Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum Hazard ratio = 0.82 (95% CI 0.69 - 0.97; p = 0.023) Absolute difference 2 years = 7% (50% to 57%; 95% CI 1% to 12%) Patients at risk Pac-Plat 392 306 167 96 43 Plat 410 295 150 68 33 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Years from randomization Proportion alive ICON 4: Overall Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum R A N D O M I Z E Gemcitabine 1,000 mg/m2 days 1 + 8 Plus Carboplatin AUC 4 day 1 every 21 days × 6 Recurrent ovarian cancer 6+ months after platinum Strata PFI (6 - 12, >12 months) 1st-line therapy (platinum ± paclitaxel) Measurable vs evaluable Primary endpoint = PFS Gem/Carbo vs Carbo: Design Carboplatin AUC 5 day 1 every 21 days × 6 Carbo = carboplatin Gem = gemcitabine PFI = progression-free interval PFS = progression-free survival Pfisterer J, et al. J Clin Oncol. 2006; 24:4699-4707. AGO OVAR 2.5 Primary Endpoint: Progression-Free Survival GCb: median = 8.6 mo Censoring: 12.4% Cb: median = 5.8 mo Censoring: 12.9% Cb Arm (N=178) GCb Arm (N=178) Log-rank p-value = 0.0038 Unadjusted HR = 0.72 (0.57 to 0.90) Adjusted HR* = 0.71 (0.57 to 0.89) * Adjusted for PFI, Tumor size Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin AGO OVAR 2.5 Efficacy Results: Overall Survival 0.0 0.8 0.2 0.3 0.4 0.5 0.6 0.7 0.9 1.0 0.1 0 6 12 18 60 54 48 42 36 30 24 Proportion Surviving Months Median = 18.0 mo Censoring: 18.5% Median = 17.3 mo Censoring: 22.5% Cb Arm (N=178) GCb Arm (N=178) * Adjusted for PFI, Tumor size and performance status Log-rank p-value = 0.7349 Unadjusted HR = 0.96 (0.75 to 1.23) Adjusted* HR = 0.92 (0.72 to 1.16) Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: < 0.5 cm > 0.5-2 cm R A N D O M I Z E 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 Completed (Target accrual 864 pts) PFS 1° endpoint Farletuzumab (MORAb-003) in Platinum-Sensitive EOC: Study Rationale FRA is overexpressed in most EOC; largely absent from normal tissue Binding of MORAb-003 to FRA blocks phosphorylation by Lyn kinase; mediates FRA-expressing tumor cell killing; suppresses tumor growth in xenograft models Phase I study of single agent MORAb-003 demonstrated no significant adverse effects and suggested efficacy in platinum-resistant EOC MORAb-003 in Platinum-Sensitive EOC: Phase II Study Design Patients with platinum-sensitive EOC in first relapse after first remission of 6-18 months duration with evaluable disease by CA125 (Enrolled N = 58; eligible n = 54) Asymptomatic relapse Single-agent Farletuzumab until progression (n = 28) Original Carbo/Taxane regimen + Farletuzumab for 6 cycles (n = 26) Symptomatic relapse Compare lengths of first and second remissions Farletuzumab maintenance Rx for responders Single-agent ORR Combination ORR Armstrong DK, et al. ASCO 2008. Abstract 5500. All arms MORAb-003: 100 mg/m2 weekly Run-in phase with 6 subjects at 37.5 and 6 at 62.5 mg/m2 Combination therapy arm every 21 days x 6 cycles Carboplatin: AUC 5-6 Taxane Paclitaxel 175 mg/m2 over 3 hours or Docetaxel 75 mg/m2 MORAb-003-002 Phase II: Treatment Arms Armstrong DK, et al. ASCO 2008. Abstract 5500. Comparison of First vs Second Remission Length: n = 6 Data as of May 5, 2008. Armstrong DK, et al. ASCO 2008. Abstract 5500. MORAb-003-002 Clinical Responses by RECIST (Combination Therapy) Best response CR: 7.4% PR: 62.9% SD: 25.9% PD: 3.7% Based on all scans submitted as of December 3, 2007 (~ 30%) By independent central reader MORAb-003 well tolerated; no increase observed in toxicity profile in combination arm ORR: 70.3% Patient benefit: 96.3% Armstrong DK, et al. ASCO 2008. Abstract 5500. Secondary Cytoreduction Controversial Inconsistent definitions Benefit appears confined to patients likely to respond to additional chemo: >12 month PFI Isolated site of recurrence Disease completely resectable Kidney Resected Liver Diaphragm Kidney Vena Cava Tumor Mass Renal Vein PFI = progression-free interval TTP mos >12 >12 >12 >17.5 >36 >24 12-24 >24 Ovarian Cancer Secondary Cytoreduction: Post-Surgery Survival Author Janicke Segna Zang Gadducci Eisenkop Munkarah Scarabelli Tay Total/Range Year 1992 1993 2000 2000 2000 2001 2001 2002 N 30 100 60 30 114 25 148 46 553 Survival Median mos 16 16.6 13 21 16.8 26 13-26 TTP mos <12 <12 <12 <17.5 <12 <24 <12 <12 Survival Median mos 8 8.8 8 15 25 42 12 6 6-42 Survival Median mos (P) 29 (0.002) 22.9 (0.007) 12 (0.02) 25 (0.04) 56.8 (0.005) 57 (NS) 32 (0.001) 39 (0.001) 12-56 TTP = time to progression GOG 213- PI Robert Coleman Surgical Candidate? Recurrent ovarian or peritoneal cancer TFI >6 mos YES NO Surgery No surgery Carboplatin + Paclitaxel Carboplatin + Paclitaxel + Bevacizumab + Bevacizumab Maintenance Randomize to Chemotherapy GOG = Gynecologic Oncology Group TFI = treatment-free interval Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Recent Phase II GOG Studies in Platinum-Resistant Ovarian Cancer Study Agents Response/comm 126-B CDDP & Cyclosporine-A 3/23 (13%) Inactive 126-C Hexamethylmelamine 3/30 (10%) Inactive 126-D Pyrazoloacridine 2/24 (8.4%) Inactive 126-E PSC833 + paclitaxel 1/16 (6%) Inactive 126-G CI-958 1/25 (4%) Inactive 126-H Topotecan (24 h) 1/25 (4%) Inactive 126-I 9-amino-camptothecin 8/58 (14%) Moderate 126-J Docetaxel 13/58 (22%) Active (post-paclitaxel) Bookman MA. Semin Oncol 2002;29(suppl 1):20-31. CDDP = c/s-diamminedichloroplatinum (cisplatin) GOG = gynecologic oncology group Recent Phase II GOG Studies in Platinum-Resistant Ovarian Cancer Study Agents Response/comm 126-K Oxaliplatin 1/25 (4%) Inactive 126-L Gemcitabine/CDDP 9/57 (16%) Moderate 126-M Ixabepilone 7/50 (14%) Moderate 126-N Paclitaxel weekly 10/48 (21%) Active (post-paclitaxel) 126-O Triapine-CDDP Not Feasible 126-P Paclitaxel & Celecoxib Closed Early 126-Q Pemetrexed 10/48 (21%) Active 126-R Abraxane Accrual in Progress Bookman MA. Semin Oncol 2002;29(suppl 1):20-31. CDDP = c/s-diamminedichloroplatinum (cisplatin) GOG = gynecologic oncology group Pemetrexed in Platinum-Resistant EOC: Phase II GOG Study Schema Miller DS, et al. ASCO 2008. Abstract 5524. Patients with persistent or recurrent platinum-resistant EOC or primary peritoneal cancer who have failed on higher priority treatment protocols Pemetrexed 900 mg/m2 IV every 21 days for 1 cycle; patients who have received previous radiotherapy will initiate pemetrexed at level I reduction dose until disease progression or adverse effect prohibits further therapy Phase II GOG Study Evaluation of Pemetrexed: Clinical Responses Miller DS, et al. ASCO 2008. Abstract 5524. *1 patient remains on therapy. Cochrane Review of Tamoxifen for Relapsed Ovarian Cancer 13 studies (11non-randomized series, 1 non-randomized phase II and 1 randomized trial) 59 of 568 women (10.4%) treated with tamoxifen achieved an objective response (RR) RR varied from 0% to 56% Stable disease, for variable periods of 4 weeks or more, in 109 of 356 (30.6%) from 8 studies Not enough data to assess duration of RR, survival, or the effect of tamoxifen on quality of life No reliable data from randomized controlled trials Williams CJ. Cochrane Database Syst Rev. 2000;(2):CD001034. RR = response rate GOG Experience GOG 160: Trastuzumab GOG 170 Human Interleukin-12 (170B) Lapatinib (170G) Gefitinib (170C) Vorinostat (170H) Bevacizumab (170D) Temsirolimus (170I) Imatinib (170E) Enzastaurin (170J) Bay 43-9006 (170F) Mifepristone (170K) Ongoing GOG Phase II Effort Insufficiently Active Too Early Active GOG = Gynecologic Oncology Group Antiangiogenic Agents in Testing for Treatment of Ovarian Cancer Agent Targets Ligand binding: Bevacizumab VEGF-A VEGF-Trap VEGF-A, -B, -C, -D, -E, PIGF-1 and -2 Receptor binding: Volociximab 51 integrin IMC-1121B VEGFR-2 Receptor tyrosine kinase inhibition: Valatanib VEGFR-1, -2, -3, PDGFR, and c-kit Sunitinib PDGFR, VEGFR-1, -2, -3, c-kit, Flt-3 AMG-706 VEGFR-1, -2, -3, PDGFR, and c-kit Sorafenib Raf, VEGFR-2, -3, Flt-3, c-kit, PDGFR-  Non-receptor kinase inhibition: Temsirolimus, everolimus mTOR Enzastaurin PKC-  Dasatinib Src kinase EGFR = epidermal growth factor receptor; Mab = monoclonal antibody; mTOR = mammalian target of rapamycin; PDGF-R = platelet derived growth factor receptor; PKC-b = protein kinase C-beta; VEGF = vascular endothelial growth factor Rationale for Targeting VEGF in Treatment of Epithelial Ovarian Cancer Human tumors VEGF over-expressed in epithelial ovarian cancers, associated with Ascites formation Malignant progression Poor prognosis Preclinical models of solid tumors Anti-VEGF therapy: Slowing of tumor progression Resolution of malignant effusions Synergy with cytotoxic agents Han ES, et al. Expert Rev Anticancer Ther. 2007;7(10):1339-1345. Burger RA. J Clin Oncol. 2007;25(20):2902-2908. VEGF = vascular endothelial growth factor Agents Targeting the VEGF Pathway VEGFR-2 VEGFR-1 Endothelial Cell Small-Molecule Inhibitors VEGF Soluble VEGFRs (VEGF-TRAP) Podar K, et al. Blood. 2005;105(4):1383-1395. VEGF = vascular endothelial growth factor VEGFR = VEGF receptor Bevacizumab - Toxicity Proteinuria (usually G1 – G2) Muco-cutaneous hemorrhage Common – G1 epistaxis Rare (possibly life-threatening) G2-G4 tumor site hemorrhage (primarily lung cancer trials) Arterial thromboembolism Uncommon (3% - 5%) Risk factors: age > 65, prior arterial TE Risk of venous thromboembolism not increased GI perforation – wound healing Perforation uncommon (2% - 4% in solid tumor population) Wound dehiscence rate 1% Han ES, et al. Expert Rev Anticancer Ther. 2007;7(10):1339-1345. Burger RA. J Clin Oncol. 2007;25(20):2902-2908. G1, G2 = immunoglobulins GI = gastrointestinal TE = thromboembolism Phase II Studies of Bevacizumab in Ovarian Cancer Cannistra SA, et al. J Clin Oncol. 2007;25(33):5180-5186. Burger RA, et al. J Clin Oncol. 2007;25(33):5165-5171. Garcia AA, et al. J Clin Oncol. 2008;26(1):76-82. CR = complete response GI = gastrointestinal PR = partial response GI Perforations with Bevacizumab in Ovarian Cancer Han E, et al. Gynecol Oncol. 2007;105(1):3-6. GI = gastrointestinal NCI Registered Phase II Trials: Anti-VEGF + Cytotoxic * Front Line **Carboplatin and Paclitaxel Bev = bevacizumab; Carbo = carboplatin Gem = gemcitabine; IP = intraperitoneal Mab = monoclonal antibody; Ox = Oxaliplatin; VEGF = vascular endothelial growth factor NCI Registered Phase II Trials: VEGF + EGFR Inhibitors Bev = bevacizumab EGFR = epidermal growth factor receptor Mab = monoclonal antibody VEGF = vascular endothelial growth factor NCI Registered Phase II Trials: Other Anti-Angiogenic Agents CT = chemotherapy; GOG = gynecologic oncology group; EGFR = epidermal growth factor receptor; Mab = monoclonal antibody; PDGF-R = platelet derived growth factor receptor; PKC-b = protein kinase C-beta; TKI = tyrosine kinase inhibitor
Slide 65 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days GC vs TC Induction Regimens Followed by T Consolidation: Response Rates Gordon A, et al. ASCO 2008. Abstract 5536. *CR required a normalized CA-125. GC vs TC Induction Regimens Followed by T Consolidation: Pt-Based Toxicity Gordon A, et al. ASCO 2008. Abstract 5536. Conventional vs Dose-Dense TC (NOVEL): Study Design Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO 2008. Abstract 5506. P = .72 Evaluated by WHO criteria Conventional vs Dose-Dense TC (NOVEL): Clinical Responses Isonishi S, et al. ASCO 2008. Abstract 5506. Conventional vs Dose-Dense TC (NOVEL): PFS 0.0 0.2 0.4 0.6 0.8 1.0 0 12 30 54 Mos From Randomization Proportion Surviving Progression Free 0.1 0.3 0.5 0.7 0.9 6 18 42 24 48 36 Isonishi S, et al. ASCO 2008. Abstract 5506. dd-TC c-TC Ovarian Carcinoma: Clinical Course Symptoms Diagnosis Chemotherapy #1 Staging Primary cytoreduction Interval Cytoreduction Progression Chemo #2 Chemo #3+ Supportive Care Death Consolidation/ Maintenance Cure Secondary Cytoreduction Second-Look Goals of Treatment: Relapsed Ovarian Cancer Prolong Survival Delay Time to Progression Control Disease-Related Symptoms Minimize Treatment-Related Symptoms Maintain or Improve Quality of Life Issues Impacting Therapy for Recurrent Ovarian Cancer Treatment-free interval Impact of consolidation/maintenance therapy Number of prior regimens Response to prior therapy Toxicity from prior therapy Prior use of growth factors Transfusion requirements Neuropathy Volume and site(s) of disease Ascites/GI symptoms Performance status Surveillance Options for Ovarian Cancer Patients in Remission Second-look laparotomy Physical examination Include pelvic examination CA-125 Imaging CT scan MRI? PET scan? CT = computed tomography MRI = magnetic resonance imaging PET = positron emission tomography Ovarian Cancer: How is Relapse Defined? Continuous rise in CA-125 CA-125 above 100 Radiographic recurrence Symptomatic recurrence Physical examination findings Combination of above When Does Ovarian Cancer Recur? Carb = carboplatin; Cis = cisplatin; Doc = docetaxel; pac = paclitaxel; GOG = Gynecologic Oncology Group; IP = intraperitoneal; Pac = paclitaxel Active Agents in Ovarian Cancer Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Refractory P R I M A R Y T R E A T M E N T Resistant Sensitive 0 3 6 12 18 24 Months “Very Sensitive” Ovarian Cancer at First Relapse Definition of Sensitivity Defined as measurable recurrence, not biochemical (CA-125) recurrence ICON 4 Schema Relapsed ovarian or primary Peritoneal requiring chemotherapy Previous platinum-based chemotherapy Conventional platinum-based chemotherapy Paclitaxel plus platinum chemotherapy R A N D O M I Z E Prior chemotherapy Carboplatin (31%) Paclitaxel/platinum (40%) Other (30%) TFI > 12 months for 75% Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group TFI = treatment-free interval ICON 4 Response (Difference of 12%; 95% CI -0.1% to 24%; p=0.06) CR = complete response; ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum; PR = partial response; Parmar MK, et al. Lancet. 2003;361:2099-2106. Proportion alive and progression-free 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Patients at risk Pac-Plat 392 179 52 25 17 Plat 410 157 45 17 7 Years from randomization Hazard ratio = 0.76 (95% CI 0.66 - 0.89; p < 0.001) Absolute difference at 1 year = 10% (40% to 50%; 95% CI 4% to 15%) Ovarian Carcinoma: ICON 4 Progression-Free Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum Hazard ratio = 0.82 (95% CI 0.69 - 0.97; p = 0.023) Absolute difference 2 years = 7% (50% to 57%; 95% CI 1% to 12%) Patients at risk Pac-Plat 392 306 167 96 43 Plat 410 295 150 68 33 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Years from randomization Proportion alive ICON 4: Overall Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum R A N D O M I Z E Gemcitabine 1,000 mg/m2 days 1 + 8 Plus Carboplatin AUC 4 day 1 every 21 days × 6 Recurrent ovarian cancer 6+ months after platinum Strata PFI (6 - 12, >12 months) 1st-line therapy (platinum ± paclitaxel) Measurable vs evaluable Primary endpoint = PFS Gem/Carbo vs Carbo: Design Carboplatin AUC 5 day 1 every 21 days × 6 Carbo = carboplatin Gem = gemcitabine PFI = progression-free interval PFS = progression-free survival Pfisterer J, et al. J Clin Oncol. 2006; 24:4699-4707. AGO OVAR 2.5 Primary Endpoint: Progression-Free Survival GCb: median = 8.6 mo Censoring: 12.4% Cb: median = 5.8 mo Censoring: 12.9% Cb Arm (N=178) GCb Arm (N=178) Log-rank p-value = 0.0038 Unadjusted HR = 0.72 (0.57 to 0.90) Adjusted HR* = 0.71 (0.57 to 0.89) * Adjusted for PFI, Tumor size Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin AGO OVAR 2.5 Efficacy Results: Overall Survival 0.0 0.8 0.2 0.3 0.4 0.5 0.6 0.7 0.9 1.0 0.1 0 6 12 18 60 54 48 42 36 30 24 Proportion Surviving Months Median = 18.0 mo Censoring: 18.5% Median = 17.3 mo Censoring: 22.5% Cb Arm (N=178) GCb Arm (N=178) * Adjusted for PFI, Tumor size and performance status Log-rank p-value = 0.7349 Unadjusted HR = 0.96 (0.75 to 1.23) Adjusted* HR = 0.92 (0.72 to 1.16) Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: < 0.5 cm > 0.5-2 cm R A N D O M I Z E 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 Completed (Target accrual 864 pts) PFS 1° endpoint Farletuzumab (MORAb-003) in Platinum-Sensitive EOC: Study Rationale FRA is overexpressed in most EOC; largely absent from normal tissue Binding of MORAb-003 to FRA blocks phosphorylation by Lyn kinase; mediates FRA-expressing tumor cell killing; suppresses tumor growth in xenograft models Phase I study of single agent MORAb-003 demonstrated no significant adverse effects and suggested efficacy in platinum-resistant EOC MORAb-003 in Platinum-Sensitive EOC: Phase II Study Design Patients with platinum-sensitive EOC in first relapse after first remission of 6-18 months duration with evaluable disease by CA125 (Enrolled N = 58; eligible n = 54) Asymptomatic relapse Single-agent Farletuzumab until progression (n = 28) Original Carbo/Taxane regimen + Farletuzumab for 6 cycles (n = 26) Symptomatic relapse Compare lengths of first and second remissions Farletuzumab maintenance Rx for responders Single-agent ORR Combination ORR Armstrong DK, et al. ASCO 2008. Abstract 5500. All arms MORAb-003: 100 mg/m2 weekly Run-in phase with 6 subjects at 37.5 and 6 at 62.5 mg/m2 Combination therapy arm every 21 days x 6 cycles Carboplatin: AUC 5-6 Taxane Paclitaxel 175 mg/m2 over 3 hours or Docetaxel 75 mg/m2 MORAb-003-002 Phase II: Treatment Arms Armstrong DK, et al. ASCO 2008. Abstract 5500. Comparison of First vs Second Remission Length: n = 6 Data as of May 5, 2008. Armstrong DK, et al. ASCO 2008. Abstract 5500. MORAb-003-002 Clinical Responses by RECIST (Combination Therapy) Best response CR: 7.4% PR: 62.9% SD: 25.9% PD: 3.7% Based on all scans submitted as of December 3, 2007 (~ 30%) By independent central reader MORAb-003 well tolerated; no increase observed in toxicity profile in combination arm ORR: 70.3% Patient benefit: 96.3% Armstrong DK, et al. ASCO 2008. Abstract 5500. Secondary Cytoreduction Controversial Inconsistent definitions Benefit appears confined to patients likely to respond to additional chemo: >12 month PFI Isolated site of recurrence Disease completely resectable Kidney Resected Liver Diaphragm Kidney Vena Cava Tumor Mass Renal Vein PFI = progression-free interval TTP mos >12 >12 >12 >17.5 >36 >24 12-24 >24 Ovarian Cancer Secondary Cytoreduction: Post-Surgery Survival Author Janicke Segna Zang Gadducci Eisenkop Munkarah Scarabelli Tay Total/Range Year 1992 1993 2000 2000 2000 2001 2001 2002 N 30 100 60 30 114 25 148 46 553 Survival Median mos 16 16.6 13 21 16.8 26 13-26 TTP mos <12 <12 <12 <17.5 <12 <24 <12 <12 Survival Median mos 8 8.8 8 15 25 42 12 6 6-42 Survival Median mos (P) 29 (0.002) 22.9 (0.007) 12 (0.02) 25 (0.04) 56.8 (0.005) 57 (NS) 32 (0.001) 39 (0.001) 12-56 TTP = time to progression GOG 213- PI Robert Coleman Surgical Candidate? Recurrent ovarian or peritoneal cancer TFI >6 mos YES NO Surgery No surgery Carboplatin + Paclitaxel Carboplatin + Paclitaxel + Bevacizumab + Bevacizumab Maintenance Randomize to Chemotherapy GOG = Gynecologic Oncology Group TFI = treatment-free interval Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Recent Phase II GOG Studies in Platinum-Resistant Ovarian Cancer Study Agents Response/comm 126-B CDDP & Cyclosporine-A 3/23 (13%) Inactive 126-C Hexamethylmelamine 3/30 (10%) Inactive 126-D Pyrazoloacridine 2/24 (8.4%) Inactive 126-E PSC833 + paclitaxel 1/16 (6%) Inactive 126-G CI-958 1/25 (4%) Inactive 126-H Topotecan (24 h) 1/25 (4%) Inactive 126-I 9-amino-camptothecin 8/58 (14%) Moderate 126-J Docetaxel 13/58 (22%) Active (post-paclitaxel) Bookman MA. Semin Oncol 2002;29(suppl 1):20-31. CDDP = c/s-diamminedichloroplatinum (cisplatin) GOG = gynecologic oncology group Recent Phase II GOG Studies in Platinum-Resistant Ovarian Cancer Study Agents Response/comm 126-K Oxaliplatin 1/25 (4%) Inactive 126-L Gemcitabine/CDDP 9/57 (16%) Moderate 126-M Ixabepilone 7/50 (14%) Moderate 126-N Paclitaxel weekly 10/48 (21%) Active (post-paclitaxel) 126-O Triapine-CDDP Not Feasible 126-P Paclitaxel & Celecoxib Closed Early 126-Q Pemetrexed 10/48 (21%) Active 126-R Abraxane Accrual in Progress Bookman MA. Semin Oncol 2002;29(suppl 1):20-31. CDDP = c/s-diamminedichloroplatinum (cisplatin) GOG = gynecologic oncology group Pemetrexed in Platinum-Resistant EOC: Phase II GOG Study Schema Miller DS, et al. ASCO 2008. Abstract 5524. Patients with persistent or recurrent platinum-resistant EOC or primary peritoneal cancer who have failed on higher priority treatment protocols Pemetrexed 900 mg/m2 IV every 21 days for 1 cycle; patients who have received previous radiotherapy will initiate pemetrexed at level I reduction dose until disease progression or adverse effect prohibits further therapy Phase II GOG Study Evaluation of Pemetrexed: Clinical Responses Miller DS, et al. ASCO 2008. Abstract 5524. *1 patient remains on therapy. Cochrane Review of Tamoxifen for Relapsed Ovarian Cancer 13 studies (11non-randomized series, 1 non-randomized phase II and 1 randomized trial) 59 of 568 women (10.4%) treated with tamoxifen achieved an objective response (RR) RR varied from 0% to 56% Stable disease, for variable periods of 4 weeks or more, in 109 of 356 (30.6%) from 8 studies Not enough data to assess duration of RR, survival, or the effect of tamoxifen on quality of life No reliable data from randomized controlled trials Williams CJ. Cochrane Database Syst Rev. 2000;(2):CD001034. RR = response rate GOG Experience GOG 160: Trastuzumab GOG 170 Human Interleukin-12 (170B) Lapatinib (170G) Gefitinib (170C) Vorinostat (170H) Bevacizumab (170D) Temsirolimus (170I) Imatinib (170E) Enzastaurin (170J) Bay 43-9006 (170F) Mifepristone (170K) Ongoing GOG Phase II Effort Insufficiently Active Too Early Active GOG = Gynecologic Oncology Group Antiangiogenic Agents in Testing for Treatment of Ovarian Cancer Agent Targets Ligand binding: Bevacizumab VEGF-A VEGF-Trap VEGF-A, -B, -C, -D, -E, PIGF-1 and -2 Receptor binding: Volociximab 51 integrin IMC-1121B VEGFR-2 Receptor tyrosine kinase inhibition: Valatanib VEGFR-1, -2, -3, PDGFR, and c-kit Sunitinib PDGFR, VEGFR-1, -2, -3, c-kit, Flt-3 AMG-706 VEGFR-1, -2, -3, PDGFR, and c-kit Sorafenib Raf, VEGFR-2, -3, Flt-3, c-kit, PDGFR-  Non-receptor kinase inhibition: Temsirolimus, everolimus mTOR Enzastaurin PKC-  Dasatinib Src kinase EGFR = epidermal growth factor receptor; Mab = monoclonal antibody; mTOR = mammalian target of rapamycin; PDGF-R = platelet derived growth factor receptor; PKC-b = protein kinase C-beta; VEGF = vascular endothelial growth factor Rationale for Targeting VEGF in Treatment of Epithelial Ovarian Cancer Human tumors VEGF over-expressed in epithelial ovarian cancers, associated with Ascites formation Malignant progression Poor prognosis Preclinical models of solid tumors Anti-VEGF therapy: Slowing of tumor progression Resolution of malignant effusions Synergy with cytotoxic agents Han ES, et al. Expert Rev Anticancer Ther. 2007;7(10):1339-1345. Burger RA. J Clin Oncol. 2007;25(20):2902-2908. VEGF = vascular endothelial growth factor Agents Targeting the VEGF Pathway VEGFR-2 VEGFR-1 Endothelial Cell Small-Molecule Inhibitors VEGF Soluble VEGFRs (VEGF-TRAP) Podar K, et al. Blood. 2005;105(4):1383-1395. VEGF = vascular endothelial growth factor VEGFR = VEGF receptor Bevacizumab - Toxicity Proteinuria (usually G1 – G2) Muco-cutaneous hemorrhage Common – G1 epistaxis Rare (possibly life-threatening) G2-G4 tumor site hemorrhage (primarily lung cancer trials) Arterial thromboembolism Uncommon (3% - 5%) Risk factors: age > 65, prior arterial TE Risk of venous thromboembolism not increased GI perforation – wound healing Perforation uncommon (2% - 4% in solid tumor population) Wound dehiscence rate 1% Han ES, et al. Expert Rev Anticancer Ther. 2007;7(10):1339-1345. Burger RA. J Clin Oncol. 2007;25(20):2902-2908. G1, G2 = immunoglobulins GI = gastrointestinal TE = thromboembolism Phase II Studies of Bevacizumab in Ovarian Cancer Cannistra SA, et al. J Clin Oncol. 2007;25(33):5180-5186. Burger RA, et al. J Clin Oncol. 2007;25(33):5165-5171. Garcia AA, et al. J Clin Oncol. 2008;26(1):76-82. CR = complete response GI = gastrointestinal PR = partial response GI Perforations with Bevacizumab in Ovarian Cancer Han E, et al. Gynecol Oncol. 2007;105(1):3-6. GI = gastrointestinal NCI Registered Phase II Trials: Anti-VEGF + Cytotoxic * Front Line **Carboplatin and Paclitaxel Bev = bevacizumab; Carbo = carboplatin Gem = gemcitabine; IP = intraperitoneal Mab = monoclonal antibody; Ox = Oxaliplatin; VEGF = vascular endothelial growth factor NCI Registered Phase II Trials: VEGF + EGFR Inhibitors Bev = bevacizumab EGFR = epidermal growth factor receptor Mab = monoclonal antibody VEGF = vascular endothelial growth factor NCI Registered Phase II Trials: Other Anti-Angiogenic Agents CT = chemotherapy; GOG = gynecologic oncology group; EGFR = epidermal growth factor receptor; Mab = monoclonal antibody; PDGF-R = platelet derived growth factor receptor; PKC-b = protein kinase C-beta; TKI = tyrosine kinase inhibitor Bev + Topotecan in Platinum Refractory Ovarian Cancer: Study Design McGonigle KF, et al. ASCO 2008. Abstract 5551. Platinum-refractory OC; recurrence < 6 mos of platinum therapy; received max of 2 previous chemotherapy regimens (N = 40) Bevacizumab 10 mg/kg Days 1, 15 + Topotecan 4 mg/m2 Days 1, 8, 15 for 28-day cycles PD as defined by RECIST criteria Excessive toxicity according to prespecified criteria Toxicity requiring topotecan delay > 2 weeks or bevacizumab delay > 2 months Topotecan-related toxicities requiring > 2 dose reductions Treatment continued until 1 of the following events Single arm, 2-site phase II trial
Slide 66 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days GC vs TC Induction Regimens Followed by T Consolidation: Response Rates Gordon A, et al. ASCO 2008. Abstract 5536. *CR required a normalized CA-125. GC vs TC Induction Regimens Followed by T Consolidation: Pt-Based Toxicity Gordon A, et al. ASCO 2008. Abstract 5536. Conventional vs Dose-Dense TC (NOVEL): Study Design Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO 2008. Abstract 5506. P = .72 Evaluated by WHO criteria Conventional vs Dose-Dense TC (NOVEL): Clinical Responses Isonishi S, et al. ASCO 2008. Abstract 5506. Conventional vs Dose-Dense TC (NOVEL): PFS 0.0 0.2 0.4 0.6 0.8 1.0 0 12 30 54 Mos From Randomization Proportion Surviving Progression Free 0.1 0.3 0.5 0.7 0.9 6 18 42 24 48 36 Isonishi S, et al. ASCO 2008. Abstract 5506. dd-TC c-TC Ovarian Carcinoma: Clinical Course Symptoms Diagnosis Chemotherapy #1 Staging Primary cytoreduction Interval Cytoreduction Progression Chemo #2 Chemo #3+ Supportive Care Death Consolidation/ Maintenance Cure Secondary Cytoreduction Second-Look Goals of Treatment: Relapsed Ovarian Cancer Prolong Survival Delay Time to Progression Control Disease-Related Symptoms Minimize Treatment-Related Symptoms Maintain or Improve Quality of Life Issues Impacting Therapy for Recurrent Ovarian Cancer Treatment-free interval Impact of consolidation/maintenance therapy Number of prior regimens Response to prior therapy Toxicity from prior therapy Prior use of growth factors Transfusion requirements Neuropathy Volume and site(s) of disease Ascites/GI symptoms Performance status Surveillance Options for Ovarian Cancer Patients in Remission Second-look laparotomy Physical examination Include pelvic examination CA-125 Imaging CT scan MRI? PET scan? CT = computed tomography MRI = magnetic resonance imaging PET = positron emission tomography Ovarian Cancer: How is Relapse Defined? Continuous rise in CA-125 CA-125 above 100 Radiographic recurrence Symptomatic recurrence Physical examination findings Combination of above When Does Ovarian Cancer Recur? Carb = carboplatin; Cis = cisplatin; Doc = docetaxel; pac = paclitaxel; GOG = Gynecologic Oncology Group; IP = intraperitoneal; Pac = paclitaxel Active Agents in Ovarian Cancer Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Refractory P R I M A R Y T R E A T M E N T Resistant Sensitive 0 3 6 12 18 24 Months “Very Sensitive” Ovarian Cancer at First Relapse Definition of Sensitivity Defined as measurable recurrence, not biochemical (CA-125) recurrence ICON 4 Schema Relapsed ovarian or primary Peritoneal requiring chemotherapy Previous platinum-based chemotherapy Conventional platinum-based chemotherapy Paclitaxel plus platinum chemotherapy R A N D O M I Z E Prior chemotherapy Carboplatin (31%) Paclitaxel/platinum (40%) Other (30%) TFI > 12 months for 75% Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group TFI = treatment-free interval ICON 4 Response (Difference of 12%; 95% CI -0.1% to 24%; p=0.06) CR = complete response; ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum; PR = partial response; Parmar MK, et al. Lancet. 2003;361:2099-2106. Proportion alive and progression-free 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Patients at risk Pac-Plat 392 179 52 25 17 Plat 410 157 45 17 7 Years from randomization Hazard ratio = 0.76 (95% CI 0.66 - 0.89; p < 0.001) Absolute difference at 1 year = 10% (40% to 50%; 95% CI 4% to 15%) Ovarian Carcinoma: ICON 4 Progression-Free Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum Hazard ratio = 0.82 (95% CI 0.69 - 0.97; p = 0.023) Absolute difference 2 years = 7% (50% to 57%; 95% CI 1% to 12%) Patients at risk Pac-Plat 392 306 167 96 43 Plat 410 295 150 68 33 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Years from randomization Proportion alive ICON 4: Overall Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum R A N D O M I Z E Gemcitabine 1,000 mg/m2 days 1 + 8 Plus Carboplatin AUC 4 day 1 every 21 days × 6 Recurrent ovarian cancer 6+ months after platinum Strata PFI (6 - 12, >12 months) 1st-line therapy (platinum ± paclitaxel) Measurable vs evaluable Primary endpoint = PFS Gem/Carbo vs Carbo: Design Carboplatin AUC 5 day 1 every 21 days × 6 Carbo = carboplatin Gem = gemcitabine PFI = progression-free interval PFS = progression-free survival Pfisterer J, et al. J Clin Oncol. 2006; 24:4699-4707. AGO OVAR 2.5 Primary Endpoint: Progression-Free Survival GCb: median = 8.6 mo Censoring: 12.4% Cb: median = 5.8 mo Censoring: 12.9% Cb Arm (N=178) GCb Arm (N=178) Log-rank p-value = 0.0038 Unadjusted HR = 0.72 (0.57 to 0.90) Adjusted HR* = 0.71 (0.57 to 0.89) * Adjusted for PFI, Tumor size Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin AGO OVAR 2.5 Efficacy Results: Overall Survival 0.0 0.8 0.2 0.3 0.4 0.5 0.6 0.7 0.9 1.0 0.1 0 6 12 18 60 54 48 42 36 30 24 Proportion Surviving Months Median = 18.0 mo Censoring: 18.5% Median = 17.3 mo Censoring: 22.5% Cb Arm (N=178) GCb Arm (N=178) * Adjusted for PFI, Tumor size and performance status Log-rank p-value = 0.7349 Unadjusted HR = 0.96 (0.75 to 1.23) Adjusted* HR = 0.92 (0.72 to 1.16) Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: < 0.5 cm > 0.5-2 cm R A N D O M I Z E 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 Completed (Target accrual 864 pts) PFS 1° endpoint Farletuzumab (MORAb-003) in Platinum-Sensitive EOC: Study Rationale FRA is overexpressed in most EOC; largely absent from normal tissue Binding of MORAb-003 to FRA blocks phosphorylation by Lyn kinase; mediates FRA-expressing tumor cell killing; suppresses tumor growth in xenograft models Phase I study of single agent MORAb-003 demonstrated no significant adverse effects and suggested efficacy in platinum-resistant EOC MORAb-003 in Platinum-Sensitive EOC: Phase II Study Design Patients with platinum-sensitive EOC in first relapse after first remission of 6-18 months duration with evaluable disease by CA125 (Enrolled N = 58; eligible n = 54) Asymptomatic relapse Single-agent Farletuzumab until progression (n = 28) Original Carbo/Taxane regimen + Farletuzumab for 6 cycles (n = 26) Symptomatic relapse Compare lengths of first and second remissions Farletuzumab maintenance Rx for responders Single-agent ORR Combination ORR Armstrong DK, et al. ASCO 2008. Abstract 5500. All arms MORAb-003: 100 mg/m2 weekly Run-in phase with 6 subjects at 37.5 and 6 at 62.5 mg/m2 Combination therapy arm every 21 days x 6 cycles Carboplatin: AUC 5-6 Taxane Paclitaxel 175 mg/m2 over 3 hours or Docetaxel 75 mg/m2 MORAb-003-002 Phase II: Treatment Arms Armstrong DK, et al. ASCO 2008. Abstract 5500. Comparison of First vs Second Remission Length: n = 6 Data as of May 5, 2008. Armstrong DK, et al. ASCO 2008. Abstract 5500. MORAb-003-002 Clinical Responses by RECIST (Combination Therapy) Best response CR: 7.4% PR: 62.9% SD: 25.9% PD: 3.7% Based on all scans submitted as of December 3, 2007 (~ 30%) By independent central reader MORAb-003 well tolerated; no increase observed in toxicity profile in combination arm ORR: 70.3% Patient benefit: 96.3% Armstrong DK, et al. ASCO 2008. Abstract 5500. Secondary Cytoreduction Controversial Inconsistent definitions Benefit appears confined to patients likely to respond to additional chemo: >12 month PFI Isolated site of recurrence Disease completely resectable Kidney Resected Liver Diaphragm Kidney Vena Cava Tumor Mass Renal Vein PFI = progression-free interval TTP mos >12 >12 >12 >17.5 >36 >24 12-24 >24 Ovarian Cancer Secondary Cytoreduction: Post-Surgery Survival Author Janicke Segna Zang Gadducci Eisenkop Munkarah Scarabelli Tay Total/Range Year 1992 1993 2000 2000 2000 2001 2001 2002 N 30 100 60 30 114 25 148 46 553 Survival Median mos 16 16.6 13 21 16.8 26 13-26 TTP mos <12 <12 <12 <17.5 <12 <24 <12 <12 Survival Median mos 8 8.8 8 15 25 42 12 6 6-42 Survival Median mos (P) 29 (0.002) 22.9 (0.007) 12 (0.02) 25 (0.04) 56.8 (0.005) 57 (NS) 32 (0.001) 39 (0.001) 12-56 TTP = time to progression GOG 213- PI Robert Coleman Surgical Candidate? Recurrent ovarian or peritoneal cancer TFI >6 mos YES NO Surgery No surgery Carboplatin + Paclitaxel Carboplatin + Paclitaxel + Bevacizumab + Bevacizumab Maintenance Randomize to Chemotherapy GOG = Gynecologic Oncology Group TFI = treatment-free interval Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Recent Phase II GOG Studies in Platinum-Resistant Ovarian Cancer Study Agents Response/comm 126-B CDDP & Cyclosporine-A 3/23 (13%) Inactive 126-C Hexamethylmelamine 3/30 (10%) Inactive 126-D Pyrazoloacridine 2/24 (8.4%) Inactive 126-E PSC833 + paclitaxel 1/16 (6%) Inactive 126-G CI-958 1/25 (4%) Inactive 126-H Topotecan (24 h) 1/25 (4%) Inactive 126-I 9-amino-camptothecin 8/58 (14%) Moderate 126-J Docetaxel 13/58 (22%) Active (post-paclitaxel) Bookman MA. Semin Oncol 2002;29(suppl 1):20-31. CDDP = c/s-diamminedichloroplatinum (cisplatin) GOG = gynecologic oncology group Recent Phase II GOG Studies in Platinum-Resistant Ovarian Cancer Study Agents Response/comm 126-K Oxaliplatin 1/25 (4%) Inactive 126-L Gemcitabine/CDDP 9/57 (16%) Moderate 126-M Ixabepilone 7/50 (14%) Moderate 126-N Paclitaxel weekly 10/48 (21%) Active (post-paclitaxel) 126-O Triapine-CDDP Not Feasible 126-P Paclitaxel & Celecoxib Closed Early 126-Q Pemetrexed 10/48 (21%) Active 126-R Abraxane Accrual in Progress Bookman MA. Semin Oncol 2002;29(suppl 1):20-31. CDDP = c/s-diamminedichloroplatinum (cisplatin) GOG = gynecologic oncology group Pemetrexed in Platinum-Resistant EOC: Phase II GOG Study Schema Miller DS, et al. ASCO 2008. Abstract 5524. Patients with persistent or recurrent platinum-resistant EOC or primary peritoneal cancer who have failed on higher priority treatment protocols Pemetrexed 900 mg/m2 IV every 21 days for 1 cycle; patients who have received previous radiotherapy will initiate pemetrexed at level I reduction dose until disease progression or adverse effect prohibits further therapy Phase II GOG Study Evaluation of Pemetrexed: Clinical Responses Miller DS, et al. ASCO 2008. Abstract 5524. *1 patient remains on therapy. Cochrane Review of Tamoxifen for Relapsed Ovarian Cancer 13 studies (11non-randomized series, 1 non-randomized phase II and 1 randomized trial) 59 of 568 women (10.4%) treated with tamoxifen achieved an objective response (RR) RR varied from 0% to 56% Stable disease, for variable periods of 4 weeks or more, in 109 of 356 (30.6%) from 8 studies Not enough data to assess duration of RR, survival, or the effect of tamoxifen on quality of life No reliable data from randomized controlled trials Williams CJ. Cochrane Database Syst Rev. 2000;(2):CD001034. RR = response rate GOG Experience GOG 160: Trastuzumab GOG 170 Human Interleukin-12 (170B) Lapatinib (170G) Gefitinib (170C) Vorinostat (170H) Bevacizumab (170D) Temsirolimus (170I) Imatinib (170E) Enzastaurin (170J) Bay 43-9006 (170F) Mifepristone (170K) Ongoing GOG Phase II Effort Insufficiently Active Too Early Active GOG = Gynecologic Oncology Group Antiangiogenic Agents in Testing for Treatment of Ovarian Cancer Agent Targets Ligand binding: Bevacizumab VEGF-A VEGF-Trap VEGF-A, -B, -C, -D, -E, PIGF-1 and -2 Receptor binding: Volociximab 51 integrin IMC-1121B VEGFR-2 Receptor tyrosine kinase inhibition: Valatanib VEGFR-1, -2, -3, PDGFR, and c-kit Sunitinib PDGFR, VEGFR-1, -2, -3, c-kit, Flt-3 AMG-706 VEGFR-1, -2, -3, PDGFR, and c-kit Sorafenib Raf, VEGFR-2, -3, Flt-3, c-kit, PDGFR-  Non-receptor kinase inhibition: Temsirolimus, everolimus mTOR Enzastaurin PKC-  Dasatinib Src kinase EGFR = epidermal growth factor receptor; Mab = monoclonal antibody; mTOR = mammalian target of rapamycin; PDGF-R = platelet derived growth factor receptor; PKC-b = protein kinase C-beta; VEGF = vascular endothelial growth factor Rationale for Targeting VEGF in Treatment of Epithelial Ovarian Cancer Human tumors VEGF over-expressed in epithelial ovarian cancers, associated with Ascites formation Malignant progression Poor prognosis Preclinical models of solid tumors Anti-VEGF therapy: Slowing of tumor progression Resolution of malignant effusions Synergy with cytotoxic agents Han ES, et al. Expert Rev Anticancer Ther. 2007;7(10):1339-1345. Burger RA. J Clin Oncol. 2007;25(20):2902-2908. VEGF = vascular endothelial growth factor Agents Targeting the VEGF Pathway VEGFR-2 VEGFR-1 Endothelial Cell Small-Molecule Inhibitors VEGF Soluble VEGFRs (VEGF-TRAP) Podar K, et al. Blood. 2005;105(4):1383-1395. VEGF = vascular endothelial growth factor VEGFR = VEGF receptor Bevacizumab - Toxicity Proteinuria (usually G1 – G2) Muco-cutaneous hemorrhage Common – G1 epistaxis Rare (possibly life-threatening) G2-G4 tumor site hemorrhage (primarily lung cancer trials) Arterial thromboembolism Uncommon (3% - 5%) Risk factors: age > 65, prior arterial TE Risk of venous thromboembolism not increased GI perforation – wound healing Perforation uncommon (2% - 4% in solid tumor population) Wound dehiscence rate 1% Han ES, et al. Expert Rev Anticancer Ther. 2007;7(10):1339-1345. Burger RA. J Clin Oncol. 2007;25(20):2902-2908. G1, G2 = immunoglobulins GI = gastrointestinal TE = thromboembolism Phase II Studies of Bevacizumab in Ovarian Cancer Cannistra SA, et al. J Clin Oncol. 2007;25(33):5180-5186. Burger RA, et al. J Clin Oncol. 2007;25(33):5165-5171. Garcia AA, et al. J Clin Oncol. 2008;26(1):76-82. CR = complete response GI = gastrointestinal PR = partial response GI Perforations with Bevacizumab in Ovarian Cancer Han E, et al. Gynecol Oncol. 2007;105(1):3-6. GI = gastrointestinal NCI Registered Phase II Trials: Anti-VEGF + Cytotoxic * Front Line **Carboplatin and Paclitaxel Bev = bevacizumab; Carbo = carboplatin Gem = gemcitabine; IP = intraperitoneal Mab = monoclonal antibody; Ox = Oxaliplatin; VEGF = vascular endothelial growth factor NCI Registered Phase II Trials: VEGF + EGFR Inhibitors Bev = bevacizumab EGFR = epidermal growth factor receptor Mab = monoclonal antibody VEGF = vascular endothelial growth factor NCI Registered Phase II Trials: Other Anti-Angiogenic Agents CT = chemotherapy; GOG = gynecologic oncology group; EGFR = epidermal growth factor receptor; Mab = monoclonal antibody; PDGF-R = platelet derived growth factor receptor; PKC-b = protein kinase C-beta; TKI = tyrosine kinase inhibitor Bev + Topotecan in Platinum Refractory Ovarian Cancer: Study Design McGonigle KF, et al. ASCO 2008. Abstract 5551. Platinum-refractory OC; recurrence < 6 mos of platinum therapy; received max of 2 previous chemotherapy regimens (N = 40) Bevacizumab 10 mg/kg Days 1, 15 + Topotecan 4 mg/m2 Days 1, 8, 15 for 28-day cycles PD as defined by RECIST criteria Excessive toxicity according to prespecified criteria Toxicity requiring topotecan delay > 2 weeks or bevacizumab delay > 2 months Topotecan-related toxicities requiring > 2 dose reductions Treatment continued until 1 of the following events Single arm, 2-site phase II trial OS: Patients With Platinum-Resistant Ovarian Cancer (N = 30) McGonigle KF, et al. ASCO 2008. Abstract 5551. 0.0 .25 .50 .75 1.0 Patients Surviving (%) Time (Mos) 0 2 4 6 8 10 12 14 16 18 20 Bev + Topotecan
Slide 67 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days GC vs TC Induction Regimens Followed by T Consolidation: Response Rates Gordon A, et al. ASCO 2008. Abstract 5536. *CR required a normalized CA-125. GC vs TC Induction Regimens Followed by T Consolidation: Pt-Based Toxicity Gordon A, et al. ASCO 2008. Abstract 5536. Conventional vs Dose-Dense TC (NOVEL): Study Design Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO 2008. Abstract 5506. P = .72 Evaluated by WHO criteria Conventional vs Dose-Dense TC (NOVEL): Clinical Responses Isonishi S, et al. ASCO 2008. Abstract 5506. Conventional vs Dose-Dense TC (NOVEL): PFS 0.0 0.2 0.4 0.6 0.8 1.0 0 12 30 54 Mos From Randomization Proportion Surviving Progression Free 0.1 0.3 0.5 0.7 0.9 6 18 42 24 48 36 Isonishi S, et al. ASCO 2008. Abstract 5506. dd-TC c-TC Ovarian Carcinoma: Clinical Course Symptoms Diagnosis Chemotherapy #1 Staging Primary cytoreduction Interval Cytoreduction Progression Chemo #2 Chemo #3+ Supportive Care Death Consolidation/ Maintenance Cure Secondary Cytoreduction Second-Look Goals of Treatment: Relapsed Ovarian Cancer Prolong Survival Delay Time to Progression Control Disease-Related Symptoms Minimize Treatment-Related Symptoms Maintain or Improve Quality of Life Issues Impacting Therapy for Recurrent Ovarian Cancer Treatment-free interval Impact of consolidation/maintenance therapy Number of prior regimens Response to prior therapy Toxicity from prior therapy Prior use of growth factors Transfusion requirements Neuropathy Volume and site(s) of disease Ascites/GI symptoms Performance status Surveillance Options for Ovarian Cancer Patients in Remission Second-look laparotomy Physical examination Include pelvic examination CA-125 Imaging CT scan MRI? PET scan? CT = computed tomography MRI = magnetic resonance imaging PET = positron emission tomography Ovarian Cancer: How is Relapse Defined? Continuous rise in CA-125 CA-125 above 100 Radiographic recurrence Symptomatic recurrence Physical examination findings Combination of above When Does Ovarian Cancer Recur? Carb = carboplatin; Cis = cisplatin; Doc = docetaxel; pac = paclitaxel; GOG = Gynecologic Oncology Group; IP = intraperitoneal; Pac = paclitaxel Active Agents in Ovarian Cancer Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Refractory P R I M A R Y T R E A T M E N T Resistant Sensitive 0 3 6 12 18 24 Months “Very Sensitive” Ovarian Cancer at First Relapse Definition of Sensitivity Defined as measurable recurrence, not biochemical (CA-125) recurrence ICON 4 Schema Relapsed ovarian or primary Peritoneal requiring chemotherapy Previous platinum-based chemotherapy Conventional platinum-based chemotherapy Paclitaxel plus platinum chemotherapy R A N D O M I Z E Prior chemotherapy Carboplatin (31%) Paclitaxel/platinum (40%) Other (30%) TFI > 12 months for 75% Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group TFI = treatment-free interval ICON 4 Response (Difference of 12%; 95% CI -0.1% to 24%; p=0.06) CR = complete response; ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum; PR = partial response; Parmar MK, et al. Lancet. 2003;361:2099-2106. Proportion alive and progression-free 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Patients at risk Pac-Plat 392 179 52 25 17 Plat 410 157 45 17 7 Years from randomization Hazard ratio = 0.76 (95% CI 0.66 - 0.89; p < 0.001) Absolute difference at 1 year = 10% (40% to 50%; 95% CI 4% to 15%) Ovarian Carcinoma: ICON 4 Progression-Free Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum Hazard ratio = 0.82 (95% CI 0.69 - 0.97; p = 0.023) Absolute difference 2 years = 7% (50% to 57%; 95% CI 1% to 12%) Patients at risk Pac-Plat 392 306 167 96 43 Plat 410 295 150 68 33 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Years from randomization Proportion alive ICON 4: Overall Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum R A N D O M I Z E Gemcitabine 1,000 mg/m2 days 1 + 8 Plus Carboplatin AUC 4 day 1 every 21 days × 6 Recurrent ovarian cancer 6+ months after platinum Strata PFI (6 - 12, >12 months) 1st-line therapy (platinum ± paclitaxel) Measurable vs evaluable Primary endpoint = PFS Gem/Carbo vs Carbo: Design Carboplatin AUC 5 day 1 every 21 days × 6 Carbo = carboplatin Gem = gemcitabine PFI = progression-free interval PFS = progression-free survival Pfisterer J, et al. J Clin Oncol. 2006; 24:4699-4707. AGO OVAR 2.5 Primary Endpoint: Progression-Free Survival GCb: median = 8.6 mo Censoring: 12.4% Cb: median = 5.8 mo Censoring: 12.9% Cb Arm (N=178) GCb Arm (N=178) Log-rank p-value = 0.0038 Unadjusted HR = 0.72 (0.57 to 0.90) Adjusted HR* = 0.71 (0.57 to 0.89) * Adjusted for PFI, Tumor size Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin AGO OVAR 2.5 Efficacy Results: Overall Survival 0.0 0.8 0.2 0.3 0.4 0.5 0.6 0.7 0.9 1.0 0.1 0 6 12 18 60 54 48 42 36 30 24 Proportion Surviving Months Median = 18.0 mo Censoring: 18.5% Median = 17.3 mo Censoring: 22.5% Cb Arm (N=178) GCb Arm (N=178) * Adjusted for PFI, Tumor size and performance status Log-rank p-value = 0.7349 Unadjusted HR = 0.96 (0.75 to 1.23) Adjusted* HR = 0.92 (0.72 to 1.16) Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: < 0.5 cm > 0.5-2 cm R A N D O M I Z E 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 Completed (Target accrual 864 pts) PFS 1° endpoint Farletuzumab (MORAb-003) in Platinum-Sensitive EOC: Study Rationale FRA is overexpressed in most EOC; largely absent from normal tissue Binding of MORAb-003 to FRA blocks phosphorylation by Lyn kinase; mediates FRA-expressing tumor cell killing; suppresses tumor growth in xenograft models Phase I study of single agent MORAb-003 demonstrated no significant adverse effects and suggested efficacy in platinum-resistant EOC MORAb-003 in Platinum-Sensitive EOC: Phase II Study Design Patients with platinum-sensitive EOC in first relapse after first remission of 6-18 months duration with evaluable disease by CA125 (Enrolled N = 58; eligible n = 54) Asymptomatic relapse Single-agent Farletuzumab until progression (n = 28) Original Carbo/Taxane regimen + Farletuzumab for 6 cycles (n = 26) Symptomatic relapse Compare lengths of first and second remissions Farletuzumab maintenance Rx for responders Single-agent ORR Combination ORR Armstrong DK, et al. ASCO 2008. Abstract 5500. All arms MORAb-003: 100 mg/m2 weekly Run-in phase with 6 subjects at 37.5 and 6 at 62.5 mg/m2 Combination therapy arm every 21 days x 6 cycles Carboplatin: AUC 5-6 Taxane Paclitaxel 175 mg/m2 over 3 hours or Docetaxel 75 mg/m2 MORAb-003-002 Phase II: Treatment Arms Armstrong DK, et al. ASCO 2008. Abstract 5500. Comparison of First vs Second Remission Length: n = 6 Data as of May 5, 2008. Armstrong DK, et al. ASCO 2008. Abstract 5500. MORAb-003-002 Clinical Responses by RECIST (Combination Therapy) Best response CR: 7.4% PR: 62.9% SD: 25.9% PD: 3.7% Based on all scans submitted as of December 3, 2007 (~ 30%) By independent central reader MORAb-003 well tolerated; no increase observed in toxicity profile in combination arm ORR: 70.3% Patient benefit: 96.3% Armstrong DK, et al. ASCO 2008. Abstract 5500. Secondary Cytoreduction Controversial Inconsistent definitions Benefit appears confined to patients likely to respond to additional chemo: >12 month PFI Isolated site of recurrence Disease completely resectable Kidney Resected Liver Diaphragm Kidney Vena Cava Tumor Mass Renal Vein PFI = progression-free interval TTP mos >12 >12 >12 >17.5 >36 >24 12-24 >24 Ovarian Cancer Secondary Cytoreduction: Post-Surgery Survival Author Janicke Segna Zang Gadducci Eisenkop Munkarah Scarabelli Tay Total/Range Year 1992 1993 2000 2000 2000 2001 2001 2002 N 30 100 60 30 114 25 148 46 553 Survival Median mos 16 16.6 13 21 16.8 26 13-26 TTP mos <12 <12 <12 <17.5 <12 <24 <12 <12 Survival Median mos 8 8.8 8 15 25 42 12 6 6-42 Survival Median mos (P) 29 (0.002) 22.9 (0.007) 12 (0.02) 25 (0.04) 56.8 (0.005) 57 (NS) 32 (0.001) 39 (0.001) 12-56 TTP = time to progression GOG 213- PI Robert Coleman Surgical Candidate? Recurrent ovarian or peritoneal cancer TFI >6 mos YES NO Surgery No surgery Carboplatin + Paclitaxel Carboplatin + Paclitaxel + Bevacizumab + Bevacizumab Maintenance Randomize to Chemotherapy GOG = Gynecologic Oncology Group TFI = treatment-free interval Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Recent Phase II GOG Studies in Platinum-Resistant Ovarian Cancer Study Agents Response/comm 126-B CDDP & Cyclosporine-A 3/23 (13%) Inactive 126-C Hexamethylmelamine 3/30 (10%) Inactive 126-D Pyrazoloacridine 2/24 (8.4%) Inactive 126-E PSC833 + paclitaxel 1/16 (6%) Inactive 126-G CI-958 1/25 (4%) Inactive 126-H Topotecan (24 h) 1/25 (4%) Inactive 126-I 9-amino-camptothecin 8/58 (14%) Moderate 126-J Docetaxel 13/58 (22%) Active (post-paclitaxel) Bookman MA. Semin Oncol 2002;29(suppl 1):20-31. CDDP = c/s-diamminedichloroplatinum (cisplatin) GOG = gynecologic oncology group Recent Phase II GOG Studies in Platinum-Resistant Ovarian Cancer Study Agents Response/comm 126-K Oxaliplatin 1/25 (4%) Inactive 126-L Gemcitabine/CDDP 9/57 (16%) Moderate 126-M Ixabepilone 7/50 (14%) Moderate 126-N Paclitaxel weekly 10/48 (21%) Active (post-paclitaxel) 126-O Triapine-CDDP Not Feasible 126-P Paclitaxel & Celecoxib Closed Early 126-Q Pemetrexed 10/48 (21%) Active 126-R Abraxane Accrual in Progress Bookman MA. Semin Oncol 2002;29(suppl 1):20-31. CDDP = c/s-diamminedichloroplatinum (cisplatin) GOG = gynecologic oncology group Pemetrexed in Platinum-Resistant EOC: Phase II GOG Study Schema Miller DS, et al. ASCO 2008. Abstract 5524. Patients with persistent or recurrent platinum-resistant EOC or primary peritoneal cancer who have failed on higher priority treatment protocols Pemetrexed 900 mg/m2 IV every 21 days for 1 cycle; patients who have received previous radiotherapy will initiate pemetrexed at level I reduction dose until disease progression or adverse effect prohibits further therapy Phase II GOG Study Evaluation of Pemetrexed: Clinical Responses Miller DS, et al. ASCO 2008. Abstract 5524. *1 patient remains on therapy. Cochrane Review of Tamoxifen for Relapsed Ovarian Cancer 13 studies (11non-randomized series, 1 non-randomized phase II and 1 randomized trial) 59 of 568 women (10.4%) treated with tamoxifen achieved an objective response (RR) RR varied from 0% to 56% Stable disease, for variable periods of 4 weeks or more, in 109 of 356 (30.6%) from 8 studies Not enough data to assess duration of RR, survival, or the effect of tamoxifen on quality of life No reliable data from randomized controlled trials Williams CJ. Cochrane Database Syst Rev. 2000;(2):CD001034. RR = response rate GOG Experience GOG 160: Trastuzumab GOG 170 Human Interleukin-12 (170B) Lapatinib (170G) Gefitinib (170C) Vorinostat (170H) Bevacizumab (170D) Temsirolimus (170I) Imatinib (170E) Enzastaurin (170J) Bay 43-9006 (170F) Mifepristone (170K) Ongoing GOG Phase II Effort Insufficiently Active Too Early Active GOG = Gynecologic Oncology Group Antiangiogenic Agents in Testing for Treatment of Ovarian Cancer Agent Targets Ligand binding: Bevacizumab VEGF-A VEGF-Trap VEGF-A, -B, -C, -D, -E, PIGF-1 and -2 Receptor binding: Volociximab 51 integrin IMC-1121B VEGFR-2 Receptor tyrosine kinase inhibition: Valatanib VEGFR-1, -2, -3, PDGFR, and c-kit Sunitinib PDGFR, VEGFR-1, -2, -3, c-kit, Flt-3 AMG-706 VEGFR-1, -2, -3, PDGFR, and c-kit Sorafenib Raf, VEGFR-2, -3, Flt-3, c-kit, PDGFR-  Non-receptor kinase inhibition: Temsirolimus, everolimus mTOR Enzastaurin PKC-  Dasatinib Src kinase EGFR = epidermal growth factor receptor; Mab = monoclonal antibody; mTOR = mammalian target of rapamycin; PDGF-R = platelet derived growth factor receptor; PKC-b = protein kinase C-beta; VEGF = vascular endothelial growth factor Rationale for Targeting VEGF in Treatment of Epithelial Ovarian Cancer Human tumors VEGF over-expressed in epithelial ovarian cancers, associated with Ascites formation Malignant progression Poor prognosis Preclinical models of solid tumors Anti-VEGF therapy: Slowing of tumor progression Resolution of malignant effusions Synergy with cytotoxic agents Han ES, et al. Expert Rev Anticancer Ther. 2007;7(10):1339-1345. Burger RA. J Clin Oncol. 2007;25(20):2902-2908. VEGF = vascular endothelial growth factor Agents Targeting the VEGF Pathway VEGFR-2 VEGFR-1 Endothelial Cell Small-Molecule Inhibitors VEGF Soluble VEGFRs (VEGF-TRAP) Podar K, et al. Blood. 2005;105(4):1383-1395. VEGF = vascular endothelial growth factor VEGFR = VEGF receptor Bevacizumab - Toxicity Proteinuria (usually G1 – G2) Muco-cutaneous hemorrhage Common – G1 epistaxis Rare (possibly life-threatening) G2-G4 tumor site hemorrhage (primarily lung cancer trials) Arterial thromboembolism Uncommon (3% - 5%) Risk factors: age > 65, prior arterial TE Risk of venous thromboembolism not increased GI perforation – wound healing Perforation uncommon (2% - 4% in solid tumor population) Wound dehiscence rate 1% Han ES, et al. Expert Rev Anticancer Ther. 2007;7(10):1339-1345. Burger RA. J Clin Oncol. 2007;25(20):2902-2908. G1, G2 = immunoglobulins GI = gastrointestinal TE = thromboembolism Phase II Studies of Bevacizumab in Ovarian Cancer Cannistra SA, et al. J Clin Oncol. 2007;25(33):5180-5186. Burger RA, et al. J Clin Oncol. 2007;25(33):5165-5171. Garcia AA, et al. J Clin Oncol. 2008;26(1):76-82. CR = complete response GI = gastrointestinal PR = partial response GI Perforations with Bevacizumab in Ovarian Cancer Han E, et al. Gynecol Oncol. 2007;105(1):3-6. GI = gastrointestinal NCI Registered Phase II Trials: Anti-VEGF + Cytotoxic * Front Line **Carboplatin and Paclitaxel Bev = bevacizumab; Carbo = carboplatin Gem = gemcitabine; IP = intraperitoneal Mab = monoclonal antibody; Ox = Oxaliplatin; VEGF = vascular endothelial growth factor NCI Registered Phase II Trials: VEGF + EGFR Inhibitors Bev = bevacizumab EGFR = epidermal growth factor receptor Mab = monoclonal antibody VEGF = vascular endothelial growth factor NCI Registered Phase II Trials: Other Anti-Angiogenic Agents CT = chemotherapy; GOG = gynecologic oncology group; EGFR = epidermal growth factor receptor; Mab = monoclonal antibody; PDGF-R = platelet derived growth factor receptor; PKC-b = protein kinase C-beta; TKI = tyrosine kinase inhibitor Bev + Topotecan in Platinum Refractory Ovarian Cancer: Study Design McGonigle KF, et al. ASCO 2008. Abstract 5551. Platinum-refractory OC; recurrence < 6 mos of platinum therapy; received max of 2 previous chemotherapy regimens (N = 40) Bevacizumab 10 mg/kg Days 1, 15 + Topotecan 4 mg/m2 Days 1, 8, 15 for 28-day cycles PD as defined by RECIST criteria Excessive toxicity according to prespecified criteria Toxicity requiring topotecan delay > 2 weeks or bevacizumab delay > 2 months Topotecan-related toxicities requiring > 2 dose reductions Treatment continued until 1 of the following events Single arm, 2-site phase II trial OS: Patients With Platinum-Resistant Ovarian Cancer (N = 30) McGonigle KF, et al. ASCO 2008. Abstract 5551. 0.0 .25 .50 .75 1.0 Patients Surviving (%) Time (Mos) 0 2 4 6 8 10 12 14 16 18 20 Bev + Topotecan PFS in Patients Receiving Bev + Topotecan by No. of Prior Regimens McGonigle KF, et al. ASCO 2008. Abstract 5551. 0.0 .25 .50 .75 1.0 0 4 10 20 Time (Mos) Patients Without PD (%) 2 6 14 18 16 8 12 Patients with 1 previous therapy (n = 16) Patients with 2 previous therapies (n = 14) P = .040 by log rank test
Slide 68 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS = progression-free survival RR = relative risk Ovarian cancer stage Ic-IV Primary peritoneal cancer N = 1077 Carboplatin AUC 5, + docetaxel 75 mg/m2 (1 h) Q3W x 6 Carboplatin AUC 5, + paclitaxel 175 mg/m2 (3 h) Q3W x 6 R A N D O M I Z E SCOTROC: Trial Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. SCOTROC = Scottish Randomized Trial in Ovarian Cancer Q3W = once every 3 weeks SCOTROC: Results Parameter DC PC Response (standard) 59% 60% Response (CA-125) 76% 77% Progression-free survival 15 mos 14.8 mos Overall survival at 24 months 64% 69% Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin SCOTROC = Scottish Randomized Trial in Ovarian Cancer SCOTROC: Conclusion PC vs DC: PC the Standard Overall toxicity clearly favors paclitaxel regimen for all except neurotoxicity and arthralgia/myalgia Differences in neurotoxicity related to taxane in each regimen should be reversible Myelotoxicity worse with docetaxel and prevents use of what may be optimal dose of carboplatin Paclitaxel/carboplatin remains the standard of care in order to maximize efficacy, minimize life-threatening toxicity Vasey PA, et al. J Natl Cancer Inst. 2004;96(22):1682-1691. DC = docetaxel-carboplatin PC = paclitaxel-carboplatin Regimen I (control) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen II (triplet A) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Gemcitabine 800 mg/m2/d IV d 1, 8 Regimen III (triplet B) Paclitaxel 135 mg/m2 IV (3 h) d 1 Carboplatin AUC 5 IV d 1 Doxil 30 mg/m2 IV d 1 Every other cycle Regimen IV (sequential module A) Carboplatin AUC 5 IV d 3 Topotecan 1.25 mg/m2/d IV d 1-3 Regimen V (sequential module A) Carboplatin AUC 6 IV d 8 Gemcitabine 1000 mg/m2/d IV d 1, 8 Regimen IV (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Regimen V (sequential module B) Paclitaxel 175 mg/m2 IV (3 h) d 1 Carboplatin AUC 6 IV d 1 Randomization All patients Equal proportions on each regimen Primary end points: PFS, OS, RR GOG 182-ICON5 International Study for Stage III/IV Regimens I, II, and III: 8 cycles, 21-d cycle interval Regimens IV and V: 4 cycles, 21-d cycle interval Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. GOG = Gynecologic Oncology Group; ICON = International Collaborative Ovarian Neoplasm Group; OS = overall survival; PFS = progression-free survival; RR = response rate GOG0182-ICON5: Progression-Free Survival Median PFS and HR (95% CI) 16.1 1.000 16.4 0.990 (0.884-1.107) 16.4 0.998 (0.891-1.117) 15.3 1.094 (0.979-1.224) 15.4 1.052 (0.940-1.176) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated liposomal doxorubicin G = gemcitabine P = paclitaxel; PFS = progression-free survival T = topotecan GOG0182-ICON5: Overall Survival Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244) 40.2 1.035 (0.888-1.206) Bookman MA. J Clin Oncol. 2006;24(18S):Abstract 5002. C = carboplatin D = pegylated lipososomal doxorubicin G = gemcitabine P = paclitaxel; 0S = overall survival T = topotecan Current GOG Frontline Trial > Microscopic residual EOC, PPC cancer Paclitaxel Carboplatin Placebo Paclitaxel Carboplatin Bevacizumab Paclitaxel Carboplatin Bevacizumab Bevacizumab ×16 cycles GOG 218 N = 2,000 patients Survival, PFS primary endpoints Biologic & QOL endpoints Placebo ×16 cycles Placebo ×16 cycles EOC = epithelial ovarian cancer FT = fallopian tube GOG = Gynecologic Oncology Group PFS = progression-free survival PPC = primary peritoneal cancer QOL = quality of life IDS Allowed IDS With Response or Stable Disease Repeat Chemotherapy SLS allowed Repeat Chemotherapy SLS allowed EORTC-55971 The EORTC Groups Web site. Gynaecological Cancer Group Active Study Protocols. http://groups.eortc.be/gcg/studyprotocols.htm#55971. Accessed June 12, 2007. EORTC = European Organisation for Research and Treatment of Cancer IDS = Interval Debulking Surgery SLS = Second-Look Surgery Cytoreductive Surgery + 3 Courses Platinum-Based Chemotherapy Upfront Debulking Surgery vs Neoadjuvant Chemotherapy Stage IIIc or IV Epithelial Ovarian Carcinoma 3 Courses Platinum-Based Chemotherapy GC vs TC Induction Regimens Followed by T Consolidation: Study Design Gordon A, et al. ASCO 2008. Abstract 5536. Anything other than CR (PR, SD, PD) Anything other than CR (PR, SD, PD) Clinical CR Single-agent crossover Paclitaxel 175 mg/m2 Day 1 Single-agent crossover Gemcitabine 1000 mg/m2 Days 1, 8 Elective T Consolidation Therapy Paclitaxel 135 mg/m2 every 28 days for 12 cycles Histologic diagnosis and prior resection of stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma Induction GC Gemcitabine 1000 mg/m2 Days 1, 8 + Carboplatin AUC 5 Day 1 x 6 cycles every 21 days Induction TC Paclitaxel 175 mg/m2 Day 1 + Carboplatin AUC 6 Day 1 x 6 cycles q 21 days GC vs TC Induction Regimens Followed by T Consolidation: Response Rates Gordon A, et al. ASCO 2008. Abstract 5536. *CR required a normalized CA-125. GC vs TC Induction Regimens Followed by T Consolidation: Pt-Based Toxicity Gordon A, et al. ASCO 2008. Abstract 5536. Conventional vs Dose-Dense TC (NOVEL): Study Design Ovarian epithelial, primary peritoneal, or fallopian tube cancer with FIGO stage II-IV Conventional TC (c-TC) Paclitaxel 180 mg/m2 Day 1 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Dose-dense weekly TC (dd-TC) Paclitaxel 80 mg/m2 Days 1, 8, 15 + Carboplatin AUC 6.0 Day 1 every 21 days for 6-9 cycles Stratified by residual disease ≤ 1 cm vs > 1 cm; FIGO stage II vs III vs IV; histology: clear cell/mucinous vs serous/others Isonishi S, et al. ASCO 2008. Abstract 5506. P = .72 Evaluated by WHO criteria Conventional vs Dose-Dense TC (NOVEL): Clinical Responses Isonishi S, et al. ASCO 2008. Abstract 5506. Conventional vs Dose-Dense TC (NOVEL): PFS 0.0 0.2 0.4 0.6 0.8 1.0 0 12 30 54 Mos From Randomization Proportion Surviving Progression Free 0.1 0.3 0.5 0.7 0.9 6 18 42 24 48 36 Isonishi S, et al. ASCO 2008. Abstract 5506. dd-TC c-TC Ovarian Carcinoma: Clinical Course Symptoms Diagnosis Chemotherapy #1 Staging Primary cytoreduction Interval Cytoreduction Progression Chemo #2 Chemo #3+ Supportive Care Death Consolidation/ Maintenance Cure Secondary Cytoreduction Second-Look Goals of Treatment: Relapsed Ovarian Cancer Prolong Survival Delay Time to Progression Control Disease-Related Symptoms Minimize Treatment-Related Symptoms Maintain or Improve Quality of Life Issues Impacting Therapy for Recurrent Ovarian Cancer Treatment-free interval Impact of consolidation/maintenance therapy Number of prior regimens Response to prior therapy Toxicity from prior therapy Prior use of growth factors Transfusion requirements Neuropathy Volume and site(s) of disease Ascites/GI symptoms Performance status Surveillance Options for Ovarian Cancer Patients in Remission Second-look laparotomy Physical examination Include pelvic examination CA-125 Imaging CT scan MRI? PET scan? CT = computed tomography MRI = magnetic resonance imaging PET = positron emission tomography Ovarian Cancer: How is Relapse Defined? Continuous rise in CA-125 CA-125 above 100 Radiographic recurrence Symptomatic recurrence Physical examination findings Combination of above When Does Ovarian Cancer Recur? Carb = carboplatin; Cis = cisplatin; Doc = docetaxel; pac = paclitaxel; GOG = Gynecologic Oncology Group; IP = intraperitoneal; Pac = paclitaxel Active Agents in Ovarian Cancer Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Refractory P R I M A R Y T R E A T M E N T Resistant Sensitive 0 3 6 12 18 24 Months “Very Sensitive” Ovarian Cancer at First Relapse Definition of Sensitivity Defined as measurable recurrence, not biochemical (CA-125) recurrence ICON 4 Schema Relapsed ovarian or primary Peritoneal requiring chemotherapy Previous platinum-based chemotherapy Conventional platinum-based chemotherapy Paclitaxel plus platinum chemotherapy R A N D O M I Z E Prior chemotherapy Carboplatin (31%) Paclitaxel/platinum (40%) Other (30%) TFI > 12 months for 75% Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group TFI = treatment-free interval ICON 4 Response (Difference of 12%; 95% CI -0.1% to 24%; p=0.06) CR = complete response; ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum; PR = partial response; Parmar MK, et al. Lancet. 2003;361:2099-2106. Proportion alive and progression-free 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Patients at risk Pac-Plat 392 179 52 25 17 Plat 410 157 45 17 7 Years from randomization Hazard ratio = 0.76 (95% CI 0.66 - 0.89; p < 0.001) Absolute difference at 1 year = 10% (40% to 50%; 95% CI 4% to 15%) Ovarian Carcinoma: ICON 4 Progression-Free Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum Hazard ratio = 0.82 (95% CI 0.69 - 0.97; p = 0.023) Absolute difference 2 years = 7% (50% to 57%; 95% CI 1% to 12%) Patients at risk Pac-Plat 392 306 167 96 43 Plat 410 295 150 68 33 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 Years from randomization Proportion alive ICON 4: Overall Survival Parmar MK, et al. Lancet. 2003;361:2099-2106. ICON = International Collaborative Ovarian Neoplasm Group; Pac = paclitaxel; Plat = platinum R A N D O M I Z E Gemcitabine 1,000 mg/m2 days 1 + 8 Plus Carboplatin AUC 4 day 1 every 21 days × 6 Recurrent ovarian cancer 6+ months after platinum Strata PFI (6 - 12, >12 months) 1st-line therapy (platinum ± paclitaxel) Measurable vs evaluable Primary endpoint = PFS Gem/Carbo vs Carbo: Design Carboplatin AUC 5 day 1 every 21 days × 6 Carbo = carboplatin Gem = gemcitabine PFI = progression-free interval PFS = progression-free survival Pfisterer J, et al. J Clin Oncol. 2006; 24:4699-4707. AGO OVAR 2.5 Primary Endpoint: Progression-Free Survival GCb: median = 8.6 mo Censoring: 12.4% Cb: median = 5.8 mo Censoring: 12.9% Cb Arm (N=178) GCb Arm (N=178) Log-rank p-value = 0.0038 Unadjusted HR = 0.72 (0.57 to 0.90) Adjusted HR* = 0.71 (0.57 to 0.89) * Adjusted for PFI, Tumor size Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin AGO OVAR 2.5 Efficacy Results: Overall Survival 0.0 0.8 0.2 0.3 0.4 0.5 0.6 0.7 0.9 1.0 0.1 0 6 12 18 60 54 48 42 36 30 24 Proportion Surviving Months Median = 18.0 mo Censoring: 18.5% Median = 17.3 mo Censoring: 22.5% Cb Arm (N=178) GCb Arm (N=178) * Adjusted for PFI, Tumor size and performance status Log-rank p-value = 0.7349 Unadjusted HR = 0.96 (0.75 to 1.23) Adjusted* HR = 0.92 (0.72 to 1.16) Pfisterer J, et al. J Clin Oncol. 2006;24:4699-4707. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie; GCb = gemcitabine; Cb = carboplatin GCIG CALYPSO Trial Ovarian Cancer Platinum Sens. Stratify: < 0.5 cm > 0.5-2 cm R A N D O M I Z E 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 Completed (Target accrual 864 pts) PFS 1° endpoint Farletuzumab (MORAb-003) in Platinum-Sensitive EOC: Study Rationale FRA is overexpressed in most EOC; largely absent from normal tissue Binding of MORAb-003 to FRA blocks phosphorylation by Lyn kinase; mediates FRA-expressing tumor cell killing; suppresses tumor growth in xenograft models Phase I study of single agent MORAb-003 demonstrated no significant adverse effects and suggested efficacy in platinum-resistant EOC MORAb-003 in Platinum-Sensitive EOC: Phase II Study Design Patients with platinum-sensitive EOC in first relapse after first remission of 6-18 months duration with evaluable disease by CA125 (Enrolled N = 58; eligible n = 54) Asymptomatic relapse Single-agent Farletuzumab until progression (n = 28) Original Carbo/Taxane regimen + Farletuzumab for 6 cycles (n = 26) Symptomatic relapse Compare lengths of first and second remissions Farletuzumab maintenance Rx for responders Single-agent ORR Combination ORR Armstrong DK, et al. ASCO 2008. Abstract 5500. All arms MORAb-003: 100 mg/m2 weekly Run-in phase with 6 subjects at 37.5 and 6 at 62.5 mg/m2 Combination therapy arm every 21 days x 6 cycles Carboplatin: AUC 5-6 Taxane Paclitaxel 175 mg/m2 over 3 hours or Docetaxel 75 mg/m2 MORAb-003-002 Phase II: Treatment Arms Armstrong DK, et al. ASCO 2008. Abstract 5500. Comparison of First vs Second Remission Length: n = 6 Data as of May 5, 2008. Armstrong DK, et al. ASCO 2008. Abstract 5500. MORAb-003-002 Clinical Responses by RECIST (Combination Therapy) Best response CR: 7.4% PR: 62.9% SD: 25.9% PD: 3.7% Based on all scans submitted as of December 3, 2007 (~ 30%) By independent central reader MORAb-003 well tolerated; no increase observed in toxicity profile in combination arm ORR: 70.3% Patient benefit: 96.3% Armstrong DK, et al. ASCO 2008. Abstract 5500. Secondary Cytoreduction Controversial Inconsistent definitions Benefit appears confined to patients likely to respond to additional chemo: >12 month PFI Isolated site of recurrence Disease completely resectable Kidney Resected Liver Diaphragm Kidney Vena Cava Tumor Mass Renal Vein PFI = progression-free interval TTP mos >12 >12 >12 >17.5 >36 >24 12-24 >24 Ovarian Cancer Secondary Cytoreduction: Post-Surgery Survival Author Janicke Segna Zang Gadducci Eisenkop Munkarah Scarabelli Tay Total/Range Year 1992 1993 2000 2000 2000 2001 2001 2002 N 30 100 60 30 114 25 148 46 553 Survival Median mos 16 16.6 13 21 16.8 26 13-26 TTP mos <12 <12 <12 <17.5 <12 <24 <12 <12 Survival Median mos 8 8.8 8 15 25 42 12 6 6-42 Survival Median mos (P) 29 (0.002) 22.9 (0.007) 12 (0.02) 25 (0.04) 56.8 (0.005) 57 (NS) 32 (0.001) 39 (0.001) 12-56 TTP = time to progression GOG 213- PI Robert Coleman Surgical Candidate? Recurrent ovarian or peritoneal cancer TFI >6 mos YES NO Surgery No surgery Carboplatin + Paclitaxel Carboplatin + Paclitaxel + Bevacizumab + Bevacizumab Maintenance Randomize to Chemotherapy GOG = Gynecologic Oncology Group TFI = treatment-free interval Effect of Platinum-Free Interval on Response Rate Markman M, et al. J Clin Oncol. 1991;9(3):389-393. Gore ME, et al. Gynecol Oncol. 1990;36:207-211. Blackledge G, et al. Br J Cancer. 1989;59:650-653. Recent Phase II GOG Studies in Platinum-Resistant Ovarian Cancer Study Agents Response/comm 126-B CDDP & Cyclosporine-A 3/23 (13%) Inactive 126-C Hexamethylmelamine 3/30 (10%) Inactive 126-D Pyrazoloacridine 2/24 (8.4%) Inactive 126-E PSC833 + paclitaxel 1/16 (6%) Inactive 126-G CI-958 1/25 (4%) Inactive 126-H Topotecan (24 h) 1/25 (4%) Inactive 126-I 9-amino-camptothecin 8/58 (14%) Moderate 126-J Docetaxel 13/58 (22%) Active (post-paclitaxel) Bookman MA. Semin Oncol 2002;29(suppl 1):20-31. CDDP = c/s-diamminedichloroplatinum (cisplatin) GOG = gynecologic oncology group Recent Phase II GOG Studies in Platinum-Resistant Ovarian Cancer Study Agents Response/comm 126-K Oxaliplatin 1/25 (4%) Inactive 126-L Gemcitabine/CDDP 9/57 (16%) Moderate 126-M Ixabepilone 7/50 (14%) Moderate 126-N Paclitaxel weekly 10/48 (21%) Active (post-paclitaxel) 126-O Triapine-CDDP Not Feasible 126-P Paclitaxel & Celecoxib Closed Early 126-Q Pemetrexed 10/48 (21%) Active 126-R Abraxane Accrual in Progress Bookman MA. Semin Oncol 2002;29(suppl 1):20-31. CDDP = c/s-diamminedichloroplatinum (cisplatin) GOG = gynecologic oncology group Pemetrexed in Platinum-Resistant EOC: Phase II GOG Study Schema Miller DS, et al. ASCO 2008. Abstract 5524. Patients with persistent or recurrent platinum-resistant EOC or primary peritoneal cancer who have failed on higher priority treatment protocols Pemetrexed 900 mg/m2 IV every 21 days for 1 cycle; patients who have received previous radiotherapy will initiate pemetrexed at level I reduction dose until disease progression or adverse effect prohibits further therapy Phase II GOG Study Evaluation of Pemetrexed: Clinical Responses Miller DS, et al. ASCO 2008. Abstract 5524. *1 patient remains on therapy. Cochrane Review of Tamoxifen for Relapsed Ovarian Cancer 13 studies (11non-randomized series, 1 non-randomized phase II and 1 randomized trial) 59 of 568 women (10.4%) treated with tamoxifen achieved an objective response (RR) RR varied from 0% to 56% Stable disease, for variable periods of 4 weeks or more, in 109 of 356 (30.6%) from 8 studies Not enough data to assess duration of RR, survival, or the effect of tamoxifen on quality of life No reliable data from randomized controlled trials Williams CJ. Cochrane Database Syst Rev. 2000;(2):CD001034. RR = response rate GOG Experience GOG 160: Trastuzumab GOG 170 Human Interleukin-12 (170B) Lapatinib (170G) Gefitinib (170C) Vorinostat (170H) Bevacizumab (170D) Temsirolimus (170I) Imatinib (170E) Enzastaurin (170J) Bay 43-9006 (170F) Mifepristone (170K) Ongoing GOG Phase II Effort Insufficiently Active Too Early Active GOG = Gynecologic Oncology Group Antiangiogenic Agents in Testing for Treatment of Ovarian Cancer Agent Targets Ligand binding: Bevacizumab VEGF-A VEGF-Trap VEGF-A, -B, -C, -D, -E, PIGF-1 and -2 Receptor binding: Volociximab 51 integrin IMC-1121B VEGFR-2 Receptor tyrosine kinase inhibition: Valatanib VEGFR-1, -2, -3, PDGFR, and c-kit Sunitinib PDGFR, VEGFR-1, -2, -3, c-kit, Flt-3 AMG-706 VEGFR-1, -2, -3, PDGFR, and c-kit Sorafenib Raf, VEGFR-2, -3, Flt-3, c-kit, PDGFR-  Non-receptor kinase inhibition: Temsirolimus, everolimus mTOR Enzastaurin PKC-  Dasatinib Src kinase EGFR = epidermal growth factor receptor; Mab = monoclonal antibody; mTOR = mammalian target of rapamycin; PDGF-R = platelet derived growth factor receptor; PKC-b = protein kinase C-beta; VEGF = vascular endothelial growth factor Rationale for Targeting VEGF in Treatment of Epithelial Ovarian Cancer Human tumors VEGF over-expressed in epithelial ovarian cancers, associated with Ascites formation Malignant progression Poor prognosis Preclinical models of solid tumors Anti-VEGF therapy: Slowing of tumor progression Resolution of malignant effusions Synergy with cytotoxic agents Han ES, et al. Expert Rev Anticancer Ther. 2007;7(10):1339-1345. Burger RA. J Clin Oncol. 2007;25(20):2902-2908. VEGF = vascular endothelial growth factor Agents Targeting the VEGF Pathway VEGFR-2 VEGFR-1 Endothelial Cell Small-Molecule Inhibitors VEGF Soluble VEGFRs (VEGF-TRAP) Podar K, et al. Blood. 2005;105(4):1383-1395. VEGF = vascular endothelial growth factor VEGFR = VEGF receptor Bevacizumab - Toxicity Proteinuria (usually G1 – G2) Muco-cutaneous hemorrhage Common – G1 epistaxis Rare (possibly life-threatening) G2-G4 tumor site hemorrhage (primarily lung cancer trials) Arterial thromboembolism Uncommon (3% - 5%) Risk factors: age > 65, prior arterial TE Risk of venous thromboembolism not increased GI perforation – wound healing Perforation uncommon (2% - 4% in solid tumor population) Wound dehiscence rate 1% Han ES, et al. Expert Rev Anticancer Ther. 2007;7(10):1339-1345. Burger RA. J Clin Oncol. 2007;25(20):2902-2908. G1, G2 = immunoglobulins GI = gastrointestinal TE = thromboembolism Phase II Studies of Bevacizumab in Ovarian Cancer Cannistra SA, et al. J Clin Oncol. 2007;25(33):5180-5186. Burger RA, et al. J Clin Oncol. 2007;25(33):5165-5171. Garcia AA, et al. J Clin Oncol. 2008;26(1):76-82. CR = complete response GI = gastrointestinal PR = partial response GI Perforations with Bevacizumab in Ovarian Cancer Han E, et al. Gynecol Oncol. 2007;105(1):3-6. GI = gastrointestinal NCI Registered Phase II Trials: Anti-VEGF + Cytotoxic * Front Line **Carboplatin and Paclitaxel Bev = bevacizumab; Carbo = carboplatin Gem = gemcitabine; IP = intraperitoneal Mab = monoclonal antibody; Ox = Oxaliplatin; VEGF = vascular endothelial growth factor NCI Registered Phase II Trials: VEGF + EGFR Inhibitors Bev = bevacizumab EGFR = epidermal growth factor receptor Mab = monoclonal antibody VEGF = vascular endothelial growth factor NCI Registered Phase II Trials: Other Anti-Angiogenic Agents CT = chemotherapy; GOG = gynecologic oncology group; EGFR = epidermal growth factor receptor; Mab = monoclonal antibody; PDGF-R = platelet derived growth factor receptor; PKC-b = protein kinase C-beta; TKI = tyrosine kinase inhibitor Bev + Topotecan in Platinum Refractory Ovarian Cancer: Study Design McGonigle KF, et al. ASCO 2008. Abstract 5551. Platinum-refractory OC; recurrence < 6 mos of platinum therapy; received max of 2 previous chemotherapy regimens (N = 40) Bevacizumab 10 mg/kg Days 1, 15 + Topotecan 4 mg/m2 Days 1, 8, 15 for 28-day cycles PD as defined by RECIST criteria Excessive toxicity according to prespecified criteria Toxicity requiring topotecan delay > 2 weeks or bevacizumab delay > 2 months Topotecan-related toxicities requiring > 2 dose reductions Treatment continued until 1 of the following events Single arm, 2-site phase II trial OS: Patients With Platinum-Resistant Ovarian Cancer (N = 30) McGonigle KF, et al. ASCO 2008. Abstract 5551. 0.0 .25 .50 .75 1.0 Patients Surviving (%) Time (Mos) 0 2 4 6 8 10 12 14 16 18 20 Bev + Topotecan PFS in Patients Receiving Bev + Topotecan by No. of Prior Regimens McGonigle KF, et al. ASCO 2008. Abstract 5551. 0.0 .25 .50 .75 1.0 0 4 10 20 Time (Mos) Patients Without PD (%) 2 6 14 18 16 8 12 Patients with 1 previous therapy (n = 16) Patients with 2 previous therapies (n = 14) P = .040 by log rank test Best Response of Bev + Topotecan by No. of Prior Regimens McGonigle KF, et al. ASCO 2008. Abstract 5551.
Slide 69 - Judith K. Wolf, MD Professor • Department of Gynecologic Oncology • University of Texas M.D. Anderson Cancer Center • Houston, TX Treatment of Ovarian Cancer 21st Century and Beyond Judith K. Wolf Professor Gynecologic Oncology Ovarian Cancer: 2010 1/71 lifetime risk1 5-year survival rates (by year of diagnosis)2 1990-1992 42.5% 1993-1995 43.5% 1996-2003 45% Mortality relatively unchanged but statistically significant improvement in 5-year survival rates 1. SEER (Surveillance, Epidemiology, and End Results) Program Web site. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 22, 2007. 2. http://seer.cancer.gov/csr/1975_2004/results_merged/sect_21_ovary.pdf. Accessed April 22, 2007. Ovarian Cancer Staging Stage I - Limited to ovaries A. Unilateral ovary B. Bilateral ovaries C. Positive cytology Stage II - Limited to pelvis A. Extends to uterus or tubes B. other pelvic organs C. Positive cytology Stage III – Spread to upper abdomen or regional lymph nodes A. Microscopic spread B. Macroscopic < 2 cm C. Macroscopic > 2 cm Stage IV - Spread outside peritoneum, pleura or parenchymal liver metastases Ovarian Cancer FIGO Staging System Stage Description Incidence Survival I Confined to ovaries 20% 73% II Confined to pelvis 5% 45% III Confined to abdomen/ 58% 21% lymph nodes IV Distant metastases 17% <5% Jelic S, et al. Program and abstracts of the 27th Congress of the European Society for Medical Oncology; 2002; Nice, France. Mocharnuk R. Medscape Web site. http://www.medscape.com/viewarticle/444134. Accessed May 2, 2007. FIGO = International Federation of Gynecology and Obstetrics Ovarian Cancer Surgical Debulking and Staging Exploration Washings/ Ascites (Staging) TAH/ BSO Biopsies (Staging) Goals (Debulking) Assessment of extent of disease Optimal tumor reduction TAH = total abdominal hysterectomy BSO = bilateral salphingo-oophorectomy First-line Therapy – Standard Treatment Options Platinum + Taxane Chemotherapy (Carboplatin + Paclitaxel) Surgery with maximum cytoreduction effort <1cm residual disease Chemotherapy Standard front-line chemotherapy in the US today is carboplatin, AUC 6 to 7.5, paclitaxel 175 mg/m2 every 21 days for 6 cycles Result of several studies over last decade GOG 1111 and OV 102 - paclitaxel/cisplatin vs cyclophosphamide/cisplatin GOG 1583 and AGO OVAR-34 - carboplatin instead of cisplatin 1. McGuire WP, et al. N Engl J Med. 1996;334(1):1-6. 2. Piccart MJ, et al. J Natl Cancer Inst. 2000;92(9):699-708. 3. Ozols RF, et al. J Clin Oncol. 2003;21(17):3194-3200. 4. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. GOG = Gynecologic Oncology Group AGO = Arbeitsgemeinschaft Gynaekologische Onkologie The Role of Paclitaxel in First-line Therapy for Ovarian Carcinoma CAP = cyclophosphamide, doxorubicin, cisplatin GOG = Gynecologic Oncology Group ICON = International Collaborative Ovarian Neoplasm Group OS = overall survival PFS = progression-free survival 1. Muggia FM, et al. J Clin Oncol. 2000;18(1):106-115. 2. International Collaborative Ovarian Neoplasm Group. Lancet. 2002;360(9332):505-515. *CR/PR rates on paclitaxel monotherapy (42%) vs cisplatin regimens (67%), P <.001 The Schedule of Paclitaxel in First-line Therapy for Ovarian Carcinoma 1. Bookman MA, et al. Int J Gynecol Cancer. 2003;13(s2):149–155. 2. du Bois AD, et al. J Natl Cancer Inst. 2003;95(17):1320-1329. AGO = Arbeitsgemeinschaft Gynaekologische Onkologie CI = confidence interval GOG = Gynecologic Oncology Group HR = hazard ratio; OS = overall survival PFS =