Late effects of childhood cancer PowerPoint Presentation

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Late Effects of Childhood Cancer Pediatric Resident Education Series

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Cancer incidence Incidence: 1 in 7000 children, 0 to 14 year Likelihood of a young person reaching adulthood and being diagnosed with cancer during childhood: 1 in 300 for males 1 in 330 for females

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Cancer mortality Leading cause of disease-related mortality Ages 0-14 @ 1500-1600 deaths annually Ages 15-19 @ 700 deaths annually

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… decreasing

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Survival 1960 28% 5-years 1998 > 75% 5-years

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… increasing Especially for certain cancers ALL Brain AML Wilms’ NHL Bone

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As of the year 2000 Originally estimated that 1 in every 1000 individuals between 20 and 29 years was a survivor of childhood cancer… Current estimates: 1 in 900

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By the year 2010 As many as 1 in every 250 persons between 20 and 29 years will be a survivor of childhood cancer Almost ½ of these survivors are likely to have or to develop disabilities that alter quality of life

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Potential Late Effects (LE) Can look at these in several ways By disease By type(s) of treatment By system affected

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… by system affected Cardiac Pulmonary Gastrointestinal Urinary tract Musculoskeletal Neurologic Neuropsychologic Endocrine Gonadal Male Female Growth Thyroid Hematologic Immunologic Second Malignancies

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Cardiac Late Effects Acute < 365 days (mean 33) Chronic > 365 days – 19+ yrs Causes Chemotherapy Radiation Pericarditis Myocarditis LV Failure Arrhythmias Coronary Artery Disease Myocardial infarction Heart Failure Death

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Cardiac LE, cont. Most often associated with specific therapies May be progressive Chemotherapy Anthracyclines: Adriamycin, Daunomycin (most common) Frequently used in leukemia & solid tumors Risk for toxicity rises with increased doses Decreased contractility and/or increased afterload due to reduced wall thickness, arrhythmias, CHF Radiation therapy Direct effects: fibrosis, constrictive pericarditis, CAD May potentiate toxicity of chemotherapeutic agents

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Cardiac LE, cont. Chemotherapy Anthracyclines: Adriamycin, Daunomycin (most common) Frequently used in leukemia & solid tumors Risk for toxicity rises with increased doses Decreased contractility and/or increased afterload due to reduced wall thickness, arrhythmias, CHF Radiation therapy Direct effects: fibrosis, constrictive pericarditis, CAD May potentiate toxicity of chemotherapeutic agents Most often associated with specific therapies May be progressive

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Risk factors: Early cardiac toxicities Individual anthracycline dose > 50 mg/m2 Cumulative anthracycline dose > 550 mg/m2 Black race Female gender Trisomy 21 Treatment with amsacrine Rate of infusion NOT significant

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Risk factors: Late cardiac toxicities Less clearly defined – based on adult data Increases with cumulative anthracycline doses Higher risk with very young and very old Higher risk for female gender Schedule and rate of administration of drug: Lower risk with lower peak plasma level Higher risk with fast infusion, large individual doses

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How bad can it be? Incidence of anthracycline cardiotoxicity ranges from 0.4 - 9% May be progressive Predicted mortality rate as high as 61% in those patients who develop symptomatic cardiomyopathy

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Pathophysiology Chemotherapy Direct myocardial cellular damage with corresponding inflammatory response Cardiac Troponin-T levels may be a marker for myocardiocyte damage Radiation therapy Vascular damage and fibrosis

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Changes in therapy - cardiac Modified dose or dosage schedules Change therapy Minimize combination of cardiotoxic chemotherapy and radiation Addition of possible cardioprotectants Dexrazoxane (to decrease anthracycline toxicity) Long-term intervention studies Enalapril (reduce work of heart: afterload reduction)

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Pulmonary Late Effects Effects may be subtle Most commonly restrictive, with fibrosis Decrease in lung volume, compliance, DLCO Caused by both radiation & chemotherapy Risk for occurrence: Related to dose and/or duration of exposure Age at exposure Exposure to other contributing agents/factors

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Pulmonary LE - Radiation May be dose related Younger ages proportionate interference with growth of lung as well as growth of chest wall more common chronic fibrosis seen less often Older children & adults stimulation of septal fibroblasts  collagen pulmonary fibrosis with consequent loss of lung volume, compliance & decrease in DLCO

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Pulmonary Radiation Who gets this? Wilms’ metastatic to the lungs Hodgkin’s with mantle or nodal irradiation Lung carcinoma Scatter from cranio-spinal irradiation

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Pulmonary LE - Chemotherapy Most common: Bleomycin Dose dependent. May be immediate or late effect. Carmustine & Lomustine (Mustard analogues) Dose dependent. May be progressive. Less common: Cyclophosphamide, Melphalan, Busulfan High doses, not predictable Vinblastine, Methotrexate Chronic pneumonitis & fibrosis Related to length of use (i.e., longer use, increased risk)

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Contributing factors Pre-existing pulmonary disease e.g., asthma Superimposed infection Smoking

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Gastrointestinal Late Effects Gut mainly radiation-induced fibrosis, adhesions, enteritis, strictures Liver related to either chemotherapy and/or radiation Hepatitis Infectious agents also, e.g., Hepatitis C Veno-occlusive disease - may be chronic and lead to Fibrosis/cirrhosis

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Kidney/Urinary Tract Late Effects Radiation – depends on area treated Nephritis  renal failure Hemorrhagic cystitis Abnormal bladder function Chemotherapy – often agent specific Cisplatin Decreased function, Fanconi’s syndrome Cyclophosphamide, Ifosfamide Fanconi’s syndrome, hemorrhagic cystitis Surgery – depends on operation

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Musculoskeletal Late Effects Bone Scoliosis Atrophy or hypoplasia Avascular necrosis Osteoporosis Soft tissue Hypoplasia Pigmentation changes Dental Tooth development Cavities, pits, discoloration Related to: Radiation (dose, location, age) Radiation Steroids (length of use, age) Steroids, Methotrexate Radiation (dose, location, age) Radiation, some chemotherapy Radiation (dose & age) Chemotherapy

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Neuropsychologic and Neurologic Function Has been best studied in patients with CNS tumors or Acute Lymphoblastic Leukemia Incidence and type of problem depends on tumor type and location as well as timing and method of CNS treatment Incidence 8 – 50%

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Risk Factors Radiation (location, dosage) Intrathecal chemotherapy (methotrexate) Young age at diagnosis or therapy Location of brain tumor (brainstem, hypothalamus, 4th ventricle) ? Obtundation at diagnosis ? Need for permanent shunting ? Postoperative complications ? Female Sex ? Somnolence syndrome ? Socioeconomic status ? Parental education

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CNS problems - focal Often related to tumor location Radiation related – not usually reversible Cataracts Necrosis of optic nerve Chemotherapy related – some may be reversible Hearing loss: cisplatin, aminoglycoside antibiotics Cataracts: steroids Sensorimotor neuropathies: vincristine, vinblastine, etoposide, cytarabine, ifosfamide, cisplatin

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CNS problems - global More commonly secondary to treatment chronic necrotizing leukoencephalopathy radiation and/or intrathecal chemotherapy range of symptoms: slight impairment of attention and verbal memory dementia, dysarthria, dysphagia, ataxia, seizures, & coma Neurocognitive deficits

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Neurocognitive deficits Radiation therapy main cause Methotrexate & intrathecal chemo also implicated Include Learning difficulties Attention capacity non-verbal processing skills Are these progressive?

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Assessment tools Parent Questionnaires Observations by Teachers/Physicians IQ Screening Tests Formal Neuropsychological Assessment

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Endocrine Late Effects Probably the most common late effect Very complex system of regulation Many different endocrine glands all of which are inter-related Most are regulated from the pituitary itself regulated from elsewhere Typical endocrine disturbances Problems with puberty / fertility Abnormal growth Thyroid dysfunction

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Typical endocrine disturbances Problems with puberty / fertility Abnormal growth Thyroid dysfunction

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Males Damage may occur to either or both germ cells or Leydig cells Effects related to age & pubertal status May be caused by radiation therapy and/or chemotherapy Manifestations: decreased or absent sperm count; infertility delayed puberty, gynecomastia

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Germ Cells CHEMOTHERAPY Dose & drug dependent cyclophosphamide mechlorethane chlorambucil procarbazine Pubertal status not important May be reversible RADIATION Increased effect with higher dose Pubertal status not important Unlikely to be reversible

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Leydig cells CHEMOTHERAPY Slower growing than germ cells, so less likely affected Effects related to age: more likely to occur after puberty RADIATION Less radiosensitive Damage is dose-dependent, inversely related to age at Rx May have normal pubertal maturation but marginal function

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Radiation effects Germ cells Increased effect with higher dose Pubertal status not important Unlikely to be reversible Leydig cells Less radiosensitive Damage is dose-dependent, inversely related to age at Rx May have normal pubertal maturation but marginal function

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Chemotherapy effects Germ cells Dose & drug dependent Cyclophosphamide, mechlorethane, chlorambucil, procarbazine, May be reversible Pubertal status not important Leydig cells Slower growing, so less likely affected Effects related to age: more likely to occur after puberty

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Females Germ cell failure and loss of ovarian endocrine function usually occur together Age & dose dependent pre-pubertal ovaries relatively resistant to injury Caused by radiation and/or chemotherapy Manifestations: delayed puberty, amenorrhea, premature menopause, ovarian failure, infertility teratogenic effects on pregnancy (if Rx while pregnant) prematurity, low birth weight of offspring

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Offspring of the childhood cancer patient Are they at increased risk of congenital anomalies? Are they at an increased risk of cancer themselves? What about the children’s children?

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Typical endocrine disturbances Problems with puberty / fertility Abnormal growth usually lack of growth… Thyroid dysfunction

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Growth Children at increased risk any child who received CNS irradiation any child with ALL (more likely if CNS radiation) any child who received spinal irradiation Diagnosis careful plotting of serial heights consideration of timing/onset of puberty

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Growth Evaluation & Therapy of Growth Problems usually done by an endocrinologist testing of thyroid, gonads may include provocative GH testing Therapy is specific to the problem thyroid or sex hormone replacement possibly growth hormone therapy

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Typical endocrine disturbances Problems with puberty / fertility Abnormal growth Thyroid dysfunction

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Thyroid dysfunction Radiation related Hypothyroidism most common non-malignant late effect Dose dependent may be reversible at low doses Occurs more often in females

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Hematologic / Immunologic Total lymphocytes counts abnormally low up to 6+ months following chemotherapy; complete CD4+ recovery may take longer Impaired humoral immunity following splenectomy or splenic/abdominal radiation Impaired cellular immunity following TBI or total nodal irradiation Intense, prolonged chemotherapy and/or radiation may reduce bone marrow reserve: prolonged thrombocytopenia, leukopenia…

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Second malignant neoplasms 10-20x lifetime risk for a second cancer Incidence 3-12% in first 20 years after Dx Second most common cause of death in long-term survivors most common cause: recurrence of 1o disease

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Second NeoplasmsPatients at Greater Risk by initial tumor retinoblastoma Hodgkin's disease bilateral Wilms’ by primary therapy radiation alkylating agents combination chemo/XRT by underlying diagnosis neurofibromatosis DNA repair deficiency Downs syndrome immunodeficiency by family history cancer families

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Two common types Secondary AML Chemotherapy Topoisomerase-II inhibitors 11q23 abnormalities may occur as early as 3 mos after Rx risk plateau @ 10 yrs Secondary solid tumors radiation therapy dose related tend to be later in occurrence median 9.5 years risk does not appear to plateau

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Why study late effects? Find ways to to prevent or mitigate effects Know ‘what’, look for ‘why’ and ‘how’ Increase understanding of pathophysiology Give better information to patients and families at time of diagnosis and during follow-up

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How do we find out? Continued careful surveillance of survivors Thoughtful examinations mindful of their past medical history close attention to details of symptoms and signs

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Questions that go along with this… How often are these survivors seeing MDs? What are their current limitations? What are their current medications? Can we predict the long term cost of survival?

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Future Concerns What will be the long term morbidity and mortality of childhood cancer survivors? How will their diagnosis/diagnoses affect their re-integration and assimilation into the population at large? Will their “risk taking” behaviors be different than the general population? How will we know?

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Late Effects of Childhood CAConclusions: Survivors of childhood cancer are a unique population with unique needs and problems. While the overall outcome is good, many specific problem areas exist and must be more clearly defined. With the appropriate research, interventions can be undertaken to prevent or reduce the occurrence of specific long term sequellae. Only with continued follow-up of the children who have received treatment will any of this occur.

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Late Effects of Childhood CATake home messages Any newly diagnosed child is Rx “for cure” This aggressive therapy gives rise to late effects that may include: any organ system intellectual function increased risk for a Second Malignancy

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Late Effects of Childhood CATake home messages These late effects are Rx & disease specific They may be missed by cursory exam They can be treated or modified for the benefit of the child

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Credits Anne Warwick MD MPH