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Late Effects of Childhood Cancer

Late Effects of Childhood Cancer. Pediatric Resident Education Series. 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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Late Effects of Childhood Cancer

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  1. Late Effects of Childhood Cancer Pediatric Resident Education Series

  2. 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

  3. 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

  4. 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

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

  6. Cardiac Pulmonary Gastrointestinal Urinary tract Musculoskeletal Neurologic Neuropsychologic Endocrine Gonadal Male Female Growth Thyroid Hematologic Immunologic Second Malignancies any system can be affected …

  7. By disease By type(s) of treatment By system affected Potential Late Effects (LE) Chemotherapy? Anthracyclines Alkylating agents Epipodophyllotoxins Anti-metabolites Vinca alkyloids Both? Radiation Amount? Location? Stem cell rescue?

  8. Daunomycin Doxorubcin Cardiac dysfunction Can be acute More often chronic, may be progressive Related to total dose (mg/m2 - not mg) Second cancers usually but not always leukemia Enhances radiation effects Chemotherapy – anthracyclines Act on DNA via intercalation and free radical damage

  9. Mechlorethane Cytoxan* Ifosfamide* Melphalan(*) Cisplatin* Carboplatin* Nitrosoureas BCNU, CCNU Dacarbazine / procarbazine Busulfan(*) Marrow suppression Scarring / bleeding of bladder (esp. cytox, ifos) Infertility, gonadal dysfunction, early menopause Secondary cancer Usually, but not always leukemia Damage, scarring of lung tissue Hearing loss (esp. platins) Kidney dysfunction Chemotherapy – Alkylating agents * used fairly often in Oncology; (*) mainly for BMT

  10. Etoposide (VP16) Teniposide (VM26) Bleomycin Secondary leukemia or other cancer Infertility or gonadal dysfunction Scarring of lungs, pulmonary fibrosis Chemotherapy – Epipodophyllotoxins, and other Inhibit Topoisomerase II Causes strand breaks Interferes w/DNA repair & RNA synthesis

  11. Anti-folates Methotrexate Anti-pyrimidines Cytarabine 5FU Anti-purines 6MP, 6TG Hepatic fibrosis esp. 6MP & 6TG neuro-cognitive changes mainly with methotrexate when given intrathecally or in high doses Chemotherapy – anti-metabolites

  12. Vincristine Vinblastine Rare weakness, sensation loss Worse if underlying charcot-marie-tooth disease Chemotherapy – Vinca alkyloids Inhibit tubulin

  13. Steroids Prednisone Dexamethasone Avascular necrosis Weight gain May increase risk for metabolic syndrome in those predisposed Chemotherapy – other agents

  14. Effects are dose and site dependent Growth inhibition Tissue changes Secondary cancers, more often solid tumors Thyroid Breast Sarcoma Neuro-cognitive changes Infertility, or other endocrine dysfunction Pre-term delivery Radiation

  15. Office approach Mix of all three By disease By type(s) of treatment By system affected Potential Late Effects (LE)

  16. ALL AML Lymphomas Hodgkin's Non-Hodgkin's Brain tumors Neuroblastoma Wilms tumor Osteosarcoma Ewing / PNET / RMS Liver tumors Germ cell tumor Retinoblastoma By disease (most common)

  17. Important to know Type of disease Low, intermediate, high, or very high risk era of treatment type(s) of treatment Anthracyclines? Epipodophyllotoxins? Alkylating agents? Radiation? Bone marrow transplant? Age at time of treatment Overall, few late effects Most common Avascular necrosis Older age, dexamethasone Neuro-cognitive problems Younger age Metabolic syndrome Growth? Endocrine dysfunction? ALL

  18. Important to know Age at diagnosis Was SCR (BMT) part of therapy? Was radiation therapy used? cardiac problems Infertility and/or other endocrine dysfunction Secondary malignancies Chronic GVHD (if allo BMT) Immune dysfunction AML

  19. Important to know Kind of lymphoma Hodgkin Non-Hodgkin Burkitt, other B-cell T-cell, …. Radiation or not? Type(s) of chemo? Cardiac problems Infertility Other endocrine thyroid Avascular necrosis Neuro-cognitive Secondary cancers Mainly leukemia unless received radiation too Immune dysfunction Lymphomas

  20. Important to know Type Location Treatment Chemo Radiation Surgery Combination….. Focal neurologic deficits related to tumor location or surgery Endocrine problems Neuro-cognitive problems Infertility Secondary cancers Pulmonary fibrosis Brain tumors

  21. Important to know Age and stage of disease at diagnosis What therapies? Chemo Radiation? How much? Where? Stem cell rescue? Cardiac dysfunction Hearing loss Cardiac dysfunction Infertility or other endocrine problem Second cancers Neuroblastoma

  22. Important to know Location, stage of tumor at diagnosis Therapy Chemotherapy agents Anthracycline? Alkylator? Epipodophyllotoxin? Radiation? Where? Fortunately, few Cardiac dysfunction Pulmonary fibrosis Liver dysfunction Pre-term births Second cancers Renal dysfunction RARE, unless predisposed to Wilms tumor Wilms tumor

  23. Important to know Therapy Musculoskeletal problems relating to tumor and/or surgery Cardiac dysfunction Hearing loss Renal dysfunction Second cancers Osteosarcoma

  24. Important to know Age at diagnosis Location of primary tumor and any metastatic disease Type(s) of therapy Chemo? Radiation? Surgery? Musculoskeletal problem related to tumor location Cardiac dysfunction Secondary cancers Infertility or other endocrine problems Bladder scarring Pulmonary fibrosis Rhabdomyosarcoma / Ewing / PNET / other soft tissue sarcomas Both?

  25. Important to know What type of tumor? Hepatoblastoma? Hepatocellular CA What type of therapy Chemo? Which agents? Cardiac dysfunction Hearing loss Renal dysfunction Liver tumors

  26. Important to know Age at diagnosis Type, stage of tumor Location of tumor Extragonadal? Gonadal? CNS? Therapy Which agents? Hearing loss Renal dysfunction Secondary cancers Endocrine problems mainly if CNS tumor Germ Cell tumors

  27. Important to know Family history Unilateral or bilateral? Therapy Chemo Cryo Surgery Radiation? Vision loss Hearing loss Renal dysfunction Secondary cancers Pituitary dysfunction if trilateral tumors Retinoblastoma

  28. Psychosocial Post-traumatic stress Family/peer relationships Social & societal function Financial Insurance? Educational Learning ability? Recurrence of primary disease Global considerations

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

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

  31. 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 Cardiac Late Effects

  32. 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

  33. 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

  34. 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

  35. 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

  36. 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

  37. 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)

  38. 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

  39. 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

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

  41. 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)

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

  43. 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

  44. 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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