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

4. … decreasing

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

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

7. 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

8. 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

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

10. any system can be affected … CardiacPulmonaryGastrointestinal Urinary tract MusculoskeletalNeurologicNeuropsychologicEndocrine –Gonadal Male Female –Growth –ThyroidHematologicImmunologic Second Malignancies

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

14. Chemotherapy – anthracyclines DaunomycinDoxorubcin Cardiac dysfunction –Can be acute –More often chronic, may be progressive –Related to total dose (mg/m 2 - not mg ) Second cancers –usually but not always leukemia Enhances radiation effects Act on DNA via intercalation and free radical damage

15. Chemotherapy – Alkylating agents MechlorethaneCytoxan*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 * used fairly often in Oncology; ( * ) mainly for BMT

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

17. Chemotherapy – anti-metabolites 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

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

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

20. Radiation 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

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

22. By disease (most common) ALLAMLLymphomas –Hodgkin's –Non-Hodgkin's Brain tumors Neuroblastoma Wilms tumor Osteosarcoma Ewing / PNET / RMS Liver tumors Germ cell tumor Retinoblastoma

23. ALL 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?

24. AML 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

25. Lymphomas 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

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

27. Neuroblastoma 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

28. Wilms tumor 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

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

30. Rhabdomyosarcoma / Ewing / PNET / other soft tissue sarcomas 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 Both?

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

32. Germ Cell tumors 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

33. Retinoblastoma 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

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

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

37. … by system affected CardiacPulmonaryGastrointestinal Urinary tract MusculoskeletalNeurologicNeuropsychologicEndocrine –Gonadal Male Female –Growth –ThyroidHematologicImmunologic Second Malignancies

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

40. 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

41. 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

42. 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

43. 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

44. 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

45. 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

46. 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)

48. 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

49. 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

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

51. 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)

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

54. 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

55. 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

56. 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

58. 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%

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

60. 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

61. 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

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

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

65. 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

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

67. 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

68. 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

69. 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

70. 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

71. 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

72. 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

73. 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?

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

75. 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

76. 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

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

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

79. 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…

81. 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 1 o disease

82. Second Neoplasms Patients 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

83. 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

84. 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

85. 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

86. 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?

87. 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?

88. Late Effects of Childhood CA Conclusions: 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.

89. Late Effects of Childhood CA Take 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

90. Late Effects of Childhood CA Take 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 / young adult

92. Credits Anne Warwick MD MPH