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

12. Cardiac Late Effects Acute Chronic Causes Pericarditis Myocarditis
< 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

13. 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

14. 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

15. 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

16. 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

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

18. Pathophysiology Chemotherapy Radiation therapy
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

19. 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)

21. 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

22. 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

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

24. 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)

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

27. 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
Gut
mainly radiation-induced fibrosis, adhesions, enteritis, strictures
Liver
mainly related to chemotherapy and/or radiation
Hepatitis
Methotrexate, 6-MP, 6-TG
Infectious agents also, e.g., Hepatitis C
Veno-occlusive disease
Dactinomycin
Pre-BMT conditioning
Fibrosis/cirrhosis
Any of the above

28. 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

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

31. 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%

32. 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

33. 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

34. 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

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

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

38. 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

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

40. 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

41. Germ Cells CHEMOTHERAPY RADIATION 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

42. Leydig cells CHEMOTHERAPY RADIATION
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

43. 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

44. 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

45. 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

46. 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?

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

48. Growth Children at increased risk Diagnosis
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

49. 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

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

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

52. 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…

54. 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

55. 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

56. Two common types Secondary AML Chemotherapy
Topoisomerase-II inhibitors
11q23 abnormalities
may occur as early as 3 mos after Rx
risk 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

57. 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

58. 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

59. 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?

60. 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?

61. 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.

62. 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

63. 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

65. Credits
Anne Warwick MD MPH