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Late Effects of Childhood Cancer

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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 ... – PowerPoint PPT presentation

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Title: Late Effects of Childhood Cancer


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
  • _at_ 1500-1600 deaths annually
  • Ages 15-19
  • _at_ 700 deaths annually

4
decreasing
5
Survival
  • 1960
  • 28 5-years
  • 1998
  • gt 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

11
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12
Cardiac Late Effects
  • Acute
  • lt 365 days (mean 33)
  • Chronic
  • gt 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 gt 50 mg/m2
  • Cumulative anthracycline dose gt 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 0.4 - 9
  • May be progressive
  • Predicted mortality rate as high as 61 in those
    patients who develop symptomatic cardiomyopathy

18
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

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)

20
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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
  • Hodgkins 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

26
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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

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, Fanconis syndrome
  • Cyclophosphamide, Ifosfamide
  • Fanconis 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 (dose, location, age)
  • 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

30
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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

37
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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
  • 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
  • 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 childrens children?

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

48
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

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
  • 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

53
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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 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

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

62
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

63
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

64
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65
Credits
  • Anne Warwick MD MPH
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