Transcript 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
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
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
Potential Late Effects (LE)
Can look at these in
several ways
By disease
By type(s) of
treatment
By system affected
any system can be affected …
Cardiac
Pulmonary
Gastrointestinal
Urinary tract
Musculoskeletal
Neurologic
Neuropsychologic
Endocrine
– Gonadal
Male
Female
– Growth
– Thyroid
Hematologic
Immunologic
Second Malignancies
Potential Late Effects (LE)
By disease
By type(s) of
treatment
By system affected
Chemotherapy?
Anthracyclines
Alkylating agents
Epipodophyllotoxins
Both?
Radiation
Amount?
Anti-metabolites
Location?
Vinca alkyloids
Stem cell rescue?
Chemotherapy – anthracyclines
Daunomycin
Doxorubcin
Act on DNA via
intercalation and free
radical damage
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 – Alkylating agents
Mechlorethane
Cytoxan*
Ifosfamide*
Melphalan(*)
Cisplatin*
Carboplatin*
Nitrosoureas
– BCNU, CCNU
Dacarbazine /
procarbazine
Busulfan(*)
* used fairly often in Oncology;
(*) mainly for BMT
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 –
Epipodophyllotoxins, and other
Etoposide (VP16)
Teniposide (VM26)
Inhibit Topoisomerase II
Secondary leukemia
or other cancer
Infertility or gonadal
dysfunction
Causes strand breaks
Interferes w/DNA repair
& RNA synthesis
Bleomycin
Scarring of lungs,
pulmonary fibrosis
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
Chemotherapy – Vinca alkyloids
Vincristine
Vinblastine
Inhibit tubulin
Rare weakness,
sensation loss
Worse if underlying
charcot-marie-tooth
disease
Chemotherapy – other agents
Steroids
– Prednisone
– Dexamethasone
Avascular necrosis
Weight gain
May increase risk for
metabolic syndrome
in those predisposed
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
Potential Late Effects (LE)
Office approach
– Mix of all three
By disease
By type(s) of
treatment
By system affected
By disease (most common)
ALL
AML
Lymphomas
– Hodgkin's
– Non-Hodgkin's
Brain tumors
Neuroblastoma
Wilms tumor
Osteosarcoma
Ewing / PNET / RMS
Liver tumors
Germ cell tumor
Retinoblastoma
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?
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
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
Brain tumors
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
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
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
Osteosarcoma
Important to know
Therapy
Musculoskeletal
problems relating to
tumor and/or surgery
Cardiac dysfunction
Hearing loss
Renal dysfunction
Second cancers
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?
Both?
Musculoskeletal
problem related to
tumor location
Cardiac dysfunction
Secondary cancers
Infertility or other
endocrine problems
Bladder scarring
Pulmonary fibrosis
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
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
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
Global considerations
Psychosocial
– Post-traumatic stress
– Family/peer
relationships
– Social & societal
function
Financial
– Insurance?
Educational
– Learning ability?
Recurrence of
primary disease
Potential Late Effects (LE)
Can look at these in
several ways
By disease
By type(s) of
treatment
By system affected
… by system affected
Cardiac
Pulmonary
Gastrointestinal
Urinary tract
Musculoskeletal
Neurologic
Neuropsychologic
Endocrine
– Gonadal
Male
Female
– Growth
– Thyroid
Hematologic
Immunologic
Second Malignancies
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
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
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
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
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
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
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)
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
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
Pulmonary Radiation
Who gets this?
– Wilms’ metastatic to the lungs
– Hodgkin’s with mantle or nodal irradiation
– Lung carcinoma
– Scatter from cranio-spinal irradiation
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)
Contributing factors
Pre-existing pulmonary disease
– e.g., asthma
Superimposed infection
Smoking
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
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
Musculoskeletal Late Effects
Bone
–
–
–
–
Scoliosis
Atrophy or hypoplasia
Avascular necrosis
Osteoporosis
Related to:
–
–
–
–
Radiation (dose, location, age)
Radiation
Steroids (length of use, age)
Steroids, Methotrexate
Soft tissue
– Hypoplasia
– Pigmentation changes
– Radiation (dose, location, age)
– Radiation, some chemotherapy
Dental
– Tooth development
– Cavities, pits, discoloration
– Radiation (dose & age)
– Chemotherapy
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%
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
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
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
Neurocognitive deficits
Radiation therapy main cause
Methotrexate & intrathecal chemo also implicated
Include
– Learning difficulties
– Attention capacity
– non-verbal processing skills
Are these progressive?
Assessment tools
Parent Questionnaires
Observations by Teachers/Physicians
IQ Screening Tests
Formal Neuropsychological Assessment
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
Typical endocrine disturbances
– Problems with puberty / fertility
– Abnormal growth
– Thyroid dysfunction
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
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
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 dosedependent, inversely
related to age at Rx
May have normal
pubertal maturation but
marginal function
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
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?
Typical endocrine disturbances
– Problems with puberty / fertility
– Abnormal growth
usually lack of growth…
– Thyroid dysfunction
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
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
Typical endocrine disturbances
– Problems with puberty / fertility
– Abnormal growth
– Thyroid dysfunction
Thyroid dysfunction
Radiation related
Hypothyroidism
– most common non-malignant late effect
Dose dependent
– may be reversible at low doses
Occurs more often in females
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…
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
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
Two common types
Secondary AML
Chemotherapy
– Topoisomerase-II
inhibitors
– 11q23 abnormalities
may occur as early as
3 mos after Rx
Secondary solid tumors
radiation therapy
– dose related
tend to be later in
occurrence
– median 9.5 years
risk plateau @ 10 yrs
risk does not appear to
plateau
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
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
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?
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?
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.
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
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
Credits
Anne Warwick MD MPH