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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 reaching adulthood and being diagnosed with cancer during childhood: 1 in 300 for males 1 in 330 for females. - PowerPoint PPT Presentation
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Late Effects Late Effects of Childhood Cancerof Childhood Cancer
Pediatric Resident Pediatric Resident Education SeriesEducation Series
Cancer incidenceCancer incidence
Incidence: 1 in 7000 children, 0 to 14 yearIncidence: 1 in 7000 children, 0 to 14 year
Likelihood of a young person reaching Likelihood of a young person reaching adulthood and being diagnosed with adulthood and being diagnosed with cancer during childhood:cancer during childhood:– 1 in 300 for males1 in 300 for males– 1 in 330 for females1 in 330 for females
As of the year 2000As of the year 2000
Originally estimated that 1 in every 1000 Originally estimated that 1 in every 1000 individuals between 20 and 29 years was individuals between 20 and 29 years was a survivor of childhood cancer…a survivor of childhood cancer…
Current estimates: 1 in 900Current estimates: 1 in 900
By the year 2010By the year 2010
As many as 1 in every 250 persons As many as 1 in every 250 persons between 20 and 29 years will be a survivor between 20 and 29 years will be a survivor of childhood cancerof childhood cancer
Almost ½ of these survivors are likely to Almost ½ of these survivors are likely to have or to develop disabilities that alter have or to develop disabilities that alter quality of lifequality of life
Potential Late Effects (LE)Potential Late Effects (LE)
Can look at these in Can look at these in several waysseveral ways
By diseaseBy disease
By type(s) of By type(s) of treatmenttreatment
By system affectedBy system affected
any system can be affected …any system can be affected …
CardiacCardiac
PulmonaryPulmonary
GastrointestinalGastrointestinal
Urinary tractUrinary tract
MusculoskeletalMusculoskeletal
NeurologicNeurologic
NeuropsychologicNeuropsychologic
EndocrineEndocrine– GonadalGonadal
MaleMale
FemaleFemale
– GrowthGrowth– ThyroidThyroid
HematologicHematologic
ImmunologicImmunologic
Second MalignanciesSecond Malignancies
Potential Late Effects (LE)Potential Late Effects (LE)
By diseaseBy disease
By type(s) of By type(s) of treatmenttreatment
By system affectedBy system affectedChemotherapy?
Anthracyclines
Alkylating agents
Epipodophyllotoxins
Anti-metabolites
Vinca alkyloids
Radiation
Amount?
Location?
Both?
Stem cell rescue?
Chemotherapy – anthracyclinesChemotherapy – anthracyclines
DaunomycinDaunomycin
DoxorubcinDoxorubcin
Cardiac dysfunctionCardiac dysfunction– Can be acuteCan be acute– More often chronic, More often chronic,
may be progressivemay be progressive– Related to total dose Related to total dose
(mg/m(mg/m22 - - not mgnot mg))
Second cancers Second cancers – usually but not always leukemiausually but not always leukemia
Enhances radiation effectsEnhances radiation effects
Act on DNA via Act on DNA via intercalation and free intercalation and free radical damageradical damage
Chemotherapy – Alkylating agentsChemotherapy – Alkylating agents
MechlorethaneMechlorethaneCytoxan*Cytoxan*Ifosfamide*Ifosfamide*MelphalanMelphalan((**))
Cisplatin*Cisplatin*Carboplatin*Carboplatin*Nitrosoureas Nitrosoureas – BCNU, CCNUBCNU, CCNU
Dacarbazine / Dacarbazine / procarbazineprocarbazineBusulfanBusulfan((**))
Marrow suppressionMarrow suppressionScarring / bleeding of bladder Scarring / bleeding of bladder (esp. cytox, ifos)(esp. cytox, ifos)
Infertility, gonadal dysfunction, Infertility, gonadal dysfunction, early menopauseearly menopauseSecondary cancerSecondary cancer– Usually, but not always leukemiaUsually, but not always leukemia
Damage, scarring of lung tissueDamage, scarring of lung tissueHearing loss Hearing loss (esp. platins)(esp. platins)
Kidney dysfunctionKidney dysfunction
* used fairly often in Oncology; (*) mainly for BMT
Chemotherapy – Chemotherapy – Epipodophyllotoxins, and otherEpipodophyllotoxins, and other
Etoposide (VP16)Etoposide (VP16)Teniposide (VM26)Teniposide (VM26)
BleomycinBleomycin
Secondary leukemia Secondary leukemia or other canceror other cancerInfertility or gonadal Infertility or gonadal dysfunctiondysfunction
Scarring of lungs, Scarring of lungs, pulmonary fibrosispulmonary fibrosis
Inhibit Topoisomerase II
Causes strand breaks
Interferes w/DNA repair & RNA synthesis
Chemotherapy – anti-metabolitesChemotherapy – anti-metabolites
Anti-folatesAnti-folates– MethotrexateMethotrexate
Anti-pyrimidinesAnti-pyrimidines– CytarabineCytarabine– 5FU5FU
Anti-purinesAnti-purines– 6MP, 6TG6MP, 6TG
Hepatic fibrosisHepatic fibrosis– esp. 6MP & 6TGesp. 6MP & 6TG
neuro-cognitive changesneuro-cognitive changes– mainly with methotrexate mainly with methotrexate
when given intrathecally or when given intrathecally or in high dosesin high doses
Chemotherapy – Vinca alkyloidsChemotherapy – Vinca alkyloids
VincristineVincristine
VinblastineVinblastine
Rare weakness, Rare weakness, sensation losssensation loss
Worse if underlying Worse if underlying charcot-marie-tooth charcot-marie-tooth diseasedisease
Inhibit tubulin
Chemotherapy – other agentsChemotherapy – other agents
SteroidsSteroids– PrednisonePrednisone– Dexamethasone Dexamethasone
Avascular necrosis Avascular necrosis
Weight gain Weight gain
May increase risk for May increase risk for metabolic syndrome metabolic syndrome in those predisposed in those predisposed
RadiationRadiation
Effects are dose and site Effects are dose and site dependentdependent
Growth inhibitionGrowth inhibition
Tissue changesTissue changes
Secondary cancers, more Secondary cancers, more often solid tumorsoften solid tumors– ThyroidThyroid– BreastBreast– SarcomaSarcoma
Neuro-cognitive changesNeuro-cognitive changes
Infertility, or other Infertility, or other endocrine dysfunctionendocrine dysfunction
Pre-term deliveryPre-term delivery
Potential Late Effects (LE)Potential Late Effects (LE)
Office approachOffice approach– Mix of all threeMix of all three
By diseaseBy disease
By type(s) of By type(s) of treatmenttreatment
By system affectedBy system affected
By disease (most common) By disease (most common)
ALLALL
AMLAML
LymphomasLymphomas– Hodgkin'sHodgkin's– Non-Hodgkin'sNon-Hodgkin's
Brain tumorsBrain tumors
NeuroblastomaNeuroblastoma
Wilms tumorWilms tumor
OsteosarcomaOsteosarcoma
Ewing / PNET / RMSEwing / PNET / RMS
Liver tumorsLiver tumors
Germ cell tumorGerm cell tumor
RetinoblastomaRetinoblastoma
ALLALL
Important to knowImportant to knowType of diseaseType of disease– Low, intermediate, high, or Low, intermediate, high, or
very high riskvery high risk
era of treatmentera of treatmenttype(s) of treatmenttype(s) of treatment– Anthracyclines?Anthracyclines?– Epipodophyllotoxins?Epipodophyllotoxins?– Alkylating agents?Alkylating agents?– Radiation?Radiation?– Bone marrow transplant?Bone marrow transplant?
Age at time of treatmentAge at time of treatment
Overall, few late effectsOverall, few late effects
Most commonMost commonAvascular necrosisAvascular necrosis– Older age, dexamethasoneOlder age, dexamethasone
Neuro-cognitive problemsNeuro-cognitive problems– Younger ageYounger age
Metabolic syndromeMetabolic syndromeGrowth?Growth?Endocrine dysfunction?Endocrine dysfunction?
AMLAML
Important to knowImportant to know
Age at diagnosisAge at diagnosis
Was SCR (BMT) part Was SCR (BMT) part of therapy?of therapy?
Was radiation therapy Was radiation therapy used?used?
cardiac problemscardiac problems
Infertility and/or other Infertility and/or other endocrine dysfunctionendocrine dysfunction
Secondary Secondary malignanciesmalignancies
Chronic GVHD Chronic GVHD (if allo BMT)(if allo BMT)
Immune dysfunctionImmune dysfunction
LymphomasLymphomas
Important to knowImportant to know
Kind of lymphomaKind of lymphoma– HodgkinHodgkin– Non-HodgkinNon-Hodgkin
Burkitt, other B-cellBurkitt, other B-cell
T-cell, ….T-cell, ….
Radiation or not?Radiation or not?
Type(s) of chemo?Type(s) of chemo?
Cardiac problemsCardiac problems
InfertilityInfertility
Other endocrineOther endocrine– thyroidthyroid
Avascular necrosisAvascular necrosis
Neuro-cognitiveNeuro-cognitive
Secondary cancers Secondary cancers – Mainly leukemia unless Mainly leukemia unless
received radiation tooreceived radiation too
Immune dysfunctionImmune dysfunction
Brain tumorsBrain tumors
Important to knowImportant to know
TypeType
LocationLocation
TreatmentTreatment– ChemoChemo– RadiationRadiation– SurgerySurgery– Combination…..Combination…..
Focal neurologic deficits Focal neurologic deficits related to tumor location related to tumor location or surgeryor surgery
Endocrine problemsEndocrine problems
Neuro-cognitive problemsNeuro-cognitive problems
InfertilityInfertility
Secondary cancersSecondary cancers
Pulmonary fibrosisPulmonary fibrosis
NeuroblastomaNeuroblastoma
Important to knowImportant to know
Age and stage of Age and stage of disease at diagnosisdisease at diagnosis
What therapies?What therapies?– ChemoChemo– Radiation?Radiation?
How much?How much?
Where?Where?
– Stem cell rescue?Stem cell rescue?
Cardiac dysfunctionCardiac dysfunction
Hearing lossHearing loss
Cardiac dysfunctionCardiac dysfunction
Infertility or other Infertility or other endocrine problemendocrine problem
Second cancersSecond cancers
Wilms tumorWilms tumor
Important to knowImportant to knowLocation, stage of Location, stage of tumor at diagnosistumor at diagnosisTherapyTherapy– Chemotherapy agentsChemotherapy agents
Anthracycline?Anthracycline?Alkylator?Alkylator?Epipodophyllotoxin?Epipodophyllotoxin?
– Radiation?Radiation?Where?Where?
Fortunately, fewFortunately, few
Cardiac dysfunctionCardiac dysfunctionPulmonary fibrosisPulmonary fibrosisLiver dysfunctionLiver dysfunctionPre-term birthsPre-term birthsSecond cancersSecond cancersRenal dysfunctionRenal dysfunction– RARE, RARE,
unless predisposed to unless predisposed to Wilms tumorWilms tumor
OsteosarcomaOsteosarcoma
Important to knowImportant to know
TherapyTherapy
Musculoskeletal Musculoskeletal problems relating to problems relating to tumor and/or surgerytumor and/or surgery
Cardiac dysfunctionCardiac dysfunction
Hearing lossHearing loss
Renal dysfunctionRenal dysfunction
Second cancersSecond cancers
Rhabdomyosarcoma / Ewing / Rhabdomyosarcoma / Ewing / PNET / other soft tissue sarcomasPNET / other soft tissue sarcomas
Important to knowImportant to know
Age at diagnosisAge at diagnosis
Location of primary Location of primary tumor and any tumor and any metastatic diseasemetastatic disease
Type(s) of therapyType(s) of therapy– Chemo?Chemo?– Radiation?Radiation?– Surgery?Surgery?
Musculoskeletal Musculoskeletal problem related to problem related to tumor locationtumor location
Cardiac dysfunctionCardiac dysfunction
Secondary cancersSecondary cancers
Infertility or other Infertility or other endocrine problemsendocrine problems
Bladder scarringBladder scarring
Pulmonary fibrosisPulmonary fibrosisBoth?
Liver tumorsLiver tumors
Important to knowImportant to know
What type of tumor?What type of tumor?– Hepatoblastoma?Hepatoblastoma?– Hepatocellular CAHepatocellular CA
What type of therapyWhat type of therapy– Chemo?Chemo?
Which agents?Which agents?
Cardiac dysfunctionCardiac dysfunction
Hearing lossHearing loss
Renal dysfunctionRenal dysfunction
Germ Cell tumorsGerm Cell tumors
Important to knowImportant to know
Age at diagnosisAge at diagnosis
Type, stage of tumorType, stage of tumor
Location of tumorLocation of tumor– Extragonadal?Extragonadal?– Gonadal?Gonadal?– CNS?CNS?
TherapyTherapy– Which agents?Which agents?
Hearing lossHearing loss
Renal dysfunctionRenal dysfunction
Secondary cancersSecondary cancers
Endocrine problems Endocrine problems mainly if CNS tumormainly if CNS tumor
RetinoblastomaRetinoblastoma
Important to knowImportant to know
Family historyFamily history
Unilateral or bilateral?Unilateral or bilateral?
TherapyTherapy– ChemoChemo– CryoCryo– SurgerySurgery– Radiation?Radiation?
Vision lossVision loss
Hearing lossHearing loss
Renal dysfunctionRenal dysfunction
Secondary cancersSecondary cancers
Pituitary dysfunction if Pituitary dysfunction if trilateral tumorstrilateral tumors
Global considerationsGlobal considerations
Psychosocial Psychosocial – Post-traumatic stressPost-traumatic stress– Family/peer Family/peer
relationshipsrelationships– Social & societal Social & societal
functionfunction
FinancialFinancial– Insurance?Insurance?
EducationalEducational– Learning ability?Learning ability?
Recurrence of Recurrence of primary diseaseprimary disease
Potential Late Effects (LE)Potential Late Effects (LE)
Can look at these in Can look at these in several waysseveral ways
By diseaseBy disease
By type(s) of By type(s) of treatmenttreatment
By system affectedBy system affected
… … by system affectedby system affected
CardiacCardiac
PulmonaryPulmonary
GastrointestinalGastrointestinal
Urinary tractUrinary tract
MusculoskeletalMusculoskeletal
NeurologicNeurologic
NeuropsychologicNeuropsychologic
EndocrineEndocrine– GonadalGonadal
MaleMale
FemaleFemale
– GrowthGrowth– ThyroidThyroid
HematologicHematologic
ImmunologicImmunologic
Second MalignanciesSecond Malignancies
Cardiac Late EffectsCardiac Late Effects
Acute Acute < 365 days (mean 33)< 365 days (mean 33)
ChronicChronic> 365 days – 19+ yrs> 365 days – 19+ yrs
CausesCauses– ChemotherapyChemotherapy– RadiationRadiation
PericarditisPericarditisMyocarditisMyocarditisLV FailureLV FailureArrhythmiasArrhythmiasCoronary Artery Coronary Artery DiseaseDiseaseMyocardial infarctionMyocardial infarctionHeart FailureHeart FailureDeathDeath
Cardiac LE, cont.Cardiac LE, cont.
Most often associated with specific therapies Most often associated with specific therapies
May be progressiveMay be progressive
ChemotherapyChemotherapy– Anthracyclines: Adriamycin, Daunomycin Anthracyclines: Adriamycin, Daunomycin (most common)(most common)
Frequently used in leukemia & solid tumorsFrequently used in leukemia & solid tumorsRisk for toxicity rises with increased dosesRisk for toxicity rises with increased dosesDecreased contractility and/or increased afterload due to Decreased contractility and/or increased afterload due to reduced wall thickness, arrhythmias, CHFreduced wall thickness, arrhythmias, CHF
Radiation therapyRadiation therapy– Direct effects: fibrosis, constrictive pericarditis, CADDirect effects: fibrosis, constrictive pericarditis, CAD– May potentiate toxicity of chemotherapeutic agentsMay potentiate toxicity of chemotherapeutic agents
Risk factors:Risk factors: EarlyEarly cardiac toxicities cardiac toxicities
Individual anthracycline dose > 50 mg/m2Individual anthracycline dose > 50 mg/m2
Cumulative anthracycline dose > 550 mg/m2Cumulative anthracycline dose > 550 mg/m2
Black raceBlack race
Female genderFemale gender
Trisomy 21Trisomy 21
Treatment with amsacrineTreatment with amsacrine
Rate of infusion NOT significantRate of infusion NOT significant
Risk factors: Risk factors: LateLate cardiac toxicities cardiac toxicities
Less clearly defined – based on adult dataLess clearly defined – based on adult data
Increases with cumulative anthracycline dosesIncreases with cumulative anthracycline doses
Higher risk with very young and very oldHigher risk with very young and very old
Higher risk for female genderHigher risk for female gender
Schedule and rate of administration of drug:Schedule and rate of administration of drug:– Lower risk with lower peak plasma levelLower risk with lower peak plasma level– Higher risk with fast infusion, large individual dosesHigher risk with fast infusion, large individual doses
How bad can it be?How bad can it be?
Incidence of anthracycline cardiotoxicity Incidence of anthracycline cardiotoxicity ranges from 0.4 - 9%ranges from 0.4 - 9%
May be progressiveMay be progressive
Predicted mortality rate as high as 61% in Predicted mortality rate as high as 61% in those patients who develop symptomatic those patients who develop symptomatic cardiomyopathycardiomyopathy
PathophysiologyPathophysiology
ChemotherapyChemotherapy– Direct myocardial cellular damage with Direct myocardial cellular damage with
corresponding inflammatory responsecorresponding inflammatory response– Cardiac Troponin-T levels may be a marker Cardiac Troponin-T levels may be a marker
for myocardiocyte damagefor myocardiocyte damage
Radiation therapyRadiation therapy– Vascular damage and fibrosisVascular damage and fibrosis
Changes in therapy - cardiacChanges in therapy - cardiac
Modified dose or dosage schedulesModified dose or dosage schedules
Change therapyChange therapy
Minimize combination of cardiotoxic Minimize combination of cardiotoxic chemotherapy and radiationchemotherapy and radiation
Addition of possible cardioprotectantsAddition of possible cardioprotectants– Dexrazoxane Dexrazoxane (to decrease anthracycline toxicity)(to decrease anthracycline toxicity)
Long-term intervention studiesLong-term intervention studies– Enalapril Enalapril (reduce work of heart: afterload reduction)(reduce work of heart: afterload reduction)
Pulmonary Late EffectsPulmonary Late Effects
Effects may be subtleEffects may be subtle
Most commonly restrictive, with fibrosisMost commonly restrictive, with fibrosis– Decrease in lung volume, compliance, DLCODecrease in lung volume, compliance, DLCO
Caused by both radiation & chemotherapyCaused by both radiation & chemotherapy
Risk for occurrence:Risk for occurrence:– Related to dose and/or duration of exposureRelated to dose and/or duration of exposure– Age at exposureAge at exposure– Exposure to other contributing agents/factorsExposure to other contributing agents/factors
Pulmonary LE - RadiationPulmonary LE - Radiation
May be dose relatedMay be dose related
Younger ages Younger ages – proportionate interference with growth of lung proportionate interference with growth of lung
as well as growth of chest wall more commonas well as growth of chest wall more common– chronic fibrosis seen less oftenchronic fibrosis seen less often
Older children & adultsOlder children & adults– stimulation of septal fibroblasts stimulation of septal fibroblasts collagen collagen– pulmonary fibrosis with consequent loss of pulmonary fibrosis with consequent loss of
lung volume, compliance & decrease in DLCOlung volume, compliance & decrease in DLCO
Pulmonary RadiationPulmonary Radiation
Who gets this?Who gets this?– Wilms’ metastatic to the lungsWilms’ metastatic to the lungs– Hodgkin’s with mantle or nodal irradiationHodgkin’s with mantle or nodal irradiation– Lung carcinomaLung carcinoma– Scatter from cranio-spinal irradiationScatter from cranio-spinal irradiation
Pulmonary LE - ChemotherapyPulmonary LE - Chemotherapy
Most common:Most common:– BleomycinBleomycin
Dose dependent. May be immediate or late effect.Dose dependent. May be immediate or late effect.
– Carmustine & Lomustine Carmustine & Lomustine (Mustard analogues)(Mustard analogues)
Dose dependent. May be progressive.Dose dependent. May be progressive.
Less common: Less common: – Cyclophosphamide, Melphalan, BusulfanCyclophosphamide, Melphalan, Busulfan
High doses, not predictableHigh doses, not predictable
– Vinblastine, MethotrexateVinblastine, MethotrexateChronic pneumonitis & fibrosisChronic pneumonitis & fibrosisRelated to length of use (i.e., longer use, increased risk)Related to length of use (i.e., longer use, increased risk)
Contributing factorsContributing factors
Pre-existing pulmonary diseasePre-existing pulmonary disease– e.g., asthmae.g., asthma
Superimposed infectionSuperimposed infection
SmokingSmoking
Gastrointestinal Late EffectsGastrointestinal Late Effects
GutGut– mainly radiation-induced fibrosis, adhesions, mainly radiation-induced fibrosis, adhesions,
enteritis, stricturesenteritis, strictures
LiverLiver– related to either chemotherapy and/or radiationrelated to either chemotherapy and/or radiation
HepatitisHepatitis– Infectious agents also, e.g., Hepatitis CInfectious agents also, e.g., Hepatitis C
Veno-occlusive disease -Veno-occlusive disease - may be chronic and lead to may be chronic and lead to
Fibrosis/cirrhosisFibrosis/cirrhosis
Kidney/Urinary Tract Late EffectsKidney/Urinary Tract Late Effects
Radiation – depends on area treated Radiation – depends on area treated – Nephritis Nephritis renal failure renal failure– Hemorrhagic cystitisHemorrhagic cystitis– Abnormal bladder functionAbnormal bladder function
Chemotherapy – often agent specificChemotherapy – often agent specific– CisplatinCisplatin
Decreased function, Fanconi’s syndromeDecreased function, Fanconi’s syndrome
– Cyclophosphamide, IfosfamideCyclophosphamide, IfosfamideFanconi’s syndrome, hemorrhagic cystitisFanconi’s syndrome, hemorrhagic cystitis
Surgery – depends on operationSurgery – depends on operation
Musculoskeletal Late EffectsMusculoskeletal Late Effects
BoneBone– ScoliosisScoliosis– Atrophy or hypoplasiaAtrophy or hypoplasia– Avascular necrosisAvascular necrosis– OsteoporosisOsteoporosis
Soft tissueSoft tissue– HypoplasiaHypoplasia– Pigmentation changes Pigmentation changes
DentalDental– Tooth developmentTooth development– Cavities, pits, discolorationCavities, pits, discoloration
Related to:Related to:– Radiation (dose, location, age)Radiation (dose, location, age)– RadiationRadiation– Steroids (length of use, age)Steroids (length of use, age)– Steroids, MethotrexateSteroids, Methotrexate
– Radiation (dose, location, age)Radiation (dose, location, age)– Radiation, some chemotherapyRadiation, some chemotherapy
– Radiation (dose & age)Radiation (dose & age)– ChemotherapyChemotherapy
Neuropsychologic and Neuropsychologic and Neurologic FunctionNeurologic Function
Has been best studied in patients with Has been best studied in patients with CNS tumors or CNS tumors or Acute Lymphoblastic LeukemiaAcute Lymphoblastic Leukemia
Incidence and type of problem depends on Incidence and type of problem depends on tumor type and location as well as timing tumor type and location as well as timing and method of CNS treatmentand method of CNS treatment– Incidence 8 – 50%Incidence 8 – 50%
Risk FactorsRisk Factors
Radiation Radiation (location, dosage)(location, dosage)
Intrathecal chemotherapy Intrathecal chemotherapy (methotrexate)(methotrexate)
Young age at diagnosis Young age at diagnosis or therapyor therapy
Location of brain tumor Location of brain tumor (brainstem, (brainstem, hypothalamus, hypothalamus, 44thth ventricle) ventricle)
? Obtundation at ? Obtundation at diagnosisdiagnosis
? Need for permanent ? Need for permanent shuntingshunting
? Postoperative ? Postoperative complicationscomplications
? Female Sex? Female Sex
? Somnolence syndrome? Somnolence syndrome
? Socioeconomic status? Socioeconomic status
? Parental education? Parental education
CNS problems - focalCNS problems - focal
Often related to tumor locationOften related to tumor location
Radiation related – not usually reversibleRadiation related – not usually reversible– CataractsCataracts– Necrosis of optic nerveNecrosis of optic nerve
Chemotherapy related – some may be reversibleChemotherapy related – some may be reversible– Hearing loss: cisplatin, aminoglycoside antibioticsHearing loss: cisplatin, aminoglycoside antibiotics– Cataracts: steroidsCataracts: steroids– Sensorimotor neuropathies: vincristine, vinblastine, Sensorimotor neuropathies: vincristine, vinblastine,
etoposide, cytarabine, ifosfamide, cisplatinetoposide, cytarabine, ifosfamide, cisplatin
CNS problems - globalCNS problems - global
More commonly secondary to treatmentMore commonly secondary to treatment– chronic necrotizing leukoencephalopathychronic necrotizing leukoencephalopathy
radiation and/or intrathecal chemotherapyradiation and/or intrathecal chemotherapy
range of symptoms:range of symptoms:– slight impairment of attention and verbal memoryslight impairment of attention and verbal memory– dementia, dysarthria, dysphagia, ataxia, seizures, & dementia, dysarthria, dysphagia, ataxia, seizures, &
comacoma
– Neurocognitive deficitsNeurocognitive deficits
Neurocognitive deficitsNeurocognitive deficits
Radiation therapy main causeRadiation therapy main causeMethotrexate & intrathecal chemo also implicatedMethotrexate & intrathecal chemo also implicated
IncludeInclude– Learning difficultiesLearning difficulties– Attention capacityAttention capacity– non-verbal processing skillsnon-verbal processing skills
Are these progressive?Are these progressive?
Assessment toolsAssessment tools
Parent QuestionnairesParent Questionnaires
Observations by Teachers/PhysiciansObservations by Teachers/Physicians
IQ Screening TestsIQ Screening Tests
Formal Neuropsychological AssessmentFormal Neuropsychological Assessment
Endocrine Late EffectsEndocrine Late Effects
Probably the most common late effectProbably the most common late effect– Very complex system of regulationVery complex system of regulation– Many different endocrine glandsMany different endocrine glands all all
of which are inter-relatedof which are inter-related– Most are regulated from the pituitaryMost are regulated from the pituitary
itself regulated from elsewhereitself regulated from elsewhere
Typical endocrine disturbancesTypical endocrine disturbances– Problems with puberty / fertilityProblems with puberty / fertility– Abnormal growthAbnormal growth– Thyroid dysfunctionThyroid dysfunction
Typical endocrine disturbancesTypical endocrine disturbances
– Problems with puberty / fertilityProblems with puberty / fertility
– Abnormal growthAbnormal growth
– Thyroid dysfunctionThyroid dysfunction
MalesMales
Damage may occur to either or both germ Damage may occur to either or both germ cells or Leydig cellscells or Leydig cells
Effects related to age & pubertal statusEffects related to age & pubertal status
May be caused by radiation therapy and/or May be caused by radiation therapy and/or chemotherapychemotherapy
Manifestations:Manifestations:– decreased or absent sperm count; infertilitydecreased or absent sperm count; infertility– delayed puberty, gynecomastiadelayed puberty, gynecomastia
Germ CellsGerm Cells
CHEMOTHERAPYCHEMOTHERAPY
Dose & drug dependentDose & drug dependent– cyclophosphamidecyclophosphamide
– mechlorethanemechlorethane
– chlorambucilchlorambucil
– procarbazineprocarbazine
Pubertal status not Pubertal status not importantimportant
May be reversibleMay be reversible
RADIATIONRADIATION
Increased effect with Increased effect with higher dosehigher dose
Pubertal status not Pubertal status not importantimportant
Unlikely to be reversibleUnlikely to be reversible
Leydig cellsLeydig cells
CHEMOTHERAPYCHEMOTHERAPY
Slower growing than Slower growing than germ cells, so less likely germ cells, so less likely affectedaffected
Effects related to age: Effects related to age: more likely to occur after more likely to occur after pubertypuberty
RADIATIONRADIATION
Less radiosensitiveLess radiosensitive
Damage is dose-Damage is dose-dependent, inversely dependent, inversely related to age at Rx related to age at Rx May have normal May have normal pubertal maturation but pubertal maturation but marginal functionmarginal function
FemalesFemales
Germ cell failure and loss of ovarian endocrine Germ cell failure and loss of ovarian endocrine function usually occur togetherfunction usually occur together
Age & dose dependentAge & dose dependent– pre-pubertal ovaries relatively resistant to injurypre-pubertal ovaries relatively resistant to injury
Caused by radiation and/or chemotherapyCaused by radiation and/or chemotherapy
Manifestations: Manifestations: – delayed puberty, amenorrhea, premature menopause, delayed puberty, amenorrhea, premature menopause,
ovarian failure, infertilityovarian failure, infertility– teratogenic effects on pregnancy (if Rx while pregnant)teratogenic effects on pregnancy (if Rx while pregnant)– prematurity, low birth weight of offspringprematurity, low birth weight of offspring
Offspring of the Offspring of the childhood cancer patientchildhood cancer patient
Are they at increased risk of congenital Are they at increased risk of congenital anomalies?anomalies?
Are they at an increased risk of cancer Are they at an increased risk of cancer themselves?themselves?
What about the children’s children?What about the children’s children?
Typical endocrine disturbancesTypical endocrine disturbances
– Problems with puberty / fertilityProblems with puberty / fertility
– Abnormal growth Abnormal growth usually lack of growth…usually lack of growth…
– Thyroid dysfunctionThyroid dysfunction
GrowthGrowth
Children at increased risk Children at increased risk – any child who received CNS irradiationany child who received CNS irradiation– any child with ALLany child with ALL (more likely if CNS (more likely if CNS
radiation)radiation)
– any child who received spinal irradiationany child who received spinal irradiation
DiagnosisDiagnosis– careful plotting of serial heightscareful plotting of serial heights– consideration of timing/onset of pubertyconsideration of timing/onset of puberty
GrowthGrowth
Evaluation & Therapy of Growth ProblemsEvaluation & Therapy of Growth Problems– usually done by an endocrinologistusually done by an endocrinologist– testing of thyroid, gonadstesting of thyroid, gonads– may include provocative GH testingmay include provocative GH testing
Therapy is specific to the problemTherapy is specific to the problem– thyroid or sex hormone replacementthyroid or sex hormone replacement– possibly growth hormone therapypossibly growth hormone therapy
Typical endocrine disturbancesTypical endocrine disturbances
– Problems with puberty / fertilityProblems with puberty / fertility
– Abnormal growth Abnormal growth
– Thyroid dysfunctionThyroid dysfunction
Thyroid dysfunctionThyroid dysfunction
Radiation relatedRadiation related
Hypothyroidism Hypothyroidism – most common non-malignant late effectmost common non-malignant late effect
Dose dependentDose dependent– may be reversible at low dosesmay be reversible at low doses
Occurs more often in femalesOccurs more often in females
Hematologic / ImmunologicHematologic / Immunologic
Total lymphocytes counts abnormally low up to Total lymphocytes counts abnormally low up to 6+ months following chemotherapy; 6+ months following chemotherapy; complete CD4+ recovery may take longer complete CD4+ recovery may take longer
Impaired humoral immunity following Impaired humoral immunity following splenectomy or splenic/abdominal radiationsplenectomy or splenic/abdominal radiation
Impaired cellular immunity following TBI or total Impaired cellular immunity following TBI or total nodal irradiationnodal irradiation
Intense, prolonged chemotherapy and/or Intense, prolonged chemotherapy and/or radiation may reduce bone marrow reserve: radiation may reduce bone marrow reserve: – prolonged thrombocytopenia, leukopenia…prolonged thrombocytopenia, leukopenia…
Second malignant neoplasmsSecond malignant neoplasms
10-20x lifetime risk for a second cancer10-20x lifetime risk for a second cancer
Incidence 3-12% in first 20 years after Incidence 3-12% in first 20 years after DxDx
Second most common cause of death in Second most common cause of death in long-term survivorslong-term survivors– most common cause: most common cause:
recurrence of 1recurrence of 1oo disease disease
Second NeoplasmsSecond NeoplasmsPatients at Greater RiskPatients at Greater Risk
by initial tumorby initial tumor– retinoblastomaretinoblastoma– Hodgkin's diseaseHodgkin's disease– bilateral Wilms’bilateral Wilms’
by primary therapyby primary therapy– radiationradiation– alkylating agentsalkylating agents– combination combination
chemo/XRTchemo/XRT
by underlying by underlying diagnosisdiagnosis– neurofibromatosisneurofibromatosis– DNA repair deficiencyDNA repair deficiency– Downs syndromeDowns syndrome– immunodeficiencyimmunodeficiency
by family historyby family history– cancer familiescancer families
Two common typesTwo common types
Secondary AMLSecondary AML ChemotherapyChemotherapy– Topoisomerase-II Topoisomerase-II
inhibitorsinhibitors– 11q23 abnormalities11q23 abnormalities
may occur as early as may occur as early as 3 mos after Rx3 mos after Rx
risk plateau @ 10 yrsrisk plateau @ 10 yrs
Secondary solid tumorsSecondary solid tumors radiation therapyradiation therapy– dose relateddose related
tend to be later in tend to be later in occurrenceoccurrence– median 9.5 yearsmedian 9.5 years
risk does not appear to risk does not appear to plateauplateau
Why study late effects?Why study late effects?
Find ways to to prevent or mitigate effectsFind ways to to prevent or mitigate effects– Know ‘what’, look for ‘why’ and ‘how’Know ‘what’, look for ‘why’ and ‘how’– Increase understanding of pathophysiologyIncrease understanding of pathophysiology
Give better information to patients and Give better information to patients and families at time of diagnosis and during families at time of diagnosis and during follow-upfollow-up
How do we find out?How do we find out?
Continued careful surveillance of survivorsContinued careful surveillance of survivors
Thoughtful examinationsThoughtful examinations– mindful of their past medical historymindful of their past medical history– close attention to details of symptoms and close attention to details of symptoms and
signssigns
Questions that go along with Questions that go along with this…this…
How often are these survivors seeing MDs?How often are these survivors seeing MDs?
What are their current limitations?What are their current limitations?
What are their current medications?What are their current medications?
Can we predict the long term cost of survival?Can we predict the long term cost of survival?
Future ConcernsFuture Concerns
What will be the long term morbidity and What will be the long term morbidity and mortality of childhood cancer survivors?mortality of childhood cancer survivors?
How will their diagnosis/diagnoses affect their How will their diagnosis/diagnoses affect their re-integration and assimilation into the re-integration and assimilation into the population at large?population at large?
Will their “risk taking” behaviors be different than Will their “risk taking” behaviors be different than the general population?the general population?
How will we know?How will we know?
Late Effects of Childhood CALate Effects of Childhood CAConclusions:Conclusions:
Survivors of childhood cancer are a unique population Survivors of childhood cancer are a unique population with unique needs and problems.with unique needs and problems.
While the overall outcome is good, many specific While the overall outcome is good, many specific problem areas exist and must be more clearly defined.problem areas exist and must be more clearly defined.
With the appropriate research, interventions can be With the appropriate research, interventions can be undertaken to prevent or reduce the occurrence of undertaken to prevent or reduce the occurrence of specific long term sequellae.specific long term sequellae.
Only with continued follow-up of the children who have Only with continued follow-up of the children who have received treatment will any of this occur.received treatment will any of this occur.
Late Effects of Childhood CALate Effects of Childhood CATake home messagesTake home messages
Any newly diagnosed child is Rx “for cure”Any newly diagnosed child is Rx “for cure”
This aggressive therapy gives rise to late effects This aggressive therapy gives rise to late effects that may include:that may include:– any organ systemany organ system– intellectual functionintellectual function– increased risk for a Second Malignancyincreased risk for a Second Malignancy
Late Effects of Childhood CALate Effects of Childhood CATake home messagesTake home messages
These late effects are Rx & disease specificThese late effects are Rx & disease specific
They may be missed by cursory examThey may be missed by cursory exam
They can be treated or modified for the benefit of They can be treated or modified for the benefit of the child / young adultthe child / young adult
CreditsCredits
Anne Warwick MD MPHAnne Warwick MD MPH