Late Effects of Childhood Cancer

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




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


Office approachOffice approach– Mix of all threeMix of all three




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


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


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


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


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


TherapyTherapy

Musculoskeletal Musculoskeletal problems relating to problems relating to tumor and/or surgerytumor and/or surgery



Renal dysfunctionRenal dysfunction

Second cancersSecond cancers

Rhabdomyosarcoma / Ewing / Rhabdomyosarcoma / Ewing / PNET / other soft tissue sarcomasPNET / other soft tissue sarcomas



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



Infertility or other Infertility or other endocrine problemsendocrine problems

Bladder scarringBladder scarring

Pulmonary fibrosisPulmonary fibrosisBoth?

Liver tumorsLiver tumors


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?




Germ Cell tumorsGerm Cell tumors



Type, stage of tumorType, stage of tumor

Location of tumorLocation of tumor– Extragonadal?Extragonadal?– Gonadal?Gonadal?– CNS?CNS?

TherapyTherapy– Which agents?Which agents?




Endocrine problems Endocrine problems mainly if CNS tumormainly if CNS tumor

RetinoblastomaRetinoblastoma


Family historyFamily history

Unilateral or bilateral?Unilateral or bilateral?

TherapyTherapy– ChemoChemo– CryoCryo– SurgerySurgery– Radiation?Radiation?

Vision lossVision loss




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


Can look at these in Can look at these in several waysseveral ways




… … 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?



– Abnormal growth Abnormal growth usually lack of growth…usually lack of growth…


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



– Abnormal growth Abnormal growth


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

Documents

Late Effects of Childhood Cancer