Clinical Considerations for the Treatment of Secondary Differentiated Thyroid Carcinoma in Childhood Cancer Survivors

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H M van Santen and others DTC treatment in childhood 183:3 P1–P10 Position cancer survivors Statement

Clinical considerations for the treatment of secondary differentiated thyroid carcinoma in childhood cancer survivors

Hanneke M van Santen1 , Erik K Alexander2, Scott A Rivkees3, Eva Frey4, Sarah C Clement5, Miranda P Dierselhuis6, Chantal A Lebbink 1, Thera P Links7, Kerstin Lorenz8, Robin P Peeters9, Christoph Reiners10, Menno R Vriens11, Paul Nathan12, Arthur B Schneider13 and Frederik Verburg14

1Department of Pediatric Endocrinology, Wilhelmina Children’s Hospital, University Medical Center Utrecht, and Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands, 2Department of Endocrinology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA, 3Department of Pediatrics, University of Florida, Florida, USA, 4Department of Pediatric Oncology, Vienna, 5Department of Pediatrics, Free University Hospital Amsterdam, Amsterdam, the Netherlands, 6Department of Pediatric Oncology, Princess Máxima Center for Pediatric Oncology, the Netherlands, 7Department of Endocrinology, University of Groningen, University Medical Center, Groningen, Netherlands Department of endocrinology, UMCG, Groningen, Netherlands, 8Department of Visceral-, Vascular-, and Endocrine Surgery, Universityclinic Halle, Germany, 9Department of Endocrinology, Erasmus Medical Center, the Netherlands, 10Department of Nuclear Medicine, Correspondence Würzburg, Germany, 11Department of Endocrine Surgery, UMC Utrecht, Netherlands, 12Department of Pediatrics, should be addressed The Hospital for Sick Children, University of Toronto, Toronto, Canada, 13Department of Endocrinology, Diabetes, to H M van Santen and Metabolism, University of Illinois at Chicago, Chicago, Illinois, USA, and 14Department of Radiology and Nuclear Email Medicine, Erasmus Medical Center, Rotterdam, the Netherlands h.m.vansanten@ umcutrecht.nl

Abstract

The incidence of differentiated thyroid carcinoma (DTC) has increased rapidly over the past several years. Thus far, the only conclusively established risk factor for developing DTC is exposure to ionizing radiation, especially when the exposure occurs in childhood. Since the number of childhood cancer survivors (CCS) is increasing due to improvements in treatment and supportive care, the number of patients who will develop DTC after surviving

European Journal of Endocrinology childhood cancer (secondary thyroid cancer) is also expected to rise. Currently, there are no recommendations for management of thyroid cancer specifically for patients who develop DTC as a consequence of cancer therapy during childhood. Since complications or late effects from prior cancer treatment may elevate the risk of toxicity from DTC therapy, the medical history of CCS should be considered carefully in choosing DTC treatment. In this paper, we emphasize how the occurrence and treatment of the initial childhood malignancy affects the medical and psychosocial factors that will play a role in the diagnosis and treatment of a secondary DTC. We present considerations for clinicians to use in the management of patients with secondary DTC, based on the available evidence combined with experience- based opinions of the authors.

European Journal of Endocrinology (2020) 183, P1–P10

Introduction

The incidence of differentiated thyroid carcinoma (DTC) for developing DTC is exposure to ionizing radiation, has increased substantially over the past several years especially when the exposure occurs in childhood (2, 3). due to increased patient and clinician awareness as well The consequences of exposure to radioactive iodine as increased use and sensitivity of neck ultrasound (1). have been described extensively after the Chernobyl Thus far, the only conclusively established risk factor disaster, where no adequate measures were taken to limit

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-20-0237 European Journal of Endocrinology https://eje.bioscientifica.com of malignancybaseduponclinical riskfactorsofwhicha factors, including the estimated pre-surgical likelihood indeterminate thyroid nodulesare influenced byseveral for state thatdecisionsregarding theextentofsurgery and therapeutic measures . As such, both ATA documents and overallprognosismustbereflectedinthediagnostic DTC. Furthermore, the histologic type, molecular etiology, different thanwhencomparedtopatientswithsporadic malignancy maybe of patientswithDTCasasecondary American ThyroidAssociation(ATA) thattheriskprofile stipulated inboththeadultandpediatricguidelinesof of childhoodcancerorradiationexposure.However, itis testing, stagingandtreatmentofpatientswithahistory childhood, includingrecommendationsforthediagnostic develop DTC as aconsequenceof cancer therapy during guidelines offernospecificdistinctionforpatientswho account the unique circumstances of CCS. Certainly, these 13 adult DTC,dependingontheageatDTCdiagnosis( usually followestablishedguidelinesforpediatricor previous childhoodmalignancy, treatmentforDTCwill a patientafterradiationexposureforthetreatmentof cancer) willriseinparallel.WhenDTCisdiagnosed thyroid childhoodcancer(secondary DTC aftersurviving it isexpectedthatthenumberofpatientswhowilldevelop improvements intreatmentandsupportivecare( (NBL) ( therapy with DTC hasalsobeendescribedtooccurafterradionuclide ( thyroid cancerof3.8(95%CI,2.7to5.1wasobserved) chemotherapy alone,astandardizedincidenceratiofor with chemotherapy. treated with Among 1344 survivors has beenreportedtobeincreasedinCCStreatedsolely ( for DTC chemotherapy with radiation has been observed (CCS), anon-synergistic(additive)associationof after radiation exposure. In childhood cancer survivors the riskremainselevatedforaslong50yearsormore long: exposure andthedevelopmentofDTCcanbevery and declines thereafter. Thelatency between radiation linearly through2–4Gy, levelsoffbetween10and30Gy, for DTC.TherelativeriskdevelopingDTCincreases to afieldincludingthethyroidglandareatincreasedrisk increase wasseenaftertheFukushimameltdown( release andimmediateexposurelimitingactions,nosuch 5 thyroidcarcinoma ( incidence ofpapillary wasobserved I-131 exposure and, consequently, aclear increase in the 3 ). Incontrast,asaconsequenceofsmallerradiation ). Comparedtothegeneralpopulation,riskforDTC Position Statement , 14 Since thenumberofCCSisincreasingdueto Children whohavebeenexposedtoexternalradiation ). Unfortunately, theseguidelinesdonottakeinto 8 , 9 ). 131 I-MIBG inchildrenwithneuroblastoma H MvanSantenandothers 10 6 ). , 11 12 7 4 ), ). , , 17 not yetbeenshowntoaffectclinicalbehavior( DTCmaybeimportant,althoughthesehave secondary Furthermore, differencesingeneticcharacteristicsof thorough literaturesearch performedfortheIGHG For thepresentpaper, recent wereferto thevery Methods carried outinaccordancewithapplicableguidelines. diagnostic ortherapeuticprocedures,theseshouldbe Furthermore, whereverthepresentdocumentrefers to these shouldbegivenpriorityoverthepresentdocument. provide specificevidence-basedguidanceforDTCinCCS, high-level evidenceislacking.WhenfutureDTCguidelines expert levelrecommendationsforclinicianstousewhere Therefore, theaimofpresentdocumentistoprovide and herewesummarizethecontentofthesediscussions. related to DTCtreatment after diagnosis were discussed, the processofdefiningIGHGrecommendations,topics and treatment of radiation-induced DTC in CCS. During lack ofevidenceabouttheoptimaldiagnosticprocedures for developingthyroidcancer( Group (IGHG)recommendationsforscreeningCCSatrisk performed fortheInternationalGuidelinesHarmonization may beassociatedwithareductioninlifeexpectancy. DTC treatment(suchasfurthersubsequentmalignancies) therapy andthetreatmentpotentiallateeffectsof malignancyandits cumulative impactoftheprimary DTC aloneisunlikelytoreducelifeexpectancy, the ( individuals, isassociatedwithanormallifeexpectancy even thoughDTCinmostpatients,especiallyyounger an unfavorable prognosis, canaffect management ( with asecondmalignancywhilestillyoung,suchasfearof the additionalpsychologicalconsequencesofbeingfaced may resultinsideeffectswhichlimitDTCtreatment. Also, malignancy example, thetreatmentofanypriorprimary differ fromtheapproachinsporadicDTCpatients.For As aconsequence,thisprocesscouldorperhapsshould DTC. may affectthediagnosisandtreatmentofsecondary considerations whichneedtobeconsideredand to basesuchaninclusionon. guidelines because there is insufficient evidence on which stratification systemusedtoguidetreatmentinthe ATA ofradiationexposureisnotincludedintherisk a history ofradiationisexplicitlynamedasone.However,history cancer survivors DTC treatmentinchildhood 18 ). Another uncertain factor is thepatients’ prognosis – ), datadonotexistspecificallyforCCS.Eventhough There areseveralmedicalandpsychosocial During the structured literature search that was Downloaded fromBioscientifica.com at09/29/202109:05:48AM 19 ), we identified a distinct ), weidentifiedadistinct 183 :3 Table 1 15 , P2 16 via freeaccess ). ). ,

European Journal of Endocrinology for benignthyroidlesions, individualsexposedto such aspatientswhohad receivedradiationtherapy evidence wasextrapolated fromotherpopulations of current age. When evidence was lacking for CCS, who were at least 2 years post-treatment, irrespective treated for cancer initially diagnosed up to an age of 21 abstraction forms.CCSweredefinedasindividuals studies and abstracted data using standardized data- in thesearch. Two independent reviewersselectedthe suggested relevantpapersthatmayhavebeenmissed was used to identify additional articles, and experts relevant titlesandabstracts.Manualcross-referencing heading termswereusedtoidentifyallpotentially search wasperformed.Keywordsandmedicalsubject all relevantliterature,anEnglishlanguagePubMed recommendations basedonthesequestions.To identify literature withtheintentofdevelopingconsensus areas ofconcordancethatwerecontroversialinthe guidelines as well asin existing DTC surveillance were developedtoaddressareasofdiscordance evaluated. Subsequently, focusedclinicalquestions and youngadolescentcancer(CAYAC) were survivors inchildrenrecommendations forDTCsurveillance Kingdom ChildhoodCancerStudyGroup(UKCCSG) Childhood OncologyGroup(DCOG)andUnited between theChildren’s OncologyGroup(COG),Dutch several stages.First,concordancesanddiscordances guideline developmentfortheIGHGgroupinvolved recommendations ( Psychological aspects Risk forcardiotoxicityand Possibility ofthepresence Previous exposureto Previous radiationdose Issue Table 1 Position Statement levothyroxine therapy prescribing syndrome predisposition of agenetic childhood cancer toxic agentsforthe and treatment from priordiagnostics Issues specificforchildhoodcancersurvivorsdevelopingsubsequentdifferentiatedthyroidcancer. 19 ). Inshort,theevidence-based Fear forunfavorableprognosissimilartothepreviouscancer Anthracycline chemotherapyagentsorchestirradiationmay Possible underlyinggeneticmutationmaybepresentboth Chest irradiationincreasestheriskforbreastcancer Total bodyirradiationor Alkylating agentsandabdominalirradiationincreasetherisk Bleomycin increasestheriskforpulmonarydysfunction High cumulativeradiationdose Example increase theriskforcardiotoxicity susceptibility todevelopcancer thyroid cancermayindicateagermlinegenetic cancer duringchildhoodandsubsequentlydevelops malignancy. Thefactthatanindividualalreadyhashad causing thechildhoodmalignancyandthyroid risk forbone-marrowtoxicityandtertiarymalignancies for gonadaldysfunction H MvanSantenandothers 131 I-MIBG treatmentincreasesthe this document. the considerationsasformulated inthefinalversionof electronic communication. All of the authors agreed with DTC. Discussionsoncontroversial pointswereheldvia whom haveextensiveexperienceinthecareofpediatric board-certified nuclear medicine physician (FAV), both of board-certified pediatric endocrinologist (HvS) and a in thetreatmentofDTC.Thiseffortwaschairedby a external specialistswithspecificexpertiseandexperience IGHG guidelinedocument,supplementedwithrelevant produced byparticipantsinthegroupinvolved arrived atbyconsensusamongthepanelmembers. of theevidenceinformingeachrecommendationwere the strengthofeachrecommendation,andquality evidence and expert opinion. Final recommendations, basedonformulated recommendationsforsurveillance (GRADE). Panelmembersdiscussedtheevidence and Development andEvaluationsWorking Group and the Grading of Recommendations, Assessment, the AmericanHeartAssociation(DataSupplement) Recommendations andLevelofEvidencecriteria methods includingtheApplyingClassificationof Childhood CancerGroupandtheIGHGusingexisting methods developedbyexpertswithintheCochrane were gradedaccordingtoevidence-basedmedicine the evidence and the strength of the recommendations bombs, andpatientswithsporadicDTC.Thequalityof radiation asaconsequenceofnuclearfalloutoratomic cancer survivors DTC treatmentinchildhood The considerationspresentedhere( The psychologicalimpactofbeing Consider keepingTSHconcentrations May influencethedecisiontouse May increasetheriskforadverse Avoidance, whenpossible,ofusing Possible consequence Downloaded fromBioscientifica.com at09/29/202109:05:48AM being diagnosedwithsporadicDTC malignancy maybehigherthan diagnosed withDTCassecondary suppressive range in thelowernormalbutnot third malignancy regards totheriskdevelopa adjuvant treatmentwithI-131 for DTC effects ofI-131inthetreatment the diagnosticsofDTC CT-scanning orlow-doseI-131in https://eje.bioscientifica.com 183 :3 Table 2 ) were P3 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com with thyroidultrasound.Instead, itisrecommendedthat stress, itiscurrentlynotadvised toscreenallCCSatrisk diagnostic andsurgicalprocedures andpsychological number offalse-positiveresults, followedbyunnecessary risk with thyroid ultrasound may result in a considerable of thyroidnodulesishigh( asspecificity forthedetection them duringsurvivorship, for allCCSwhenvisitingthephysician who caresfor recommended asroutinepartofthephysicalexamination thyroid glandorbyultrasound.Neckpalpation is of the advantages and disadvantages of DTC surveillance. in consultationwiththeCCSaftercarefulconsideration shouldbemadebythehealthcare provider surveillance recommended that thedecision to undergoperiodic who receivedtherapeutic to externalradiationandneuroblastomasurvivors whosethyroidglandwasexposed reasonable insurvivors forDTCis it wasnonethelessconcludedthatsurveillance ordecreasesDTC-relatedmorbidity,DTC-related survival positivelyimpacts intensified thyroidcancersurveillance was foundthatnodirectevidenceexistsastowhether depth bytheIGHGthyroidcancergroup ( be screenedforthisdiseasehasbeendealtwithin morbidity andmortality( been showntohavepositiveeffectonrecurrencerate, which maybefavorableasearlydetectionofDTChas at asmallertumorsizeand/orlessadvancedstage( the neckisnoticed.ThismayresultindiagnosisofDTC swift medicalattentionwhenalumporlymphnodein increased awareness,mostCCSaremorelikelytoseek to theirpriorexperiencewithmalignantdiseaseand clinic.Due screened forDTCinanout-patientsurvivor ultrasound, becausemostCCSwillbeseenregularlyand be foundonscreening,eitherbypalpationorthyroid however, amalignantthyroidnodulewillfrequently lymphnode.InCCS, a persistentlyenlargedcervical children withDTCmaypresentmorefrequently the patient’s peers.WhencomparedtoadultswithDTC, neck, detected by the patient, the patient’s familyor the non-irradiated patient is a growingnodule in the surveillance. consideration oftheadvantagesanddisadvantagesDTC healthcare provider inconsultationwiththeCCSaftercareful shouldbemadebythe decision toundergoperiodicsurveillance Consideration 1 Screening Position Statement Screening forDTCmaybeperformedbypalpatingthe The questionofwhetherCCSatriskforDTCshould The mostcommonclinicalpresentationofDTCin

: In CCSatriskforthyroid carcinoma, the 21 ). 22 131 ). AsscreeningallCCSat I-MIBG. Itwasfurther H MvanSantenandothers 19 ). Whileit 20 ), Diagnostics 1. InCCSatriskforthyroidcarcinoma,thedecisionto Screening thyroid cancerinchildhoodsurvivors. Table 2 10. TreatmentforDTCinCCSshould occurinanexperienced Organization ofcare 9. ForCCSwhodevelopasecondaryDTC,thepsychological Psychosocial aspects 8. AsCCSwhodevelopasecondaryDTCmaybeatincreased 7. SinceCCSarelikelytobeatincreasedriskofcomplications 6. ThemedicalhistoryofCCSshouldbeconsideredcarefully Patient characteristicsandbackgroundthatmayaffect 5. Thereisinsufficientgeneticorclinicalevidencetosupport Clinical behavior 4. InCCSwithastrongsuspicionordiagnosisofDTC,further 3. Incaseofasuspiciousorunclearbiopsycytologyresult, 2. Ifasuspiciousthyroidnoduleisdetectedinpatientwho additional diagnosticsorsurgicalprocedures. experienced thyroid radiologist, to minimize unnecessary done inacenterwithexpertisethyroidcancerbyan ultrasound ischosenasscreeningmodality, thisshouldbe ( well astheneedsand wishes ofthesurvivor with, forexample,thyroidultrasoundinthelocalteamas considerations onthepresenceofspecificexpertise andshouldinclude be madetogetherwiththesurvivor the decisiontoscreenwithpalpationorneckultrasound cancer survivors DTC treatmentinchildhood of DTCsurveillance careful considerationoftheadvantagesanddisadvantages healthcare providerinconsultationwiththeCCSafter undergo periodicsurveillanceshouldbemadebythe previously namedconsiderations include a(pediatric)oncologist toenabletheaddressingof thyroid centerandthemultidisciplinary teamshould paid toprovidingpsychologicalsupport impact willbesubstantialandspecialattentionshould purpose ofthyroidremnantablation or fortreatmentofadvanceddisease,butnotonlythe I-131 therapyshouldbegiveneitherasadjuvanttreatment I-131 therapyisadvocatedinthispopulation.Ingeneral, risk fordevelopingother(tertiary)cancers,restrictiveuseof in CCS possibility shouldbeperformedbeforethyroidsurgery during andafteranesthesia,acarefulevaluationofthis therapeutic modalities effects frompriortreatmentmayelevatetheriskofsome in choosingDTCtreatment,sincecomplicationsorlate treatment DTC inCCS a moreaggressivetreatmentstrategyforsecondary necessary, MRIisthepreferredimagingmodality Should anatomicalmedicalimagingnonethelessbe preoperative diagnosticsshouldbekepttoaminimum. considered diagnostic hemi-thyroidectomyshouldbestrongly cytology ofthislesionsisrecommended has beenexposedtoneckradiation,fine-needleaspiration Considerations forthetreatmentofdifferentiated Downloaded fromBioscientifica.com at09/29/202109:05:48AM 183 :3 19 ). Ifthyroid

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European Journal of Endocrinology one to opt for surgical intervention. Alternatively,one tooptforsurgicalintervention. more ofradiation,couldcause several factors,includinghistory stating that,forindeterminate FNACofthyroidnodules, This is consistent with the current ATA recommendation certainty intheformofhistologicalanalysisnodule. perform adiagnostichemithyroidectomyinordertoobtain and wishesoftheindividualCCS,itmaybepreferable to of an indeterminate FNAC result,depending on the needs lymph nodes, or signs of extracapsular invasion). In case margins, missinghalosign,microcalcifications,suspicious for malignancy (i.e. showing features such as irregular unless ultrasoundinvestigationishighlysuspicious FNAC in lesions individuals, diagnostichemithyroidectomyispreferred. given the with sonography may be advised. In Bethesda 5 lesions, suspicious featuresonultrasound,followingthenodule For subjectswithBethesda3and4lesions,no molecular testingmaybelessreliableasarule-outtest. for anoduletobemalignantmaydifferentinCCS, DTC. Sincethefactthatpre-testriskofmalignancy should be different in CCS cancers compared to sporadic classification 3,4or5),additionaldiagnostictesting nodules withanindeterminateFNACresult (Bethesda evidence that,incaseofcomparativelysmallthyroid characteristics suspiciousofmalignancy. Thereisno autonomous nodules, which on ultrasound may show should beperformedinordertoruleoutthepresenceof function testsshowthyrotoxicosis,thyroidscintigraphy preferably underultrasoundguidance( with orwithoutaspiration(FNAC)isrecommended, node enlargement),cytologicalevaluationbyfine-needle ultrasound featuresand/orconcurrentsuspiciouslymph for thyroidmalignancy( lymph nodes,isadvised.Incaseofsonographicsuspicion of theneck,includingthyroidglandandcervical necessary, MRIisthepreferred imagingmodality. minimum. Shouldanatomicalmedicalimagingnonethelessbe preoperative diagnosticsshouldbekepttoa of DTC,further Consideration 4 strongly considered. or cytologyresult, diagnostichemithyroidectomy shouldbe Consideration 3 needle aspirationcytologyofthislesionsisrecommended. in apatientwhohasbeenexposedtoneckradiation,fine- Consideration 2 Diagnostics Position Statement Despite a history ofirradiation,wedonotrecommend Despite ahistory If athyroidnoduleispalpatedinCCS,anultrasound a priori : : increasedriskforDTCinirradiated : < In CCS with a strong suspicion or diagnosis

Incaseofasuspicious or unclearbiopsy If a suspiciousthyroid nodule is detected 1.0 cm in children or adult CCS, > 1 cmand/orsuspicious H MvanSantenandothers 13 ). Ifthyroid

an excellent negative predictive value and a very high an excellentnegative predictive value and a very Tc-99m-methoxy-isobutyl-nitril (MIBI)scintigraphyhas for thenextdiagnosticstep.Molecularimagingsuchas results, evidence is lacking that it has direct consequences finding aBRAFmutationinBethesda5cases,butforother Molecular testing may be of additional value in the case of expression orgenesequencingclassifier(whereavailable). with genetictestingontheFNACspecimenagene in theCCSsetting.Additionaldiagnosticsmaybedone however, these tests have not been studied specifically certainty, additionaldiagnostictestsmaybeconsidered; ifpossible. rather avoidsurgery they donothaveanewmalignancy, whileotherswould desire for the greatest possible degree of certainty that of shareddecision-making.SomeCCSwillhaveastrong This decisionshouldbediscussedwiththepatientaspart be consideredinsteadofdiagnostichemithyroidectomy. frequent follow-upwith6–12monthlyultrasoundcan DTC will, in most cases, be higher than the exposure of DTC will,inmostcases,be higherthantheexposureof exposure ( were associatedwiththeir previous low-doseradiation young adultsfollowingthe Chernobylaccident,which expression havebeenreportedinDTCchildrenand sporadic cases.Subtle,yetsignificant,differencesingene suggest thatradiation-inducedDTCbehavesdifferently to RET/PTC rearrangements),thereisinsufficientevidence to have adifferentgeneticprofilethansporadicDTC(more DTCinCCS. secondary a more aggressiveevidence to support treatment strategy for Consideration 5 Clinical behavior dose chestCTscanningmaybeconsidered. MRI ispreferred.Fordetectionoflungmetastases,low- sufficient imaging. When additional imaging is required, lymph nodes,ultrasoundinvestigationwillusuallybe cases where there are known or suspicions of locoregional radiation attimeoftreatmentfortheirpreviouscancer. In may alreadyhavebeenexposedtohighdosesofchest scanning inCCSforpreoperativestagingofDTC. We recommendagainsttheacquisitionofadditionalCT advised inchoosingthemodalityforpreoperativeimaging. tests canbeperformeddependsonlocalavailability. to haveoverlookedaDTCcase)( unlikely value (meaning that a negative test result is very sensitivity; however, ithasalimitedpositivepredictive cancer survivors DTC treatmentinchildhood For those who desire the greatest possible degree of While radiation-induced DTC has been shown to While radiation-inducedDTChasbeenshownto In casedisseminateddiseaseissuspected,caution 25 ). The radiation exposure of CCS at risk for ). Theradiationexposureof CCSatriskfor :

There is insufficient genetic or clinical Downloaded fromBioscientifica.com at09/29/202109:05:48AM https://eje.bioscientifica.com 23 , 183 24 ). Whichofthese :3 P5 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com cytotoxic chemotherapy, and/or cranial,cervical malignancy,primary previoustreatmentmayinclude medical history. Dependingonthenatureoftheir childhood cancerusuallyhaveanextensivesurvived purpose ofthyroid remnant ablation. treatment orfortreatment ofadvanceddisease,butnotforthe In general,I-131therapyshouldbegiveneitherasadjuvant restrictive useofI-131therapyisadvocatedinthispopulation. cancers; may beatincreased riskfordevelopingother(tertiary) Consideration 8 inCCS. thyroid surgery before evaluation ofthispossibilityshouldbeperformed risk ofcomplicationsduringandafter Consideration 7 the riskfortoxicityofsometherapeuticmodalities. complications or late effects from prior treatment may elevate be considered carefully inchoosingDTCtreatment, since Consideration 6 affect treatment Patient characteristicsandbackgroundthatmay radiation-induced DTCinchildrenandadultCCS. of interesttocomparethedifferencesingeneticsbetween correlated withclinicalbehavior. Inthislight,itwouldbe induced DTCinCCSmustbeunraveledfurtherand of thetumor. based ongeneticcharacteristicsorclinicalbehavior recommend more aggressive treatment for DTC in CCS evidence thatitsprognosisisworse( is insufficientevidencetosubstantiatethisandthereno DTC ismoreaggressivethansporadicDTC,todatethere studies suggestingthatbehaviorofradiation-induced be determinedinfuturecohorts.Althoughtherearesome to significance andimplicationsofthesefindingswillhave mutations whoweretreatedwithradiotherapy( with and without P/LP was similar between survivors neoplasm incidence ofdevelopinganysecondary RB1 mutation carriers, although the overall cumulative cancer developedinSUFU,PTCH1,TP53,BRCA2,and whole-genome sequencing.Inthiscohort,thyroid genes to their second neoplasm risk was evaluated using pathogenic (P/LP)mutationsincancerpredisposition the contribution of pathogenic/likely cancer survivors, in thegeneticpatternofDTC.Inarecentstudy3006 be questionedwhetherthiswillleadtofurtherdifferences the thyroidinpopulationChernobyl,anditcan Position Statement Children, youngadolescents andadultswho In thecomingyears,geneticlandscapeofradiation- In ouropinion,currentevidenceisinsufficientto : : :

SinceCCSare likelytobeatincreased

As CCS who develop a secondary DTC As CCSwhodevelopasecondary The medical history ofCCSshould The medicalhistory H MvanSantenandothers

anesthesia , 28 , 29 ). , acareful 26 ). The ). The

These potentialcardiacriskfactorsmustbetakeninto function andevencardiacfailurelaterinlife( cardiac problems,suchasdecreasedleftventricular or radiationtothechestduringchildhoodmayinduce Treatment withanthracyclinechemotherapeuticagents Cardiac effects performing surgery. reference totheactualfunctionalorganstatus,before anesthesia evaluationshouldbeperformed,with anesthesia ( at increasedriskofcomplicationsduringandafter planning anesthesia as thesepatientsare likely to be effects laterinlifemustbetakenintoaccountwhen adversepotential tocausecardiacorpulmonary in thetreatmentofDTC( These formertherapiesmayinfluencedecision-making thoracic radiationtherapy, ortotalbodyirradiation. pulmonary function shouldalwaysbeevaluatedinCCS pulmonary with previousbleomycintreatment ( fibrosis, especiallyifitisgivenincombination pulmonary metastasesis pulmonary patients withextensivemiliary lethal adverseeffectsofradioiodine therapyinDTC Although infrequent, one of the mostserious and potential bleomycin or thoracic radiation therapy ( after treatmentwith in Hodgkinlymphomasurvivors late effects in CCS may occur,Pulmonary for example, Pulmonary effects growth andminimizingcardiacrisk. strike areasonablebalancebetweenminimizingDTC suboptimal fromaDTCperspective,thiswillnonetheless term medianTSHlevelbelow2mU/L( to keepTSHlevelsinthelowernormalrange,withalong- nature ofDTCallowsadosinglevothyroxinetherapy therapy notbeadvisable,thecomparativelyindolent suppressive levothyroxinetherapy. Shouldsuppressive cardiotoxic treatmentbeforeintroductionofTSH cardiac functioninallCCSwithDTCwhohavereceived treatment. Forthisreason,weadviseevaluationof for cardiacproblemsduetopreviouschildhoodcancer may be unfavorable in patients alreadyatincreasedrisk as diastolic dysfunction and atrial tachycardia ( established, hasbeenshowntohavecardiaceffectssuch intermediate risk DTC until a disease freestatushasbeen therapy, whichisindicatedforhighandsome suppressive levothyroxinetherapy. TSHsuppressive account whendecidingontreatmentforDTCwithTSH cancer survivors DTC treatmentinchildhood 30 ). Forthisreason,inallCCS,acareful Downloaded fromBioscientifica.com at09/29/202109:05:48AM Table 1 ). Forexample,their 183 37 34 ). Forthisreason, :3 ). Whileperhaps 35 33 31 , ). This , P6 32 36 via freeaccess ). ). ).

European Journal of Endocrinology has hadcancer during childhoodand subsequently DTC patients( evidence ofanincreasedincidence inpost-radioiodine glandandbreast)wherethereissome colon, salivary the caseformanyothermalignancies (stomach,bladder, activity andincidenceofdisease;however, thisisnot relationship between the cumulative administered I-131 ( been describedwithanincreasedincidenceof2.7–8.7% malignanciesafterradioiodine therapyhas primary In sporadicDTCpatients,theoccurrenceofsubsequent Risk oftertiarymalignancies of remainingdisease. case ofalow-orintermediate-riskDTCwithoutevidence from adjuvantpostoperativeradioiodinetreatmentinthe may beareasontoconsiderpostponingorabstaining cancer,for their primary the desire for future pregnancies risk forprematureovarianinsufficiencyduetotreatment radioiodine maybenecessary. AsfemaleCCSmaybeat after therapyandincaseasecondtreatmentwith allow forasufficientdecayofanyremainingradioiodine at least6monthsafterradioiodinetherapyinorderto the administrationofradioiodinetherapy. males, werecommend considering sperm banking before the possibilityofsucheffectsoccurring.Inpost-pubertal patients and/orparentsshouldbecounseledregarding be assessedbeforeradioiodineisadministeredandall Depending onage,werecommendthatgonadalfunction in serumAMHconcentrationsorpregnancyrate( showed no abnormalities a Dutch cohort DTC survivors arecentstudyof therapy maydecreaseovarianreserve, While thereissuggestionintheliteraturethatI-131 transient maleandfemalegonadaldysfunction( radiation ( agents, suchasalkylatingagentsandabdominal/pelvic or testicular failure due to treatment with gonadotoxic CCS maybeatriskforprematureovarianinsufficiency Gonadal damage function shouldbemandatory. additional courses ofI-131therapy, evaluating pulmonary the administeredI-131activity( radioiodine uptakearenotexceededwhilemaximizing toascertainthatsafetylimitsforpulmonary dosimetry Furthermore, it isadvisabletoperform pre-therapeutic disease. pulmonary who developmetastaticmiliary 43 Position Statement , It iscurrentlyadvisedthatpregnancybedelayedfor 44 ). Foracutemyeloidleukemia,thereisaproven 39 , 40 42 ). Radioiodinehasbeenassociatedwith ). Thefactthatanindividual already H MvanSantenandothers 38 ). Beforedecidingon 42 41 ). ). regarding the administration of postoperative radioiodine cancer ( may alreadybeatincreasedrisktodevelopbreast of chest irradiation For instance, CCS with a history body irradiationor previous treatments, such as previous exposure to total radioiodine exposureduetoextravulnerabilityfrom risk ofdevelopingathirdsubsequentmalignancyafter Furthermore, CCSwithDTCmayhaveanincreased with theionizingradiation generating agent, radioiodine. taken intoaccountwhendecidingonadjuvanttreatment This possibleincreasedgeneticsusceptibilitymustbe cumulative activities(radiation dose)ofI-131-MIBG, whoweretreatedwithhigh for neuroblastomasurvivors marrow suppressiveagents. Thismayalsobethecase body irradiationorafter treatment withotherbone- of childhood leukemia, after total especially in survivors In CCS,thebonemarrowmaybeparticularlyvulnerable, shown toresultinatransientdecreaseofplatelets( insignificant. Radioiodinetreatmenthasalsobeen however, even these are rare and usually clinically common are mild leucopenia and thrombocytopenia; after therapy and are reversible within 3months. Most commonly, the effects occur within the first 4–6weeks and are hardly ever of a clinically relevant magnitude. Most rare,evenafterhighactivity therapy( therapy arevery Immediate bone-marrowproblemsafterradioiodine Myelotoxicity of neckultrasound. levels andregularassessmentofthethyroidbedbymeans decreasing, thepatientcanbefollowedbymonitoringTg no metastatic disease is found and serum Tg is stable or CT (togethercalledSPECT/CT)orI-124withFDG/PET. If I-123 combinedwithintegratedsinglePET(SPECT)and thyroid bedincludeadiagnosticwholebodyscanwith whether anymetastaticdiseaseispresentoutsideofthe for postoperativeradioiodinetherapyortodetermine methods, althoughexpensive,tosafelyselectpatients disease aftersurgery, I-131treatmentisessential.Possible risk patients,butforpatientswithresidualinoperable therapy inCCS.Itcanlikelybeavoidedmanylow- or geneticmechanism instead of a causalrelation ( also beforeDTCdiagnosis,suggestingacommonetiologic tumorsisnotonlyelevatedafter,non-DTC primary but cancer. In fact, it has been shown that the incidence of susceptibility orpredispositionsyndrometodevelop develops thyroidcancermayimplicateagermlinegenetic cancer survivors DTC treatmentinchildhood Hence weproposeanabundanceofcaution 46 , 47 ). 131 I-MIBG (thesecondhit-model). Downloaded fromBioscientifica.com at09/29/202109:05:48AM https://eje.bioscientifica.com 183 :3 P7 49 45 48 via freeaccess ). ). )

European Journal of Endocrinology https://eje.bioscientifica.com cancer is(inmostcases)different interms of behavior, thyroid understandsthatsecondary that thesurvivor be paidtotheissuespresented previously. Itiscrucial addressing ofpreviously namedconsiderations. team shouldincludea( in anexperiencedthyroid Consideration 10 Treatment ofDTCinCCS the sameageandgender( impaired in DTCpatients compared to apopulation of under 45yearsofageatdiagnosis,lifeexpectancyisnot most cases.Itcanbestressedthat,especiallyinpatients excellent prognosis,whichenablespositivecounselingin appropriate. Fortunately, thyroidcancerhasan secondary indicated andtotheirparents,care-giverspartnersas oncological counseling of the patient with DTC where reason that special attention should be paid to psycho- can leadtoanxietyandworriesunnecessarily. Itisforthis survivor. Screeningmaygivefalse-positiveresultswhich screening forDTCmustbedoneinagreementwiththe traumatic giventhispriorhistory. Itisforthisreasonthat diagnosis ofDTCinsuchapatientcanbeparticularly and theassociated uncertainties and worries.The disease, itsdiagnosis,hospitalizationfortreatment, closest relatives have already experienced one malignant the patientandhis/herfamily. Thesepatientsandtheir adolescent oradultwillhaveasubstantialimpacton attention shouldbepaidtoproviding psychologicalsupport. the psychologicalimpactwillbesubstantialandspecial Consideration 9 Psychosocial aspects activity ( in thebloodnothigherthanmaximumtolerable be to administer the activity corresponding to the dose 80 Gytometastases( absorbed doseof300Gytothethyroidbedandatleast effective activity which will still lead to a radiation radioiodine therapymayhelptodeterminetheminimum priorto patients withmetastaticdisease,lesiondosimetry should beappliedinthechoiceofI-131activity. In caution having lessthanoptimalbone-marrowreserve, suppression. as MIBGhasalsobeendescribedtocausebone-marrow Position Statement The diagnosisofasecondmalignancyaschild, Especially inpatientswhoareatincreasedriskof In the treatment of DTC in CCS, attention must 38 ). :

: For CCS who develop a secondary DTC, For CCS who develop a secondary

Treatment forDTCinCCSshouldoccur 50 pediatric

, center 18 51 ). ). Anotherapproachcould , and the multidisciplinary , andthemultidisciplinary ) oncologisttoenablethe H MvanSantenandothers

Conclusions specialization inpsycho-oncology. a lateeffectsphysicianandideallypsychologistwith nuclear medicine physician, apathologist, a geneticist, a thyroidexpertradiologist,anendocrinesurgeon, endocrinologists and (pediatric) oncologist, as well teamshouldincludeboth(pediatric) multidisciplinary the previouscancertreatmentandonthyroidcancer, the the factthatexpertiseisneededinmodalitiesusedfor recommended inanexperiencedthyroidcenter. Dueto previously named reasons, treatment for DTC in CCSis malignancy.impact ofhavingasecondary Forallofthe special attentionshouldbepaidtothepsychological modalities requiredforthetreatmentofDTC.Lastly, drugs orradiationtherapyinadditiontothetreatment aware ofthepossibletoxicitypreviousadministered childhood cancer. Thetreatingphysicianshouldbe treatment toxicityandprognosisthanotherformsof Skinner R,WassermanJD,WynnT,and HudsonMM. C M, Ronckers R R, Rijn van K C, Oeffinger M, J E Dijkum van Nieveen J, S Neggers L, R Mulder A, S Huang M, M Heuvel-Eibrink den van A, F, Heinzel Felicetti M, M, V Drozd Goldfarb A, C H, Dinauer S, J L Constine E, Simmons Brignardello E, M, Bardi C L Kremer namely thyroid for surveillance, group cancer working IGHG the of members all thank authors The Acknowledgements the public,commercialornot-for-profitsector. This research did not receive any specific grant from any funding agency in Funding which he is listed as an author. The other authors have nothing to disclose. He was not involved in the editorial or peer-review process of this paper, on Frederik Verburg is Associate Editor of the Declaration ofinterest relevant andthatheorshecancomprehenduse. provided, inatimelyfashion,withtheinformationthatis decision-making (individualizedcare).TheCCSshouldbe procedures forthespecificCCSandincludesin the mostoptimalplanfordiagnosticandtherapeutic we recommendthatthecaregiverindividuallydesigns regarding DTC in CCS. As each case will have unique aspects, literature onlateeffectsinCCSandthepublished caregiver basedonourclinicalexperience,theavailable We can,however, providerecommendationstoguidethe little evidenceuponwhichtobasetheseconsiderations. patients. As DTC in CCS is relatively uncommon, there is DTC inCCSshouldbedifferentcomparedtosporadic It maybequestionedwhetherdiagnosticsortreatmentof cancer survivors DTC treatmentinchildhood Downloaded fromBioscientifica.com at09/29/202109:05:48AM European Journal ofEndocrinology European 183 :3 P8 via freeaccess .

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