Copyright© AE&M all rights reserved. Correspondence to: Buenos Aires,Argentina University ofBuenos Aires, 1 DOI: 10.20945/2359-3997000000090: Accepted onOct/30/2018 Received onMar/18/2018 [email protected] Fabián Pitoia 636 trial (3). Acute myeloid and bladder cancer intheDECISION of patientsinthesorafenib group in3.4% (SCCs)occurred Squamous cellcarcinomas of2.3%ineach case. withafrequency arm describedinpatientsonthe staphylococcal sepsiswere and failure, respiratory arrest, pneumonia, respiratory the ZETA aspiration failure, study (2), acute heart In rare. considered patients intheclinicaltrialswere The a in theZETA, DECISION,andSELECTstudies(2-4). inupto90%ofpatients reported well known.Theywere (1). or localapproaches surgery or symptomaticdiseasethatcannotbemanagedwith or distant metastatic disease, and/ locally progressive cancer(MTC)with thyroid (DTC) ormedullary cancer thyroid differentiated radioiodine refractory inpatientswith shouldbeconsidered of thesedrugs Theuse carcinoma. patients withadvancedthyroid T INTRODUCTION original article original Division ofEndocrinology, The profile of adverse events of these drugs isusually ofadverseeventsthesedrugs The profile has led to a radical change in the treatment of has ledtoaradicalchangeinthetreatment he adventofmultikinaseinhibitor(MKI)therapy dverse events that occurred inlessthan5%of dverse eventsthatoccurred Rare complicationsofmultikinase Multikinase inhibitors;rareadverseevents;;vandetanib;thyroidcarcinoma Keywords Endocrinol Metab. 2018;62(6):636-40 be aware ofpotentiallyseriousandrareorunreported effects adverse thatcanbelife-threatening. effectsto adverse inthemajorityofpatients. Although mostofthemaremanageable,westillneedto Conclusions: squamous cellcarcinomaandoophoritiswithintestinalperforationduringvandetanibtreatment. were: ,,andsquamouscellcarcinoma during sorafenibtherapyand 12 months,range6-32),5/29(17.2%) events. patientspresentedrareadverse effects These rareadverse under sorafenibtreatment. in 6 patientswithMTCand disease as second-line treatment in twopatients with progressive patient withadvanced medullary (MTC). Vandetanib was treatment indicated as first-line treatmentto23patientswithdifferentiatedfirst-line thyroid cancerandassecond-linetreatmenttoone these patients was (range 20-70), and 75.9% of them were women. Sorafenib 53 years was prescribed as ofEndocrinology,our Division treatmentwithMKIs. 29(3.8%)received The medianageatdiagnosisof in our hospital. eventsthatoccurred adverse inlessthan5%ofpatientsclinicaltrialsasubsettreated of patientswithadvancedthyroid carcinoma. The aimofthismanuscriptistocommunicaterare Objective: ABSTRACT Erika Abelleira Fabián Pitoia inhibitor treatment The adventofmultikinaseinhibitor(MKI)therapyhasledtoaradicalchange inthetreatment About 3 to 5 years afterAbout 3to5years theapproval ofMKItherapy, welearnedthatMKIsusually lead Subjects andmethods: 1 ,Schmidt Angélica 1 , Fernando Jerkovich Results: During thefollow-up oftreatment (mean13.7 ±7months,median DTC and as second-line treatment inonepatientwith DTC andassecond-line treatment to23patients with as first-linetreatment prescribed disease atthetimeofMKI initiation.Sorafenibwas with MKIs.Allofthemhadprogressive treatment in ourDivisionofEndocrinology, 29(3.8%) received cancer,Out of760patientswiththyroid followedup case-seriesstudy. aretrospective The authorsperformed SUBJECTS ANDMETHODS to theuseof intheclinical settingdue adverse eventsthatoccurred grade ≥3,0)(4). (any grade, 0.4%; encephalopathy syndrome reversible (any grade,1.5%;grade≥3,0.8%),andposterior fistula (grade≥3,0.4%),gastrointestinal hepatic failure (anygrade,4.2%;grade≥3,1.9%), failure acute renal lenvatinibwere: inpatientswhoreceived reported adverse events (3).Rare attributed tothestudydrug infarction diedduetomyocardial on thesorafenibarm describedin2.1%ofcases(3).Only onepatient were The aim of this manuscript is to communicate rare The aimofthismanuscriptistocommunicaterare Out of 760 patients with thyroid cancer followed upwithin 1 , Fernanda Bueno 1 se drugs. 1 , Arch Metab. Endocrinol 2018;62/6 Arch Arch

Arch Metab. Endocrinol 2018;62/6 received treatmentwithmultikinaseinhibitors(MKIs) Table 1. 1). ofpatients(Figure forourcohort not reached was survival adverseevent-free estimated medianrare adverse events.The of MKIsanddevelopmentrare showsthetimebetweeninitiation curve Meier survival inTable presented these 5patientsare 2.AKaplan- adverse events. The characteristics and outcomes of rare range 6-56),5/29(17.2%)patientspresented follow-up (mean13.7±7months,median12 inTable 1.Duringthetreatment can beobserved withMKIs treatment cancerwhoreceived thyroid The baselinecharacteristicsofthe29patientswith RESULTS Events (CTCAE,v5.0). Institute’s CommonTerminology CriteriaforAdverse assessedusingtheNationalCancer Adverse eventswere 3monthsthereafter. 2, 4,8,and12weeksevery chemistry, hematology, at1, andurinalysisperformed parameters,vitalsigns,clinical electrocardiogram including12-lead an assessmentprotocol treatment. diseaseundersorafenib two patientswithprogressive in assecond-line treatment inourcountry) program availableonlyunderthecompassionateuse is currently in6patientswithMTCand lenvatinib (which treatment advanced MTC.Vandetanib wasindicatedasfirst-line Duration ofMKItreatment(months) Second-line treatment First-line treatment Histology Age atdiagnosisofthyroidcancer(years) Gender Variable Median (range) Lenvatinib Vandetanib Sorafenib Vandetanib Sorafenib thyroidcancer Medullary Differentiated thyroidcancer Median (range) Female Male All patientsundergoing MKItherapyfollowed Baseline characteristicsof29patientswiththyroidcancerwho 22 (75.9%) 53 (20-70) 7 (24.1%) 12 (6-56) 23 (79%) 23 (79%) (n =29) 6 (21%) 6 (21%) 2 (7%) 0 (0%) 1 (3%) or arrhythmia leadingtosuddendeath. or arrhythmia failure the heart the eventthatcouldhaveprecipitated anyothermedicationpriorto patient did notreceive she died5monthslater;itwasasuddendeath.This However, anyotherMKItreatment. did notreceive to55%.Thepatient withdrawal, theEFincreased developed.Onemonthaftersorafenib failure heart to25%when was67%,whichdecreased prescription wasalsonormal. Theelectrocardiogram failure. of heart During thisevent,weexcludedothercommoncauses failure. heart She cametoourhospitalwithsevere a stable disease. after sorafenib initiation, we observed withsorafenib800mg/day.was treated Ninemonths cancer,insular thyroid metastatictolungsandbones, A 49-year-old womanwithapoorlydifferentiated Heart failure new lesions (two in the forearm andoneintheear) new lesions(two intheforearm developed SCConhisback, and23monthslater, three Twenty-two monthsaftertheMKI initiation, he tosorafenibtreatment. response metastases withpartial with pulmonary carcinoma thyroid papillary progressive a 70-year-old man withadiagnosisofadvancedand Two patientsdevelopedSCC.Thefirstpatientwas Squamous cellcarcinoma(SCC) to RECIST1.1criteria. according tosorafenibtreatment, response withapartial treatment after30monthsof wasobserved thrombocytopenia at 400 mg/day,was restarted and no evidence of range.Sorafenib count wasagaininthenormal observed. were celllinagereductions marrow butnootherbone other causesofthrombocytopenia, studytoexclude detected. We abonemarrow performed No other bleeding manifestations were resolution. withspontaneous subconjunctival hemorrhage and sorafenibwasdiscontinued.Thepatientpresented (25,000/mm a grade3 thrombocytopenia Fourmonthsaftersorafenib initiation, then prescribed. disease,sorafenib800mg/daywas local unresectable metastases.Dueto local masstogetherwithpulmonary of a computerized tomography showed progression cancer. (FGD)PET/ An18-fluorodeoxyglucose thyroid ofpapillary 63 monthsafterinitialtreatment A 67-year-old womandevelopeddysphagiaanddyspnea Thrombocytopenia The initial ejection fraction (EF) before sorafenib The initialejectionfraction(EF)before Two weeksaftersorafenibwithdrawal,theplatelet Multikinase inhibitors rare adverse events 3 ) developed 637

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. F: female;M: male;CHF: congestiveheartfailure;SCC: squamouscellcarcinoma; VEGFR: vascularendothelialgrowthfactorreceptor;PDGFR- 638 Figure 1. MAPK: mitogen-activatedproteinkinase;RAI: radioiodine. Table 2. control. strict dermatologic andwith totreatment response dosage withpartial at400mg/day initiation, hecontinuesthetreatment Currently,removed. 56monthsaftersorafenib were Multikinase inhibitors rare adverse events 5 4 3 2 1 also diagnosed as SCC. All of them were surgically also diagnosedasSCC.Allofthemwere Characteristicsandoutcomesof6patientswithrareadverseevents(AEs) occurringaftermultikinaseinhibitor(MKI)treatment Age, gender Kaplan-Meier curve showingthe timebetweeninitiationofmultikinase inhibitor(MKI)anddevelopmentof rareadverseevents. Kaplan-Meier curve 70, M 64, M 37, F 67, F 49, F

intestinal perforation intestinal perforation 00 0 04 06 08 0 Thrombocytopenia Diverticulitis and Cardiomyopathy Oophoritis and resections) (4 surgical 4 SCC (CHF) SCC AE 0 Histology Medullary Medullary Papillary Papillary Classic Classic Insular 0 Vandetanib Vandetanib Sorafenib Sorafenib Sorafenib Sorafenib MKI mediastinum lymphadenectomy). Three years afterthe mediastinum lymphadenectomy). Three lymphadenectomy, right laterallymphadenectomy, and with central and left lateral times (total thyroidectomy three surgery cervical MTC. Heinitiallyunderwent 40 The secondcaseisa64-year-old patientwithadvanced developing theAE initiation before Time after (months) 1.5 15 12 22 4 9 60 reinitiation with400 Improvement after withdrawal (800 Recovery after Recovery oophorectomy mg/day) and suspension Outcome β Unilateral salpingo- Arch Metab. Endocrinol 2018;62/6 Surgery Surgery mg/day : platelet-derivedgrowthfactorreceptor 80 affection secondary affection secondary Activation ofMAPK Inhibition of VEGFR Inhibition Mechanism that was probably Bone marrow Inhibition of Inhibition of VEGFR and PDGFR- involved Unknown pathway VEGFR to RAI β β ;

Arch Metab. Endocrinol 2018;62/6 (2-4). rare usuallyconsidered trialsare in prospective vandetanib(2). than30% ofpatientsreceiving more in occurred rash,nausea,and diarrhea, (3).IntheZETAweight loss,andhypertension trial, alopecia,rash, diarrhea, handfootsyndrome, were patients insorafenibtreated adverseeffects reported majority ofpatients. the adverseeventsthatwillinexorablyoccurin ofMKIsinord prescription for the team is always necessary A multidisciplinary DISCUSSION months aftervandetanibwithdrawalduetosepsis. immediately. recurred Cushing's syndrome She died3 oophoritis. Vandetanib wasthen stopped, andthe ofsalpingo- examination alsodescribedthepresence Thepathological toanilealperforation. pain secondary withacuteabdominal at theemergency department without complications,but1yearlater, shepresented She continued with the treatment Cushing's syndrome. ofsignsandsymptoms withimprovement cortisol the24-hoururinary-free shenormalized treatment, After 1 monthof 300 mg/daywasprescribed. vandetanib Therefore, ectopic Cushing'ssyndrome. distant metastasesinherliverandlungsassociatedwith Sixteen yearsaftertheinitialdiagnosis,shedeveloped A 37-year-old womanwasdiagnosedwithMTC. Oophoritis andgastrointestinalperforation generalizedsepsis. patient diedfrom Two monthslater,due toacolonicperforation. the Thepatientwasthenhospitalized acute diverticulitis. duetoevidenceof days later, sorafenibwasinterrupted Forty asasecond-linetreatment. day wasprescribed diseaseandsorafenib800mg/ developed progressive he SCC. After21monthsofvandetanibtreatment, and theotheroverhisouterear. Thebiopsyshowed detected,oneoverhischest were rapid progression twoskintumors with After 15monthsoftreatment, lobe. Thus,vandetanib300mg/daywasprescribed. oftherightlower was locatedinthesubpleuralregion nodewas2.2cminsizeand The largest pulmonary metastasesoccurred. nodes andhepaticpulmonary but 5yearslater, ofmediastinum lymph progression ofesophagusinfiltration, indicated duetothepresence radiotherapy(4500 cGy)was cervical initial treatment, Adverse effects occurring inless than5%ofpatients occurring Adverse effects In theDECISIONtrial,mostcommonly er tomonitorandmanage sorafenib withdrawal, which was probably not related not related sorafenib withdrawal, which was probably asudden deathafter Our patienteventuallypresented of3.2%and1.4%,respectively. failure congestive heart MKIs showedanincidenceofall-gradeandhigh-grade withVEGFR- 10,553 patientswithcancertreated oftheEFaftersorafenibwithdrawal. improvement months aftertheinitiationofsorafenibtherapywith 7 failure Case 1developedsystoliccongestiveheart (7). The patient in overload-induced stress pressure to in the response been implicated as playing a role factor(VEGF)pathwayinhibition(6)has receptor- completely understood,butplatelet-derivedgrowth with oneofourpatients(Case1).Thistoxicityisnot asoccurred failure, dramaticsymptomsofheart very with (5).Patientsmay present failure congestive heart is systolic and diastolic with MKI prescription promote keratinocyte alteration and proliferation keratinocytealteration andproliferation promote Sorafenibseemsto SCC duringsorafenibtreatment. SCC (3).We apatientwhodevelopedskin reported the DECISIONstudy, including7patientswith skin with sorafenib in in 4.3% of patients treated reported ofthedrug. which wassolvedwithadosereduction withgrade3thrombocytopenia, in Case2presented (3).Thepatient reported grade 3or4eventswere No versus9.6%intheplacebogroup. sorafenib arm was 18.4% for the ofthrombocytopenia the frequency (12).IntheDECISIONtrial, for theplacebogroup withsorafenibversus0% in only1%ofthosetreated patients (TARGET occurred Study),thisadverseeffect cellcarcinoma (11),andinrenal the placebogroup withsorafenib versus1%for only 4%forthosetreated was ofgrade3-4thrombocytopenia the frequency patients(SHARPstudy), withsorafenib.In inpatientsbeingtreated presented associated withVEGFRinhibitors(10). cardiotoxicity findings showedsignssuggestiveofchronic histopathologic out,andthepostmortem was ruled disease,Chagas’sandmyocarditis artery coronary infarction, myocardial and cols.(10).Inthisreport, byScheffel wasreported months ofvandetanibtreatment and cols.(9). bySchutz only onecaseinthemeta-analysisperformed in Suddendeathwasreported to theMKItreatment. The meta-analysisofQiandcols.(8)including adverseeventassociated A seriousandinfrequent On the other side, secondary malignancies were malignancieswere On theotherside,secondary Thro Interestingly, after14 failure afatalcaseofcardiac mbocytopenia is another rare adverse effect adverse effect mbocytopenia isanotherrare β (PDGFR- Multikinase inhibitors rare adverse events β ) andvascularendothelial 639

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 640 1. REFERENCES declare. to oftheauthorshavenoconflictsinterests ratories. Therest ring CommitteeBayer. Labo ConsultancyforSanofiandRaffo FabiánPitoiaismedicaladvisor,Disclosure: speakerandStee worseoutcomes. toprevent team isofvitalrelevance medical Therapidcontactwiththetreating threatening. thatcanalsobelife- adverseeffects orunreported and rare ofpotentially serious manageable, westillneedtobeaware in themajorityofp usually lead to adverse events that these drugs learned and vandetanib(n=2)treatment. undersorafenib(n=3) in clinicaltrials)adverseeffects offrequency (lessthan5%interms who developedrare (OR 2.99,95%CI0.85-10.58,p=0.089)(16) incomparisonwithcontrols perforation gastrointestinal theriskof inhibitorsdidnotsignificantlyincrease theuseofVEGFR tyrosine under vandetanibtreatment, However, including300patients inasystematicreview (16). leading tovasoconstrictionandthrombosis hasbeenassociatedwith perforation Theriskofgastrointestinal vandetanib treatment. andsalpingo-oophoritisduring an intestinalperforation cannotbecompletelyexcluded. vandetanib treatment to the Case 5 was related skin SCC in the patient from we donotbelievethisisthecase,possibilitythat target forheadandneckSCC(15).However, although EGFR andVEGFRhasbeenimplicatedasatherapeutic VEGFR-3, andEGFR(14).Indeed,theinhibitionof SCC. Vande to sorafenib,vandetanibwasnotassociatedwithskin with subsequentactivationofCRAF(13).Contrary kinase path activation of the mitogen-activated protein through Multikinase inhibitors rare adverse events

About 3 to 5 years after their approval, we About 3to5yearsaftertheirapproval, ofpatients 5casereports In conclusion,wepresent Finally, the case ofa patient whopresented wereported thyroid cancer. Thyroid. 2016;26(1):1-133. lines foradultpatientswiththyroid nodulesanddifferentiated forov YE, etal. American thyroid associationmanagementguide Haugen BR, Alexander EK,BibleKC, Doherty G,MandelSJ, Niki way and BRAF/CRAF heterodimerization, way andBRAF/CRAFheterodimerization, tanib worksbyblockingRET, VEGFR-2, atients. Althoughmo VEGFR st of them are st ofthemare inhibition, inhibition, . have have - - - - 9. 8. 7. 6. 5. 4. 3. 2. 16. 15. 14. 13. 12. 11. 10.

Schutz FAB, Je Y, Richards CJ, Choueiri TK. Meta-analysisofran of 36clinicaltrials.BrJClinPharmacol.2014;78(4):748-62. asystematicreviewandmeta-analysis tyrosine kinaseinhibitors: cancer patientstreatedwithvascularendothelialgrowthfactor Qi WX, Shen Z, Tang LN, Yao Y. heart Congestive failure risk in Invest. 2010;120(2):472-84. nent ofthemousecardiacresponsetoload-inducedstress.JClin al. Cardiomyocyte PDGFR-betasignalingisanessentialcompo Chintalgattu V, Ai D,LangleyRR,ZhangJ, BanksonJA, Shih TJ, et VEGF therapyforcancer. BrJCancer. 2007;96(12):1788-95. Kamba T, McDonaldDM.Mechanisms effects ofadverse ofanti- cancer. J Thyroid Res. 2011;2011:985780. ated withtyrosinekinaseinhibitortherapyformetastaticthyroid Cabanillas ME,HuMI,DurandJB,BusaidyNL.Challengesassoci thyroid cancer. NEnglJMed.2015;372(7):621-30. sei R,etal.Lenvatinib placeboinradioiodine-refractory versus Schlumberger M, Tahara M, Wirth LJ, Robinson B,BroseMS,Eli blind, phase3trial.Lancet.2014;384(9940):319-28. metastatic differentiated thyroid cancer:arandomised,double- al. Sorafenibiodine-refractory, inradioactive locallyadvancedor Brose MS,Nutting CM,Jarzab B,EliseiR,SienaS,BastholtL,et trial. JClinOncol.2012;30(2):134-41. : a randomized, double-blind phase III et al. Vandetanib inpatientswithlocallyadvancedormetastatic Wells SA, Robinson BG, Gagel RF, DralleH,Fagin JA, Santoro M, meta-analysis. CritRev OncolHematol.2014;89(3):394-403. a systematicreviewand factor receptortyrosinekinaseinhibitors: foration incancerpatientstreatedwithvascularendothelialgrowth Qi WX, Sun YJ, Tang LN,ShenZ, Yao Y. Riskofgastrointestinal per 2012;34(9):1269-76. tion inheadandneck squamouscellcarcinoma.HeadNeck. Kim S. Antitumor effect ofvandetanibthroughEGFR inhibi Klein JD,Christopoulos A, Ahn SM,Gooding WE, GrandisJR, Drug DesDevel Ther. 2015;9:3459-70. al. Selectiveuseofvandetanibinthetreatmentthyroid cancer. Fallahi P, DiBariF, Ferrari SM,SpisniR,MaterazziG,MiccoliP, et mia. JClinOncol.2016;34(20):70-2. of sorafenibfortreatmentFLT3-mutant acutemyeloid leuke ofthe skin related to use al. Extensive Fathi AT, Lin WM, Durazzo T, Piris A, Sadrzadeh H,BernardoL,et Engl JMed.2007;356(2):125-34. M, etal.Sorafenib inadvanced clear-cell renal-cellcarcinoma.N Escudier B,Eisen T, Stadler WM, SzczylikC,OudardS,Siebels 2008;359(4):378-90. Sorafenib inadvancedhepatocellular carcinoma.NEnglJMed. Llovet JM,RicciS,Mazzaferro V, Hilgard P, GaneE,BlancJF, etal. Eur JEndocrinol.2013;168(6):K51-4. lated tovandetanib:acasereport withhistopathologicalanalysis. AL. Toxic cardiomyopathy leadingtofatalacutecardiacfailurere Scheffel RS, Dora JM, SiqueiraDR,Burttet MR, Maia LM,Cerski 2012;30(8):871-7. JClinOncol. endothelial growthfactortyrosinekinaseinhibitors. related mortality inpatientswithcancertreatedvascular domized controlled trials for the incidence and risk of treatment- Arch Metab. Endocrinol 2018;62/6 ------