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 leukemia and bladder cancer intheDECISION of patientsinthesorafenib group in3.4% (SCCs)occurred Squamous cellcarcinomas of2.3%ineach case. withafrequency vandetanib 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;sorafenib;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: heart failure,thrombocytopenia,andsquamouscellcarcinoma during sorafenibtherapyand 12 months,range6-32),5/29(17.2%) events. patientspresentedrareadverse effects These rareadverse under sorafenibtreatment. in 6 patientswithMTCand lenvatinib disease as second-line treatment in twopatients with progressive patient withadvanced medullary thyroid cancer (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