1 184

P Fallahi and others Endocrine-metabolic effects 184:1 R29–R40 Review of TKIs

THERAPY OF ENDOCRINE DISEASE Endocrine-metabolic effects of treatment with multikinase inhibitors

Poupak Fallahi1, Silvia Martina Ferrari2, Giusy Elia2, Francesca Ragusa2, Sabrina Rosaria Paparo2, Stefania Camastra2, Valeria Mazzi2, Mario Miccoli2, Salvatore Benvenga3,4,5 and Alessandro Antonelli2

1Department of Translational Research and New Technologies in Medicine and Surgery, 2Department of Clinical and Correspondence Experimental Medicine, University of Pisa, Pisa, Italy, 3Department of Clinical and Experimental Medicine, Section of should be addressed Endocrinology, 4Master Program on Childhood, Adolescent and Women’s Endocrine Health, University of Messina, to A Antonelli Messina, Italy, and 5Interdepartmental Program on Molecular & Clinical Endocrinology, and Women’s Endocrine Email Health, University hospital, A.O.U. Policlinico Gaetano Martino, Messina, Italy alessandro.antonelli@med. unipi.it

Abstract

Tyrosine kinase inhibitors (TKIs) are emerging as potentially effective options in the treatment of cancer, acting on the pathways involved in growth, avoidance of apoptosis, invasiveness, angiogenesis, and local and distant spread. TKIs induce significant adverse effects, that can negatively affect patients’ quality of life. The most common adverse events (AEs) include fatigue, hand–foot skin reaction, decreased appetite, nausea, diarrhea, hypertension, vomiting, weight loss, endocrinopaties and metabolic disorders. Patients in therapy with TKIs can develop endocrine-metabolic disorders, including dyslipidemia (~50%), diabetes (~15–40%), and dysthyroidism (~20%). In some cases, patients show an improved glycemia or hypoglycemia. The effects of TKIs on adrenal or gonadal function are still not completely known. It was shown a higher prevalence of subclinical hypocortisolism in patients treated with imatinib, while an increase of cortisol was reported in patients receiving vandetanib. Long-term treatment with imatinib could impact significantly the ovarian reserve and embryo developmental capacity. It is important to evaluate patients, measure European Journal of Endocrinology glucose levels, and manage hyperglycemia. Mild treatment-related hyperglycemia can be controlled modifying the diet and with exercise, while grade 3 and 4 hyperglycemia can lead to dose reductions and/or oral antihyperglycemic therapy. Regarding thyroid dysfunctions, it is recommendable to measure the thyroid-stimulating hormone (TSH)/free thyroxine (FT4) levels before starting the therapy, and every 3–4 weeks during the first 6 months as changes in FT4 levels precede the changes in TSH by 3–6 weeks. Additional studies are necessary to definitely clarify the mechanism of TKIs-induced endocrine-metabolic effects.

European Journal of Endocrinology (2021) 184, R29–R40

Invited Author’s profile Alessandro Antonelli (Professor of Internal Medicine, MD) is Director of the Immuno-Endocrine Section of Internal Medicine, and Head of the Laboratory of Primary Human Cells, University of Pisa, Italy. His principal areas of expertise are autoimmune thyroid disorders, type 1 diabetes, systemic autoimmune disorders, chemokines and cytokines, HCV-associated thyroid disorders and thyroid cancer.

https://eje.bioscientifica.com © 2021 European Society of Endocrinology Published by Bioscientifica Ltd. https://doi.org/10.1530/EJE-20-0683 Printed in Great Britain Downloaded from Bioscientifica.com at 09/30/2021 09:24:38PM via free access

-20-0683 European Journal of Endocrinology (FGFR) areTKreceptors,importantincancerogenesis( Furthermore, RETandfibroblastgrowthfactorreceptor invasiveness, angiogenesis,andlocaldistantspread( pathways involvedingrowth,avoidanceofapoptosis, the treatmentofcancer, actingontheaforementioned multiple activatedTKsisthebestwaytoactagainstcancer. treatment. Forthisreason,theconcurrentinhibitionof TKs couldbeactivated,aswelltheresistancetoTKIs inhibiting onlyonekinasereceptor, othercompensatory https://eje.bioscientifica.com cascade, leadingtoangiogenesis andtumoralgrowth( bond toligandsactivate an intracellular phosphorylation angiogenesis( lympho-angiogenesis andembryogenic can activateangiogenesis,whilethatofVEGFR-3activates VEGFR-1, -2,and-3.VEGFR-1VEGFR-2induction growth factor, that bindtoVEGFR,thatcomprises VEGF-A, VEGF-B,VEGF-C,VEGF-D,andtheplacental ( and theyareconsideredmultikinaseinhibitors( pathways ( TKs, preventingtheactivationofintracellularsignaling ( domains, andaffectTKdependentoncogenicpathways compete withtheATP bindingsitesoftheTKcatalytic receptor (VEGFR),etc.)havebeendeveloped( receptor (EGFR),RAS,vascularendothelialgrowthfactor (Rearranged duringtransfection(RET),BRAF, EGF compounds whichtargetcertainalteredpathways molecular pathogenesisoftumors,therapeutic antitumoral compounds( leading totheideaoftyrosinekinaseinhibitors(TKIs)as been implicatedinoncogenesisdifferenttumors, in various molecules. The altered activation of TKs has regulators, thatcatalyzetyrosineresiduephosphorylation Tyrosine kinases(TKs)aretheprincipalsignalingpathway apoptosis, owingtocellsignalingpathwayalterations. cellular growthrelatedtoanimbalanceinproliferation/ underlying molecularmechanisms( have beenproposed,basedontheunderstandingof and chemotherapy, butinthelast20yearsnewapproaches standard treatmentsincludedsurgery, radiationtherapy Cancer isoneofthemaincausesdeath.Inpast, Introduction 6 3 ). VEGFcontributestoangiogenesis,consistingof Review , 4 TK receptorsarelocatedoncell membranes,andtheir TKIs areemergingaspotentiallyeffectiveoptionsin TKIs arespecifictooneorvarioushomologousTKs, Thanks totheincreasedunderstandingof Malignant carcinomas showanautonomous Angiogenesis has a leading role in embryogenesis Angiogenesis hasaleadingroleinembryogenesis ), inhibiting the auto-phosphorylation/activation of ), inhibitingtheauto-phosphorylation/activation Fig. 1 ). 2 ). P Fallahiandothers 1 ). 3 , 4 ). TKIs 5 ). By 6 6 7 4 ). ). ). ). pathways. TKs, hinderingtheactivationofintracellularsignaling pathways, inhibitingtheauto-phosphorylation/activationof catalytic domains,andaffectTKdependentoncogenic pathways. TKIscompetewiththeATPbindingsitesofTK Multikinase inhibitorsexerciseinhibitoryeffectsonseveral Figure 1 with TKIs. metabolic treatments ( or metabolicdisorderscausedbyantitumoral initial endocrinepathologies,butwithendocrinopathy endocrinologists will probably deal with patients with no to maximizetreatmentbenefits( effective AEpreventionandmanagementareimportant endocrinopathies andmetabolicdisorders.Therefore, nausea, diarrhea, vomiting, hypertension, weight loss, fatigue, hand–footskinreaction,decreasedappetite, of life.Themostcommonadverseevents(AEs)include adverse effects, that can negativelyaffect patients’ quality cytotoxic chemotherapy, buttheycaninducesignificant Agency (EMA).TKIsare not considered as toxic as and DrugAdministration(FDA),EuropeanMedicines of TKIs Endocrine-metabolic effects This reviewwilltakeintoconsideration theendocrine- Several multitarget TKIs are now approved by US Food

side effects derived from the treatment 1 ). Downloaded fromBioscientifica.com at09/30/202109:24:38PM

8 , 184 9 ). Inthefuture, :1 R30 via freeaccess

European Journal of Endocrinology (BCR-ABL) gene,nilotinib caninducehyperglycemia cluster regiongeneand Abelson murineleukemia’ leukemia (CML)andtarget the fusionof‘breakpoint imatinib, anddasatinibare used totreatchronicmyeloid hyperglycemia ( belonging tothesameclasscanleadbothhypo- or different proposedmechanismsandpathways,TKIs worsening ofqualitylife. or kidneyfailure,retinopathy, etc.)andto aprogressive ( i.e.cardiovasculardisease,neuropathy, nephropathy untreated, it can lead to life-threatening complications vision, anorexia,nausea,fatigueanddiarrhea)( polydipsia, renal insufficiency, weight loss, unclear constitutional symptoms(i.e.polyuria,dehydration, Hyperglycemia hassystemiceffectsthatcancause Hyperglycemia/hypoglycemia venous glycemiashouldbedone( stimulating hormone(TSH),lipidprofileandfasting hypoglycemia ( some cases,patientsshowanimprovedglycemiaor diabetes (~15–40%), and dysthyroidism (~20%). In metabolic disorders,includingdyslipidemia(~50%), thyroiditis) ( (i.e. dysthyroidismassociatedwithnon-autoimmune secretion, oronsetofinsulinresistance)destructive (i.e. alterationofhormonetransportorinsulin be discussedbetweenoncologistandendocrinologist( to endocrineside-effects,andmoleculewithdrawalshould and the relative measures to be taken, are not applicable particular, thyrotoxicosis). For this reason, AE grading, anticancer regimencanbesuspendedinsevereforms(in generally managedbyhormonereplacementtherapy. The deficiency,in hypothyroidismorpituitary thatare 3 or 4. Treatment interruption is usually not suggested for endocrineside-effects)( difficult todistinguish betweengrades 2and 3,particularly 4 Cancer Institute2009):1 effects are commonly graded on a1-to-5 scale (National Adverse Events(CTCAE)v5.0,antitumoraltherapyside- According totheCommonTerminology Criteriafor Endocrine effectsofTKIs = Review ietraeig 5 life-threatening, TKIs caninfluenceglucosemetabolismthrough Before initiatingthetreatmentwithaTKI,thyroid- Patients intherapywithTKIscandevelopendocrine- Pathophysiological mechanismscanbefunctional Endocrine ormetabolicside-effectsarerarelygrade 1 ). 11 13 ). ). Forexample,evenif nilotinib, =

death relatedtoAE (even ifitis = id 2 mild, 10 ). P Fallahiandothers 11 = oeae 3 moderate, ). = severe, 12 ). If 11 ). test, stimulateshyperglycemiainrats( insulin receptorkinasesand,afteroralglucosetolerance the typeIinsulin-likegrowthfactorreceptor(IGF-1R)and to rociletinibcouldbedueametabolitewhichinhibits reported thathyperglycemiaorhyperinsulinemiarelated with AZD9291orrociletinib( not reportcasesofhypoglycemiainpatientsadministered hyperglycemia hasbeendescribed,whileclinicaltrialsdo patients, butnotcrizotinib( Ceritinib can induce hyperglycemia in about 49% of carcinoma (NSCLC),andhavedistincteffectsonglucose. (ALK) inhibitorsareutilizedtotreatnon-small-celllung axitinib, alectinib)canleadtohyperglycemia( by theFDA/EMA,5(dabrafenibandtrametinib,ceritinib, imatinib cancausehypoglycemia( in approximately40%ofpatients,whiledasatiniband glycogenolysis ( resistance, raisedgluconeogenesis, and/orhepatic induced byGSK690693was relatedtoperipheralinsulin dose. Themechanismatthe basisofthehyperglycemia and hyperglycemia for approximately 6 h after the evaluated, showingraisedglucoseandinsulinlevels, inhibitor GSK690693onhyperglycemiahasbeen reported intype2diabetes(T2DM)( the reductionofbeta-cellfunction,similarlytowhat pathways throughtheincreaseofinsulinresistanceand Alpelisib), thataffectsdownstreamkeyinsulinsignaling Akt-mammalian targetofrapamycinpathway(such as able toinhibitthephosphoinositide3-kinase(PI3K)- limiting AEwashyperglycemia( daily to1000mgtwicedaily).Theonlycommondose- with thehydrogenbromide salt (HBr)form(500mgtwice (150 mgoncedailyto900twicedaily),andtheothers patients were treated with the free-base form of rociletinib twice daily, or750mgtwicedaily).Thefirstenrolled57 administered with rociletinib (500 mg twice daily, 625 mg inhibitor. PatientswithT790Mpositivediseasewere had progressedinaprecedingtherapywithanEGFR 130 patientswithEGFR-mutatedNSCLCwhosedisease homology ( inhibitors alsoblockinsulinreceptorowingto cell growthandinhibitapoptosis.SeveralIGF-1R MAPK/ERK andPI3K/AKT/mTORpathways,thatcontrol of TKIs Endocrine-metabolic effects Considering EGFRTKIstargetingT790M,only TKIs belongingtoanaplasticlymphomakinase Among the28oncologicalTKIsapprovedatpresent In ratsandmice,theeffectofpan-Aktkinase Hyperglycemia hasbeendescribedwithcompounds In aphaseI/IIstudy, rociletinibwasadministeredto IGF-1R isacellsurfacereceptor, activatingtheRas/ 12 ). 18 ). Downloaded fromBioscientifica.com at09/30/202109:24:38PM

14 ). https://eje.bioscientifica.com 17 13 ). 14 ). Preclinicalstudies 13 184 ). 16 ). :1 ). 15 ). R31 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com in 27 patients with chronic phase (CP)-CML ( risk wereevaluated,before and duringnilotinibtherapy, hyperlipidemia; respectively ( hyperlipidemia; 22.2months and100.0%withgradeIII I hyperlipidemia;14.0monthsand60.7%withgrade II months and 23.9%; 12.9 monthsand 54.0% with grade (RR) forpatientswithnormalbloodlipidswere8.0 (mPFS)and responserate progression-free survival 68.1, 78.6,27.5and61.9%,respectively. The median with sunitinib,pazopanib,sorafenibandfamitinibwas ( pazopanib, sorafenib,famitinib)showedhyperlipidemia renal cellcarcinoma (mRCC)underTKIs(sunitinib, were shownalsobyotherstudies( treatment (at adoseof 400 mg daily) ( within one month from the beginning of imatinib syndrome, in8ofwhomplasmalipidlevelsnormalized with hyperlipidemia and CML,orthehypereosinophilic ameliorate lipid profile( to differenttypesofTKI,forexampleimatinibseems Aggravation orimprovementofdyslipidemiaarerelated Dyslipidemia four testedagents( c-kit andPDGFR hypoglycemic effectofthesedrugsisstillnotknown,but hypoglycemia. Themechanismatthebasisof in treatmentwithsunitinibdevelopedsymptomatic including insulininsomeofthem.Onediabeticpatient of thepatientswithdiabetesdiscontinuedtheirdrugs, sunitinib, and53mg/dLwithdasatinib.Forty-seven% with imatinib,12mg/dLsorafenib,14 significant declinesofbloodglucoselevelswere:9mg/dL patients treatedwithdifferentTKIs( blood glucoselevelsin17diabeticand61non-diabetic hypoglycemia ( pazopanib, ponatinib,andvandetanib)canleadto previous T2DM. and imatinibimprovehyperglycemiainpatientswiththe and insulin resistance in peripheral tissues ( (TNF- effect exertedonPDGFRandtumornecrosisfactoralpha activating nuclear factor-kappa B (NF- as demonstrated imatinib) actonglucosemetabolisminhumanbetacells, 25 Review ). The percentage of patients showing hyperlipidemia On thecontrary, 85/155 patients withmetastatic Other TKIs(includingsorafenib,axitinib,sunitinib, Multikinase ABLinhibitors(i.e.dasatiniband The plasmalipidprofile and globalcardiovascular α ) canaffectthestimulationofbetacellapoptosis 19 in vitro β arethecommontargetkinasesof ). Apaperretrospectivelyevaluated 20 ). fromchemical-inducedapoptosis, 21 ). A paper reported 9 patients 25 ). P Fallahiandothers 23 20 , 24 ). Meanstatistically κ B). The inhibitory B). Theinhibitory ). 22 ). Similar data 14 ). Dasatinib 26 ). The even ifitworsenestheglycometabolicprofile( syndrome moreextensivelythanimatinibordasatinib, not induceDMorimpairedfastingglucosemetabolic imatinib, dasatinibornilotinib,reportedthatnilotinibdid another studyin168patientswithCP-CMLtreated than patientsreceivingdasatinib( significantly higherincidenceofT2DMorhyperlipidemia line treatment.Patientsadministeredwithnilotinibhada CML receivingdasatinibornilotinibasfirst-second- incidence ofT2DMandhyperlipidemiainpatientswith in triglycerides was reported ( 12 months.Ontheotherhand,asignificantreduction HDL cholesterollevelsdiminishedfrom40.7to7.4%by in 22.2%ofthem.Thepercentage of patientswithlow months, causingcholesterol-loweringdrugintervention optimal LDLcholesterolraisedfrom48.1to88.9%by12 cholesterol withinthreemonths,andpatientswithnon- total, low-(LDL)andhigh-density(HDL)lipoprotein therapy withnilotinibledtoasignificantincreaseof studied clinicalmodelfor 10years.Thyrotoxicosisis weeks ( hypothyroidism occursafter amediandurationof22 (1–70 weeks),athyrotoxic phase isoftenreported,then ( destructive thyroiditis,probablyduetovasculardamage thyroid disorder( patient’s backgroundandtheexistenceofanassociated developing TKI-induceddysthyroidismdependsonthe accuracy oftheseAEs( the types of thyroid monitoring, and the recording according to thetypeof molecule, the dose administered, hyper-thyroidism) relatedtoaTKIvariesconsiderably The prevalenceofthyroiddysfunctions(TD)(hypo-or Thyroid dysfunctions(TD) that canleadtoatherosclerosis( functions andstimulatesdyslipidemiahyperglycemia vascular permeability. Moreover, nilotinibaltersplatelet endothelial cellsandcanleadtoatherogenesisincreasing patients, whereasponatinib,nilotinib,anddasatinibaffect its potentialprotectingcardiovascularactivityinthese that imatinibinduceslowratesofthrombosis,indicating imatinib lesseffective( are nowpresentagainstBCR-ABLmutations,rendering and dasatinib)third-generation(ponatinib)TKIs treatment ofCML,whilesecond-(nilotinib,bosutinib, of TKIs Endocrine-metabolic effects 30 , Sunitinib-induced thyroid toxicityhasbeenthemost Iatrogenic TDrelatedtoTKIsismainlycausedby Imatinib isthefirst-in-classBCR-ABLTKIusedfor 32 ). Afteramediantreatmentdurationof6weeks 1 – 135 ) ( 33 30 ). , 31 ). 30 Downloaded fromBioscientifica.com at09/30/202109:24:38PM 29 ). Moreover, theprobabilityof

). Scientificevidenceshows 26 29 ). A paper evaluated the ). 27 184 ). Onthecontrary, :1 28 ). R32 via freeaccess European Journal of Endocrinology P high-grade hypothyroidism of 13.95 (95% CI: 6.91–28.15; subjects in7randomizedtrials reportedaRRofall-and of 0.4%(95%CI:0.3–0.5%). Ameta-analysisof2787 incidence of9.8%(95%CI: 7.3–12.4%),andhigh-grade eligible trials ( 6678 patientsadministeredwithsunitinibfrom24 need oftreatment( TKIs haveatransientincreaseofTSHlevels,withoutany levothyroxine. Around30–35%ofpatientstreatedwith absorption and of the enterohepatic reabsorption of thyroid autoimmunity, andalterationoftheintestinal inhibition ofperoxidase, blocking of iodineuptake, (TH) metabolism,inhibitionofiodineorganification, caused byblockingVEGF, higherthyroidhormone regression ischemic thyroiditis due to a marked capillary hypothyroidism through several mechanisms, such as are responsibleforinducingit( sunitinib, sorafenib,cabozantinib,vandetanib,lenvatinib) thyroid dysfunction( Hypothyroidism isthemostfrequentTKIs-induced Hypothyroidism persist alsowhenthetherapyisdiscontinued( reported morefrequently(18%ofpatients),anditcan late and prolonged, easy toberecognized and therefore thyrotoxicosis. Theoccurrenceofhypothyroidismis rather toastateoftransient,mostoftensubclinical, patients undergoing TKI therapy ( 5.38, hypothyroidism witharelativeriskof3.59(95%CI2.40– these drugshadasignificantlyhigherriskofall-grade exclusion of ineligible studies. Patients administered with sunitinib, 4withcediraniband2axitinib),afterthe only ifasuspectofGraves’disease(GD)ispresent( autoantibodies (TRAb)areoftenabsentandmeasured range, insubclinicalhyperthyroidism),TSHreceptor phase, TSHislowandFT4increased(orintothenormal the therapy is prolonged ( could beresponsibleforpermanenthypothyroidismif parenchyma isshownwithhypotrophyoftheglandthat of treatment,areducedvascularizationthethyroid on/off patternisprescribed,andafterseveralcycles occur. Thisisrepeatedateachcyclewhenanintermittent associated withTKI-inducedcelllysis,andhypothyroidism, reported firstly, thenatransientincreaseinthyroglobulin

Review < 0.00001)and4.78(95% CI: 1.09–20.84; An incidenceanalysiswasconductedconsidering Hyperthyroidism affectsanaverageof15.8% A meta-analysisevaluated12clinicaltrials(6with P

≤ 0.0001)( 31 33 ). All-gradehypothyroidismhadan Table 1 ). 34 , 36 ) ( 30 ), anddifferentTKIs(including 37 ). During the thyrotoxicosis ). 34 P Fallahiandothers 33 , 37 , 34 ). TKIscanpromote ) and corresponds 35 P ).

= 30 0.04), ). frequency ofinducedhypothyroidismwas43%( in a non-screened group of patients with mRCC. The hypothyroidism in593/1671(35.5%)( was 22.7weeks,grade day on a 4-weeks-on and 2-weeks-off schedule. The mPFS patients withmRCC,aninitialoraldoseof50mg/ 11% ofpatients( hypothyroidism wasshownasatreatment-relatedAEin on a4-weeks-on-2-weeks-offschedule.All-grade administered withoralsunitinib,50mgperday access trialin4543patientswithmRCC,whowere hypothyroidism ( reported asignificantlyincreasedincidenceofall-grade with sunitinibforalongerperiodoftime( respectively. Asubgroupanalysisinpatientstreated 91 µg/m range, andthelevothyroxine dosewasincreasedfrom raised TSHlevels,whileFT4 remainedintothenormal 6 months.The11athyreotic patients hadsignificantly with single-drugtreatment vandetanibformorethan submitted tothyroidectomy, andallwere administered screened, andamongthem,11(85%)hadbeenpreviously endocrine neoplasiatype2B(MEN2B)andMTCwere trials ofvandetanib( thyroidcancer(MTC)involvedin phaseI/II medullary (FT4), andlevothyroxineinadolescentschildrenwith increase inthyroidreplacementtherapy( cabozantinib haveelevatedTSHlevelsandrequirean 49% ofthosetreatedwithvandetaniband57% about 90% of patients have prior thyroidectomy, and and 2%inthosereceivingsorafenib( grade waspresentin16%ofpatientsreceivinglenvatinib ( eligible 954/1492patientsreceivedrandomlysorafenib or sorafenib(400mgtwicedailyin28-daycycles).The < ( recruiting, is conducted in patients with unresectable HCC gov, numberNCT01761266),stillactive,butnot sunitinib andthosewhodidnot( between patientswhodevelopedhypothyroidismduring or sorafenib,didnotreportasignificantdifferenceinPFS retrospective andprospectivestudies,treatedwithsunitinib of TKIs Endocrine-metabolic effects n 42 60 kg,8mg/day;forbodyweight = 476)orlenvatinib( ). Patientsreceivedorallenvatinib(forbodyweight A meta-analysisof500patientswithmRCCin11 Another studyinvestigatedtheeffectofsunitinib A prospectivestudyinvestigatedsunitinibinJapanese A paper reported the data from a global, expanded- A paperevaluatedthedataaboutTSH,freethyroxine In phaseIIIstudiesofvandetanibandcabozantinib, A phaseIII,open-label,multicentretrial(ClinicalTrials. 2 /day ( ± 24) to116µg/m 38 31 ). ). 44 ). Thirteenpatientswithmultiple n Downloaded fromBioscientifica.com at09/30/202109:24:38PM ≥ = 478).Hypothyroidismofany

3 AEsoccurredin70%,with https://eje.bioscientifica.com 2 41 /day ( ). ≥ 184 42 60 kg,12mg/day), 39 ). :1 ± ). 43 24). Inthetwo ). 40 P

= ). R33 0.02) via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com patients with advanced nonclear cell RCC, administered remained normalinthefollow-up ( patients notpreviouslythyroidectomized, FT4andTSH metastatic renalcellcarcinoma;MTC,medullarythyroidcancer;TSH,thyroid-stimulating hormone;T3,triiodothyronine. AE, adverseevent;FT4,freethyroxine;HCC,hepatocellularcarcinoma;MCC, merkelcellcarcinoma;MEN2B,multipleendocrineneoplasiatype2B;mRCC, Dasatinib, nilotinib,imatinib, Lenvatinib Lenvatinib Lenvatinib Sunitinib vscabozantinib Cabozantinib Cabozantinib Vandetanib Lenvatinib orsorafenib Sunitinib orsorafenib Sunitinib Sunitinib Sunitinib Sorafenib Sunitinib, cediraniband Sunitinib Drugs Table 1 Review axitinib, sorafenib,sunitinib cabozantinib, VEGFR-TKI, axitinib The effectofcabozantinib has beenevaluatedin17 Multikinase inhibitorsandinducedhypothyroidism. A reviewevaluatedtheAEsoftargetedtherapyonthyroidfunction inoncological A retrospectivestudyinvestigatedlenvatinib(24mgoncedaily) in5patientswith A clinicaltrialisconductedinpatientswithhistologically/clinically confirmed A studyevaluated59patientswithunresectableprogressiveMTCadministered The randomizedphaseIICABOSUNtrialcomparedsunitinibwithcabozantinibin A prospective,phaseIItrialenrolledpatientswithplatinum-failure,recurrent/ The effectofcabozantinib(60mgonceadayin28dayscycles)hasbeenevaluated Thirteen patientswithMEN2BandMTCwereevaluated.Amongthem,11hadbeen An open-label,phaseIII,multicentre,trialisconductedinpatientswithunresectable A meta-analysisof500patientswithmRCCin11retrospectiveandprospective This studyinvestigatedtheeffectofsunitinibin58non-screenedpatientswithmRCC. A prospectivestudyinvestigatedsunitinibinJapanesepatientswithmRCC,an The finalresultsfromaglobal,expanded-accesstrialin4543patientswithmRCC, Fifty-seven consecutivepatientswithHCC,treatedsorafenib,wereevaluated. A meta-analysisevaluated12clinicaltrials(6withsunitinib,4cediraniband2 Incidence analysiswasconductedin6678patientsadministeredwithsunitinibfrom Main outcomes in 33.2% patients (in22originalstudiesand1641patients).Hypothyroidism occurred ATC, and80%showedhypothyroidismofanygrade was presentin21.7% administered withlenvatinib(12mgoncedailyin28-daycycles). Hypothyroidism advanced HCC,notsubmittedtosurgicalresectionorlocaltreatments, and progression, withdrawal,ordeath.AnincreaseinbloodTSHlevelsoccurred20% lenvatinib (24-mgdaily,28-daycycles)untilunmanageabletoxicity,disease developed hypothyroidism,and4/72(6%)treatedwithsunitinib patients withadvancedRCC.Eighteen/78(23%)receivingcabozantinib progression). Hypothyroidismoccurredin50% metastatic MCCwhoreceivedoralcabozantinib(60mgdailyuntildisease hypothyroidism was24% 17 patientswithadvancednonclearcellRCC.Thefrequencyofinduced the follow-up the 2patientsnotpreviouslythyroidectomized,FT4andTSHremainednormalin FT4 remainedintothenormalrange,andlevothyroxinedosewasincreased.In than 6months.The11athyreoticpatientshadsignificantlyraisedTSHlevels,while previously thyroidectomized,andallwereadministeredwithvandetanibformore of patientsreceivinglenvatiniband2%inthosesorafenib receiving sorafeniborlenvatinib.Hypothyroidismofanygradewaspresentin16% those whodidnot in PFSbetweenpatientswhodevelopedhypothyroidismduringsunitiniband studies, treatedwithsunitiniborsorafenib,didnotreportasignificantdifference Hypothyroidism occurredin43%ofthem Hypothyroidism occurredin35.5% initial oraldoseof50mg/dayona4-weeks-onand2-weeks-offschedule. schedule), reportedall-gradehypothyroidismin11%ofpatients administered withoralsunitinib(50mgperdayona4-weeks-on-2-weeks-off × TSH orFT4abovethenormalrange,andserumT3/reverseT3ratio(T3/T4) Thyroiditis wasdevelopedby7%.Amongtheotherpatients,30%hadelevationof hypothyroidism wasshown with axitinib),aftertheexclusionofineligiblestudies.Ahigherriskall-grade 7.3–12.4%), andhigh-gradeof0.4%(95%CI0.3–0.5%) 24 eligibletrials.All-gradehypothyroidismhadanincidenceof9.8%(95%CI 100 ratiodecreased P Fallahiandothers 44 ). 24% ( toxicities. Thefrequencyof induced hypothyroidismwas owingto dose reductionsto40or20 mgwerenecessary with thedoseof60mgonce adayin28dayscycles,and of TKIs Endocrine-metabolic effects 45 ). Downloaded fromBioscientifica.com at09/30/202109:24:38PM

184

:1 References ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( 51 50 49 48 47 46 45 44 42 41 40 39 38 35 33 31 R34

) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) via freeaccess European Journal of Endocrinology AE, adverseevent;GD,Graves’disease; mRCC,metastaticrenalcellcarcinoma. Cabozantinib Sunitinib Sorafenib, imatinib Dasatinib, nilotinib,imatinib, Drugs Table 2 TD, toevaluatetheAEsoftargetedtherapyonthyroid A paperreviewedthepublishedliteratureonTKI-induced Hyperthyroidism of anygrade( with ATC and4/5patients(80%)showedhypothyroidism investigated lenvatinib(24mgoncedaily)in5patients 10/46 (21.7%)( at leastoneAE,andhypothyroidismwaspresentin once dailyin28-daycycles.All46patientsexperienced local treatments,wereadministeredwithlenvatinib12mg HCC, whowerenotsubmittedtosurgicalresectionor patients withhistologically/clinicallyconfirmedadvanced another study(ClinicalTrials.gov, numberNCT00946153), patients hadanincreaseinbloodTSHlevels( progression, interruption, or death. Twelve/59 (20%) daily, 28-day cycles) until unmanageable toxicity, disease progressive MTCadministeredwithlenvatinib(24-mg sunitinib ( developed hypothyroidism, and 4/72 (6%) treatedwith Eighteen/78 (23%)patientsreceivingcabozantinib weeks on/2off)orcabozantinib60mgdaily. RCC randomized 1:1 to sunitinib 50 mg daily (4 sunitinib withcabozantinibinpatientsadvanced (50%) hadhypothyroidism( toxicity andlackofresponses.Fourtheeightpatients accrued, thenthestudywasclosedprematurelyowingto daily untildiseaseprogression( carcinoma (MCC)whoreceivedoralcabozantinib60mg platinum-failure, recurrent/metastaticMerkelcell Review axitinib, sorafenib,sunitinib cabozantinib, VEGFR-TKI, A studyevaluated59patientswithunresectable The randomizedphaseIICABOSUNtrialcompared A prospective,phaseIItrialenrolledpatientswith Multikinase inhibitorsandinducedhyperthyroidism. 47 ). 50 ). 49 ). Furthermore,aretrospectivestudy 46 ). Main outcomes A studyevaluatedthyroidfunction inpatientsenrolledtwophaseIIclinical A studyinvestigatedtheincidenceandclinicalcourseofthyrotoxicosis in62 A 57-year-oldmanwithlumbarchordomareceived800mgsorafenib daily. A reviewevaluatedtheAEsoftargetedtherapyonthyroidfunction in 46 P Fallahiandothers thyrotoxicosis, andthenhypothyroidism cancer andmetastaticsofttissue sarcoma.Twopatientshadatransient trials. Thirty-threepatientsreceived cabozantinibformetastaticbladder preceded hypothyroidismin3.2% patients withmetastaticmRCCtreatedsunitinib.Thyrotoxicosis recurred duringtreatmentwithimatinib positive TRAb,evenifpre-treatmentTSHwasnormal.Moreover, GD Upon 18weeksoftherapy,thepatientdevelopedhyperthyroidism with Hyperthyroidism occurredin3.14% oncological patients(in22originalstudiesand1641patients). ). Eightpatientswere 48 ). In

a higher prevalence of subclinical hypocortisolism was completely known.Inpatientstreatedwithimatinib, The effectsofTKIsonadrenalfunctionarestillnot Adrenal dysfunctions enrolled intwophaseIIclinicaltrials( treated withsunitinib.Amongthe62enrolledpatients, of thyrotoxicosisinpatientswithmetastaticmRCC important classeffect( two different TKIs indicates that it could be a rare but treatment withimatinib.ThefactthatGDoccurredafter treatment TSHwasnormal.Moreover, GDrecurredduring hyperthyroidism withpositiveTRAb,evenifpre- ( receiving 800mgsorafenibdailyhasbeenreported (3.14%) ( and developedhyperthyroidismwere47/1498patients (33.2%) patients.Thepatientswhoweretested( developed TD. Hypothyroidism was shownin545 TKIs as,amongthe1641includedpatients,751(45.8%) and 1641patientswereincluded.TDisacommonAEof on diseaseprognosis( function inoncologicalpatients,andtheimpactofTD transient thyrotoxicosis,andthenhypothyroidism( subclinical hypothyroidism.Two patientshada TD in93.1%ofpatients,withapreponderance thyroid function testswereavailable for 31, reporting cancer andmetastaticsofttissuesarcoma, andfollow-up patients receivedcabozantinibformetastaticbladder thyrotoxicosis precededhypothyroidismin2(3.2%)( of TKIs Endocrine-metabolic effects 52 ). Upon18weeksoftherapy, thepatientdeveloped A studyinvestigatedtheincidenceandclinicalcourse The caseofa57-year-oldmanwithlumbarchordoma A studyevaluatedthyroidfunctioninpatients Table 2 ) ( 51 ). 52 51 Downloaded fromBioscientifica.com at09/30/202109:24:38PM ). ). Twenty-two originalstudies

https://eje.bioscientifica.com 184 :1 54 ). Thirty-three References n ( ( ( ( 54 53 52 51 = 1498) ) ) ) ) R35 54 53 via freeaccess ). ). European Journal of Endocrinology https://eje.bioscientifica.com fertility ( studies inhumansdidnot show effectsofTKIsonmale sperm incomparisontonilotinib andimatinib.However, effect oncount,volume,motility, andmorphologyof with normal morphology ( such asspermmotility, totalsperm,andthe percentage stimulating hormone(FSH)levelssignificantlydecreased, testosterone, luteinizinghormone(LH),andfollicle- 4 months from the beginning of TKItherapy. Serum men withCMLhavebeenevaluatedbeforeandafter and hyperactivation( impacting spermmembranepotential,cellmotility, TKs couldsignificantlyaffectcapacitation,negatively and subsequentfertilization.TKIsthattargetthesesperm cell ishyperactivated,leadingtotheacrosomereaction increase sperm cell motility. After capacitation, a sperm to hormones and signal molecules that are necessary the expositiontofemalereproductivetract,thathas which spermatozoonachievesfertilizingcapacityupon sperm motility. Capacitation is the phenomenon through TKIs mayalsoaffectfunction,suchasfertilizationand turning on thedifferentiation process ofspermatogenesis. imatinib, anddasatinib)isthoughttobeimplicatedin spermatogenesis, andC-kit(targetofnilotinib,sunitinib, and dasatinib,appeartobeinvolvedinmeiosisIof targetofimatinib example, thec-ablTKs,primary be duetoadirectactionexercised onmeiosis( The possibleeffectofTKIsonspermatogenesiscould Spermatogenesis Gonadal effects therapy withlenvatinibandvandetanib( 4.03, indicatingthatPAI caninduce fatigue duringthe fatigue improved,asestimatedbytheCTCAEversion with cortisoneacetatereplacementtreatment,and adrenal insufficiency(PAI). Patientswith PAI weretreated stimulation, inagreementwiththediagnosisofprimary and 6ofthemhadacortisolresponseuponACTH hormone (ACTH)increaseandnormalcortisollevels, patients withfatiguehadagradualadrenocorticotropic receiving, respectively, lenvatiniborvandetanib.Ten differentiatedthyroidcancer(DTC)andMTC, refractory function in12patientswithadvancedradioiodine 14 patientsreceivingvandetanib( shown ( Review The effectsofdasatinib,nilotinib,andimatinibin A study assessed the basal and stimulated adrenal 55 60 ), whileanincreaseofcortisolwasreportedin ). 58 ). 59 ). Dasatinib had a minor P Fallahiandothers 56 ). 57 ). 58 ). For led toapromptdecreaseintestosterone,LHandFSH in 2patients,whohadearliernormaltestosteronelevels, with crizotinib( patients (32%) with metastatic NSCLC not administered 19/19 (100%)mentreatedwithcrizotinib,andin6/19 crizotinib. Total testosteronewaslow( patients with NSCLC treated,and19 not treated,with further directgonadaleffect( elevated, supportingtheideathatcrizotinibhasalsoa in othersLHandFSHremainedthenormalrangeor effect,while has acentral(hypothalamicorpituitary) and FSH decreased in some patients, indicating crizotinib according todoseinterruptionsandrestartoftherapy. LH within daysfromthebeginningofcrizotinib, even NSCLC. Astrongdecreaseintestosteroneisreported kinase, has shown notable effectiveness in ALK-positive Crizotinib, acompetitiveinhibitorofALKandc-Met Hypogonadism maintenance offunctionthe corpusluteum( the processofselectionand luteinizationoffolliclesand express VEGF, andVEGF/VEGFRsystemisinvolvedin luteum. Moreover, oocytesandsomatic cellsstrongly implicated in angiogenesis during the formation of corpus determinant intheinitialactivationoffolliclesandmaybe and granulosacellproliferation.PDGFRitsligandare ofoocytes primordial germcells,growthandsurvival Kit-L arecrucialtoestablishprimordialfollicleactivation, and ovarian insufficiency is possible. Thec-Kit and its ligand follicles, andforthisreasonanassociationbetweentherapy ofoocytesand for theformation,maturationandsurvival The kinasesignalingpathwaystargetedbyTKIsarecrucial Infertility chronic AE( trend,indicatingthatthiscouldbea had aconfirmatory ( for hypogonadismat The incidenceofhypogonadismwas77%;oddsratio mRCC treatedwithpazopanib,sunitinib,andaxitinib. excluded ( supposed, butfurtherdirecteffectsontestismaynotbe of testosterone in male patients. Acentraleffectwas suggested thatcrizotinibcancausearapidreduction back tonormaltestosteronelevels.Thereporteddata within 14–21days.Theinterruptionoftherapyled of TKIs Endocrine-metabolic effects P

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61 ). 184 :1 < 241 ng/dL)in 64 ). R36 via freeaccess European Journal of Endocrinology clinical data,patientsneeding anticancertherapycan levels, andmanagehyperglycemia ( it isimportanttoevaluate patients,measureglucose dose reductionsordiscontinuations. Forthesereasons, and affectnegativelythepatientqualityoflifecausing Hyperglycemia canleadtolife-threateningcomplications treatment withTKIs Management ofendocrineeffects elevated TSHlevels( extent, alsosunitiniborsorafenib,isassociatedwith thyroidectomized patients.Axitinib,andwithalower the needforhigherlevothyroxinereplacementdosesin orhypothalamiclevel,increasingTSHand the pituitary the directinhibitionofthyroidhormonefeedbackat axis,perhapsthrough hypothalamic–pituitary–thyroid The treatmentwithTKIscancausederangementsinthe thyroid axis Effects onthehypothalamic–pituitary– developmental capacity( andembryo could impactsignificantlytheovarianreserve data indicatedthatlong-termtreatmentwiththisTKI inner cellmasstoincreasedtrophectodermcells.These fewer totalcells( Blastocysts obtainedfromfemalesreceivingimatinibhad effects onfertilizationratesorovulationwerereported. follicles( and secondary primary development, andfewerprimordialfollicles,buthigher drug for4–6weeks.Thetreatmentledtoashiftinfollicle mice receivingdailyintraperitonealinjectionsofthis quality,follicle developmentandembryo inadultfemale mice couldhavelitters( the twogroups.Upontreatmentinterruption,allfemale and growingfolliclesnumbers comparison tocontrolmice( good markeroftheamountgrowingfollicles)levelsin cells ofpreantralandsmallantralfolliclescanbea (belonging to TGF ( ovary treatment significantlydecreasedcorporaluteanumber/ with sunitinib(50mg/kg/day)orvehiclealone.Sunitinib 6-week-old femalemicetreatedfor5weeks,oncedaily, Review The effectoflong-termimatinibwasevaluatedon A studyevaluatedovariantoxicityofsunitinibin P

< 0.01)andserumAntiMullerianhormone P β

family, that is expressed in granulosa < 66 0.05),andasignificantshiftfrom ). 64 65 ). ). P

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< 13 0.05), while no ). Inreal-world secretagogues, anSGLT2 inhibitor, orinsulin)( (SGLT2) inhibitor;orothers,suchasinsulinsensitizer, as metformin)orasodium/glucosecotransporter2 receptor/IGF-1R inhibitors,insulinsensitizers(such therapy (categorizedbymechanisms;forinsulin lead todosereductionsand/ororalantihyperglycemic and withexercise, whilegrade3and4hyperglycemiacan hyperglycemia canbecontrolledbymodifyingthediet resistance (byinsulinlevels).Mildtreatment-related and periodic hemoglobin A1c testing) and for insulin levels (inpatientswithanalreadydiagnoseddiabetes) measuring fastingand/orpostprandialbloodglucose patients canbeevaluatedforhyperglycemia (by still develophyperglycemia( monitoring, andeventhoseconsideredlowriskcan conditions cansuggestwhich of themwouldneedclose diabetes. Forthisreason,evaluatingpatientsforthose have glucose intolerance, and previous or undiagnosed started ( and asupportivetreatment withlevothyroxinecanbe hypothyroidism, the can besolved,followedornot byhypothyroidism.During monitoring ofTSHandFT4isnecessary. Hyperthyroidism to hypothyroidismafterthyrotoxicosis,theregular ophthalmopathy ( tremors. CorticosteroidsareusedinthecaseofGraves’ contraindication, to controlcardiothyrosisand β can beinitiatedincludinglow-dosenon-cardioselective does notcontraindicatethecontinuationofTKIs( 3–6 weeks.TheoccurrenceofTDs,usuallygrade1or 2, as changesinFT4levelsprecedetheTSHby therapy, 3–4weeksduringthefirst6months andevery to measuretheTSH/FT4levelsbeforestarting treatment isnotrecommended( thyroglobulin antibodies,TRAbs)beforeinitiationofthe autoimmunity (anti-thyroperoxidaseantibodies,anti- the initiationofTKIs,andscreeningforanti-thyroid oncologic prognosis( At present,guidelinescanbeappliedincaseofagood hypothyroidism, thatisresponsibletoimpairtheformer. besides thethyroidalprofile,sinceTKIscanleadto risk factors( and health status,prognosis,cardiovascularhistory and thetargetlevelsareselectedaccordingtogeneral not different from that of non-iatrogenic dyslipidemia of TKIs Endocrine-metabolic effects -blockers, suchaspropranolol,intheabsenceof Diagnosis ofdyslipidemiaduringTKIstreatmentis In caseofthyrotoxicosis,asymptomatictreatment ofthyroiddisordersdoesnotcontraindicateA history 30 ). 21 ). Thelipidprofileshouldbemonitored 30 ). Considering the riskofprogression 67 β -blocker treatmentisdiscontinued ). Downloaded fromBioscientifica.com at09/30/202109:24:38PM

12 https://eje.bioscientifica.com 30 ). Duringthetherapy, ). Itisrecommendable 184 :1 12 , R37 30 15 ). ). via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com the public,commercialornot-for-profit sector. This research did not receive any specific grant from any funding agency in Funding be could that interest of conflict perceived asprejudicingtheimpartialityofthisreview. no is there that declare authors The Declaration ofinterest mechanism ofTKIs-inducedendocrine-metaboliceffects. continuation ofTKIs( of TDs,usuallygrade1or2,doesnotcontraindicatethe precede thechangesinTSHby3–6weeks.Theoccurrence weeks during the first 6 months as changes in FT4 levels TSH/FT4 levelsbeforestartingthetherapy, 3–4 andevery hypothyroidism, thatisresponsibletoimpairtheformer. beside thethyroidalprofile,sinceTKIscanleadto dyslipidemia andthelipidprofileshouldbeassessed treatment isnotdifferentfromthatofnon-iatrogenic therapy ( lead todosereductionsand/ororalantihyperglycemic and withexercise, whilegrade 3and4hyperglycemiacan hyperglycemia canbecontrolledbymodifyingthediet periodic hemoglobinA1ctesting).Mildtreatment-related patients withanalreadydiagnoseddiabetes)and fasting and/orpostprandialbloodglucoselevels(in patients can be screened for hyperglycemia (by measuring levels, andmanagehyperglycemia.Duringthetherapy, hypoglycemia ( some cases,patientsshowanimprovedglycemiaor diabetes (~15–40%), and dysthyroidism (~20%). In metabolic disorders,includingdyslipidemia(~50%), disorders. hypertension, weightloss,endocrinopatiesandmetabolic reaction, decreased appetite, nausea, vomiting, diarrhea, The most common AEs include fatigue, hand–foot skin effects, thatcannegativelyaffectpatients’qualityoflife. chemotherapy, buttheycanleadtosignificantadverse and EMA.TKIsarenotconsideredastoxiccytotoxic of theunderlyingmolecularmechanisms( approaches havebeenevaluated,basedontheunderstanding therapy andchemotherapy, butinthelast20years,new Cancer standard treatments include surgery, radiation Conclusion Review Additional studies are necessary to definitely clarify the todefinitely clarifythe Additional studiesarenecessary Regarding TDs,itisrecommendabletomeasurethe It isimportanttoevaluatepatients,measureglucose Patients intherapywithTKIscandevelopendocrine- Various multitargetTKIsareapprovedbyUSFDA, 12 ). ThediagnosisofdyslipidemiaduringTKIs 11 ). 30 ). P Fallahiandothers 1 ). 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Accepted 20October2020 Revised versionreceived7October2020 Received 19June2020

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