Successful treatment of c-kit-positive metastatic Adenoid Cystic Carcinoma (ACC) with a combination of curcumin plus imatinib: A case report

ContentslistsavailableatScienceDirect

Complementary

Therapies

in

Medicine

j ou rn a l h o m epa ge : w w w . e l s e v i e r h e a l t h . c o m / j o u r n a l s / c t i m

Successful

treatment

of

c-kit-positive

metastatic

Adenoid

Cystic

Carcinoma

(ACC)

with

a

combination

of

curcumin

plus

imatinib:

A

case

report

M.

Demiray

_,

_H.

_Sahinbas

_,

_S.

_Atahan

_,

_H.

_Demiray

_,

_D.

_Selcuk

_,

_I.

_Yildirim

_,

A.T.

Atayoglu

a_{MedicanaInternationalIstanbulHospital,DepartmentofMedicalOncology,Istanbul,Turkey}

b_{InstituteforHyperthermiaResearch,PartneroftheMarienHospitalHerne,HospitaloftheRuhr-UniversityBochum,Germany} c_{Pato.netPathologyLaboratory,Bursa,Turkey}

d_{MedicanaInternationalIstanbulHospital,DepartmentofNuclearMedicine,Istanbul,Turkey} e_{MedicanaInternationalIstanbulHospital,DepartmentofRadiology,Istanbul,Turkey} f_{AliOsmanSonmezOncologyHospital,DepartmentofRadiationOncology,Bursa,Turkey}

g_{MedipolUniversityMedicalFaculty,DepartmentofFamilyMedicine,TurkishHolistic&IntegrativeMedicineAssociation,Istanbul,Turkey}

a

r

t

i

c

l

e

i

n

f

o

Articlehistory: Received3May2016

Receivedinrevisedform27June2016 Accepted30June2016

Availableonline1July2016 Keywords:

Adenoidcysticcarcinoma Imatinib

Curcumin Integrativemedicine Arantal

a

b

s

t

r

a

c

t

Adenoidcysticcarcinoma(ACC)isanaggressivemalignantneoplasmofthesecretoryglands. Conven-tionalchemotherapyhaspooreffectivenessagainstmetastaticACC.Thus,anoveleffectivetherapyis neededagainstmetastaticACC.

AmajorityofACCs(upto94%)expressc-kit.Imatinibismonoclonalantibodywithspecific activ-ityagainstc-kitbuthasnotbeenfoundtobeeffectiveintreatingpatientswithACCinwhichc-kitis overexpressedandactivated.TheNF-␬BandmTORpathwayshavebeenshownthatubiquitouslyand concurrentlyactivated,indicatingthattheinhibitionofthesepathwaysmayrepresentanovel treat-mentapproachforpatientswithACC.CurcuminhasbeenshowntoinhibitNF-␬BandNF-␬B-related pathways.43-year-oldpatientwasdiagnosedACCfromsubmandibularsalivarygland.Aftercomplete resectionoftumoradjuvantradiotherapywasinitiated.Sevenyearslatermultiplelungmetastaseswere detectedandACCwasconfirmedbyre-biopsy.First-linechemotherapyfailed.NF-␬Bandc-kitwere over-expressedinthemetastaticspecimens.Therefore,wetreatedthepatientwithmetastaticchemoresistant ACCwithimatinib400mg/dayandintravenouscurcumin225mg/m2_{twiceaweekplusoralbioavailable}

curcuminArantal®_{2×84mg/day.At24months,weobservednearcompleteanatomicandcomplete}

metabolicresponse.Toourknowledge,thisisthefirstreportofapatientwithac-kit-positiveACCthat issuccessfullytreatedwiththecombinationofimatinibandcurcumininanintegrativeapproach.

©2016TheAuthors.PublishedbyElsevierLtd.ThisisanopenaccessarticleundertheCCBY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction

Adenoidcysticcarcinoma(ACC),alsoknownascylindroma,isa rarebuthighlyaggressiveadenocarcinomaarisingwithin secre-toryglands. It mainly occurs in thesalivary glands and breast tissue.1–3 _{ACC accounts for approximately 22% of all salivary}

glandmalignanciesandrepresentsapproximately1%ofallhead

∗ Correspondingauthor.

E-mailaddresses:drdemiray@gmail.com(M.Demiray),

hssahinbas@googlemail.com(H.Sahinbas),dratahan@gmail.com(S.Atahan), hulyaademiray@hotmail.com(H.Demiray),drdoganselcuk@yahoo.com(D.Selcuk), driyildirim@hotmail.com(I.Yildirim),atayoglu@gmail.com(A.T.Atayoglu).

and neck malignancies.4 _{ACCs typically grow at a slower pace}

thanothercarcinomas.However,ACCisregardedasahigh-grade neoplasm,withradicalresectionpredominantlyfollowedby post-operativeradiotherapyconsequentlyasthecurrenttreatmentof choice.5–7_{Nonetheless,regionalanddistantrecurrencesare}

rel-atively common following the local treatment of primary ACC tumors.Hematogenousmetastasisiscommon,particularlytolung, bone,andliver.5,8

There is currently no consensus regarding the most appro-priatetreatmentofmetastatic ACC,withACCtypicallyresistant tosystemicchemotherapy.Laurie etal.evaluatedthe effective-ness of chemotherapy for ACC and reported a mean survival of 11 months in a patient with metastatic ACC and that the majorobjective responses wererare, withstable diseasebeing http://dx.doi.org/10.1016/j.ctim.2016.06.009

0965-2299/©2016TheAuthors.PublishedbyElsevierLtd.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4. 0/).

morecommon.9_{Moleculartargetedtherapieshavethereforebeen}

evaluatedbecauseofthepoorresponse ofACC toconventional chemotherapy.Upto94%ofpatientswithACCsreportedlyexpress c-kit(alsoknownasCD117)proto-oncogene,10_whichmay

repre-sentafuturetherapeutictarget.Imatinibisaninhibitorofseveral protein-thyrosinekinases,includingthoseassociatedwith break-point cluster region-abelson (Bcr-Abl), platelet-derived growth factorreceptors(PDGF-R),andc-kit.11_{Imatinibhasdemonstrated}

antitumoractivityfortheinhibition oftyrosine-kinaseproteins. Thetumorcontrolrateofimatinibisreportedlyover80%inpatients with Gastrointestinal Stromal Tumors (GIST). Six studies have previously assessedthe impactof imatinibin the treatmentof ACC,withonlytwoobjectiveresponsesreportedin71evaluable patients.9_{Itissuggestedthatc-kitmayplayakeyroleby}

accelerat-ingmobilizationoftumorcells.12_{However,sincethedataregarding}

theeffectofc-KitinhibitiononACCareconflicting,reducingc-Kit activitymaynotbesufficienttoinhibitACC’sprogression.12

Curcumin,apolyphenol,isthemajorbiologicallyactive com-ponentofturmericthatisderivedfromthedriedrhizomeofthe Curcumalonga plant.13 _{Recentevidencehasindicatedcurcumin}

suppressesallthreestagesofcarcinogenesis:initiation,promotion, andprogression.14_{Curcuminisahighlypleiotropicmoleculethat}

modulatesnumeroustargetsincludingtheactivationof transcrip-tionfactors,receptors,kinases,cytokines,enzymes,andgrowth factors.15_{Duetothepleiotropicnatureofcurcumin,curcuminhas}

beenshowntopotentiatetheeffectivenessofimatinibandhave utilityin overcomingimatinibresistance.16,17 _Sunetal.

demon-stratedcurcuminasapotentinhibitorofACCprogressioninvitro andinvivo.18

Herein,wereportapatientwithac-kit-positiveACCtreated withcurcuminplusimatinib.

2. Casepresentation

InSeptember2013,a50-year-oldmalepatientwithaseven year-historyofACCwasadmittedtoourOncologyClinicbecause ofmultiplelungmetastasesandfailureoffirst-linechemotherapy. Sevenyearsago,inOctober2006,thepatientpresentedtothe Ear,Nose,and Throat(ENT) Clinicwitha complaintofpainless, slow-growingmassunderthejawforabouttwoandahalfyears.He wasmedicallyfit.Clinicalexaminationrevealedafreelymobilefirm submandibularmass,measuringapproximately3×3cm.Therest oftheheadandneckexaminationwaswithinnormallimits,with noevidenceoflymphadenopathy.Patientwaslifetimenon-smoker andhedidnothaveanycomorbiddisease.Ultrasonographic evalu-ationdetectedasubmandibularmassoriginatingfromthesalivary glandandmeasuring3.5×3cminsize.Becauseofthesuspicious sonographicappearance,fineneedleaspirationbiopsywas per-formedstat.TheresultconfirmedthediagnoseofAdenoidCystic Carcinoma(ACC),andaftersurgeryitwasstagedasT2(3.5cm)N0 M0stageIII.Perineurial,butnotlymphaticinvasionwasobserved. Radiotherapyatatotaldoseof60Gywasinitiatedfollowing resec-tionwitha1-mmsafemargin.

Sevenyearslater,thepatientwasre-admittedwithfatigueand shortnessofbreath.Multiplemetastaticmasseswithamaximum diameterof75mmweredetectedbycomputedtomography(CT) imaging.Re-biopsyofametastaticmasswasperformedand con-firmedmetastaticACCtolung(Figs.1and2).Astandard3-week regimenofcisplatin(80mg/m2_{day1)plusetoposide(100mg/m}2

days 1–3) wasinitiated in the hospital. However,the patient’s conditionworsened aftertwo cyclesof chemotherapy, withCT scanimagingdemonstratedprogressionofthemetastaticlesions. Patient’sEasternCooperativeOncologyGroup(ECOG)performance statushaschangedfromECOG0to1duringlast3monthsbefore hisadmissiontoourclinic.

Fig.1.StainingofthebiopsyspecimenofametastaticmasswithPapanicolaou(Pap) stain.(PAPstaining;×100).

Fig.2. Tubulesandcribriformnestsofbasaloidcellsliningcysticspacesfilledwith homogenousmaterial[hematoxylinandeosin(H&E);×200].

Fig.3. Adenoidcysticcarcinomademonstratingc-kitexpression(c-kit×400).

Inourclinic,firstlytumortissuec-kitandNuclearFactorkappa B(NF-␬B)expressionwereevaluatedfromre-biopsymaterial. c-kitimmunohistochemistrydemonstratedstrongly positive,with 60%oftumoralcellsfoundtoexpressc-kit(Fig.3).NF-␬Bp65over expressionwasshownwithimmunohistochemicalmethod. Patho-logical evaluationshowed +3positive staining(Fig.4a, b).F-18 fluorodeoxyglucose(FDG)PositronEmissionTomography– Com-putedTomography(PET/CT)wasusedinrestagingandconfirming metabolicallyactivemultiplelungmetastases(lungmassesSUVmax

4.81g/mlandmediastinallymphnodesSUVmax4.52g/ml;Fig.5a,

Fig.4. (aandb).Immunohistochemistryadenoidcysticcarcinomatissuelabelling NF-kBp65(phospho S536)with ab86299at1/200(1␮g/ml).Detection:3,3

-Diaminobenzidine(DAB).[(a)×100,(b)×400].

Afterthefirstevaluation,weplannedacombinationtreatment withimatinibandoff-labeluseofcurcuminintegratively.Informed consentwasprovided by thepatient,and treatmentwith ima-tinib400mg/dayandcurcuminadministrationwasinitiatedboth orallyandintravenously.Weusedwatersolubleandintravenous administrablecurcumin(Burg-Apotheke,Germany,Patent appli-cationnumber:DE102012219219A1).Oneoftheauthorsofthe current case report (i.e. HS) has extensiveexperience of intra-venouscurcumintreatment.Accordingtohisexperience,dosages below450mg/m2_{iswelltoleratedbyhumanandonlyminorand}

reversiblehematologicalchangessuchasechinocyteformationand

somesignsof hemolysisare observeddosedependently,above thedosagesof300mg/m2_{(unpublisheddata).Ourpreclinicaldata}

showsthat 225and 300mg/m2dosehassimilareffect (unpub-lisheddata).Intotal,225mg/m2_{curcuminin1000mlnormalsaline}

was administered intravenously over 2–3h, using a non-di-(2-ethylhexyl)phthalate (non-DEHP)in-linefiltertwicea week.At 30minpriortotheadministrationofcurcumin,diphenhydramine 50mgandranitidine50mgin50-mlnormalsalinewas adminis-teredintravenouslyoveraperiodof20min.

OralcurcuminArantal®_{2×2capsuleswerealsoadministered.}

Arantal®_{whichcontains42mgcurcumin,isahighlybioavailable}

turmericextractwithasolubilityinwater4000timesgreaterthan free curcumin. Two capsulesof Arantal® _{(84mg) are 15 times}

more bioavailable than free curcuminin terms of final plasma concentration.19

Tumorresponsestotreatmentwereevaluatedafter2months oftreatmentbyCTandPET.AccordingtoRECIST(Response Evalua-tionCriteriaInSolidTumours)criteria,stablediseasewasobserved. MetabolicresponsewasdefinedaccordingtothePETresponse cri-teriaoftheEuropeanOrganizationforResearchandTreatmentof Cancer,20_{withapartialmetabolicresponseachieved(lungmasses}

SUVmax2.30g/mland mediastinallymphnodesmetabolic

inac-tive).Accordingly,thepatient’sconditionwasseentoimprove.The sameregimenwascontinuedfor 6months,witha PET/CTscan atthis time indicatinganatomically significantreduction ofthe tumormasses.Thelung lesionswereseentohavedecreasedby 80%involume,withmetabolicallysignificantregressionobserved (SUVmax 1.03g/ml) and no uptake in mediastinal lymph nodes

(completemetabolicresponse;Fig.6a,b).Oralbio-optimized cur-cuminArantal®_{2×84mg/dayandimatinib400mg/dayhavebeen}

administeredsincecessationofthe6monthsi.v.curcumin treat-ment.AtthemostrecentevaluationperformedinAugust2015, PET/CTimagingdemonstratednearcompleteanatomicand com-pletemetabolicresponse(Fig.7a,b).ThelastcheckupdoneinApril 2016showedthatphysicalexaminationandlaboratoryevaluation werenormal.

No side effects were observed during the treatmentperiod. Hematologicandliverfunctionparameterswereevaluatedweekly duringthefirst2months,every2weeksduringthenext2months, andthenevery4months.Intravenouscurcuminwaswell toler-atedwithnotoxicityoradversereactionsobserved.Bio-optimized curcumin(Arantal®_{)waswelltoleratedwithnotoxicityobserved.}

Fig.6. PET/CTimagingoftheThoraxat6months.

Fig.7.PET/CTimagingofthelungat24months.(a,b)PET/CTimagingat24monthsdemonstratingsignificantFDGuptakeinresidualfibronodulardensitiesinthelung (completemetabolicresponse).

3. Discussion

Overexpressionofc-kit hasbeenreportedinthemajorityof patientswith ACC.10 _{Imatinibis a specific inhibitor of Bcr-abl,}

PDGFR,andc-kitandhasdemonstratedsignificanteffectiveness in thetreatment of mutation-positivediseases such aschronic myelocyticleukemia(CML)andGIST.21,22_{Sixstudiesinvolving71}

patientshavepreviously assessedimatinibactivityinACC with objectiveresponsesobservedinonlytwopatients.9_However,

sta-blediseasewasobservedin34(47%)patients.

Severalpossibilitiesmayexplainthelackofactivityofimatinib inpatientswithmetastaticACCwithwild-typec-kitexpression. Heinrichetal.reportedresponserates toimatinibwere depen-dentontheexacttypeofmutationpresentin127patientswith GIST.23_{Inpatientsharboringexon11c-kitmutation,thepartial}

responseratewas83.5%,whereaspatientswithexon9c-kit muta-tionhadapartialresponserateof47.8%.Incontrast,noobjecting responseswereobservedinpatientswithoutdetectablec-kitor PDGFRmutations.23_{However,Vilaetal.reportedc-kitmutations}

aremostfrequentlyobservedonexons11and9.24_Spontaneous

genomicalterationsduringdiseaseprogressionmayalsoexplain thefailureofimatinib.Thiseffecthasbeenwelldocumentedin

patientswithofCML.Intheprogressionphase(acceleratedand blasticphase)ofCML,additionalgenomicalterationsdevelop, sen-sitivity toward imatinib decreases and, ultimately, the disease becomes entirely resistant. An analogous pattern may also be involvedintheprogressionofmetastaticACC.

Sun et al. demonstrated the Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Akt/Inhibitor of nuclear factor kappa-Bkinasesubunitalpha(IKK-␣)/NF-␬Bpathwayis ubiqui-touslyactivatedinACCandplaysanessentialroleintheevasion of apoptosis.25 _{These experiments indicated agents associated}

withdownregulationofthePI3K/Akt/IKK-alpha/NF-␬B signaling pathwaymayrepresentpromisingtherapiesforACC.Meanwhile, Guo et al. reported curcumin and imatinib exert synergetic antileukemiaeffectsthroughtheinhibitionofimatinib-mediated overactivation of Akt/mammalian target of rapamycin (mTOR) signalinganddownregulationofBcr-Ablgeneexpression.26

Curcumininhibitscellularproliferationanddownregulates con-stitutiveactivationofgrowth-signalingpathwaysinbothnewly diagnosed patients and imatinib-resistant patients.26 _{Sunet al.}

assessedtheactivationstatusofbothmTORandNF-␬Bpathways inrelationtoPI3K/Akt/IKKsignalingbothinvivoandinvitro.18_This

ubiqui-touslyandconcurrentlyactivatedinpatientswithACC.However, curcuminhasbeenshowntosignificantlyinhibitinvitrogrowth, migration,invasion,andangiogenesisinACCcellsandpreventthe invivogrowthandangiogenesisofACCtumorsinmicethroughdual inhibitionofbothNF-␬BandmTORpathwaysviathePI3K/Akt/IKK signalingaxis.17_{Theyalsoreportedthatconcurrentactivationof}

themTORandNF-␬Bpathwayswascorrelatedwithmalignant pro-gressioninACC.Further,Zhangetal.reportedNF-␬Bisinvolvedin themalignantprogressionofACC.27

CurcuminhasbeenshowntoinhibitNF-␬BandNF-␬B-related proteinsand pathways.28,29 _{Although almostall ACCs are c-kit}

mutationpositive,theeffectivenessof imatinibin suchcases is limited.Sixdifferenttrialsevaluatedtheeffectivenessofimatinib inmetastaticACCanddemonstratedanoverallpartialresponse rateof2.8%.WebelieveoursisthefirstcaseofACCsuccessfully treatedwithcurcuminplusimatinib,indicatingtheNF-␬Bpathway isinvolvedinthedevelopmentandprogressionofACC.However, theeffectivenessofcurcumintreatmentaloneforACCtreatment wasnotevaluated.Webelievecombinationtherapy(imatinibplus curcumin) representsthe most appropriate therapy for ACC in patientswherec-kitandNF-␬Bpositivityaredetected.

Todate,nostudieshavereportedanytoxicityassociatedwith theuseofcurcuminineitheranimalsorhumans.30_{;however,there}

isalowpotentialforCYP450-mediateddruginteractionsat phys-iologicserumconcentrationsofcurcumin.Ourclinicalexperience withmorethan3000curcumininfusionsincancerpatients sug-geststhatcurcuminissafeasnoseriousnegativedruginteractions havebeenobserved.Preliminarydataalsoindicatecurcumindoes notinteractwithotherchemotherapyagentsmetabolizedand/or eliminatedviatheprimarydrugmetabolizingCYP450pathways.31

3.1. Strengthsandlimitations

Therefore,thestrengthofthisstudyliesinthatpreclinicalin vivoandinvitrodatasupportthehypothesisofthestudythat cur-cuminisasafesupplementandhaspotentialclinicalutilityinthe treatmentofmetastaticACCtherapy.Ontheotherhand,thisstudy hasseverallimitations.Thefindingsarebasedonasinglepatient withoutanycomparisongroup;therefore,statisticalsignificance cannotbeevaluatedinthatreport.Inadditiontothis,although follow-upcareisespeciallyimportantinthefirstfiveyearsafter thetreatment,thedatapresentedinthisstudyhasbeenlimited bytheobservationsof30monthdurationofthetreatment.Dosage arrangementofcurcuminisbasedontheunpublisheddocuments andpreviousexperienceoftheauthors.Recurrentcasereportingor caseseriesmayhelptostrengthentheevidenceofthiscasereport. 4. Conclusions

Uptodate,theeffectivenessofcurcuminandimatinib,either alone or in combination, has not been validated in terms of improvingprogression-freesurvivalwithcompletemetabolicand radiologic responses in patients with ACC. However, curcumin apparentlypotentiatesandovercomesresistanceto chemothera-peuticsandsmallmoleculecancerdrugs.

Wesuggestthatbesidesc-kit,activationofNF-␬BandmTOR pathwaysshouldbeevaluatedinallACCpatients,andifNF-␬Band relatedpathwaysactivationisidentified,addingcurcumin supple-mentationtotreatmentplanshouldbeconsidered.

Integrativemedicinebringsconventionalandcomplementary approachestogetherinacoordinatedway.Webelievethatthisis thefirstreportofACCtreatmentwithintravenousandoral bio-optimizedcurcuminwithimatinib. Well designed clinicaltrials arerequestedtodeterminethecriteriaofpatientswhoaremost suitableforcurcumincombination.

Consent

WriBTeninformedconsentwasobtainedfromthepatientfor publicationofthis casereportandanyaccompanyingimages.A copyofthewrittenconsentisavailableforreviewbythe Editor-in-Chiefofthisjournal.

Competinginterests

Theauthorsdeclarenopotentialconflictofinterest. Authorcontributions

MD,astheprimarymedicaloncologistofthepatient,carriedout thetreatmentprotocol,

HS,consultedasaradiationoncologist, IY,carriedouttheimagingstudies, DS,carriedouttheimagingstudies, HD,carriedoutthePETscanning,

IY,consultedasthepreviousradiationoncologistofthepatient, SA,carriedouttheimmunoassays,

ATA,consultedasintegrativemedicinespecialist. References

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