Braz. j. . vol.82 número3

BrazJOtorhinolaryngol.2016;82(3):285---288

www.bjorl.org

Brazilian

Journal

of

OTORHINOLARYNGOLOGY

ORIGINAL

ARTICLE

Electrochemotherapy

as

palliative

treatment

in

patients

with

thyroid

papillary

carcinoma

夽

Juan

José

Grau

_,

_Miguel

_Caballero

,

Cristobal

Langdon

,

Manuel

Bernal-Sprekelsen

_,

_Jose

_Luis

_Blanch

a_{DepartmentofMedicalOncology,HospitalClínicdeBarcelona,Institutd’InvestigacionsBiomèdiquesAugustPiiSunyer}

(IDIBAPS),UniversidaddeBarcelona,Barcelona,Spain

b_{ENTSurgicalOncologySection,DepartmentofMedicalOncology,HospitalClínicdeBarcelona,IDIBAPS,}

UniversidaddeBarcelona,Barcelona,Spain

c_{DepartmentofOtorhinolaryngology,HospitalClínicdeBarcelona,IDIBAPS,UniversidadeBarcelona,Barcelona,Spain}

Received4December2014;accepted7May2015 Availableonline21September2015

KEYWORDS

Bleomycin;

Electrochemotherapy; Headandneck cancer;

Palliativetherapy; Thyroid

Abstract

Introduction:Localprogressionofpapillarythyroidcarcinoma(PTC)afterfailureofstandard therapiesmaycausepain,ulceration,andbleeding.Aspatientsarefullyawareofthetumor growth,theymightsufferhighgradeanxiety.Electrochemotherapy(ECT)isanewlocal pallia-tivetreatmentforskinmetastasesofmalignantmelanomaorothertumors,includingsquamous headeneckcancerpatients.

Objective: ToevaluatetheimpactofECTinpatientswithlocalprogressionofPTC.

Methods:Four patients with local progression of PTC were treated with ECT based on Bleomycin,andevaluatedaccordingtotumorresponse,localpainandsideeffects.

Results:Inallcases,somegradeoftumorresponsewasobserved,lasting6,7,12and8months, respectively. Also,reductionoflocal painandanxietywas registeredinallpatients.Tumor infiltratedskinnecrosiswastheonlycollateraleffectofthetreatment.ECTinducedatumor responseinallPTCpatientswithimprovementofsymptoms.

Conclusions: ECTmaybeanoptionfor localpalliative treatmentinPTCpatients withlocal tumorprogression.

© 2015Associac¸˜aoBrasileira de Otorrinolaringologiae CirurgiaC´ervico-Facial.Publishedby ElsevierEditoraLtda.Allrightsreserved.

夽 _{Pleasecitethisarticleas:GrauJJ,CaballeroM,LangdonC,Bernal-SprekelsenM,BlanchJL.Electrochemotherapyaspalliativetreatment}

inpatientswiththyroidpapillarycarcinoma.BrazJOtorhinolaryngol.2016;82:285---8.

∗_{Correspondingauthor.}

E-mail:mcaba@clinic.ub.es(M.Caballero). http://dx.doi.org/10.1016/j.bjorl.2015.05.008

286 GrauJJetal.

PALAVRAS-CHAVE

Bleomicina;

Eletroquimioterapia; Câncerdecabec¸ae pescoc¸o;

Terapiapaliativa; Tireoide

Eletroquimioterapiacomotratamentopaliativoempacientescomcarcinomapapilar datireoide

Resumo

Introduc¸ão:Aprogressãolocaldocarcinomapapilíferodetireoide(CPT)apósafalhadaterapia derotinapodecausardor,ulcerac¸ãoesangramento.Considerandoqueospacientesestão per-feitamente cientesdo crescimento tumoral, podem apresentarum alto grau deansiedade. A eletroquimioterapia (EQT) é um novo tratamento paliativo para metástases de pele de melanomamaligno oude outrostumores, inclusive em pacientescomcarcinoma escamoso decabec¸aepescoc¸o.

Objetivo:AvaliaroimpactodaEQTempacientescomprogressãolocaldeCPT.

Método: QuatropacientescomprogressãolocaldeCPTforamtratadoscomEQTcombaseem bleomicina,eavaliadosemrelac¸ãoaograuderespostatumoral,dorlocal,efeitoscolaterais.

Resultados: Emtodososcasos,foiobservadoalgumgrauderespostatumoral,queperdurou por6,7,12e8meses,respectivamente.Damesmaforma,foiregistradadiminuic¸ãodador localedaansiedadeemtodosospacientes.Necrosecutâneanainfiltrac¸ãotumoralfoioúnico efeitocolateraldotratamento.EQTinduziurespostatumoralemtodosospacientescomCPT, commelhoradossintomas.

Conclusões:EQTpodeserumaopc¸ãoparaotratamentopaliativotópicoempacientescomCPT comprogressãotumorallocal.

©2015Associac¸˜aoBrasileira deOtorrinolaringologiaeCirurgiaC´ervico-Facial.Publicadopor ElsevierEditoraLtda.Todososdireitosreservados.

Introduction

Localrelapseor regional neck metastasesafter failureof standardtherapiesofpapillarythyroidcarcinoma(PTC)are rare.However,patientsdevelopinglocalor regionaltumor progressionmaysufferfromanxiety,localpain,exudation, orbleeding.

Electrochemotherapy(ECT)isanewexperimental tech-nologybasedonincreasingcellmembranepermeabilityof the tumor cells (electroporation) to molecules. ECT con-sistsofthe administrationof electric pulses inthe tumor duringperfusionof chemotherapytofacilitate drug deliv-ery into malignant cells.1,2 _{ECT is now being used as a}

palliativetherapy for cutaneousmetastases andheadand

neckcancer.3---7 _{A recentlypublished meta-analysisof 915}

patientsstudiedtheresultsofskin-directedtherapyforlocal

cutaneousmetastases,includingelectrochemotherapy,

pho-todynamictherapy,radiotherapy,intralesionaltherapy,and

topicaltherapy.8_{Thehistologyofprimarytumorswasmainly}

melanoma andbreast carcinoma,and none of themwere

thyroid carcinoma. ECT was more active than the other

skin-directed therapies, as a 59% complete response rate

wasreported,andtransientlocalpainoccurringin 49%of

patientsthatresolvedwithinamonthwasthemorecommon

sideeffect.

The authors present the preliminary results of a pilot

study ofthyroid cancer patients withprogressionof local

recurrenceorneckmetastasestreatedwithECT.

Methods

Inclusioncriteria

Patientsresistant to radioiodine and to anti-targetagent

Sorafenib with local tumor progression of PTC after

primary therapy (thyroidectomy, cervical neck dissection,

and adjuvant radioiodine), and after treatment of the

relapse (salvage cervical surgery and radiotherapy) were

included. Sorafenibresistancewasconsidered whena20%

increase inthe sumof diametersof thetarget lesionwas

observed.

Additionalinclusioncriteria:EasternCooperative

Oncol-ogyGroupperformancestatusof2orless,lifeexpectancyof

atleastthreemonths,noactiverespiratorydiseaseor

seri-ouschronicpulmonarydisease,absolutewhitebloodcount

above 4000cells/␮L, hemoglobin greater than 10g/dL,

platelet count above100,000␮L, and noprevious clinical

historyofallergytobleomycin.

The study was approved by the Institutional Review

Board.Informedconsentwasobtainedfromallpatients.

Treatment

Under total anesthesia, with an inspired oxygen fraction

(FiO2) of 36%or less, bleomycin,20mg/m2 IVwas

admin-isteredinabolus.Betweeneightand28minlater,electric

pulsesof100␮sand1000Vwereadministeredtothetarget

tumorbyanelectrode(modelN-30-HG;IGEAS.r.l.---Carpi,

Italy),poweredbyacommercial pulsegeneratorfor

elec-troporationtreatments(CLINIPORATOR;IGEAS.r.l.---Carpi,

Italy). Tumor tissue wastreated homogeneously, covering

theentiretargetvolume.

Responsecriteria

Radiological evaluation was performed at 0, 6, and 12

weeksafterECT,accordingtoResponseEvaluationCriteria

in Solid Tumor (RECIST) criteria (version 1.1).9 _Symptom

Electrochemotherapyandthyroidcancer 287

Figure1 Case1:ExternalaspectandCT-scanofalowerleftcervicalmassprior(leftimages)andafterfourweeks(rightimages) oftheelectrochemotherapy.

Edmonton Symptom Assessment System before treatment

and 12weeks after ECT.The patients subjectivelyscored

theintensityofthesesymptomsonavisualanalogicalscale

(VAS) between 0 (absence) and 10 (maximum intensity).

Toxicity and adverse events related to ECT were also

evaluatedat6,12,and24haftertheprocedure.

Duringthefollow-upperiod,thepatientswereevaluated

atleasteverythreemonthsorwhendiseaseprogressionwas

observed.

Results

Four consecutive patients, one male and three females,

wereenrolledinthestudy.Theagerangedbetween51and

60years.Thetargettumorwasalargecervicalmassinthree

patientsandskinmetastases(lessthan2cm)inone.

A clinical response was observed in all four patients

within the first three weeks after ECT (Fig. 1). These

findings were consistent with the radiological evaluation,

showingpartialresponse(PR)intwopatientsandtwocases

ofdisease stabilization withlowertumor burden, butnot

reachingthePRcriteriaasdefinedbyRECIST.

Thetargetedlesions’sizedecreasedoverthenextthree

monthsandremainedwithout progressionduringsixto12

months after the procedure. Three of the patients died

becauseofvisceral metastases, andtherewasnodisease

progressioninthetargetedlesionstreatedwithECT.Inone

case,thepatientdied18monthsafterECTduetolocaland

metastaticdiseaseprogression.

Thesymptomevaluationshowedamoderatedecreasein

thereportedmediannumericalscaleforanxiety(10---7)and

mildreductioninpain(7---6).Nosevereadverseeventswere

observedinthenext24h afterECT,apartfrommildlocal

paincontrolledwithnon-opioidanalgesia. The changesin

thetargetedlesionincludedpainlessskinnecrosis.

Discussion

ThisisthefirstreporttoassesstheclinicalefficacyofECTas

288 GrauJJetal.

using RECIST version 1.1.9 _{There were some difficulties}

in the interpretation of the RECIST criteria. Firstly, some

increaseinthesizeofthelesioncouldbefound,especially

inthefirstfewweeks,attributedtothelocalinflammatory

reaction after ECT. In the two cases reported as ‘‘stable

disease’’, tumor response was observed in the central

partof thetumor, butthisis notevaluatedin theRECIST

criteria.

Patientsreported amoderate improvement in the two

most frequent tumor-derived symptoms: local pain and

anxiety. The treatment was well tolerated, and as the

administereddose of bleomycinwas below the maximum

tolerateddose, the procedure couldhave been repeated.

Noneofthepatientshadthetoxicitiesfrequentlyassociated

totreatmentswithbleomycin.10

PTC is commonly considered resistant to bleomycin

becauseitsunavailabilitytodiffusethroughthecell

mem-brane.ECTinduceselectroporationofthecellmembrane,

facilitatingtheentranceofbleomycinintothecellfromthe

plasma.2,11,12_{Oncethere,bleomycinappearstoactstrongly}

against cell growth, inducing cell apoptosis that can be

observeduptoseveralweeksaftertheprocedure.13

The present results showed that ECT may be a valid

option as palliative local treatment in PTC patients with

local relapseor skin metastases. The number of patients

initiallyrecruited wassmall, but thatcould be explained

sincepapillarythyroid cancer is a highly curabledisease,

andbecausepatientswithprogressivediseasearerareand

allthecaseswerefromauniqueinstitution.Moreover,other

systemicchemotherapyagentsarecurrentlyunder

investi-gationforsuchpatients.

Itappearsthatthisproceduremayhaveanantitumoral

effect,particularlyin lesionssmaller than3cm.5 _Another

meta-analysispublishedon413patientswithcutaneousand

subcutaneous tumors indicated that ECT had significantly

(p<0.001) higher effectiveness (by more than 50%) than

bleomycinorcisplatinaloneandthatECTwasmore

effec-tivein sarcoma thanin melanoma or carcinoma patients.

Nopatients withthyroid carcinoma werereported.14

Fur-therclinicaltrialswithmorepatientswillclarifytheroleof

thisprocedure.

Also,itshouldbedeterminedwhetheralargerelectrode

wouldenablereachingthetumormoreextensively,

poten-tiallyleadingtoimprovedresults.

Conflict

of

interest

Theauthorsdeclarenoconflictsofinterest.

Acknowledgement

This study was supported by a research project grant

(PI09/90664)fromtheSpanishMinistryforScienceand

Inno-vationandbyaresearchprojectgrant(EC10-067)fromthe

Spanish Ministry of Health, Department of Pharmacy and

HealthProducts.

References

1.MiklavˇciˇcD,MaliB,KosB,HellerR,SerˇsaG. Electrochemother-apy:fromthedrawingboardintomedicalpractice.BiomedEng Online.2014;13:29.

2.LarkinJO,CollinsCG,AaronsS,TangneyM,WhelanM,O’ReilyS, etal.Electrochemotherapy:aspectsofpreclinicaldevelopment andearlyclinicalexperience.AnnSurg.2007;245:469---79. 3.GargiuloM,PapaA, Capasso P,MoioM,CubicciottiE,

Paras-candoloS.Electrochemotherapyfor non-melanomaheadand neck cancers: clinical outcomes in 25 patients. Ann Surg. 2012;255:1158---64.

4.LandstromFJ,NilssonCO,CrafoordS,ReizensteinJA,Adamsson GB,LofgrenLA.Electroporationtherapyofskincancerinthe headandneckarea.DermatolSurg.2010;36:1245---50. 5.MaliB,MiklavcicD,Campana LG,CemazarM, SersaG, Snoj

M,etal.Tumorsizeandeffectivenessofelectrochemotherapy. RadiolOncol.2013;47:32---41.

6.Mir LM, Orlowski S, Belehradek J Jr, Paoletti C. Elec-trochemotherapy potentiation of antitumour effect of bleomycinbylocalelectricpulses.EurJCancer.1991;27:68---72. 7.ReinholdU.Electrochemotherapyforprimaryskincancerand skinmetastasisrelatedtoothermalignancies.AnticancerDrugs. 2011;22:711---8.

8.SprattDE,GordonSprattEA,WuS,DeRosaA,LeeNY,Lacouture ME,etal.Efficacyofskin-directedtherapyforcutaneous metas-tases from advanced cancer: a meta-analysis. JClin Oncol. 2014;32:3144---55.

9.EisenhauerEA,Therasse P,Bogaerts J,Schwartz LH,Sargent D, Ford R, et al. New response evaluation criteria in solid tumours:revisedRECISTguideline(version1.1).EurJCancer. 2009;45:228---47.

10.AlbiolS, GrauJJ,Pereira A, Reguart N, Gascon P.Epidemic hemolytic-uremicsyndromerelatedtobleomycin. Haematolog-ica.2001;86:E10.

11.MirLM,OrlowskiS.Mechanismsofelectrochemotherapy.Adv DrugDelivRev.1999;35:107---18.

12.MMirLM,OrlowskiS.Thebasisofelectrochemotherapy. Meth-odsMolMed.2000;37:99---117.

13.MirLM, TounektiO, OrlowskiS.Bleomycin: revivalofanold drug.GenPharmacol.1996;27:745---8.