ContentslistsavailableatScienceDirect
Critical
Reviews
in
Oncology/Hematology
j ou rn a l h o m e pa g e :w w w . e l s e v i e r . c o m / l o c a t e / c r i t r e v o n c
The
Third
Italian
Consensus
Conference
for
Malignant
Pleural
Mesothelioma:
State
of
the
art
and
recommendations
S.
Novello
a,∗,
C.
Pinto
b,
V.
Torri
c,
L.
Porcu
c,
M.
Di
Maio
a,
M.
Tiseo
m,
G.
Ceresoli
d,
C.
Magnani
e,
S.
Silvestri
f,
A.
Veltri
a,
M.
Papotti
a,
G.
Rossi
g,
U.
Ricardi
a,
L.
Trodella
h,
F.
Rea
i,
F.
Facciolo
j,
A.
Granieri
k,
V.
Zagonel
l,
G.
Scagliotti
aaDepartmentofOncology,UniversityofTurin,Italy
bMedicalOncologyUnit,IRCCS—ArciospedaleSantaMariaNuova,ReggioEmilia,Italy cDepartmentofOncology,IRCCS—IstitutodiRicercheFarmacologicheMarioNegri,Milan,Italy dThoracicOncologyUnit,HumanitasGavazzeni,Bergamo,Italy
eCancerEpidemiology,UniversityofEasternPiedmontandCPO-Piemonte,Novara,Italy fIstitutoperloStudioelaPrevenzioneOncologica,Florence,Italy
gOspedalePoliclinico,DivisionofHumanPathology,Modena,Italy hDepartmentofRadiotherapy,CampusBio-MedicoUniversity,Rome,Italy iAziendaOspedaliera,DivisionofThoracicSurgery,Padua,Italy jReginaElenaCancerInstitute,DivisionofThoracicSurgery,Rome,Italy kUniversityofTorino,DepartmentofPsychology,Italy
lVenetoOncologyInstitute,IRCCSPadova,Italy
mDivisionofMedicalOncology,AziendaOspedalieraUniversitariadiParma,Italy
Contents
1. Introduction...10
2. Methods...10
3. Epidemiology,publichealthandsurveillanceevidence...10
4. Diagnosticpathologyandclinicallaboratory ... 11
5. Imagingandendoscopicassessment...12
5.1. Diagnosticimaging...12
5.2. InvasivediagnosiscomparedtowhatwasalreadydiscussedinthesecondItalianConsensusConference,nonewinvasive diagnosticmodalitieshavebeenimplemented...13
6. Surgery...13
6.1. Roleofsurgeryindiagnosis...13
6.2. Treatmentofmalignantpleuraleffusion...13
6.3. Resectabledisease...14
7. Radiotherapy...14
7.1. Radiotherapyforport-siteprophylaxis...14
7.2. Adjuvantradiotherapy...14
7.3. Palliativeradiotherapy...14
8. Chemotherapy...15
8.1. First-linechemotherapy ... 15
8.2. Second-linechemotherapy ... 15
9. Continuityofcare,painmanagement,psycho-socialandlegalissues...16
Futureareasofresearch...16
∗ Correspondingauthorat:UniversityofTurin—DepartmentofOncology,SanLuigiHospital,RegioneGonzole10,10043Orbassano,Torino,Italy. E-mailaddress:silvia.novello@unito.it(S.Novello).
http://dx.doi.org/10.1016/j.critrevonc.2016.05.004 1040-8428/©2016ElsevierIrelandLtd.Allrightsreserved.
AppendixA...16
Contributors...16
Methodologicalworkinggroup...16
Epidemiologyandpublichealthpanel ... 16
Pathologyandlaboratorypanel...17
Radiology,nuclearmedicineandrespiratorymedicinepanel...17
Surgerypanel...17
Radiotherapypanel...17
Systemictherapypanel...17
Continuityofcare,painmanagement,psycho-socialandlegalissuespanel...17
AppendixA. Supplementarydata...17
References...17
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Articlehistory:Received19November2015
Receivedinrevisedform17March2016 Accepted10May2016
Keywords:
MalignantPleuralMesothelioma Recommendations Epidemiology Diagnosis Therapy Supportivecare Endoflife
a
b
s
t
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t
MalignantPleuralMesothelioma(MPM)remainsarelevantpublichealthissue,andasbestosexposureis themostrelevantriskfactor.Theincidencehasconsiderablyandconstantlyincreasedoverthepasttwo decadesintheindustrializedcountriesandisexpectedtopeakin2020–2025.InItaly,a standardized-rateincidencein2011amongmenwas3.5and1.25per100,000inmenandwomen,respectively,and widedifferencesarenotedamongdifferentgeographicareas.Thediseaseremainschallengingintermsof diagnosis,stagingandtreatmentandanoptimalstrategyhasnotyetbeenclearlydefined.TheThirdItalian MultidisciplinaryConsensusConferenceonMalignantPleuralMesotheliomawasheldinBari(Italy)in January30–31,2015.ThisConsensushasprovidedupdatedrecommendationsontheMPMmanagement forhealthinstitutions,cliniciansandpatients.
©2016ElsevierIrelandLtd.Allrightsreserved.
1. Introduction
Thispaperreportsaboutthestateoftheartand recommenda-tionsrelatedtopublichealthandsurveillanceissues,diagnosticand therapeuticaspectsforMalignant PleuralMesothelioma(MPM), basedontheThirdItalianConsensusConference,heldinBarion January29–30,2015andendorsedbytheAssociazioneItalianadi OncologiaMedica(AIOM—ItalianAssociationofMedicalOncology). ForfurtherdetailsaboutpreviousItalianconsensusconferences onMPM,thereadersshouldrefertopreviouspaperspublishedin 2011(Pintoetal.,2011)and2013(Pintoetal.,2013).
2. Methods
Theconsensus conferenceadopted the GRADEmethodology (http://www.gradeworkinggroup.org/)todesignandbuildupthe recommendations.Intheplanningphase,eachpanel(seeAppendix A)definedrelevantquestions,chosetheendpointsforeach ques-tionandrankedtheirrelevance.Amethodologicalworkinggroup organizedthe electronic search,selected the relevant evidence accordingto thepanelindications, produced summary of find-ings,tablesandratedthequalityofevidenceaccordingtoGRADE (Sch ¨unemannetal.,2008).Theseevidenceprofilesrepresentedthe basisforthepaneldiscussionandrecommendations.TheGRADE approachwaslimitedtoquestionsrelativetotreatmentefficacy comparisons.Forquestionsrelatedtodiagnosisandepidemiology theapproachremainedthesameasusedintheprevious consen-sus.Thelistofquestionsfordiscussionandconsensusproposedto eachpanelofexpertsisreportedinSupplementaryTables1and2 (electronicallyonly).
3. Epidemiology,publichealthandsurveillanceevidence InItalyin 2011MPMincidencewas3.49and1.25casesper 100,000person/yearsinmenandwomenrespectivelywith1428 (1035inmenand393inwomen)reportedasincidentcases(Anon,
2015).NationalincidenceandmortalitytrendsforMPMarestarting toleveloff.
The Second Italian Consensus Conference on MPM adopted a mathematical model for the prediction of MPM incidence in humansafterexposuretoasbestos(Pintoetal.,2013).Arecent pooledanalysis(Reidetal.,2014)showedthat,afterabout45years sincefirstexposure,thetrendinincidenceandmortalityincrease isslowingdown,althoughthesamereductionisnotobservedfor peritonealMM.Furtherstudiesareappropriate.
For cumulative exposurein the dose-response relationships therearenochangescomparedtothestatementsoftheSecond ItalianconsensusConference(Pintoetal.,2013).
Thedose-responserelationshipmaybeusedtoassessthe pro-portionalcausalweightofanydistinctexposureperiod(Priceand Ware,2005;Mastrangeloetal.,2014).However,itisnecessaryto adoptassumptionsaboutseveralkeyfactorsthatinmostinstances arenotpreciselyknown,amongothers,therelativepotencyofthe differenttypesofasbestos,theexposureintensity,andtheduration ofthepreclinicalphasesofMPM.
Itisrelevanttoassessincidenceinrelationtolong-term expo-surepatterns,whichoftenconsistofacomplextemporalsequence of exposures, which are difficult to analyse separately untan-glingtherelativerelevanceofduration,intensity,andcumulative exposure (Lubin and Caporaso, 2006; Vlandereen et al., 2013; Richardsonetal.,2012).Cumulativeexposureisasummary expo-sureindex,successfullyusedinseveralfieldsincancerresearch (Thomas,2013)butitdoesnotallowtodistinguishwhichofits components,durationorintensity,maypossiblyplayaprominent role,neitheritallowstoestablishwhetherthetemporalsequenceof exposuresisimportant(Checkowayetal.,2004).Sixdifferent stud-iesofferedevidencethatdurationandintensityareindependent determinantsofMMoccurrence.
Eveniftheanalysisoflatencyisintuitivelyappealing,underthe assumptionofa shorterlatencyforthemostexposed,itis mis-leadingbecausetheresultsarenotdependantontherelationship betweenexposureanddisease,butonthetimeboundariesofthe
observation(PikeandDoll,1965).Furthermore,incohortstudies, latencycanbedeterminedonlyforaminorityofindividualsatrisk, duetothecombinedeffectofcensoringandcompetingmortality (Langholzetal.,1999).Anincreaseinexposurecausinganincrease inincidenceinthetargetpopulationnecessarilyentailsthe acceler-ationoffailuretime(i.e.latencytime),astherelationshipbetween theincreaseinincidenceandaccelerationoffailuretimeis math-ematicallydetermined(Berry,2007);neverthelessandcontraryto whatintuitionmightsuggest,theaveragelatencyisunaffected.1
Non-occupational exposure to asbestos is more difficult to detectthantheoccupationalexposure,anditsrelativeimportance islikelytoincrease.InItalyincidenceofMPMamongwomenis veryhigh,forbothnon-occupational(environmentaland domes-tic)andoccupationalasbestosexposure.TheItalianMPMincidence surveillance system documented that 10.2% of MPM cases are duetonon-occupationalexposuretoasbestos(RegistroNazionale Mesoteliomi,2012).The potentialofsharingdatabases for case identificationandfor theassessmentofexposureiscrucial,and promptandexhaustiveimplementationhasbeenstrongly recom-mended.
Recentlyissuesrelatedtoairborneasbestosfibersinthe envi-ronment have been raised. Information from Italian regions is scanty: a recent monitoringcampaignconducted in thecity of Modenashowedanaverageconcentrationaround0.1fibers/l, sim-ilartothedatareportedintheInternationalAgencyforResearch onCancer (IARC)monograph n.100(IARC InternationalAgency for Research on Cancer (IARC), 2012).WHO estimated that for a continuous exposureto 0.4–1 fiber/l(as measuredwith cur-rentmethodology),a lifetimerisk ofMM would be from(4to 10)×100,000.Linearextrapolationtothe0.1fiber/l(current back-groundlevel)wouldcorrespondtolifelongexcessintheorderof onecase(from0.4to2.5)ofMPMevery100,000persons(World HealthOrganizationRegionalOfficeforEurope,2000).
Thepresenceofasbestosinwaterisbecomingamatterof con-cernforalargepartofthepopulation,howeverthereisnoevidence ofriskforpleuralMMrelatedtoingestedfibers.Riskofexposure toairborneasbestosfibersbecauseoftheuseofasbestos contami-natedwatercanoccurindoorandoutdoorincircumstanceswhen animportantlevel(millions/l)offibersinwaterisdetected.
EpidemiologicalstudiesandcasereportsfromReNaM under-linedthecausalroleoftalccontainingasbestosfibers(Finkelstein, 2012).The need for greater understanding of this material, its source,whereandhowit wasusedinItaly,wasacknowledged, withpriorityforepidemiologicalstudies.
Fibrous fluoro-edenite hasbeenclassifiedas carcinogenicto humansbyIARConthebasisofsufficientevidenceincludingMPM inhumans.InItaly,exposureisknownintheareaofBiancavilla (Sicily);itwasalsodetectedinothervolcanicareasinJapan. Sili-conCarbide(SiC)whiskerswereclassifiedasprobablycarcinogenic tohumans,inabsenceofhumandatabutwithclearevidenceof MPMinexperimentalanimals.TheIARCMonographconsidered differenttypesofCarbonNanotubes(CNT),ofwhichaspecifictype (MWCNT-7)wasclassifiedas‘possiblycarcinogenic’,whilethe clas-sificationcouldnotbeextendedtootherCNTsforlackofconsistent data(Grosseetal.,2014).
TheproportionofhereditaryMPMcasesinItalyisbetween1.3 and2.5%,consideringonlypopulation-basedsurveys(Ascolietal., 2007;Ascolietal.,2014).Inthepopulationlivingorworkingin Wit-tenoom,MPMcasesamongrelativesrepresented7%,andatwofold increaseofMPMriskforbloodrelativesofcaseswasestimated, afteradjustmentforasbestosexposure(deKlerketal.,2013).The
1Note:C.Bianchididnotagreeandexpressedthefollowingcomment,sentduring
therevisionofthereport:“ClaudioBianchibelievesthataninverserelationship existsbetweenintensityofasbestosexposureandlengthofthelatencyperiod¨.
roleofBAP1germ-linemutationsislimitedtothecasesoccurringin familialaggregationscorrespondingtotheBAP1cancersyndrome, whileitisnegligible(atmost1.4%)forsporadicMPMcases(Betti etal.,2015).
Health surveillance programs aimed to workers formerly exposedtoasbestosoroccupationswithpotentialasbestos expo-surearedefinedaccordingtocurrentItalianlaws[257/2006and 81/2008]. Sofar, nodiagnostic test hasenough sensitivity and specificityhighenoughtobeadoptedforearlydiagnosisofMM inasymptomaticsubjects.Healthsurveillanceactivityshould pro-videalsoinformationonrisksandonmedicalperspective,collect informationonoccupationalhistory,especiallyregardingasbestos exposures,andprovidecounsellingforsmokingcessation.
Health surveillance programs of asbestos exposed workers should: (1) inform asbestos exposed subjects about their risk relatedto(presentorpast)asbestosexposures;(2) inform rela-tivesofasbestosexposed subjectsoftheirpossiblehealthrisks; (3) Fully reconstruct occupational history, especially regarding asbestosexposures;(4)provideinformationaboutdiagnostictools, therapyandforensicmedicineperspectives;(5)supportclaimsfor compensation;(6)givecounselingonsmokingcessationandon otherrelevantmattersrelatedtohealthandlifestyle.
InItaly,areliableestimateoftheeconomicburdenassociatedto mesothelioma,includingmedicalcare,insuranceandfiscalcosts, andhumancapitalcostsrelatedtoproductivityloss,providedan estimateof250,000EuroperMMcase(Iavicolietal.,2014).
4. Diagnosticpathologyandclinicallaboratory
Thedifferentialdiagnosiswithbothpleural benign asbestos-induced disease and pleural metastases from adenocarcinomas (mainlyfromlung,breastandkidneytumours)mayrepresenta dif-ficulttask.Itshouldalwaysbekeptinmindthatmetastatictumours tothepleuragreatlyoutnumberprimaryMPM(SmithandColby, 2014).
Theconventional lightmicroscopyfeatures ofMPM arewell established,especiallyintheepithelialvariant,butMPMmayshow abroadspectrumofunusualmorphologicappearances(Ordó ˜nez, 2013a, 2012a,b,c;Churg etal., 2014)and a definitivediagnosis ofMPMinindividualcasesmayrequireinformationabout clini-caldataandothermalignancies.ThediagnosisofMPMismainly dependentonanadequatepleuralsampling,intermsofboth tis-suequantityandquality.Thoracoscopyisconsideredthepreferred biopsytechnique,allowingmultiple(aminimumoffivebiopsiesis recommended),largeanddeepbiopsiescomprisingsofttissuesof theparietalpleuraorthelung.Ultrasound-guidedand computed-tomography-guidedbiopsiesmayhaveahighdiagnosticyield(up to90%)(Pintoetal.,2013;Scherpereeletal.,2010;vanZandwijk etal.,2013).
Cytology cannot assess invasion into sub-pleural tissues or lung parenchyma, but careful examination of cytologyfindings (hypercellularity,three-dimensionalmorular/papillarystructures, macronucleoli,cell cannibalism, multinucleated cells, squamoid cells,blebbing,intracytoplasmicvacuoles,monomorphic popula-tion of atypical cells, pinkhaze around cells) mayconsistently suggestadiagnosisofepithelialMPM(Kawaietal.,2014;Paintal etal.,2013;Hjerpeetal.,2015;Hendersonetal.,2013a).The diag-nosisofsarcomatoidMPMoncytologyisextremelydifficultand oftenrequiresacell-blockandaclosecorrelationwithclinicaldata andimagingstudies.Inselectedcasesfulfillingthecytological cri-teriaofmalignancyandimmunohistochemistry(IHC)evidenceof mesothelialcelldifferentiation,adefinitivediagnosisofMPMon pleuraleffusioncanbeperformed.
Table1
Proposalforimmunohistochemistryinvestigation.
−Anantibodybatteryconsistingoftwomesotheliomapositive markers(alwaysincludingcalretinin)andtwomarkersforthe carcinomaphenotype(onebeingcarcino-embryonicantigen/CEA) shouldbeperformed.
−Asecond-runofantibodiesusefulforthedifferentialdiagnosis, alwaysinthecontextofmicroscopicfindingsandclinicalinformation, includesD2-40,WT1andCK5forthemesothelialphenotypeand claudin-4,BerEP4,CD15(LeuM1),MOC31andTTF1forthecarcinoma phenotype.
−Theabove-mentionedmarkersarenotentirelyreliablefor sarcomatoidmesothelioma:aninitialinvestigationwithcombination ofantibodiesagainstcytokeratinsisrecommended,subsequently integratedbyadditionalIHCmarkerssuchascalretinin,WT1and D2-40.
−Immunonegativityforsuchmarkersdoesnotexcludethediagnosis ofMPM,since30%presenta“null”phenotype.
AccordingtotheWorldHealth Organizationclassification of
pleuraltumors(Churgetal.,2015),MPMissubdividedintothree
basichistologicaltypes:epithelioid,biphasicandsarcomatous. MPMtypicallypresentswithlungencasementandrelative spar-ingof thelung parenchyma, but pathologists shouldbe aware ofunusualpresentations,includingcasesofMPMwithabsentor inconspicuouspleuralinvolvementmanifestingasmetastatic dis-easeinusualsites(e.g.,skin,softtissues)ormimickinginterstitial lungdiseases(Larsenetal.,2013).
IHCisthemosthelpfulancillarytechniqueinintegratingthe diagnosisofMPM (Ordó ˜nez,2013b; Bettaet al.,2012)and dif-ferentiatingepithelioidMPMfrompulmonaryorextrapulmonary adenocarcinomas involving the pleura. IHC markers including calretinin,D2-40(podoplaninantibody),Wilms’tumor-1 protein (WT-1), cytokeratins 5/6, mesothelin and thrombomodulin are recommended.NegativeIHCmarkers include carcinoembryonic antigen(CEA),BerEP4,MOC-31,claudin-4,CD155(Hendersonetal., 2013b;Lonardietal.,2011;Joetal.,2014).NapsinAandTTF-1, CDX2,PAX-8,apocrinemarkersandhormonalreceptorsallow dif-ferentialdiagnosisbetweenpleuralmetastasesandMPM(Table1). VariantsoftheBRCA1-associated protein1 (BAP1),resulting innuclearproteinloss,werereportedinhereditaryandsporadic mesothelioma.Inarecentstudy,BAP1wasexpressedinallbenign mesothelialtumors,whereas139outof212(66%)mesotheliomas wereBAP1negative,especiallyinepithelioid/biphasiccompared withsarcomatoid/desmoplasticsubtypes (69%vs15%). In biop-siesinterpretedasreactivemesothelialproliferation,BAP1losswas 100%predictiveofmalignancy,whereasonly3outof36(8%) BAP1-positivecasesprogressedtomesothelioma.Oncytology/cellblocks, benignmesothelialcellswereinvariablypositiveforBAP1,whereas 64%of mesotheliomas showedloss ofprotein. BAP1 immunos-tainingrepresentsanexcellentbiomarkerwithanunprecedented specificity(100%)inthedistinctionbetweenbenignandmalignant mesothelialproliferations(Cigognettietal.,2015).
IHCplaysalimitedroleforthediagnosisofsarcomatoidMPM (Ordó ˜nez,2013a;Scherpereeletal.,2010).Mostofsarcomatoid MPM express pan-cytokeratins, vimentin and even markers of smooth muscle differentiation (e.g., smooth muscle actin), but mesothelialmarkersoftenfailtorecognizemesothelial differen-tiation of sarcomatoid MPM or rather show a weak and focal expression,only.ThemostusefulmarkersforsarcomatoidMPM includeD2-40andcalretinin(Pintoetal.,2013;Ordó ˜nez,2013a; Scherpereel et al., 2010; Churg et al., 2015; Henderson et al., 2013b).Theavailabilityofclinicalandimagingdataandatleast twopan-cytokeratinsandtwonon-mesothelialmarkersisrequired tosupporta diagnosisofsarcomatoidMPM (Pintoetal., 2013; Ordó ˜nez,2013a;Scherpereeletal.,2010;Churgetal.,2015).
Soluble mesothelin-relatedpeptide(SMRP), osteopontin and fibulin-3havesofarbeenproposedaspromisingMPMmarkersin
Table2
Recommendationsofthepathologyandlaboratorypanel. −Atthoracoscopy,aminimumoffivedeepbiopsiesare recommended,wheneverpossible.
−Cytologyaloneisareliablediagnostictoolforexperienced cytopathologists,preferablywithadditionalimmunocytochemical characterisation.However,tissueconfirmationofthecytologic diagnosisisalwaysadvisable,wheneverpossible.
−Intraoperativeexaminationmaybeusedindefiningtheadequacyof removedtumourtissueinthesuspectofMPM,butdoesnotprovide informationabouttheMPMsubtype.
−Standardizedreportincludingsubtypingofmesotheliomainto epithelioid,sarcomatoidandbiphasicisadvisable.
−Immunohistochemicalmarkersantibodypanelsarerecommended foramoreprecisesubtypeclassification(seeTable1).
−Mesothelin,fibulin-3andotherserumbiomarkers(e.g.osteopontin) arestillunderevaluationindiagnosis,prognosisandmonitoringMPM. Theiruseisnotrecommendedinclinicalpractice.
bothserumandpleuraleffusionfluid(Laoetal.,2014;Creaneyetal., 2011;Hollevoetetal.,2011;Hollevoetetal.,2010;Luoetal.,2010; Wheatley-Priceetal., 2010;Creaney et al.,2014a;Franceschini etal.,2014).However,theirclinicalapplicationischaracterizedby lowsensitivity,specificityandreproducibility,thenrequiring fur-thervalidationbeforetheirapplicationasdiagnosticorscreening tools(vanZandwijketal.,2013;Kawaietal.,2014;Paintaletal., 2013;Hjerpeetal.,2015;Hendersonetal.,2013a;Churgetal., 2015;Larsenetal.,2013;Ordó ˜nez,2013b).
Datareportedsofardonotprompttheimmediateuseofany newtest(including methylation-specificreal-timePCR analysis, oligonucleotide Array-BasedCGH or micro-RNA) in theroutine diagnosticsetting (Creaneyet al., 2014b;de Assisetal., 2014). Prospectivestudiesareworthbeingcarriedout,toevaluatethe reproducibilityofdataproducedbydifferentlaboratories.
TheroleofBAP1andNF2inpromotingsporadicandhereditary mesotheliomashasbeeninvestigated(Bettaetal.,2012;Weber etal.,2014;Testaetal.,2011;Yoshikawaetal.,2012;Cheungetal., 2013).Nextgenerationsequencingstudiesidentifiedgenetic vari-ationsclusteredinthep53/DNArepair(TP53,SMACB1,andBAP1) andPI3K-AKTpathways(PDGFRA,KIT,KDR,HRAS,PIK3CA,STK11, andNF2)asthemostcommonlyidentifiedandvalidated(Ladanyi etal.,2012).
Finally,astandardizationofthediagnosisofMPMon patho-logicreportisrecommendedinordertopreventmisinterpretation ofmorphologicandIHCdataamongpathologistsandclinicians. Recommendationsfromthepathologypanelaresummarizedin Table2.
5. Imagingandendoscopicassessment 5.1. Diagnosticimaging
Dependingfromthepresenceorabsenceof pleuraleffusion, itsextent(localized or diffuse,unilateral orbilateral) andfrom thepresenceorabsenceofcalcified lesionsatthepleurallevel, thecontributionofimagingmaybesignificantlydifferent.Imaging identifiespleuralthickening,differentiatebenignfrommalignant pleuralthickening,and,ifpossible,contributetothedefinitionof etiology(Surekaetal.,2013).
Generally,inpresenceofnon-conclusivefindingsatchestX-ray (CXR),particularlywhenpleurallesionsaresuspected,computed tomography(CT)istherecommendedsecond-stepstudy.
Ultrasounds(US),includingcontrast-enhancedUS(CEUS),may be sometimes useful in identifying pleural abnormalities. US mayquantifypleuraleffusionsandthickening.Discretemalignant nodulesmaybeidentifiedandevaluatedonthebasisoftheir vas-cularization(Sartorietal.,2013).
WhenCT-baseddiagnosiswascomparedwithhistological find-ings,CT scandemonstrated asensitivityof 68%(95%CI62–75%) andaspecificityof78%(95%CI72–84%).Asignificantproportion ofpatientswithpleuraleffusionhadmalignancy,despitea nega-tiveCTreport.Therefore,inthecaseofapatientwithundiagnosed pleuraleffusion,thedecisiontoplanapleuralbiopsyshouldnotbe basedonCTalone(Hallifaxetal.,2015).
The role of fluorodeoxyglucose positron emission tomography (FDG-PET)remainsasreportedinthepreviousconsensuspaper (Pintoetal.,2013).
ThereisnosinglemodalitytoconfirmMPMdiagnosispriorto surgery,butsofaravailablestudieshaveshownthatPET-CTis supe-riortoFDG-PET,magneticresonanceimaging(MRI)andCTinterms ofspecificityandsensitivityinthedetectionofMPM(Zahidetal., 2011).
5.2. Invasivediagnosiscomparedtowhatwasalreadydiscussed inthesecondItalianConsensusConference,nonewinvasive diagnosticmodalitieshavebeenimplemented
Inpatientswithpleuraleffusion,thoracentesisremainsthefirst minimallyinvasivediagnosticmaneuver;malignanteffusionscan bediagnosedbypleuralfluidcytologyinabout60%ofcases. US-guidanceimprovesthe successrateand reducescomplications, includingpneumothorax(Hooperetal.,2010).
CT-orUS-guidedbiopsydefinitelyreplacedblindneedlebiopsy ofpleural thickeningsorlesionsclearly identifiedwithimaging techniques(Maskelletal.,2003;QureshiandGleeson,2006;Adams etal.,2001;Metintasetal.,2010a).Ablindneedlebiopsymaybe stillconsideredonlywhenthepleuralcavityisinaccessibledueto extensivepleuraladhesion.
Thoracoscopyisthemostreliableinvasivetechniqueto diag-noseMPMwithadiagnosticyieldofover90%(Churgetal.,2014; BoutinandRey,1993;Hansenetal.,1998;Galbisetal.,2011;Brims etal.,2012),allowingextensivesamplingofthepleuraandthe sub-sequentpleurodesis.Inthelackofstudiescomparingimage-guided biopsyandthoracoscopy,thediagnosticchoiceisbasedonthe clin-icalevaluationofeachindividualcase(Metintasetal.,2010b).
The assessment through thoracoscopy of visceral pleura involvementiscrucialtoestablishtheextentofdiseaseandto for-mulateacorrectTNMclassification(AmericanJointCommitteeon Cancer,2010).Theinvolvementoftheparietalanddiaphragmatic pleuraorthevisceralpleura,limitedorextensive,hasprognostic value(Kaoetal.,2011).
Endobronchialultrasound(EBUS)fornodalstaginginMPMis anewpromisingtechniquewithsomeadvantagescomparedto mediastinoscopy(lesscomplications,minimaltraumato peritra-chealtissue,accesstohilarlymph-nodesusuallyinaccessibleto mediastinoscopy)withasimilaraccuracy.Esophagealendoscopic ultrasound(EUS)isindicatedwhensuspectednodesareidentified onimagingstudiesatthosesiteswhicharenotassessablebyEBUS (Riceetal.,2009;Tournoyetal.,2008;Zielinskietal.,2010;Richards etal.,2010).
Forstagingpurposes,CTmayunderestimateearlychestwall invasion, diaphragmatic and peritoneal involvement, as for its well-known limitationinassessment ofnodal disease,and MRI can be used to complement CT in detecting invasion of chest wallor mediastinum,or trans-diaphragmatic extension.PET/CT canaccuratelydemonstrateintrathoracicandextrathoracic lym-phadenopathyandmetastaticdisease(Truongetal.,2013a;Nickell etal.,2014;Basuetal.,2011;Erasmusetal.,2005).
SeveralstudiesindicatedPET/CTfornodalstaging,withsuperior sensitivity, specificity and accuracy than other imaging tech-niques (Rice et al., 2009; Flores et al., 2003). However,PET/CT hasa well knownlimitation in theassessment of lymphnodal micrometastaticdisease(Sørensen etal.,2008).Consequently,a
surgicalstaging is recommended (mediastinoscopy, EBUS, EUS-FNA and laparoscopy), especially for candidatesto multimodal treatment(Truongetal.,2013b).
Themeasurement oftumorthicknessonCT scanis the cur-rentstandardintheassessmentofresponsetotherapy.However, inter-observervariabilityrepresentsanissue.AlternativeCT-based tumor response criteria, such as direct measurement of tumor volumechanges, havebeen suggestedasa surrogatefor tumor response(Armatoetal.,2013).Computer-aideddetection(CAD) protocols,usingdedicatedsoftwareorotherautomatedmethods forvolumetricevaluationoftheresponsetotherapy,havebeen pro-posed(Frauenfelderetal.,2011;Labbyetal.,2013a;Labbyetal., 2013b).PETparametersthatmeasuretumoractivityandfunctional tumorvolumeweresuggestedasindicatorsofpatientprognosis (Armatoetal.,2013).
Sofar,modified RECISTcriteria, whichtakeintoaccountthe irregularmorphologyofthetumorbymeasuringtumorthickness perpendicular tothechestwallormediastinum intwo sitesat threedifferentlevelsontheCTscan,remainsthestandardforthe assessmentofthetherapeuticresponseofMPM.(ByrneandNowak, 2004)
6. Surgery
6.1. Roleofsurgeryindiagnosis
Iffeasible,thoracoscopyisrecommendedfordiagnostic pur-poses.Multiplebiopsiesofbothnormalandseeminglyabnormal pleura,includingsub-pleuraltissue,arerecommendedtominimize false negative results(Churg et al.,2014).Even ifthe diagnos-ticperformance ofuniportalthoracoscopicpleuralbiopsyisnot equivalenttothatofanopenbiopsy(Greillieretal.,2007;Bueno etal.,2004;AttanoosandGibbs,2008),thoracoscopyispreferable becauseoftheincreasedriskoftumorimplantationinthechest wallandthehighermorbidityrateofopensurgery(Churgetal., 2004).
Mediastinoscopyor laparoscopyare recommendedfor those patientswithmediastinalnodalinvolvementorabdominaldisease extension,respectively, thatwould precludesurgical considera-tion.
6.2. Treatmentofmalignantpleuraleffusion
Pleuraldrainagereducespleuraleffusion,dyspnea,chestpain orpersistentcoughinpatientswhodemonstrateatrappedlung onchestX-ray.Thetimingforchesttubeinsertion after unsuc-cessfulpleuraldrainageisdictatedby:(a)presenceoftheabove mentionedsymptomsassociatedtoatimetorecurrenceshorter than10days;(b)contraindicationstomoreinvasiveproceduresor generalanesthesia;(c) radiographicdemonstrationofatrapped lungsyndrome.Withachesttubeinplace,talcpoudragecanbe performedbyinjectingapulverized,naturalhydratedmagnesium silicateintothepleuralcavity,astalcslurryunderlocalanesthesia. Alternatively, patients who tolerate general anesthesia can undergo thoracoscopyand talc insufflationunder direct vision, which ensures a thoroughdistribution of the agent.This tech-niqueis also recommendedin patientswho are candidatesfor extendedpleurectomy/decortication(P/D)andextra-pleural pneu-monectomy(EPP)becausepleuraladhesionfacilitatessubsequent extrapleuraldissectionwhileminimizingthechancefortumor dis-semination.Contraindicationtotalcpoudrageisthetrappedlung syndromeand,inthiscases,VATSpleurectomyhasbeenadvocated (Walleretal.,1995;Halsteadetal.,2005;Martin-Ucaretal.,2001; Nakasetal.,2008).
Table3
Recommendationsofthesurgicalpanel.
−Amultidisciplinaryteamincludingsurgeons,medicaloncologists, respiratoryphysicians,radiologistsandradiationoncologistsis recommendedtodefinethebesttreatmentstrategyineachindividual patient.
−Thetwoprocedureswithcurativeintentareextrapleural
pneumonectomy(EPP)andextendedpleurectomy/decortication(P/D). Thesesurgicalproceduresshouldbeperformedinclinicallyand functionallyselectedpatientswithpre-treatmentstagesIandII,and selectedstageIII,preferablyinthecontextofclinicalstudies.Apriority goalofresearchistoidentifythecorrectsurgicalcontributionandtype ofintervention,inordertouniformproceduresandresults.
−Inthecontextofamultimodalityapproachincludingsurgery, chemotherapycanbeadministeredeitherinthepre-orpost-operative setting,althoughintheabsenceofprovenevidence.Adjuvant radiotherapycouldbepartofthemultimodalapproach. −Surgicalproceduresperformedwithcurativeintentshouldbe reservedtoreferralthoracicsurgicalcenterswithdedicatedexpertise.
6.3. Resectabledisease
Consensuswasalsoobtainedaboutthoroughevaluationofthe
performancestatusandthecardiopulmonaryreserveofsurgical
candidatesaswellasfortheneedofa correctdefinitionofthe
surgicalinterventions,intheattempttouniformproceduresand
results(Riceetal.,2011Aug).EPPandextendedP/Dmaybe
con-sideredin stages I,IIand selected(N0)stage IIIMPM,without distantspreading. If deemed good surgicalcandidates,patients shouldreceivesurgicalresection(P/DorEPP),adjuvantradiation therapy(hemithoracicexternalbeamorintensitymodulated radi-ationtherapy),andeitherneoadjuvantoradjuvantchemotherapy (cisplatin-pemetrexedfor4cycles).Theoptimalprecisesequence of treatments withinthe trimodality is unclear,and shouldbe decideduponbyamultidisciplinaryconsensusforeachindividual patient(GomezandTsao,2014).
Evenifrandomizedclinicaltrialscomparingthetwosurgical approachesarelacking(Treasureetal.,2014),recentstudies sug-gestthatextendedP/Dhaslowermortality,lessercomplications thanEPPandcomparable survivalrates(FloresPassandSeshan etal.,2008;Lang-Lazdunskietal.,2012).In2015,ameta-analysis including1.512patientstreatedwithP/Dand1.391treatedwith EPP(Taiolietal.,2015)showedthatperioperative30-daymortality wassignificantlyhigherafterEPPthanafterP/D.Theseresultswere confirmedbyanothermeta-analysis(Caoetal.,2014).
Inthecase ofdiscordancebetweenCT andFDG-PETfindings inassessingthenodalstatus,athoroughpreoperativeexploration of themediastinum is recommended (Sugarbaker et al., 2014). Cervicalmediastinoscopyandendoscopicprocedures(EBUSand EUS)maybeconsidered(aloneorincombination)todetectnodal metastasesotherwiseinaccessibletomediastinoscopy(Nakasetal., 2012).
Recommendationsfromthesurgerypanelaresummarizedin Table3.
7. Radiotherapy
7.1. Radiotherapyforport-siteprophylaxis
Threerandomizedtrialshavebeenconductedtoevaluatethe efficacyofprophylacticirradiationinterms of tract-metastases-freesurvival. Aninitialstudy(Boutinetal.,1995)waspositive, evenifwithsomecriticismsduetothelimitednumberofenrolled patients and the high rate of port-site failure in patients not receivingradiotherapy(20%).Morerecently,tworandomizedtrials (Bydderetal.,2004;O’Rourkeetal.,2007)didnotdetectany bene-fit.Globallyconsidered,thequalityofthesestudiesismodest,with qualityassessment,accordingtoGRADEcriteria,negatively
influ-encedbyimprecision.Currently,thereisnoconvincingevidencein offeringsystematicallyradiotherapyforport-siteprophylaxis.An ongoingUKstudy(SMARTtrial)islookingatthebesttimetogive radiotherapytopreventmesotheliomaspreadingafteraprocedure tothechestwall.
7.2. Adjuvantradiotherapy
Therearenorandomizeddata tosupportadjuvantpost-EPP radiotherapy,buthistoricalcomparison suggeststhat radiother-apyatthetotaldoseof54Gycouldbeassociatedwithasignificant reductioninlocalfailure(11%comparedtopreviousvaluesinthe rangeof30–40%withradiationdosesbelow50Gy)(Ruschetal., 2001).
Initialdatawithintensitymodulatedradiotherapy(IMRT),due toitsplanningcapabilityintreatingaveryirregularlyshapedPTV (planningtargetvolume)and inreducingdosetoorgansatrisk (liver,heart,kidney,lung)werehighlyencouraging,withlocal con-trolratesaround90%(Forsteretal.,2003).However,severetoxicity wasrelevant compared to classical 3D-conformalradiotherapy, includingdeathsfromradiationpneumonitis,evenifdosimetric predictorsofradiationinjurywerebelowthenormallyaccepted constraints(i.e.,V20<20%).Withtheuseofstrictdoseconstraints
forlungexposure(V20<10%,meanlungdose<8.5Gy),morerecent
experiencesofIMRTafterEPPdidnotreportunexpectedexcessive toxicity(Riceetal.,2007).Despitethelackofrandomized stud-iescomparing3D-ConformalRTandIMRTafterEPP,IMRT(mainly volumetricIMRT)iscurrentlypreferred,sinceitallowsamore con-formalirradiationoftheaffectedhemithorax.ASwissprospective phaseIIrandomizedtrial(SAKK17/04,NCT00334594)(Staheletal., 2014)evaluated theroleof hemithoracicRTafterneo-adjuvant chemotherapyandEPP.Theprimaryendpointof1-yearincreasein loco-regionalrelapse-freesurvivalwasnotmet.Fewretrospective clinicaldataareavailableaboutradiotherapyasadjuvant treat-ment after P/D. The treatment volume in hemithoracic pleural irradiationshouldincludeallthepleuralspace(CTVdefinedasthe entirehemithoraxincludingtheparietalandvisceralpleura,the entirediaphragmandinvolvedipsilateralhilarlymphnodestations, withoutinclusionofthefissures,withoptimalimagingfortarget definitionstilltobedefined).However,evenwiththemodern radi-ationtechniques,itwouldbedifficulttoadequatelysparethelung itself,withtheriskofasevereradiationpneumonitis.
Preliminaryexperiencesoflungsparinghemithoracicpleural IMRThavebeenpresented(Rosenzweigetal.,2012;Minateletal., 2014;Chanceetal.,2015)andshowedpotentiallypromisingresults forbothefficacyandsafety(witha20%rateofseverepneumonitis). 7.3. Palliativeradiotherapy
Retrospectiveanalysesindicatedaclinicalbenefitintermsof symptomcontrolinabout50%ofpatientstreatedwithpalliative radiotherapy.Chestinfiltratingtumormassescausingpain repre-sentthemainindication.Inthissetting,therearefewprospective trials(Bissettetal.,1991;Lindénetal.,1996;MacLeodetal.,2015) andhypofractionatedschedulesaregenerallyused(dose/fraction intherange3–5Gy),withtotaldosesfrom20to40Gy.Pain con-trolisachievedmorefrequentlywithfractionslargerthan3Gy;the mediandurationofpainreliefisgenerallysatisfactory.Palliative irradiationisnoteffectiveinthetreatmentofdyspneasecondaryto pleuraleffusionormediastinalinvasion.Theverywidefieldsoften requiredtopalliatesymptomsmaycausesignificantacute toxic-ity,mainlyfatigue;therefore,prospectivestudieswithadequate clinicalendpoints,includingqualityoflife,areneeded.Theefficacy ofpalliativeradiotherapycannotbeevaluatedaccordingtoGRADE methodologyandcriteria,becausetherearenocomparativetrials.
Table4
Recommendationsoftheradiotherapypanel. 4.1Radiotherapyforport-siteprophylaxis
−Systematicadjuvantirradiationofthoracictractsisnotroutinelyindicated. 4.2Radiotherapyasapartofamultimodalityapproach
−Themostappropriatetimingofdeliveringradiotherapyshouldbediscussed upfrontinamultidisciplinaryboard.
−ForpatientswithresectableMPM,whoundergoEPP(afterneo-adjuvant chemotherapy),adjuvantradiotherapycanberecommendedfor“highly selectedpatients”(goodperformancestatus,epitheliodhistology,female),to improvelocalcontrol.
−RTshouldbeconsideredonlyforpatientswhomeetthefollowingcriteria: ECOGPS≤1,FEV1>80%andgoodfunctionalpulmonarystatus,adequaterenal function,absenceofcontrolateralchestdisease.
−DoseofradiationforadjuvanttreatmentfollowingEPPshouldbe50–54Gy in1.8–2Gydailyfractions,with60Gydeliveredtomacroscopicresidual tumors,ifany.
−IMRTmaybeconsideredincenterswithanadequateexperienceinthisfield andinthecontextofclinicaltrials.Radiationexposureoftheremaininglung shouldbestrictlylimited,giventhehighriskoffatalpneumonitiswhenstrict limitsarenotapplied(seetext).
−Theclinicaltargetvolume(CTV)forpost-EPPRTshouldencompassthe entirepleuralsurface(entiresurgicalbedofthewholehemithorax),andany potentialsiteswithmicroscopicresidualdisease.
−Thegrosstumorvolume(GTV)shouldincludeanygrosslyvisibletumor, withsurgicalclipsindicativeofgrossresidualtumor;electivenodalirradiation (regionalnodes)isnotrecommended.
−Theplanningtargetvolume(PTV)shouldconsidertargetmotionanddaily set-uperrors,withmarginsofexpansiondependentonsinglepatientand singleinstitutionassessment.
−AdjuvantirradiationafterP/D(lungsparinghemithoracicpleuralIMRT)is usuallynotrecommended,butmaybeconsideredwithcautionandunder strictdoselimitsoforgansatrisk,onlyinthecontextofprospectiveclinical trials.
4.3Radiotherapyforsymptompalliation
−Aroleforpalliativehypofractionatedradiotherapy(dailydosesof3–5Gy) forthecontrolofsecondarychestpainisproven.However,acarefulclinical evaluationismandatoryineverysinglepatient,especiallyconsideringthat suchtreatmentsmaybeassociatedwithacutetoxicities.
Recommendationsfromtheradiotherapypanelaresummarizedin
Table4.
8. Chemotherapy 8.1. First-linechemotherapy
TheroleofchemotherapyinMPM,aswellastheoptimaltiming ofchemotherapy,havebeenreviewedbyFenneletal.(Fennelletal., 2008)andinthepreviousconsensuspaper(Pintoetal.,2013).
Theonlyavailablerandomizedclinicaltrialcomparingactive symptom control (ASC) alone versus ASC in combination with chemotherapy(mitomycin,vinblastineandcisplatinfor4cyclesor singleagentvinorelbineweeklyfor12cycles)showedasmall,not significantincreaseinoverallsurvivalwithchemotherapy(Muers etal.,2008).TheevidenceprofileofGRADEappliedtothis random-izedtrialsuggestedamoderatequalityofinformationregarding bothefficacyandsafety.
Platinum-baseddoubletcontainingathird-generation antifo-late(pemetrexedorraltitrexed)isthefront-linestandardofcare (Vogelzangetal.,2003;VanMeerbeecketal.,2005).Theevidence profileofGRADEappliedtorandomizedtrialsconductedinthe front-linesettingsuggestsahighqualityofinformationregarding bothefficacyandsafety.Thepemetrexed-containingcombination issupportedbyagreateramountandqualityofclinicalinformation (Muersetal.,2008).
Pemetrexedcanbesafely administeredin combination with carboplatin, with efficacy comparable to cisplatin-pemetrexed (Santoroetal.,2008).Thecombinationofcarboplatinand peme-trexedcouldbeanalternativetreatmentoptionforpatientswho arenotcandidatestocisplatin-basedtherapy.Ontheotherhand,
inpatientsunfitforplatinum-basedchemotherapy,theuseof sin-gle agentvinorelbine asfirst-line therapy couldbe considered, althoughtheconsensuspanelwasnotunanimous,duetothe lim-itedevidencesupportingthistreatment(Fennelletal.,2008).
Abetterknowledgeofmajormolecularpathwaysinvolvedin MPMbiologyhasleadtotheidentificationofpotentialnew ther-apeutictargets(Staheletal.,2015).A randomizedphaseIItrial testingtheadditionoftheanti-VEGFantibodybevacizumabversus placebo to gemcitabine–cisplatin reported nosignificant differ-ence,neitherintermsofprogression-freesurvivalnorinoverall survival (Kindler et al., 2012).The randomized phase II MAPS (MesotheliomaAvastinplus Pemetrexed-cisplatinStudy), evalu-atingtheadditionofbevacizumabtopemetrexed–cisplatin,met itsphaseIIitsprimaryendpoint(Zalcmanetal.,2010).Data pre-sentedattheAmericanSocietyofClinicalOncologyannualmeeting in2015fromthephaseIIIstudy,conductedin448patients, demon-strateda2.7-monthimprovementinmediansurvival,mirroredbya 2.1-monthbenefitinmedianPFS(Zalcmanetal.,2015).Inaphase II,single-armstudytestingtheadditionofamatuximab,an anti-mesothelinmonoclonalantibody,topemetrexedandcisplatin,the experimentalcombinationwaswelltoleratedandassociatedwith anobjectiveresponserateof40%.AlthoughPFSwasnot signifi-cantlydifferentfromhistoricalcontrols,apromisingmedianOSof 14.8monthswasobserved(Hassanetal.,2014).
Therearenodataabouttheoptimalduration of chemother-apyinpatientswithMPM.Inthecurrentpractice,chemotherapy isadministeredforamedianof4–6cycles,unlessprogressionor severetoxicityoccurs.Althoughasmallstudyhasshownthat con-tinuationofpemetrexedaloneafterinductionwithcisplatinand pemetrexedis feasible(vandenBogaert etal.,2006), thereare norandomizedtrialssupportingtheefficacyofthemaintenance approach.Arandomizedstudytestingtheefficacyofswitch main-tenancewiththalidomideversusnofurthertreatmentshowedno survivalimprovement(Buikhuisenetal.,2013).AphaseII random-izedstudy ofcontinuous maintenance withpemetrexed (Anon, 2016a), and another one testing theswitch maintenance strat-egywiththefocaladhesionkinaseinhibitordefactinibareongoing (Anon,2016b).
Inelderlypatients,withthewarningofagreaterhematologic toxicity, the efficacy of platinum and pemetrexed is compara-bletowhatobservedinyoungerpatients(Ceresolietal.,2008). GRADEmethodologywasnotadoptedfortheissueoftreatmentof elderlypatients,becauseofthelackofrandomizedtrialscomparing activetreatmentversusbestsupportivecarespecificallyinelderly patients,andparticularlyforsubjectsolderthan75years. How-ever,theConsensuspanelagreedthatelderlypatientswithgood performancestatusandwithoutclinicallyrelevantcomorbidities mightbecandidatetochemotherapy(Ceresolietal.,2014). 8.2. Second-linechemotherapy
Theroleofsecond-linechemotherapywasevaluatedina ran-domizedphaseIIItrialcomparingpemetrexedplusbestsupportive care(BSC)versusBSCaloneinpatientspreviouslytreatedwitha first-lineregimennotincludingpemetrexed.Thestudyenrolled 243 patients, and showed a statistically significant increase in objectiveresponserate,diseasecontrolrateandtimeto progres-sion for pemetrexed, but without significant benefit in overall survival(Jassemetal.,2008).
Therearenoapprovedagentsforsecond-linetreatmentofMPM patients,andthisremainsadiseasesettingtotestnewagents. Con-sequently,patientsshouldbeencouragedtoparticipateinclinical trials.Whenaclinicaltrialisnotavailable,single-agent chemother-apycouldbeconsideredforfitpatients,althoughthepanelwasnot unanimousaboutthisissue.Bestsupportivecareremainsavalid option(Ceresoli,2014).
Table5
Recommendationsforsystemictherapy. 5.1First-linechemotherapy
−Chemotherapywiththecombinationofathird-generationantifolate plusplatinum(cisplatinorcarboplatin)isrecommendedforpatients withadvancedMPMandgoodperformanceStatus(PS)(ECOG0–1). −Chemotherapyshouldbestartedassoonaspossiblefollowingthe diagnosis,andadministeredfor4–6courses,withoutmaintenance. −InaphaseIIIstudy,bevacizumabaddedtocisplatinandpemetrexed significantlyimprovedprogression-freeandoverallsurvival.Inthe contextofpreviouslynegativestudies,aconfirmatorystudyis recommended.
−Inelderlypatientswithgood(ECOG0–1)PSandwithoutsignificant comorbiditiesachemotherapytreatmentcanbeconsidered. 5.2Second-linechemotherapy
−Inpatientswithgood(ECOG0–1)PSwithoutcomorbidities,not pretreatedwithpemetrexed-basedregimens,singleagentpemetrexed isconsideredthestandardoption.
−Forpatientswithatimetoprogression≥6monthsfollowing first-linepemetrexed-basedchemotherapy,re-treatmentwithsingle agentpemetrexedmaybeconsideredatreatmentopportunity. −Inpatientsprogressingafterapemetrexed-basedregimen,thereis nostandardsecond-linetherapy,andthisremainsasettingtotestnew agents.Patientsshouldbeencouragedtoparticipatetoclinicaltrials. −Whenatrialisnotavailable,orpatientsarenoteligibleforan experimentalapproach,single-agentchemotherapycouldbea possibleoptionforpalliation.Thepanelwasnotunanimousaboutthis recommendation.
−InpatientswithrapidlydecliningPS,olderageorrelevant co-morbidities,theuseofsupportivecaremeasuresaloneis consideredappropriate.
Severalpublishedandongoingclinicalinvestigationsare
explor-ingthepotentialbenefitoftargetedtherapiesinsecondlinebutso
farthereisnopositiveevidence.(Ceresoli,2014).InalargephaseIII
trial,conductedin661patientswithpreviouslytreatedMPM,the histonedeacetylaseinhibitorvorinostatfailedtoshowanybenefit (Krugetal.,2015).Followinginitialevidencefromasmallphase IItrial(Calabròetal.,2013),arandomizeddouble-blind, placebo-controlledphaseIIItrialoftheanti-CTL4antibodytremelimumab hasbeenperformed,butresultsarestillpending(Anon,2016c). Severalimmune-checkpointinhibitorsarecurrentlyunder eval-uationinthissetting.InaphaseIbstudy,theanti-PD1antibody pembrolizumabwaswelltolerated,andprovidedevidenceof anti-tumoractivityinpatientswithadvancedPD-L1+MPM(Alleyetal., 2015).
Re-treatmentwithpemetrexedmaybeapotentialsecond-line option in patientswith MPM achieving a durable (≥6months) diseasecontrol withfirst-linepemetrexed-based chemotherapy (Ceresolietal.,2011;Bearzetal.,2012;Zucalietal.,2012). How-ever,thereisnoevidencefromcontrolledclinicaltrialssupporting thisstrategy andfurtherprospectiveevaluationis needed. Rec-ommendationsfromthechemotherapypanelaresummarizedin Table5.
9. Continuityofcare,painmanagement,psycho-socialand legalissues
For the population at risk, psychologicalsupport should be planned and provided by psychologists with specific expertise (Ceresolietal.,2011;Bearzetal.,2012;Zucalietal.,2012;Granieri etal.,2013;Grattanetal.,2011;O’LearyandCovell,2002;Palinkas, 2012;Boardmanetal.,2008;DowneyandWilligen,2005;Drescher etal.,2014).It shouldbedirected toindividuals orgroups and aimedtoobtainarealisticconsciousnessoftheriskinits effec-tivedimension,tofavoracoexistencewithit,tocontainanguish andtoreduceaninappropriateuseofthesocialhealthcareservices (Bearzetal.,2012;Grattanetal.,2011;Barnesetal.,2002;Couch andColes,2011;Crightonetal.,2003;FosterandGoldstein,2007; Guglielmuccietal.,2014).
ForMPMpatients,amultidisciplinaryapproach,involvinga psy-chologistspecializedin takingcareof cancerpatientsand their families,isrecommended.Thepsychologicalinterventionispart ofthecommunicative-relationalprocessduringtheentirecourse ofthedisease,fromtheknowledgeoftheclinicalconditiontothe selectionoftherapies(ortherefusaloftreatment)andtodecisions relatedtotheendoflife(Guglielmuccietal.,2014;Baum,1993; BritishLungFoundation,2013;Glik,2007).
Adequatesupportshouldbeprovidedtorelativesoranysubject closetothepatient.Inanycase,theirinvolvementshouldrespect thepatient’swill1(Granierietal.,2013;BritishLungFoundation, 2007).
Inordertosecuretheaccessofthepatientstowelfareandsocial securitybenefits,thephysicianinchargemustcomplytoallhis legaldutiesrelatedtocertificationsineverycaseofdiagnosedor suspectoccupationaldisease(reportunderItalianDPRno1124of 1965andsubsequentamendments;certification–withtheconsent oftheinterestedperson–ofoccupationaldiseasefortheaccessto workercompensationbenefits;legaldutytoreport).
Everyhealthfacilitymustadoptinformationpolicies(suchas dedicatedinformationdesks,brochures)usefulfortheacquisition, bythepatient,offullknowledgeofhisrights(insurance,welfare andanyotherright)andregardingtheduelegalprocedures.
Oncology units should define and establish the most suit-ableorganizationalmodel,inordertoensureproperapproachto patientsneedingpalliativecare(Partridgeetal.,2014).
Consideringthecharacteristicsofthisspecifictypeofcancerand thelimitedlifeexpectancy,itisrecommendedamultidisciplinary approachsincediagnosis,withthepresenceofaphysicianexpert inpalliativecareforthecontrolofsymptoms,inordertoensure thebestqualityoflifetopatients(Huietal.,2015;Anon,2016d; Chernyetal.,2010;Smithetal.,2012).
Futureareasofresearch
Unfortunately,theefficacyofcurrenttherapiesisverylimited, andtheoverallprognosisremainsquitepoor.Inordertoimprove survival of MPM patients, effective strategy of early diagnosis andeffectivetreatmentstrategiesarehighlyneeded.Unlikeother cancers,MPMhasnotbeenwellcharacterizedinmanyaspects. Therefore,itisquiterelevanttoidentifybiomarkersofearlydisease, tobetterunderstandtumorbiology,todevelopnoveldiagnostic approachesaswellasnewtreatmentoptions,suchas immunother-apyandtargetedtherapiesdirectedagainstgenomicabnormalities. AsummaryoffutureareasofresearchissummarizedinTable6. AppendixA.
Contributors
The following epidemiologists, public health and occupa-tionalphysicians,pathologists,radiologists,respiratoryphysicians, nuclearmedicinephysicians, surgeons, medical oncologistsand radiationoncologistshavetakenpartintheThirdItalianConsensus ConferenceofMalignantPleuralMesothelioma.
Methodologicalworkinggroup ValterTorri,LucaPorcu. Epidemiologyandpublichealthpanel
CorradoMagnani(Torino),StefanoSilvestri(Firenze),Claudio Bianchi(Monfalcone-Gorizia),ElisabettaChellini(Firenze),Dario Consonni (Milano), Bice Fubini (Torino), Alessandro Marinaccio
Table6
Futureareasofresearch.
-Integrationofgenomics,trascriptomicsandproteomicinformation oridentificationofnewtargetsinmesothelioma
-Blood-basedbiomarkersofearlydisease
-EvaluationoftheroleofBAP1ingerm-lineandsporadic mesothelioma
-Evaluationoftheroleoffunctionalimagingindiagnosisandin planningradiotherapytreatment
-Improvementintheassessmentofresponsetotherapies -TNMstagingofmesothelioma
-Evaluationoftheroleofextendedpleurectomy/decorticationversus nopleurectomy/decortication
-Evaluationoftheroleofpleurectomypluschemotherapyin advanceddisease
-Evaluationoftheroleofintrapleuralcriotherapyandphotodynamic therapy
-Evaluationoftrimodalityandcombinedmodalityapproachesinearly stagemesothelioma
-Evaluationofrisksandbenefitofintensitymodulatedradiation therapy
-Evaluationoftheroleofprophylactictraitsirradiation -Identificationofoptimaltreatmentstrategiesintheelderly -Evaluationoftheroleofearlypalliativecare
-Evaluationoftheefficacyofanti-angiogeneticagents
-Evaluationoftheefficacyofanti-mesothelinmonoclonalantibodies aloneandincombinationwithtoxinsandcytotoxicagents -Evaluationoftheefficacyofimmunecheckpointinhibitors -Evaluationofdendriticcellimmunotherapy
-Evaluationofallogeneictumorcellvaccine -Evaluationofgenetherapy
(Roma),MassimoMenegozzo(Napoli),EnzoMerler(Padova),Dario
Mirabelli (Torino), Marina Musti (Bari), Enrico Oddone (Pavia),
EnricoPira(Torino),AntonioRomanelli(ReggioEmilia),Carlo
Zoc-chetti(Milano),PietroComba(Roma).
Pathologyandlaboratorypanel
MauroGiulio Papotti,(Torino), Giulio Rossi (Modena),
Vale-riaAscoli(Roma),MattiaBarbareschi(Trento),MassimoBarberis
(Milano),Arrigo Bondi (Bologna),Gerardo Botti(Napoli),Marco
Chilosi(Verona),CamillaComin(Firenze),AlfonsoCristaudo(Pisa),
GaetanoDeRosa(Napoli),GiorgioGardini(ReggioEmilia),Massimo
Gion(Mestre-Venezia), Paolo Graziano (SanGiovanniRotondo),
Bruno Murer (Mestre-Venezia), Oscar Nappi (Napoli) Giuseppe
Pelosi(Milano),AndreaTironi(Brescia),FabrizioZanconati
(Tri-este),RobertaLibener(Alessandria),FrancescaPentimalli(Milano),
GabriellaSerio(Bari).
Radiology,nuclearmedicineandrespiratorymedicinepanel
GiordanoBozzola(Brescia),MauroCaterino(Roma),Domenico
Ghio (Milano), Marco Patelli (Bologna), Ezio Piccolini
(Monfer-rato),RoccoTrisolini(Bologna),AndreaVeltri(Torino),CarloGurioli
(Forli)SilviaLucchini(Brescia),GianfrancoTassi(Brescia).
Surgerypanel
FrancescoFacciolo(Roma),FedericoRea(Padova),Luca
Ampol-llini (Parma), Francesco Ardissone (Torino), Caterina Casadio
(Novara),GiorgioCavallesco(Ferrara),MaurizioCortale(Trieste),
Paolo Fontana (Mestre-Venezia), Felice Mucilli (Chieti), Paolo
Sardelli(Bari),MauroBenvenuti(Brescia),CristianoBreda(Mestre),
Paolo Carbognani (Parma), Pierluigi Filosso (Torino), Giacomo
Leoncini(Genova),GianlucaPariscenti(Brescia).
Radiotherapypanel
UmbertoRicardi(Torino),LucioTrodella(Roma),LorenzoLivi
(Firenze),GiampieroFrezza(Bologna),RenzoMazzarotto(Verona),
Alessandra Mirri(Roma),Rolando Polico(Meldola—FC),Roberto
Orecchia (Milano), Marta Scorsetti (Humanitas Milano),
San-droTonoli (Brescia), MarcoTrovò (Aviano),Elisabetta Garibaldi
(Torino),StefanoArcangeli(Roma),NunziaD’Abbiero(Parma).
Systemictherapypanel
Giovanni Luca Ceresoli (Bergamo), Silvia Novello (Torino),
AndreaArdizzoni(Bologna),FabrizioArtioli(Carpi),Fausto
Barbi-eri(Modena),AnnaCeribelli(Roma),EvaristoMaiello(S.Giovanni
Rotondo),MassimoDiMaio(Torino),AdolfoFavaretto(Padova),
Domenico Galetta (Bari), Francesco Grossi (Genova),
Gioven-zio Genestretti (Bologna), Federica Grosso (Alessandria), Paola
Mazzanti (Ancona), Barbara Melotti (Bologna), Manlio
Men-coboni(Genova),GiammauroNumico(Alessandria),CarminePinto
(Parma),SalvatorePisconti(Taranto),GiorgioScagliotti(Torino),
MarcelloTiseo(Parma),PaoloZucali(Milano),MariaGraziaViganò
(Milano), Vincenzo Minotti (Perugia), Antonio Rossi (Avellino),
Antonio Passaro (Milano) Roberta Perlazzi (Gorizia), Francesca
Zanelli(ReggioEmilia),LuanaCalabrò(Siena).
Continuityofcare,painmanagement,psycho-socialandlegal
issuespanel
Antonella Granieri (Torino), LuigiGaudino (Udine), Vittorina
Zagonel(Padova),NicolaPondrano(AFEVA),FulvioAurora(AEA),
AnnaCostantini(Roma),VittorioFranciosi(Parma),Angela
Goggia-mani(INAIL),BrunoPesce(AFEVA),NicolaPondrano(AFEVA).
AppendixA. Supplementarydata
Supplementarydataassociatedwiththisarticlecanbefound,in
theonlineversion,athttp://dx.doi.org/10.1016/j.critrevonc.2016.
05.004.
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