Consensus of the Brazilian Society of Infectious Diseases and Brazilian Society of Clinical Oncology on the management and treatment of Kaposi's sarcoma

The

Brazilian

Journal

of

INFECTIOUS

DISEASES

w w w . e l s e v i e r . c o m / l o c a t e / b j i d

Review

article

Consensus

of

the

Brazilian

Society

of

Infectious

Diseases

and

Brazilian

Society

of

Clinical

Oncology

on

the

management

and

treatment

of

Kaposi’s

sarcoma

Érico

Arruda

_,

_Alexandre

_Andrade

_dos

_Anjos

_Jacome

_,

Ana

Luiza

de

Castro

Conde

Toscano

_,

_Anderson

_Arantes

_Silvestrini

_,

André

Santa

Bárbara

Rêgo

_,

_Evanius

_Garcia

_Wiermann

_,

_Geraldo

_Felicio

_da

_Cunha

_Jr.

_,

Heloisa

Ramos

Lacerda

de

Melo

_,

_Karen

_Mirna

_Loro

_Morejón

_,

Luciano

Zubaran

Goldani

_,

_Luiz

_Carlos

_Pereira

_Jr.

_,

_Mariliza

_Henrique

_Silva

_,

Mauro

Sergio

Treistman

_,

_Mônica

_Cristina

_Toledo

_Pereira

_,

Patricia

Maria

Bezerra

Xavier

Romero

_,

_Rafael

_Aron

_Schmerling

_,

Rodrigo

Antonio

Vieira

Guedes

_,

_Veridiana

_Pires

_de

_Camargo

b_{HospitalMaterDei,BeloHorizonte,MG,Brazil}

c_{InstitutodeInfectologiaEmílioRibaseCentrodeReferênciaeTreinamentoemDST/AIDS,SãoPaulo,SP,Brazil} d_{SociedadeBrasileiradeOncologiaClínicaeGrupoAcreditar,Brasília,DF,Brazil}

e_{HospitalSantaLúcia,Brasília,DF,Brazil}

f_{SociedadeBrasileiradeOncologiaClínica,Brasília,DF,Brazil} g_{HospitaldaBaleia,BeloHorizonte,MG,Brazil}

h_{HospitaldasClínicas,UniversidadeFederaldePernambuco(UFPE),Recife,PE,Brazil} i_{HospitaldasClínicasdaFaculdadedeMedicinadeRibeirãoPreto,RibeirãoPreto,SP,Brazil} j_{HospitaldeClínicasdePortoAlegre,PortoAlegre,RS,Brazil}

k_{HospitalDia,InstitutodeInfectologiaEmilioRibas,SãoPaulo,SP,Brazil} l_{CentrodeReferênciaeTreinamento-DST-AIDS,SãoPaulo,SP,Brazil}

m_{Servic¸odeInfectologiadeRedeHospitalarPrivadaeCâmaraTécnicadeDoenc¸asInfecciosasdoCREMERJ} n_{Fundac¸ãoHospitalardoEstadodeMinasGerais,BeloHorizonte,MG,Brazil}

o_{HospitalSãoCamilo,SãoPaulo,SP,Brazil}

p_{CentrodeOncologiaAntonioErmiriodeMoraes,SãoPaulo,SP,Brazil} q_{CentrodeOncologiadoHospitalSírio-Libanês,SãoPaulo,SP,Brazil}

r_{InstitutodoCâncerdoEstadodeSãoPauloedoHospitalSírioLibanês,SãoPaulo,SP,Brazil}

a

r

t

i

c

l

e

i

n

f

o

Received27September2013 Accepted23January2014 Availableonline11February2014

a

b

s

t

r

a

c

t

Kaposi’ssarcomaisamultifocalvascularlesionoflow-gradepotentialthatismostoften presentinmucocutaneoussitesandusuallyalsoaffectslymphnodesandvisceralorgans. Theconditionmaymanifestthroughpurplishlesions,flatorraisedwithanirregularshape, gastrointestinalbleedingduetolesionslocatedinthedigestivesystem,anddyspneaand

∗ _{Correspondingauthorat:Av.DoutorArnaldo,165,SãoPaulo,SP,01246-900,Brasil.} E-mailaddress:analuizaconde@ig.com.br(A.L.C.C.Toscano).

1413-8670/$–seefrontmatter©2014ElsevierEditoraLtda.Allrightsreserved.

316

hemoptysisassociatedwithpulmonarylesions.Intheearly1980s,theappearanceofseveral casesofKaposi’ssarcomainhomosexualmenwasthefirstalarmaboutanewlyidentified epidemic,acquiredimmunodeficiencysyndrome.In1994,itwasfinallydemonstratedthat thepresenceofaherpesvirusassociatedwithKaposi’ssarcomacalledHHV-8orKaposi’s sar-comaherpesvirusanditsgeneticsequencewasrapidlydeciphered.Theprevalenceofthis virusisveryhigh(about50%)insomeAfricanpopulations,butstandsbetween2%and8% fortheentireworldpopulation.Kaposi’ssarcomaonlydevelopswhentheimmunesystem isdepressed,asinacquiredimmunodeficiencysyndrome,whichappearstobeassociated withaspecificvariantoftheKaposi’ssarcomaherpesvirus.

TherearenotreatmentguidelinesforKaposi’ssarcomaestablishedinBrazil,andthus theBrazilianSocietyofClinicalOncologyandtheBrazilianSocietyofInfectiousDiseases developedthetreatmentconsensuspresentedhere.

©2014ElsevierEditoraLtda.Allrightsreserved.

Introduction

GeneralaspectsofKaposi’ssarcoma

Kaposi’ssarcomaisamultifocalvascularlesionoflow-grade potentialthatismostoftenpresentinmucocutaneoussites andusuallyalsoaffects lymphnodesand visceralorgans.1

Kaposi’ssarcoma wasfirst described in1872byHungarian dermatologistMoritz Kaposi.From that timeto the identi-ficationofhumanimmunodeficiency virus(HIV) associated withacquired immunodeficiencysyndrome(AIDS),Kaposi’s sarcomaremainedararetumor.Whilemostofthecases iden-tified in Europe and in North America occurred in elderly menofItaliandescentorEasternEuropeanJews,the neopla-siaalsooccursinseveralotherdifferentpopulations:young blackAfricanmen,childreninpre-adolescence,receiversof allergenic renaltransplant and other patients treated with immunosuppressive therapy. The disseminated and fulmi-nantformofKaposi’ssarcomaassociatedwithAIDSisreferred toasepidemic Kaposi’ssarcomatodistinguish itfrom the classical,Africanand transplant-relatedforms.Inaddition, Kaposi’ssarcomawasidentifiedinhomosexualmenwithout HIVvirus.2,3

AlthoughthehistopathologyofdifferenttypesofKaposi’s tumorsis essentially identical among the various affected groups,theclinicalmanifestationsandcourseofthedisease differdramatically.2_{Akeytounderstandingthe}

pathogene-sisofKaposi’ssarcomawasthediscoveryin1994ofagamma herpesvirus,humanherpesvirustype8(HHV-8),alsoknown asherpesvirusofKaposi’ssarcoma.4_HHV-8hasbeen

iden-tifiedin tissuebiopsiesofKaposi’s sarcomaofvirtually all patientswithdifferentformsofthedisease(classical,African, transplant-relatedandAIDS-associated),butwasabsentinthe tissuenotinvolvedbytheneoplasia.2

Consideredararedisease,Kaposi’ssarcomainitsclassical formoccursmoreofteninmales,witharatioofabout10–15 menforeverywomanaffected.AmongAmericansand Euro-peans,theusualageofonsetisbetween50and70yearsof age.2

Inthe1950s,Kaposi’ssarcomawasrecognizedasa rela-tivelycommon endemicneoplasia innative populationsof equatorialAfrica,comprisingabout9%ofallcancersseenin malesinUganda.InAfrica,indolentorlocallymore aggres-siveformsofKaposi’ssarcomaoccurataman/womanratio

comparabletothatobservedfortheclassicaltumorseenin North Americaand Europe.However,patientsinAfrica are significantlyyoungerthanEuropeanpatients.A lymphadeno-pathic formisalso seenin Africa,primarilyinchildrenin preadolescence,atamale/femaleratioof3casesto1,2,5_and

mortalityrateofnearly100%in3years.5,6

In1969,thefirstcaseofKaposi’ssarcomaassociatedwith immunosuppressive therapy ina patient with renal trans-plantation wasdescribed.Sincethen,it hasbeenobserved that several patients receiving renal transplants and other allergenictransplantswhoweretreatedwithprednisoneand azathioprine developed Kaposi’s sarcoma shortly after ini-tiation of immunosuppressive therapy.2,7 _{Estimates of the}

incidenceofKaposi’ssarcomaamongrenaltransplant recip-ientssubjectedtoimmunosuppressivetherapyarebetween 150and200timeshigherthantheexpectedincidenceofthe tumorinthegeneralpopulation.Theaveragetimetodevelop Kaposi’ssarcomaaftertransplantationis16months.2

EpidemiologicalaspectsofepidemicKaposi’ssarcoma In1981,adisseminatedandfulminantformofKaposi’s sar-comawasdescribedinhomosexualorbisexualmenandwas firstreportedaspartofanepidemicnowknownasAIDS.8_The

etiologyofAIDSisaretroviruswithtropismforTlymphocytes known as HIV.9 _{The immune deficiency that characterizes}

AIDSisaprofounddisorderofcell-mediatedimmune func-tions. This immune dysfunction and deregulation of the immunesystempredisposepatientstothedevelopmentofa widerangeofopportunisticinfectionsandunusualneoplasm suchasKaposi’ssarcoma.HIVcanplayanindirectroleinthe developmentofKaposi’ssarcoma.9_{Approximately95%ofall}

casesofepidemicKaposi’ssarcomaintheUnitedStateswere diagnosedinhomosexualorbisexualmen.Inthepast, approx-imately26%ofallmalehomosexualswithHIVpresentedwith ordevelopedKaposi’ssarcomaoverthecourseofAIDS.Asa comparison,lessthan 3%ofall heterosexualinjectiondrug userswithHIVdevelopedKaposi’ssarcoma.Theproportion of AIDS patients with Kaposi’s sarcoma has declined dra-maticallysincetheoutbreakofthediseasewasidentifiedin 1981.10 _{About 48%ofpatientsdiagnosedwithAIDSin1981}

presentedwithKaposi’ssarcomaatdiagnosis.ByAugust1987, thisproportionhaddeclinedtolessthan20%.The introduc-tionofhighlyactiveantiretroviraltherapy(HAART)delayedor

900 800 700 600 500 400 300 200 100 0 1980 0 0 0 0 1 1 0 9 0 0 2 12 14 13 30 39 54 58 59 102 87 110 83 79 93 77 82 102 86 83 72 64 68 58 65 56 20 27 116 167 297 398 485 585 656 754 760 786 721 633 541 559 448 398 408 376 423 353 311 308 282 269 291 268 269 111 Feminino Número de casos Masculino

Source: SINAN-ministry of health [16]

1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012

Fig.1–IncidenceofKaposi’ssarcoma–Brazil1980toJune/2012.

Source:SINAN–MinistryofHealth.16

preventedtheemergenceofHIVstrainsresistanttotreatment and profoundly decreased viral load, leading to increased survivalanddecreasedincidenceofopportunisticinfections amongAIDS patients.11,12 _{The use ofHAART is associated}

withasubstantialandsustaineddeclineintheincidenceof Kaposi’ssarcomaamongpatientswithAIDS.13–15

InBrazil,casesofKaposi’ssarcomarelatedtoAIDSmust bereportedtotheInformationSystemforNotifiableDiseases (SINAN),whichisfedmainlybythereportingand investiga-tionofcasesofdiseasesandconditionswhichappearonthe nationallistofdiseases subjecttocompulsorynotification.

Fig.1showsagraphwiththenumberofnewcasesofKaposi’s sarcomasincethebeginningoftheepidemicto06.30.201216_:

weobserveadeclineindiseaseincidencefollowingthe avail-abilityofHAARTin1996.

ClinicalmanifestationsofepidemicKaposi’ssarcoma

TheepidemicorAIDS-relatedKaposi’ssarcomahasahighly variableclinicalcourse,andcanappearasminimal mucocu-taneousdiseaseorasdisseminateddiseasewithinvolvement ofotherorgans.Thelesionscaninvolvetheskin,oralmucosa, lymphnodesandvisceralorgans.Mostpatientspresentwith cutaneousdisease,butoccasionallythevisceraldiseasemay precedecutaneousmanifestation.Skinlesionscanoccurat any location, but are typically concentrated in the lower extremitiesandtheheadandneck.Thelesionscanbe macu-lar,papular,nodularorlooklikeplaques,andtheyarealmost allpalpableandnon-pruritic.Thesizeoftheskinlesionscan varyfromafewmillimeterstoseveralcentimetersin diam-eter,and can bebrown,pink or violet. Thelesions can be discreteorconfluentandtypicallyappearinasymmetrical lin-eardistributionalongtensionskinlines.Mucousmembrane involvementiscommon(e.g.,palate,gumandconjunctiva), andulceratedorbulkytumorscaninterferewithspeechand chewing.Thelymphedemaassociatedwiththetumor, typi-callymanifestedinthelowerextremitiesortheface,seems tobecausedbysecondaryobstructionoflymphaticvessels. Pain when walking can be present in the case of lesions involvingthesoles.Lesionscanoccuranywhereinthe gas-trointestinal tract, usually an indicator of more advanced HIV infection, manifesting itself through symptoms that includeodynophagia,dysphagia,nausea,vomiting, abdomi-nalpain, hematemesis,hematochezia,melenaorintestinal

obstruction.Pulmonaryinvolvementcanbedifficultto dis-tinguishfromopportunisticinfectionsandcanbeexpressed by cough, dyspnea, hemoptysis, or chest pain. Pulmonary lesions can be an asymptomatic radiographic finding and pleuraleffusionsareoftenexudativeandhemorrhagic. Lym-phadenopathycanbetheonlymanifestationofthedisease, whichrequiresalymphnodebiopsyandcanleadtosignificant lymphedema.1,17–20

The introduction ofHAART in orderto controlHIV has caused a major change in the behavior of Kaposi’s sar-coma related to AIDS: it was accompanied by a dramatic decreaseinincidenceofdiseaseanditslessaggressive pre-sentation,but thedisease remainsasevereprobleminthe Western world, as in the case of its manifestation with pulmonary involvement.21,22 _{HAART can cause partial or}

completeregressionofKaposi’ssarcoma,withpartialor com-plete disappearanceofspindle-shapedcells.23 _Exacerbation

ofKaposi’s sarcoma (flare)can beseen aftercorticosteroid therapy orrituximab oras partofthe immune reconstitu-tioninflammatorysyndromewhichcanoccuruponinitiation ofHAARTbypatients.Theimmunereconstitution inflamma-tory syndrome isa pathological exaggerated inflammatory response thatisdue toanexuberantimmune responseto opportunisticinfectionseitherapparentorconcealed,or can-cers.TheexacerbationmechanismofKaposi’ssarcomaafter treatment with corticosteroids appears to be linked to an upregulationoftheexpressionofsteroidreceptors.24,25

DiagnosisofepidemicKaposi’ssarcoma

AlthoughapresumptivediagnosisofKaposi’ssarcomacanbe oftenmadebasedontheclinicalhistoryandappearanceof skinlesions,thishypothesisshouldbeconfirmedbybiopsy ofthelesions,wheneverpossible.Biopsyisespecially impor-tant for atypical lesions that are associatedwith systemic symptoms or progress rapidly toward discarding bacillary angiomatosis.26_{Therearethreehistologicalfindingsthatare}

characteristic of Kaposi’s sarcoma, both in cutaneous and visceralforms:angiogenesis,inflammationandproliferation. Thelesionsusuallypresent twomainabnormalities,which are spindle-shapedcells,arrangedinasnail-like formwith leukocyteinfiltrationandneovascularizationwithabhorrent proliferationofsmallvessels.Thesetinyvesselslacka base-line membrane,whichgivesrise tomicrohemorrhages and

318

Table1–ACTG–classificationofKaposi’ssarcoma. Lowrisk(0)

Anyofthefollowingfindings

Highrisk(1)

Anyofthefollowingfindings

Tumor Confinedtotheskinand/orlymphnode

and/orminimumoraldiseasea

•Edemaorulcerationassociatedwithtumor •Extensiveoraldisease

•Gastrointestinaldisease

•Visceraldiseaseotherthanlymphnode

Immunesystem CD4cells≥200␮L−1 _{CD4cells<200␮L}−1

Systemicdisease •Absenceofhistoryofopportunistic infectionsorcankersores

•AbsenceofsymptomsB •Performancestatus(PS)≥70

•Historyofopportunisticinfectionsorcanker sores

•PresenceofsymptomsB •Performancestatus<70

•AnotherHIVrelateddisease(neurological, lymphoma)

a _{Non-nodulardiseaseconfinedtothepalate;symptomsB=unexplainedfever,nightsweats,>10%weightlossorpersistentdiarrhealasting}

morethan2weeks;PS=Karnofskyscale;adaptedfromACTG–AIDSClinicalTrialsGroupOncologyCommittee.

depositionofhemosiderinintissue.Withtheprogressionof thedisease,lesionsevolvefromstaintoplaquesandthento anodularform.Thestandardhistologicalcharacteristicdoes notdifferamongtheepidemiologicalgroupsaffectedbythe disease.27_{Additionalsupplementarytestsmightbeneededfor}

patientswithsystemicsymptomswhichmightmeanvisceral involvementofthedisease.28

Stagingandprognosticfactors

Thereis nouniversallyaccepted classificationavailablefor epidemicKaposi’ssarcoma,andstagingschemesthat incor-poratelaboratoryparametersandclinicalfindingshavebeen proposed.The majorityof patientswith epidemicKaposi’s sarcomado notdie due tothe disease; factors other than the tumor load are apparently involved in the survival of patients.TheconventionsusedtostageKaposi’ssarcomaand themethodsusedtoassessthebenefitsoftreatmentcontinue toevolvebecauseofchanges inthe treatmentofAIDSand therecognitionofthe shortcomingsofthe standard evalu-ationofthetumor.TheclinicalcourseofKaposi’ssarcoma, treatmentselectionand responsetotreatmentare strongly influencedbythesubjacentdegreeofimmunedeficiencyand theoccurrenceofopportunisticinfections.TheAIDSClinical TrialsGroup[ACTG]OncologyCommitteepublishedcriteria fortheevaluationofepidemicKaposi’ssarcoma.Thestaging systemincorporatesmeasuresofdiseaseextent,severityof immunodeficiencyand presenceofsystemicsymptoms. As canbeseeninTable1,ACTGcriteriacategorizetheextentof thetumoraslocalizedordisseminated,CD4cellcountashigh orlow,andsystemicdiseaseasabsentorpresent.29

Asubsequentprospectiveanalysisof294patientswho par-ticipatedinclinicalstudiesforKaposi’ssarcomaoftheACTG groupbetween1989and1995showedthateachvariable of

Table1(tumor,immunesystemand systemicdisease)was independentlyassociatedwithpatientsurvival.30

Multivari-ateanalysesshowedthatworseningoftheimmunesystem wasthemostimportantindividualpredictor ofsurvival.In patients with relatively high CD4 cell counts, tumor stage waspredictive;aCD4countof150cells/mm3_canbea bet-terdiscriminatingindexthan thelimitof200cellsinitially adopted.31,32Noneofthepreviousstudieswasconductedina

timewhenHAARTwasalreadyreadilyavailable.Theimpactof thistherapyonsurvivalincasesofKaposi’ssarcomarequires continuedevaluation.31–34

In2003,anItalianstudygrouppublishedaresearchinorder to evaluate new prognostic factors and validatethe ACTG stagingsystemforKaposi’ssarcomarelated toAIDSinthe HAART era. Clinical,epidemiological, and staging informa-tion,aswellassurvivaldatawerecollectedfrom211patients withAIDS-relatedKaposi’s sarcomaincludedintwoItalian cohortstudiesonHIVasof1996,theyearinwhichHAART becameavailableinItaly.Inlightoftheresults,researchers proposed to refine the application of the stage system in whichtheimmunesystemshouldbeeliminatedwitha deter-miningprognosisand onlytheextentofthe tumor(T) and systemicdisease(S)shouldberegardedaspredictivevariables ofsurvival.Two categoriesofriskfordeathwere identified: (a) high risk (T1S1)and low risk(T0S0, T1S0 and T0S1). In addition, researchers showed that pulmonaryinvolvement predicts survival better than the extent ofthe tumor and identifiesthecategorywiththehighestriskregardlessofthe variableS(systemicdisease).Noteworthy,survivalanalysisof theinteractionbetweenpulmonarydiseaseandsystemic dis-ease appearstoprovideabetterdistributionofriskamong groupsofpatients,withhazardratios(HR)progressivetoward death(Tp1S1>Tp1S0>Tp0S1>Tp0S0)whencomparedtothe interactionbetweentheclassicalextentofthetumorand sys-temicdisease.35

Therapeutic

approach

in

epidemic

Kaposi’s

sarcoma

AlthoughthebenefitsoftheuseofHAARTareindisputable, Kaposi’ssarcomahasnotdisappearedasaclinicalproblem. DuetothefactthatHAARTcaninducetumorregressionand thattheappropriatetreatmentofHIVinfectionrequiresthe administrationofthattherapy,distinguishingtheantitumor effectsofHAARTfromthoseinducedbyachemotherapeutic agentforKaposi’ssarcomapresentsdifficulties.21,22_Moreover,

asdescribedbelow,thescientificevidencesuggeststhattumor responsetoisolateduseofHAARToccursmainlyinpatients whowerenotusingthistherapy.

Majortreatment goalsare to relievesymptoms, prevent disease progressionand decrease the size ofthe tumor to alleviateedema,involvementofapossibleaffectedorganand psychologicalstress.36_{Manylow-riskpatientsinaccordance}

withthe ACTG (AIDSClinical Trials Group Oncology Com-mittee)classificationpresent tumorregressionwithHAART alone.37_{High-riskpatientsusuallyrequirethecombinationof}

HAARTandchemotherapy,whichissuspendedafter disap-pearanceofskinlesions.37

HAART

Therearenorandomizedclinicaltrialscomparingthe treat-mentofKaposi’ssarcomawithHAARTversusthetreatment without HAART, since it is virtually recommended for all patientswithAIDS-relatedKaposi’ssarcoma.61_The

introduc-tionofthistherapyisassociatedwithasubstantialdecrease inthe incidenceand severity ofcasesofKaposi’s sarcoma recentlydiagnosedinpatientswithHIVinfection.AFrench study that analyzed a database with 54,999 patients with over180,000patient-yearsoffollow-upshowedthatthe inci-dence rate of Kaposi’s sarcoma dropped from 32 per 1000 person-yearsin1993–1994downto3per1000person-years after1999.38_{Furthermore,theincidenceofvisceral}

involve-mentbyKaposi’ssarcomaupondiagnosisdroppedfromover 50%to lessthan 30%.38 _{ASwiss cohort study showedthat}

therelativeriskofdevelopmentofKaposi’ssarcomabetween 1997 and 1998 (HAART era) compared to the time period between1992 and 1994(pre-HAART era) was 0.08 (95% CI, 0.03–0.22).39_{TheadditionofHAARTtosystemic}

chemother-apyalsoincreasedthesurvivalofpatientswithpulmonary involvementbyKaposi’ssarcoma.40

Observationalstudiesindicatethatthenaturalhistoryof AIDS-relatedKaposi’ssarcomahaschangedsincethe intro-ductionofHAART,alongwithdecreasedtumorincidence.41,31

A retrospective study that analyzed cases of Kaposi’s sar-comainadatabaseof4439peoplewithHIVinfectionfrom pre-HAARTtherapy(1990–1996)andaftertheintroductionof HAARTtherapy(1997–2002)showedthatthemeancountof CD4cells and meanlevels ofHIVRNA weresimilar inthe 366patientspre-HAARTandinthe40patientsintheHAART era.However,theoverallriskofdeathwassignificantlylower in the HAART era (HR, 0.24).31 _{Due to the control of HIV}

infection, immune reconstitution is the most likely expla-nationforthischangedprognosis,muchmorethanadirect effectonthetumor.AlthoughinhibitorsofHIVproteasehave antiangiogenicpropertiesandblockthedevelopmentand pro-gressionof lesionsresembling Kaposi’s sarcoma inmice,42

therewasnodifferenceinthepossibilityofclinicalresponse associatedwiththeuseoftheseagents.41,43_{Furthermore,the}

decreasedincidenceofKaposi’ssarcomahasbeenobserved withtheuseoftreatmentregimensthatdonotcontain pro-teaseinhibitors.38_{Recentchemotherapyisassociatedwiththe}

improvementofKaposi’ssarcoma;recentlowviralloadofHIV and HAARTare associatedwiththe improvementand res-olutionofKaposi’ssarcoma.Theresponseisnotassociated withthetypeofHAARTregimen(inhibitorofnon-nucleoside reverse transcriptase, protease inhibitor, or enhanced with proteaseinhibitorritonavir).44

Although treatment with HAART promotes increased counts of CD4 cells to levels above those typically associ-atedwithincreasedsusceptibilitytoinfection,somepatients develop AIDS-related Kaposi’s sarcoma despite the appar-entcorrectionoftheirimmunodeficiency.45_{Insomepatients}

with HIVwho haveKaposi’s sarcomadisease (moderateto advanced) HAART used in isolation may not be sufficient totumortreatment,makingitnecessarytouseother adju-vanttherapysuchassystemicchemotherapy,whichshowed goodefficacyandresultedinsignificantclinicalimprovements whencombinedwithantiretroviraltherapy,asdemonstrated byphaseIIIstudiescomparingHAARTinisolationwithHAART combined with systemic chemotherapy.46–49 _{A systematic}

reviewcarriedoutinthepost-HAARTerawiththeaimof deter-miningwhetherpatientswithadvancedKaposi’ssarcomacan respondtoHAARTinisolationwas notexplanatory. Ofthe availablestudies,therewereonlyfivecasesinwhichpatients withadvancedKaposi’ssarcoma(T1)respondedtoHAARTin theabsenceofconcomitanttherapyforthedisease.37

Immunereconstitutioninflammatorysyndrome

Theexpression “immunereconstitution inflammatory syn-drome” is usedtodescribe aseries ofhostresponses that can occur soon after the start of HAART and has been linkedtotheprogressionofKaposi’ssarcomainthreetosix weeksafterinitiationoftreatment.Therelationshipbetween immunereconstitutioninflammatorysyndromeandKaposi’s sarcomawas shownintwostudies:(1)aseries ofcasesof 150 treatment-naïve patients who presentedwith Kaposi’s sarcoma,10(7%)developedtumorprogressionwhenHAART wasinitiated;theriskoftheimmunereconstitution inflam-matorysyndromeseemedenhancedinpatientswithhigher countsofCD4cellsorwithedemaassociatedwithKaposi’s tumor; despite tumor progression,maintenance of HAART therapywaspossibleinthosepatients50_{;(2)inanotherseries}

ofninepatientsinaninstitution,progressionofKaposi’s sar-comaoccurredinanaverageoffiveweeksafterinitiationof HAARTtherapyandwasassociatedwithincreasesinCD4cells anddecreaseinviralload;inallpatientsinwhomsystemic chemotherapywasusedweobservedtumorregression,and interruptionofantiretroviraltherapywasnotnecessary.51

Antiviralagents

AlthoughHHV-8viremiaisassociatedwithanincreasedriskof developingKaposi’ssarcoma,52_{thereiscurrentlyno}

consen-susonthetherapeuticbenefitsoftheuseofantiviraldrugs inthisgroupofpatients.Invitrostudiesdemonstrating sen-sitivityofHHV-8toantiviralagentsareindisagreement.One studydemonstratedthatHHV-8issensitivetoantiviralagents suchascidofovirandgancyclovir,andweaklysensitiveto acy-clovir.However,thesedrugsdonotactinthelatentformofthe virusanditisunlikelytheyareeffectiveagainstestablished tumorlesions.53_{Anotherstudy,however,foundnosensitivity}

toacyclovirbutshowedactivitytogancyclovir,foscarnetand cidofovir, alsointhe replicativephase.54 _{Inaclinicalstudy}

ofpatientswithAIDSandcytomegalovirusretinitis,patients who were treatedwithoralorintravenousgancyclovir had reducedriskofdevelopingKS.55However,thedrugsstudiedto

320

Table2–EpidemicKaposi’ssarcoma–therapeutic approaches. Localtreatment Retinoids Radiotherapy Intralesional chemotherapy Systemictreatment Chemotherapy •Liposomaldoxorubicin •Liposomaldaunorubicin •Bleomycin •Vincristine,vinblastine •Paclitaxel

datehaveimportantsystemiceffectswithintravenous admin-istration,makingtheirprophylacticuseimpracticalinthelong run.

Localtreatments

SmalllocalizedlesionsofKaposi’ssarcomaweretreatedusing electrodissectionandcurettage,cryotherapy,orthrough sur-gicalexcisioninthepre-HAARTera.Kaposi’stumorsarealso generallyveryresponsivetolocalradiotherapy,withexcellent resultsbeingobtainedwith20Gyorslightlyhigherdoses.56–58

Radiationtherapyisgenerallyreservedfortreatinglocalized skin areas and in the oral cavity. It is less used to con-trol pulmonarylesions,lesionsofthe gastrointestinaltract or other sites of Kaposi’s sarcoma. Localized lesions also tendtobeeffectivelytreatedwithintralesionalinjectionsof vinblastine.59_{Alitretinoingel0.1%wasalsoeffectiveinlocal}

controlofthelesionsofKaposi’ssarcomainaprospective mul-ticenterrandomizedtrialinwhichthesubstancewasusedtwo timesadayfor12weeks;overallresponseratewas37%.60

Cytotoxicagents

InepidemicKaposi’ssarcoma,systemicchemotherapyis gen-erallyusedinpatientswithadvanceddiseaseorwhenthere isevidenceofrapiddisease progression.61 _{Whentreatment}

isindicated,the use ofpegylated liposomaldoxorubicinor liposomaldaunorubicinisusuallyrecommendedasfirstline treatment.61_{Otherchemotherapeuticagentsalsousedinthe}

treatmentofepidemicKaposi’ssarcomaincludebleomycin, vincristine,vinblastine,etoposideandpaclitaxelas monother-apy or in combination therapy.61,62 _{Indications generally}

accepted for the use of systemic chemotherapy as adju-vant therapy to antiretroviral agents include: (a) extensive involvementofskin(e.g., morethan 25 lesions), (b) exten-sive cutaneousKaposi’s sarcoma that does notrespond to localtreatment,(c)extensiveedema,(d)symptomaticvisceral involvement and (e) immune reconstitution inflammatory syndrome.61_{Themodeofuseofvariousdrugsconsideredin}

chemotherapyforthetreatmentofKaposi’ssarcomaisbriefly describedinTable2.

Liposomalanthracyclines,doxorubicin anddaunorubicin constitute a considerable advance in the chemotherapy of Kaposi’ssarcoma.Theadvantagesofliposomalformulation includeincreaseddruguptakebythetumor,whichleadsto amorefavorablepharmacokineticprofile.Clinicalstudiesof

liposomalanthracyclinesinthetreatmentofKaposi’ssarcoma associatedwithHIV/AIDSwereconductedinpre-HAARTera, butclinicianscontinuetoregardthemasfirst-linetreatment agents of Kaposi’s sarcoma. Both liposomal daunorubicin (40mg/m2 _{everytwoweeks) andpegylatedliposomal} doxo-rubicin (20mg/m2 _{every two to threeweeks) showed good} antitumor activity. Toxicity profileof both agentsis better than thatofotheranthracyclines,and thereare noreports of either cardiotoxicity or significant alopecia, even with high cumulative doses. However, these agents still cause significantmyelosuppressionandoccasionalemesis.In addi-tion,infusion-relatedhypotensionand hand-footsyndrome are newadverse events seen withthe use ofsuch liposo-malformulations.61_{AphaseIIIrandomizedstudycomparing}

liposomal daunorubicin and ABV regimen (doxorubicin, bleomycinandvincristine)revealednodifferenceintermsof overallresponserates(partialresponse+completeresponse), time totreatment failureandsurvivalduration.63 _Two

ran-domized phase III studies compared pegylated liposomal doxorubicin withconventionalchemotherapycombinations (ABVinastudyandBV[bleomycin+vincristine]inanother) as first-line treatment for patients with Kaposi’s sarcoma whowerenotreceivingHAART.Thetwostudiesshowedthat response rateswere higher amonggroups ofpatients who receivedpegylatedliposomaldoxorubicin,butresponseswere notsustainedovertime.64,65_{Thethreestudiesmentioned}

can-notbedirectlycompared.Asmallrandomizedstudyincluded 79patientswithKaposi’ssarcomawhowererandomizedto receivepegylatedliposomaldoxorubicin(20mg/m2_)or liposo-maldaunorubicin(40mg/m2_{)everytwoweeksforuptosix} cycles.Differenceshavebeenshownfavoringpegylated lipo-somaldoxorubicin.66

Myelosuppression(e.g.,neutropenia)isamajorsideeffect ofpegylatedliposomaldoxorubicin,representing alimiting factor inthetherapeuticregimenforthetreatmentof neo-plasia.Patientswhodevelopneutropenicfever(definedbythe presence offever,oraltemperature >38.3◦Cor ≥38.3◦_Cfor morethan1h;whereasneutropeniaisdefinedasneutrophil count<500mm−3orbetween500and1000mm−3andtendto fallinthenext48h)inthecourseofchemotherapyshouldbe carefullyevaluatedforwhethertheyshouldreceivetreatment withmyeloidgrowthfactors.67_{Inthecaseofusingfilgrastim,}

thedailydoseis5␮g/kg/day,treatmentshouldbecontinued untilabsoluteneutrophilcountsreachtheirnormalvalue.67

Hand-foot syndromeis aset ofsigns and symptomsof acutenatureaffectingthepalmsofthehandsandsolesofthe feet,beingstronglyassociatedwithantineoplastic chemother-apy, occurring to a lesser extent in patients treated with liposomalanthracyclinescomparedwithotherchemotherapy agents suchas5-fluorouracil and derivatives. In treatment schemes where thereis anexpected rate ofoccurrenceof thissyndrome,itisimportantthatpatientsbeableto recog-nizeearlysigns,sothattherapycanbeadjustedimmediately. Changes indose or systemic and localapproaches can be used. Once symptoms have subsided, therapy can usually be restartedaccordingto initialplanning.Uponrecurrence ofsymptoms,especiallyifmoresevere,dose adjustmentis required.68

Pyridoxine (vitamin B6) has shown benefits as sys-temic therapyofhand-foot syndrome.There arereportsof

completedisappearanceofhand-footsyndromewithdoses of50–150mgdaily.However,somepatientsmaynotrespond tothisdrug.Althoughtheexactmechanismofactionisnot yet fully understood, pyridoxine can alsobe used prophy-lactically.Anti-inflammatoryinhibitorsofcyclooxygenase-2 (COX-2)havealsoproveneffectiveintheprophylaxisof hand-footsyndromeassociatedwithchemotherapy.Highpotency corticosteroids and disinfectant treatment of vesicles and erosionswere effectivewhenconsideringatopicaltherapy. Preventiveuseofglucocorticoids,bycontrast,proved ineffec-tive.Inmildcasesofthesyndrome,avoidmechanicalirritation oftheskinonthepalmsofhandsandsolesoffeet,andtheuse ofemollientcreamsorsoftgelsisenoughforcontrolandrelief ofsymptoms.Coolingoftheaffectedareasusingcoldbathsof handsandfeet(withoutintensivewashing)alsohelpsinrelief ofsymptoms.Dependingontheseverityofthesyndrome,cure occursinamatterofdaysorweeks.68

Althoughpaclitaxelispotentiallymoretoxicthan liposo-malanthracyclines,ithasremarkableefficacyassecond-line treatmentofKaposi’s sarcoma,69,70 _{and can bean}

alterna-tivetoinitialtherapyofpatientswithadvancedsymptomatic disease.Theeffectivenessofpaclitaxelwasoriginally demon-stratedinaphaseIIstudywith28evaluablepatientsinwhich 20(71%)hadhigherresponsestothetreatmentregimenof 135mg/m2_{every3weeks(18partialresponses,onefull} clini-calresponseandonefullresponse).Responseswereobserved inallfivepatientswithpulmonarylesionsofKaposi’ssarcoma andallfourpatientshadreceivedprioranthracycline-based chemotherapy.Treatment toxicity included grade4 throm-bocytopenia in 6 of the 29 enrolled patients and grade 4 neutropenia in 22 of the 29 patients treated without the use of hematopoietic growth factors.71 _{Treatment regimen}

ofpaclitaxel100mg/m2 _{every2 weekswascompared with} the use of pegylated liposomal doxorubicin in a dose of 20mg/m2 _{every3weeksinarandomizedclinicaltrial} con-ducted after the introduction of routine treatment with HAART.46 _{Inthis study,73 evaluable patientswithKaposi’s}

sarcomaassociatedwithAIDSwere includedbetween1998 and2002(the trialwas prematurelyterminatedbecause of low patient inclusion). There were no statistically signif-icant differences between the two treatment regimens in terms ofresponserate, progression-free survivalor overall survival. The two treatment regimens propitiated consid-erable improvement of pain and of edema secondary to tumor.46

Myelosuppression(e.g.,neutropenia)inducedbypaclitaxel is an important side effect, representing a limiting factor inthe therapeuticregimenfor the treatmentof neoplasia. Patientswhodevelopneutropenicfever(definedbythe pres-enceoffever,oraltemperature>38.3◦Cor≥38.3◦_Cformore than1h;whereasneutropeniaisdefinedasneutrophilcounts <500mm−3orbetween500and1000mm−3andtendtofall inthe next48h)inthe courseofchemotherapyshould be carefullyevaluatedforwhethertheyshouldreceivetreatment withmyeloidgrowth factors.67 _{Inthecaseoftheuseof}

fil-grastim,thedailydoseis5␮g/kg/day,andtreatmentshould becontinueduntilabsoluteneutrophilcountreachesnormal value.67

BeforetheeraofHAART,severalotherchemotherapeutic agents(e.g.,bleomycin,doxorubicin,vinblastine,vincristine,

andetoposide)wereactiveinthetreatmentofKaposi’s sar-coma related to AIDS in case reports and in small phase IItrials thatevaluateddifferentcombinations anddosesof thesedrugs.61_{Thepercentageofpatientsachievingadecrease}

of ≥50% in number of lesions ranged from 58% to 90% undertreatmentwithvincaalkaloids,from74%to76%with etoposidewas97%withthecombinationofvinblastineand bleomycin.However,clinicalstudiesthatevaluatedthese regi-menspresentedlowqualityduetothelackofastandardized classificationofdisease activityand clinicaloutcomes ana-lyzed.Therefore,evidencefortheeffectivenessofanyofthese treatmentregimens isoflowqualityand doesnotsupport recommendationofanyoftheseregimensinparticular.72

For the duration of treatment with HAART, both pegy-latedliposomaldoxorubicinandpaclitaxelareisolatedactive agentsinthetreatmentofepidemicKaposi’ssarcoma,with responseratescloseto50%.61

Immunotherapy

The use of biological response modifier interferon-␣ was approved for the treatment of Kaposi’s sarcoma before the availability of HAART and liposomal anthracyclines. Interferons-␣ were extensively studied and showed objec-tiveresponserateof40%inpatientswithepidemicKaposi’s sarcoma.73,74_{Inthesestudies,responsesdifferedsignificantly}

according tothe prognosticfactors ofdisease extent,prior or coexistent opportunistic infections, previous treatment with chemotherapy, CD4 lymphocyte counts of less than 200cells/mm3_{,presenceofcirculatingacid-labileinterferon-␣} andincreased␤2-microglobulin.

Responsetointerferon-␣oftenrequirescontinuous treat-mentfor6monthsormore,sinceresponsetimeistypically longerthanfourmonths.Interferon-␣shouldnotbe consid-eredasatherapeuticoptionincaseofprogressiveorvisceral disease.Toxicityofhighdosesofinterferon-␣(e.g.,fever,chills, neutropeniaanddepression)iscommonand lowresponses are observed inthe presenceoflow countsofCD4 cells.61

Interferon-␣isnotveryoftenusedtodayduetoitstoxicity profileandbecauseitdoes notwork wellinmanypatients withAIDS.28

Interleukin-12hasshownaresponserateof71%(95%CI, 48–89%)inthetreatmentofKaposi’ssarcomain24evaluable patientsinaphaseIstudy.75

Summary

of

therapeutic

recommendations

for

epidemic

Kaposi’s

sarcoma

Table2shows possibletherapeuticapproaches forpatients withepidemicKaposi’ssarcoma.Specifically,Table3presents maincytotoxicagentswhichcanbeusedinthechemotherapy treatmentofepidemicKaposi’ssarcoma.

Recommendations

Based on the increased risk of mortality in the groups below,thiscommitteemakesthefollowingrecommendations related upondiagnosis and treatmentofepidemicKaposi’s sarcoma.

322

Table3–CytotoxicagentsusedinthetreatmentofepidemicKaposi’ssarcoma. Pegylatedliposomal doxorubicin Daunorubicincitrate liposome Doxorubicin hydrochloride

Bleomycinsulfate Vincristinesulfate Vinblastinesulfate Paclitaxel

Doseschedule 20mg/m2_everytwo orthreeweeks Fordoses<90mg: dilutein250mlof glucosesolutionat 5%(50mg/ml).For doses>90mg:dilute in500mlofglucose solutionat5% (50mg/ml) 40mg/m2_15/15days Shouldbedilutedin glucosesolutionat 5–100mlfor1mg/ml concentrationand infusedwithin 60min 10–20mg/m2 Itshouldbe dissolvedin0.9% sodiumchlorideor sterilewaterfor injections Recommended concentrationis 2mg/ml 10U/m2_(1U=1mg) 15/15days Dilutein20mlsaline solution Applyin10min 0.01–0.03mgperkg ofbodyweight,as singledoseevery7 days;or0.4to 1.4mg/m2_ofbody surface,assingle doseevery7days Reconstitutein diluentprovided withtheproduct (benzylalcohol)and onlyadminister intravenously Weeklydosewhen isolatedand15/15 daysincombination withother chemotherapeutic agents Initialdoseof 3.7mg/m2_ofbody surfaceperweek Sequentialincreases shouldfollowfrom 1.8to1.9mg/m2_of bodysurfaceat weeklyintervals Dilutewithsaline solutionatthe concentrationof 1mg/ml Administerbolusin 10–15minin“Y” 135mg/m2_every3 weeksOR100mg/m2 every2weeks Premedicatewith diphenhydramine, 50mgEV, dexamethasone 20mgEVand cimetidine,300mg (orranitidine,50mg EV)beforepaclitaxel

Guidelinesand precautions

Theinitialdoseis administeredata ratenotexceeding 1mg/min.Ifno infusionreactionis observed, subsequent infusionscanbe administeredovera periodof60min Incasesof palmar-plantar erythrodysesthesia, hematologictoxicity andstomatitis,the dosecanbereduced ordelayed

Shouldnotbe administeredwith other

chemotherapeutic drugs(nostudieson interactions) Heartfailurecan occurwith cumulativedose above300mg/m2 Maycause myelosuppression (especiallyof granulocyticseries) Leucopeniareaches itslowestpointin 10–14days,with Retrieval approximatelyon day21 Cumulativedose above550mg/m2_: riskofheartfailure. Significantfinding onECG:QRSvoltage reduction

Canbeusedwith other chemotherapeuticc agents Whenin combinationwith vincristine, administerit previouslyasit increasessensitivity tobleomycin.Riskof pulmonaryfibrosis increaseswith cumulativedoses above400U Lowmyelotoxicity. Canbeassociated withother chemotherapeutic agents Commonoccurrence ofneuropathy Little Myelosuppressive effect

Canbeusedwith other chemotherapeutic agents Donotadminister withdoxorubicin Whenadministered withbleomycin, applyvinblastine beforehand Alopecia Dose-dependent leukopenia Someantiretroviral drugsareenzyme inducersandcan interferewiththe activityofpaclitaxel byincreasing metabolism UseG-CSFor peg-GCSFasprimary prophylaxiswhen thereisriskof neutropenicfever >20%orsecondary tofilgrastim5 mcg/kg/dayor pegfilgrastima6mg subcutaneouslyper dose(onlyifthe intervalbetween cycles>2weeks).

Note:Alwaysstart 24haftertheendof chemotherapy

Diagnosticapproach

• PatientswithconfirmedKSandwhofitincategoryS1must besubmittedtoupperandlowerendoscopyaswellas bron-choscopy,regardlessofthepresenceofclinicalsymptoms. • Ifthereisnocontraindication,investigationofpulmonary

involvementbybronchoscopy shouldbeperformedinall patientswithKS.

• Investigationofviscerallesionsusingendoscopic examina-tionsshouldbeperformedinsymptomaticpatients. • Investigation ofvisceral lesions using endoscopic

exam-inations should be performed in patients unable to immediately start HAART or with virological failure to antiretroviraltherapy.

• Investigationofviscerallesionsusingendoscopic examina-tionsshouldbeperformedinpatientswhodevelopedKSin regularuseofHAART.

Therapeuticapproach HAART

Becauseit isan AIDS-defining disease,all patients should receiveHAART,regardlessofCD4count.76

Chemotherapy

• Systemicchemotherapyshouldbeinitiatedin: • S1T1patients.

• Patientswithpulmonaryinvolvement. • Patientswithsymptomaticviscerallesions.

• PatientswithlymphedemasecondarytoKaposi’ssarcoma. • Patientswithrapidlyprogressiveskindisease.

• Patientswithprogressionofclinicaldiseaseafter introduc-tionofHAART.

• Patients with immune reconstitution inflammatory syn-dromebyKaposi’ssarcoma.

• PatientswhodevelopedKaposi’ssarcomainregularuseof HAART,regardlessofdiseasestage.

Systemicchemotherapyshouldbeconsidered:

• PatientsunabletoimmediatelystartHAARTorwithcurrent virologicalfailuretoantiretroviraltherapy.

• Patientswithcosmeticallydisfiguringlesionsthatdidnot respondtolocaltherapy.

- Forinitialchemotherapytreatment,itisrecommendedto usealiposomalanthracycline(eitherpegylatedliposomal doxorubicinorliposomaldaunorubicin[evidencelevel1b]). Othercytotoxicagentscanbeusedincombinationin loca-tionswhereliposomalanthracyclinesarenotavailable. - Forpatientswhosediseasehasprogressedfollowing

treat-mentwithliposomalanthracycline,itisrecommendedto usechemotherapywithpaclitaxel(evidencelevel3B). - ForpatientswhopresentKaposi’ssarcomaorlimited

dis-ease causing symptoms or cosmetic disfigurement, it is recommended touselocaltreatmentadjuvanttoHAART (evidencelevel2C).

- Forpatientswhopresentsmalllesions,itisrecommended touseintralesionalchemotherapy(evidencelevel2C);for thosepatientswithgreaterlesionsthatcannotbetreated

withintralesionalchemotherapyandwhodonothavean indicationofsystemicchemotherapy,itisrecommendedto useradiotherapy(evidencelevel2C).

- Liposomalanthracyclinescannotbeusedincombination withotherdrugs.

- Cytotoxic agents vincristine, bleomycin and doxorubicin (non-liposomalformulation)canbeusedinisolationorin combination.Thesumoftheadverseeffectsofthe respec-tivedrugsshouldbemonitored.

Criteriaofresponsetochemotherapy

Definitions recommended for criteria of response to chemotherapy29aredescribedbelow.

Fullresponse (FR):absenceofanydetectable residual dis-ease,includingtumor-associatededema,persistingforatleast 4 weeks.In patients in whom macular pigment (brown or beige)skinlesionspersistafterapparentFR,biopsyofatleast onerepresentativelesionisrequiredtodocumenttheabsence ofmalignantcells.Inpatientsknowntohavehadvisceral dis-ease,revaluationwithappropriateendoscopicorradiological proceduresshouldbemade.Iftherearecontraindicationsfor suchproceduresthepatientcanbeclassifiedashavingclinical FR.

Partialresponse(PR):adecreaseof50%ormoreinthe num-berand/orsizeofpre-existinglesionsmaintainedforatleast 4weekswithouttheappearanceofnewskinlesionsororal lesions orviscerallesionsor worseningofeffusions/edema associatedwiththetumor,oranincreaseof25%ormorein theproductoftwo-dimensionaldiametersofanyindicative lesion.

Stabledisease:anyresponsethatdoesnotmeetcriteriafor partialresponse(PR)orprogressivedisease.

Progressivedisease:anincreasegreaterthanorequalto25% inthenumberorsizeofpre-existinglesionsand/or appear-anceofnewlesions.

Inpatientswithanindicationforsystemicchemotherapy, thiscommitteerecommendsthattreatmentbediscontinued inthefollowingsituations:

• afterregressionofcutaneouslesions;

• aftercompleteremissionoflesionsintherespiratorytract, ifany;

• afterremissionofsymptomsinviscerallesions,ifany; • ifthereisevidenceofclinicalbenefitofcontinuing

treat-ment.

Final

considerations

Aboverecommendationshavebeenpreparedconsideringthe prognosisofpatientswithKaposi’ssarcomainuseofHAART. Wherethistherapyisnotusedforanyreason,patientswith visceral lesions, evenasymptomatic, should be considered inaccordancewiththeclassificationofACTG(AIDSClinical TrialsGroupOncologyCommittee)andtreatmentshouldbe optimized.

Conflicts

of

interest

324

Appendix

A.

Levels

of

scientific

evidence

used

in

guidelines

(according

to

the

Oxford

Centre

for

Evidence-Based

Medicine)

Levelof recom-mendation

Evidencelevel Treatment/prevention-etiology Diagnosis

A 1A Systematicreview(withhomogeneity)

ofRCTs

Systematicreview(withhomogeneity)of level1diagnosticstudies,level1Bdiagnostic criterion,indifferentclinicalcenters 1B RCTusingnarrowCI Validatedcohortusinggoodreference

standard,diagnosticcriteriontestedina singleclinicalcenter

1C Therapeuticresultsofthe“allor nothingatall”type

Sensitivityandspecificitycloseto100%

B 2A Systematicreview(withhomogeneity)

ofcohortstudies

Systematicreview(withhomogeneity)of diagnosticstudieslevel>2.

Exploratorycohortusinggoodreference standard,diagnosticcriterionderivedor validatedinfragmentedsamplesordatabase 2B Cohortstudy(includingRCTsoflower

quality)

2C Observationoftherapeuticresults. Ecologicalstudy

3A Systematicreview(withhomogeneity) ofcase-controlstudies

Systematicreview(withhomogeneity)of diagnosticstudiesoflevel>3B

3B Case-controlstudy Non-consecutiveselectionofcasesor referencestandardappliedinanotvery consistentmanner

C 4 Casereport(includingcohortor

case-controloflowerquality)

Case-controlorpoorreferencestandardor notindependent

D 5 Opinionwithoutcriticalevaluationor

basedonbasicmaterials(physiological studyoranimalstudy)

r

e

f

e

r

e

n

c

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