15 Cancer de Ovario Epitelial

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15.OvarianEpithelialCancer|BrazillianManualofMedicalOncology
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15.OVARIANEPITHELIALCANCER
Updatedon15/10/14,afterASCO2014.
STAGING(FIGO,2014)/TNM(AJCC,2010)
Definition
Stage I: tumor limited to the ovaries IA/T1a: tumor limited to one ovary, absence of malignant cells in
peritonealwashingorinascites,andabsenceoftumorontheexternalsurfaceoftheovaryandintactovarian
capsuleIB/T1b:similartoIA,buttumorlimitedtobothovariesandIC/T1c:tumorlimitedtooneorbothovaries
with one of the following characteristics: IC1/T1c1: surgical rupture IC2/T1c2L: capsule ruptured prior to
surgeryortumorinvadingtheovariansurfaceIC3/T1c3:presenceofmalignantcellsintheperitonealwashing
or ascitic fluid. Stage II/T2: tumor invading one or two ovaries with extension to pelvic cavity IIA/T2a: tumor
extension and/or implant on uterus and/or tubes and/or ovaries IIB/T2b: extension to other pelvic tissues.
StageIII:tumorinvadingoneortwoovarieswithcytologicorhistologicinvolvementofextrapelvicperitoneum
and/or involvement of retroperitoneal lymph nodes IIIA1/T1T2/N1: retroperitoneal lymph node involvement
alone IIIA2/T3a2N0/N1: microscopic involvement of extrapelvic peritoneum with or without positive
retroperitoneallymphnodesIIIB/T3bN0/N1:abdominalperitoneumimplants2cm,withorwithoutmetastasis
to retroperitoneal lymph nodes IIIC/T3cN0/N1: abdominal peritoneum implants > 2 cm with or without
metastasis to retroperitoneal lymph nodes, including tumor extension to the liver capsule or spleen without
parenchymal involvement Stage IV: distant metastasis, including peritoneal metastasis IVA: pleural effusion
with positive cytology IVB/M1: parenchymal metastasis and metastasis to extraabdominal organs, including
inguinallymphnodesorlymphnodesoutsidetheabdominalcavity.
TNMgrouping(AJCC)
I: T1N0M0 IA: T1aN0M0 IB: T1bN0M0 IC: T1cN0M0 II: T2N0M0 IIA: T2aN0M0 IIB: T2bN0M0 IIC:
T2cN0M0III:T3N0M0IIIA:T3aN0M0IIIB:T3bN0M0IIIC:T3cN0M0T1T3N1M0andIV:T13N01M1.
Practicaltip. The FIGO staging was recently modified [Int J Gynaecol Obstet 124:1, 2014 Gynecol Oncol
133:401, 2014]. Although controversial, intraoperative capsule rupture seems to jeopardize the prognosis
[Lancet357:176,2001ObstetGynecol113:11,2009 GynecolOncol122:83,2011].Consequently,thenew
FIGOstagingcontemplatesthisscenarioasstageIC1.Inthesecases,completesurgicalstagingoperationand
adjuvant platinumbased chemotherapy may revert this negative effect on the prognosis [Eur J Surg Oncol
39:279,2013].TheabsolutevalueofCA125instageIpatientsseemstocorrelatewith5yearoverallsurvival
(OS) ( 30 U/mL 95% versus > 30 U/mL 82%, p=0.028) and may be used in combination with other
prognosticfactorsinthedecisiontouseadjuvanttherapy[JClinOncol23:5938,2005 ].
STAGINGWORKUP
Recommendation. Obtain chest xray, computed tomography (CT) of the abdomen and pelvis, and CA
125todefineifthepatientisacandidateforeitherprimarycytoreductivesurgeryorneoadjuvanttherapy.
Ovarian cancer staging is pathological, but primary cytoreductive surgery is not always possible. Biopsy
guidedbyimagingorvialaparoscopyinordertoexcludetumorsinothersitessuchasthegastrointestinal
tractshouldbeobtainedpriortoinitiationofchemotherapywhenneoadjuvanttherapyisplanned.
Note. Surgical staging involves the collection of ascitic fluid or peritoneal washing, inspection of the
entireperitonealcavity,totalhysterectomy,bilateralsalpingooophorectomy,omentectomy,bilateralpelvic
andparaaorticlymphnodesampling,andremovalofsuspiciousareas.Randombiopsiesoftheperitoneal
surface, including the parietocolic gutter and diaphragmatic area, are indicated in case there are no
suspicious areas. In a series with 40 patients initially subjected to incomplete surgery for stage IIIIA
tumors, restaging procedures performed by a gynecologic oncology (GYO) surgeon led to upstaging in
50% of the cases with modification of postoperative chemotherapy planning in 53% [Surg Oncol 21:31,
2012].StudiesdemonstratethatovariancancersurgeryperformedbyGYOsurgeonsimpactsnotonlythe
prognosis, but also the choice of postoperative therapy [Cochrane Database Syst Rev 4:CD006014,
2013 Cancer106:589,2006 JNatlCancerInst98:172,2006 ].Appendectomyshouldbeperformed
in case of mucinous tumors, since a macroscopically normal appendix can be the site of a primary
mucinous tumor of the appendix with metastasis to the ovary. Although every suspicious lymph node
should be removed, the role of systematic lymphadenectomy remains controversial. A retrospective
analysisoftheSurveillance,Epidemiology,andEndResults(SEER)databasefoundthattheremovalof0,
19, or 10 lymph nodes is associated with a 5year causespecific survival of 37%, 62%, and 71%,
respectively (p<0.001) [BJOG 117:1451, 2010 ]. However, two randomized prospective studies did not
demonstrate an impact on OS with this procedure either in early stage I and II [Br J Cancer 95:699,
2006 ]orinadvancedstageIIIandIVdisease[JNatlCancerInst97:560,2005 ].Alargeretrospective
series with 240 clear cell ovarian cancer patients demonstrated that systematic lymphadenectomy was
associatedwithgreaterPFSineverystageandimprovedOSinadvancedstages[IntJGynecolCancer
21:1063,2011].AnotheranalysisoftheSEERdatabasecomprising1,897patientswithstageIclearcell
ovarian cancer demonstrated that resection of > 10 lymph nodes was associated with superior OS
(HR=0.71 95% CI: 0.491.02 p=0.064) [Int J Gynecol Cancer 23:1226, 2013]. Optimal cytoreduction is
defined as when the diameter of the largest residual tumors is 1 cm suboptimal is when any residual
tumoris>1cm.Nevertheless,exploratoryanalysisofthreeEuropeanprospectivetrials(AGOOVAR3,5
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tumoris>1cm.Nevertheless,exploratoryanalysisofthreeEuropeanprospectivetrials(AGOOVAR3,5
and 7) revealed that the greatest impact on OS is observed in patients with complete resection and no
evidenceofanymacroscopictumor.ThemedianOSforthegroupwithoutmacroscopicdiseasewas99.1
months compared to 36.2 and 29.6 months for those with residual disease between 0.11 and >1 cm,
respectively [Cancer 115:1234, 2009 ]. A metaanalysis from 18 studies with 13,257 patients
demonstrated that at every 10% increase in the proportion of patients subjected to surgery without
absence of residual disease there was an increase of 2.3 months in OS (p=0.011) compared to an
increase of 1.8 months in the group with complete resection (< 1 cm) [Gynecol Oncol 130:493, 2013].
Similar benefit seems to occur in the cytoreduction of stage IV patients, with OS rates of 54.6, 25.8 and
23.9 months observed if residual disease of 0, 110 or > 10 mm, respectively [Ann Surg Oncol 17:1642,
2010].Althoughnotvalidated,somecriteriacanbesuggestiveofsurgicallyunresectabledisease,suchas
CA125500U/mL,visceraldiseaseorstageIV,ascites>1,000mL,neoplasticimplant>12cminthe
superior floor of the abdomen, diaphragmatic disease or disease in the mesenteric root, extensive
peritonealcarcinomatosis,orsuprarenaladenopathy[JSurgOncol101:13,2010GynecolOncol108:271,
2008]. Laparoscopy allows for biopsy and evaluation of resectability [Gynecol Oncol 131:341, 2013], but
requires caution to avoid the seeding of cancer cells in the port site [Am J Obstet Gynecol 199:642,
2008 ].Preservationoftheuterusandcontralateralovary(fertilitysparingsurgery)instageIpatientsat
reproductive age is safe, as long as the principles of cytoreductive surgery are respected. Biopsy of the
contralateralmacroscopicallynormalovaryisnotrecommended.Inasystematicreviewof15studieswith
913 patients, the rate of recurrence was only 11.4%. Risk was greater in stages IB/IC and grades 2/3
[Onkologie36:436,2013].Corroboratingthesedata,aretrospectivestudywith211patientsdemonstrated
that the recurrence rate after fertilitysparing procedures was only 8.5%, and 96.8% of the patients
presented regular menstrual periods irrespective of exposure to adjuvant chemotherapy [J Clin Oncol
28:1727,2010 ].Thesameappliestowomenwithearlystagemucinousadenocarcinoma[GynecolOncol
122:334,2011].
INITIALTREATMENT
PathologicalstageI
Recommendation.AdjuvantchemotherapyinpatientswithstageIAgrade3,stageIBgrades2or3,stage
ICofanygrade,aswellasallstageswithclearcellcarcinoma.Wefavorcarboplatin,AUC56IVonD1
withpaclitaxel,175mg/mIVonD1every3weeksfor6cyclesor,alternatively,carboplatin,AUC2IV
with paclitaxel, 60 mg/m IV, both on D1, D8, and D15 every 3 weeks. The weekly regimen is the
preferredoptionforpatientswithcomorbidities.Singleagentcarboplatin,AUC6IVevery3weeksisan
optionforpatientswithseverecomorbiditiesorwhocannottoleratepolychemotherapy.
Note. The role of platinumbased adjuvant chemotherapy in highrisk earlystage ovarian cancers (IA
grade 3, IB grade 2 or 3, IC, and IIA) and all patients with clear cell carcinoma is well established and
based mainly on two phase III randomized studies of platinumbased adjuvant chemotherapy versus
observation that included a total of 925 patients. These studies were conducted by the International
CollaborativeOvarianNeoplasm(ICON)andbytheEuropeanOrganizationforResearchandTreatmentof
Cancer (EORTC) through the Adjuvant ChemoTherapy in Ovarian Neoplasm (ACTION) trial. Together,
these studies showed a significant increase in 5year recurrencefree survival (RFS) (HR=0.64, 95% CI:
0.500.82, p=0.001) and 5year OS (HR=0.67, 95% CI: 0.500.90, p=0.008) in favor of the arm that
contained the platinum agent [J Natl Cancer Inst 95:105, 2003 ]. An update of the ICON 1 trial, which
included477patientswithmedianfollowupof10years,demonstratedanabsolutebenefitof9%inthe10
yearOSinfavorofimmediatechemotherapy(HR=0.71,95%CI:0.520.98,p=0.04)[AnnOncol25:1165,
2014 ]. A recent metaanalysis including 1,277 patients from five randomized studies reported
improvementinPFS(HR=0.67,95%CI:0.530.84)andareductionintheriskofdeath(HR=0.71,95%CI:
0.530.93) with the use of adjuvant chemotherapy. According to this metaanalysis, the benefit was
restricted to patients with incomplete staging or those with pathological characteristics of high risk
[CochraneDatabaseSystRev3:CD004706,2012].Thenumberofchemotherapycycleswasevaluatedin
aphaseIIItrialconductedbytheGynecologicOncologyGroup(GOG)inwhich427patientswithhighrisk
stageIorstageIIwererandomizedto3or6cyclesofcarboplatinandpaclitaxel.Inamedianfollowup
of 6.8 years, there was a 24% relative reduction in the rate of recurrence (p=0.18) with estimated
probability of recurrence in 5 years of 20.1% versus 25.4% for 6 versus 3 cycles, respectively [Gynecol
Oncol102:432,2006].The5yearRFSinpatientswithserouspapillaryhistologywassuperiorinthearm
that received 6 cycles (83 versus 60%, p=0.007) [Gynecol Oncol 116:301, 2010]. Therefore, we favor 6
cyclesofadjuvantchemotherapyinhighriskstageIpatients.Inthisstage,thepreferencefortheregimen
withcarboplatinandpaclitaxelisbasedonitsstrengthinmoreadvancedstages.Traditionally,themost
commonly used regimen consisted of both agents every 3 weeks. The recommendation for weekly
carboplatin and paclitaxel is based on the study of stage IC to IV disease, in which this regimen
demonstratedsimilarefficacybutlesstoxicityandimprovedqualityoflifewhencomparedtocarboplatin
andpaclitaxeladministeredevery3weeks(seenextonStagesIItoIV)[LancetOncol15:396,2014].We
recommendsingleagentcarboplatin,AUC6IVover30mininpatientswithlowperformancestatus(PS)
orcomorbiditiesthatimposeahighriskoftoxicitywithpolychemotherapy.Inarandomizedtrialwith2,074
patients,carboplatinwassimilarintermsofOStotheschemeswithcyclophosphamide, doxorubicin,
andcisplatinorcarboplatinandpaclitaxel[Lancet360:505,2002].Theimpactofchemotherapyonearly
stageclearcellcarcinomaremainscontroversial.AJapanesestudyevaluatedtheprognosisof131stageI
patients with various histologies. In this study, 87 patients received adjuvant chemotherapy and 44 were
observed.Therecurrencesinthosewithclearcellcarcinoma(n=38)occurredinallsubstagesI,whilethere
wasnorecurrenceinpatientswithnonclearcellhistologyinstageIA.InpatientswithstageICclearcell
histology, the recurrence rates were 80% for those who did not receive chemotherapy versus 18.8%
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histology, the recurrence rates were 80% for those who did not receive chemotherapy versus 18.8%
(p=0.02) for those treated with adjuvant chemotherapy, suggesting benefit of this strategy in stage I
patients[JClinOncol31:abstr5552,2013].
StagesIItoIV
Patientswithlowdiseaseburden
Definition.PatientswithoutascitesorwhohavesmalldiseasevolumeontheCToftheabdomenandpelvis
and in whom a gynecologic oncologist believes an optimal surgical cytoreduction can be achieved with low
morbidity.
Recommendation.Surgeryperformedbyagynecologiconcologistorsurgicaloncologistaimedatoptimal
cytoreduction. Postoperative therapy is based on the type of cytoreduction: Optimal primary
cytoreduction in stage III: in patients with stage III subjected to optimal cytoreduction (defined as
diameterofthelargestresidualtumor1cm),withnocomorbiditiesandtreatedinreferralcenters,asolid
option is intraperitoneal (IP) and IV chemotherapy consisting of cisplatin, 75 mg/m (original study used
100mg/m)dilutedin2LofNS,warmedup,andinfusedasfastaspossibleviaIPonD1andpaclitaxel,
175 mg/m IV over 3 h on D1, as well as 60 mg/m IP on D8 (diluted in 2 L of warm NS) for 6 cycles.
Anotheroptionconsistsof6cyclesofchemotherapywithcarboplatin,AUC6IVonD1andpaclitaxel,80
mg/m IV on D1, D8, and D15 every 3 weeks. In patients with more limiting general condition and/or
comorbidities,asolidoptionconsistsofcarboplatin,AUC2IVwithpaclitaxel,60mg/mIV,bothonD1,
D8,andD15repeatedevery3weeksfor6cycles.Werecommendcarboplatin,AUC56IVonD1with
paclitaxel,175mg/mIVonD1every3weeksincasetherearelogisticallimitationsthatprohibitweekly
therapy. In patients with stages II to IV who are not candidates for polychemotherapy, we recommend
singleagent carboplatin, AUC 6 IV over 30 min for 6 to 9 cycles. An option for patients who are
candidatesforchemotherapybutcannotacceptalopeciaisthecombinationofcarboplatin,AUC5IV,and
pegylated liposomal doxorubicin (PLD), 30 mg/m IV on D1 every 4 weeks for 6 cycles. Adjuvant
chemotherapy should be initiated without delay in patients subjected to optimal cytoreduction. Patients
withstagesIIIandIVandwithsuboptimalprimarycytoreduction,despitethemaximumeffortsof
cytoreduction by an experienced surgeon: consider as first line carboplatin, AUC 6 IV on D1 with
paclitaxel, 80 mg/m IV on D1, D8, and D15 every 3 weeks. We favor carboplatin, AUC 2 IV with
paclitaxel,60mg/mIV,bothonD1,D8,andD15every3weeksfor6cyclesforthosewithmorelimiting
general condition and/or comorbidities. We recommend carboplatin, AUC 56 IV on D1 with paclitaxel,
175mg/mIVonD1every3weeksincasetherearelogisticallimitationsthatprohibitweeklytherapy.In
patients with stages II to IV who are not candidates for polychemotherapy, we recommend singleagent
carboplatin,AUC6IVover30minfor6to9cycles.ForstageIVorselectedstageIIIcases(basedon
large burden of residual disease and on the location of lesions), consider the combination of
bevacizumab,15mg/kgIVevery3weekswithcarboplatinandpaclitaxel,bothevery3weeks,starting
inthesecondcycle,followedbybevacizumab,15mg/kgIVmaintenanceevery3weeksfor15months.
Note.Elderlypatientswithgoodperformancestatusandwithoutsignificantcomorbiditiesshouldnotbe
deprived of aggressive cytoreduction, since their rates of complication are similar to those of younger
patients[EurJSurgOncol38:1204,2012].ThejustificationforIPchemotherapyinstageIIIpatientswith
optimalcytoreductionisbasedmainlyonatrialconductedbytheGOG[NEnglJMed354:34,2006 ].In
thistrial,429stageIIIpatientswiththelargestdiameteroftheresidualtumor1cmwererandomizedto
paclitaxel,135mg/mIVover24honD1andcisplatin,75mg/mIVonD2versuspaclitaxel,135mg/m
IVover24honD1andcisplatin,100mg/mIPonD2followedbypaclitaxel,60mg/mIPonD8for6
cycles.Eventhoughonly42%ofthepatientsintheIParmreceivedtheassignedtreatment,usuallydueto
problemswiththeperitonealcatheter,anincreaseinprogressionfreeinterval(18.3versus 23.8 months
HR=0.80, 95% CI: 0.641.0, p=0.05), as well as OS (49.7 versus 65.6 months HR=0.75, 95% CI: 0.58
0.97,p=0.03),wereobservedinfavorofIPchemotherapy.TheIPchemotherapyarmhadmoretoxicityin
termsofpain,aswellashematologic,gastrointestinal,metabolic,andneurologictoxicitywithconsequent
worseningofthequalityoflifeduringtreatment.Inviewofthehighertoxicityprofileofthistreatment,we
recommendthatonlypatientswithoptimalcytoreduction,withoutsignificantcomorbiditiesorthosewithout
severeintestinaladhesions,receiveIP/IVtreatment[NEnglJMed354:34,2006 ].Inaddition,duetothe
elevated toxicity of cisplatin at the dose of 100 mg/m, we have used, as suggested by Markman and
Walker[JClinOncol24:988,2006],asmallerIPcisplatindose(75mg/m).Arecentupdateofthisstudy
reported that in patients subjected to optimal cytoreduction without macroscopic residual disease (36%),
PFS and OS were 43.2 and 110 months, respectively [Gynecol Oncol 130:12, 2013]. A metaanalysis
including2,119patientsfromninestudiesreportedareductionintheriskofprogression(HR=0.7895%
CI:0.700.86)andriskofdeath(HR=0.8195%CI:0.720.90)infavorofIPchemotherapyattheexpense
of greater toxicity [Cochrane Database Syst Rev 9:CD005340, 2011]. A Japanese phase III randomized
trial with 637 stage II to IV patients compared the conventional regimen of carboplatin, AUC 6 IV with
paclitaxel,180mg/mIVbothonD1every3weeksfor6cyclesversuscarboplatin,AUC6IVonD1with
paclitaxel, 80 mg/m IV on D1, D8 and D15 repeated every 3 weeks also for 6 cycles. After a median
followup of 6.4 years, the differences in PFS (28.2 versus 17.5 months HR=0.76 95% C.I.: 0.620.91
p=0.0037)andOS(100.5versus62.2monthsHR=0.7995%CI:0.630.99p=0.039)weresignificantin
favor of the dosedense regimen [Lancet Oncol 14:1020, 2013]. No OS benefit was observed with the
dosedenseregimeninthesubgroupofpatientswithmucinousorclearcellhistology(HR=0.9295%C.I.:
0.531.61 p=0.776). Since the incidence of hematologic toxicity is greater with the weekly regimen, it is
recommended that a minimum creatinine of 0.7 mg/dL be used in order to avoid overestimation of the
creatinineclearance[JClinOncol30:abstr5045,2012].Inordertoevaluateaweeklyregimencontaininga
platinum and a taxane, an Italian study randomized 808 recently diagnosed patients with stage ICIV
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platinum and a taxane, an Italian study randomized 808 recently diagnosed patients with stage ICIV
ovarian cancer between carboplatin, AUC 2 IV and paclitaxel, 60 mg/m IV both on D1, D8, and D15
every3weeksversuscarboplatin,AUC6IVwithpaclitaxel,175mg/mIV,bothonD1every3weeks,
botharmsforatotalof6cycles.PFSwassimilarbetweenarms(18.3versus17.3months,respectively,
HR=0.9695%CI:0.81.16p=0.66).Theweeklyregimendemonstratedlowernegativeimpactonquality
of life and fewer adverse events, including hematologic toxicity [Lancet Oncol 15:396, 2014]. The Italian
and the Japanese trials cannot be directly compared in view of the differences in dose and population.
However,intheGOG262study,twoofthefourarms(n=112)comparedcarboplatinandpaclitaxelevery
3weeksversustheweeklyregimen,similartotheJapanesetrial,demonstratingthattheweeklyregimen
wasassociatedwithbetterPFS(14versus10monthsHR=0.695%CI:0.370.96)[IntJGynecolCancer
23 (suppl 1):9, 2013 ]. See more details on this study in the discussion on bevacizumab. The weekly
regimen from the Italian study may be a good option for patients with poor performance status or with
multiplecomorbidities.Inessence,theintraperitoneal/intravenousandtheJapaneseregimenwithweekly
IVpaclitaxel combined with carboplatin, AUC 6 IV on D1 were the only schemes to present significant
improvement in PFS and OS in comparison to conventional therapy with carboplatin and paclitaxel IV
every 3 weeks. Since there is no direct comparison between these 2 studies, the choice of regimen will
dependonfactorssuchasclinicalstatusandexperienceofthemedicalteam.Despitepromisingresultsin
phase II trials, hyperthermic intraperitoneal chemotherapy still requires validation in prospective
randomizedtrialsandshouldnotberoutinelyused[GynecolOncol122:215,2011Int J Gynecol Cancer
22:778,2012AnnSurgOncol19:2352,2012EurJSurgOncol39:1435,2013].Paclitaxelcanbesafely
substituted with docetaxel according to comorbidities, such as neuropathy [J Natl Cancer Inst 96:1682,
2004 ].TheuseofthecombinationofcarboplatinandPLDIVinfirstlineisbasedonastudywith820
patients of stages IC to IV randomized between this regimen or carboplatin and paclitaxel IV. OS was
61.6 and 53.2 months, respectively (p=0.32). The arm with carboplatin and PLD presented lower
incidence of alopecia and neurotoxicity, but greater rate of myelosuppression [J Clin Oncol 29:3628,
2011 ]. As described in stage I, we recommend singleagent carboplatin for patients with poor PS or
comorbidities that impose a high risk of toxicity with polychemotherapy [Lancet 360:505, 2002].
Maintenance treatment for ovarian cancer has not shown benefits in terms of OS, but higher toxicity,
particularly peripheral neuropathy, and should not be routinely used [Cochrane Database Syst Rev
6:CD007414, 2013 Gynecol Oncol 122:89, 2011 Gynecol Oncol 114:195, 2009 J Clin Oncol
27:4642,2009 ].Arecentretrospectivestudyevaluating3,326patientstreatedwithplatinumandtaxanes
in three randomized trials demonstrated inferior OS rates in patients who were subjected to optimal
cytoreduction but received delayed adjuvant chemotherapy (HR=1.08 95% CI: 1.001.17 p=0.03), while
thedelaydidnotimpactOSinpatientswithsuboptimalcytoreduction[EurJCancer49:142,2013 ].The
additionofbevacizumabmaybeconsideredforpatientsdiagnosedwithstageIVwhoarenoteligiblefor
cytoreduction(asthosewithboneinvolvementormultiplevisceralmetastasis)orselectedcasesinwhom
optimal primary cytoreduction was not possible who are left with high burden of residual disease. This
recommendationisbasedontworandomizedstudiesthatevaluatedtheadditionofbevacizumab to the
combinationofcarboplatinandpaclitaxelevery3weeks.TheGOG218studywasadoubleblindedtrial
thatincluded1,873stageIIIpatientswithsuboptimalcytoreduction(despitemaximumattempt)orstageIV
andrandomizedbetweenpaclitaxel,175mg/mIVover3handcarboplatin,AUC6IV,bothonD1for6
cycles(controlarm)versusthesamechemotherapyregimenwiththeadditionofbevacizumab,15mg/kg
IVevery3weeksstartingincycle2untilcycle6(chemotherapywithinductionbevacizumabarm),versus
thesamechemotherapyregimenwiththeadditionofbevacizumab,15mg/kgIVevery3weeksstartingin
cycle2untilcycle22(chemotherapywithinductionandmaintenancebevacizumabarm).Duringthetrial,
stage III patients with optimal cytoreduction were added and accounted for one third of the study
population.Inthisstudy,improvementinPFSwasnotedinpatientswhoreceivedbevacizumabinduction
andmaintenanceincomparisonwiththecontrolarm(14.1versus10.1monthsHR=0.7195%CI:0.62
0.82 p<0.001). The arm treated with chemotherapy and induction bevacizumab without maintenance
therapy did not present any advantage in comparison to the control arm in terms of PFS. There was no
significant OS difference or in the incidence of fistulas or gastrointestinal perforations between the three
therapeuticarmsofGOG218[NEnglJMed365:2473,2011 ].Intheotherstudy,ICON7,1,528patients
withstagesItoIV(stageIifhighrisk,grade3orclearcellsubtype)wererandomizedbetweenpaclitaxel,
175 mg/m IV over 3 h and carboplatin, AUC 56 IV, both on D1 for 6 cycles (control arm) versus the
sameregimenwiththeadditionofbevacizumab,7.5mg/kgIVevery3weeksfromcycle1untilcycle18
(armwithchemotherapyandbevacizumabinductionandmaintenance).Inthisstudy,70%ofthepatients
presentedstageIIICorIVand72%hadbeensubjectedtooptimalcytoreduction.ImprovementinPFSin
thechemotherapy+bevacizumabinductionandmaintenancewasobservedincomparisontothecontrol
arm(19versus17.3monthsHR=0.8195%CI:0.700.94p=0.004).SimilartotheGOG218study,there
wasnodifferenceinOSorincidenceoffistulas/bowelperforationbetweenarms[NEnglJMed365:2484,
2011 ].InapreplannedsubgroupanalysisoftheICON7study,highriskpatients(FIGOIVorFIGOIII
with residual disease after cytoreduction) who received bevacizumab presented significant improvement
in OS (28.8 versus 36.6 months HR=0.64 95% CI: 0.480.85 p=0.002). These data suggest that the
combination of bevacizumab and chemotherapy may result in greater impact in patients with larger
disease volume. However, the GOG 262 study presented at ESGO 2013 provided some valuable
information in this issue. Patients with stage I to IV ovarian cancer (> 90% stage III/IV and > 60% not
optimallycytoreduced)wererandomizedtocarboplatinAUC6andpaclitaxel,175mg/mevery3weeks,
versus carboplatin, AUC 6 every 3 weeks and paclitaxel, 80 mg/m weekly. The addition of
bevacizumab was optional in both arms, being administered in more than 80% of the patients (n=580).
Therewasnostatisticaldifferencebetweenarmsinthegroupwhoreceivedbevacizumab(15monthsin
both arms HR=1.06 95% CI: 0.861.31), demonstrating that bevacizumab does not add benefit if the
weeklyregimenischosen[IntJGynecolCancer23(suppl1):9,2013 ].Pazopanib,anotherangiogenesis
inhibitor(multikinaseoralinhibitorofVEGFR1,2,3,PDGFRalpha,,andcKit),demonstratedbenefit
by sustaining the usually short response of adjuvant chemotherapy in ovarian epithelial carcinoma for a
longerinterval,buthasnotbeenapprovedforthisindication[JClinOncol31:abstrLBA5503,2013].The
appendix should always be evaluated in case of mucinous carcinoma histology, and careful study of
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appendix should always be evaluated in case of mucinous carcinoma histology, and careful study of
cytokeratinexpressionshouldbeperformedtoassistinthedeterminationoftheprimarysite(cytokeratin
20 (+) and CDX2 (+) suggest intestinal primary). Mucinous and clear cell carcinomas have worse
outcomesandseemtobelessresponsivetoplatinumbasedchemotherapywithorwithouttaxanes[JClin
Oncol 31:abstr 5534, 2013 Gynecol Oncol 122:541, 2011 Int J Gynecol Cancer 22:394, 2012 Int J
GynecolCancer22:801,2012GynecolOncol117:491,2010 AnnOncol21:2377,2010 ].Ananalysis
ofsevenrandomizedtrialswith8,704stageIII/IVovariancancerpatientsdemonstratedmediansurvivalof
21.3and14.6monthsforclearcellandmucinoushistology,respectively,incomparisonto40.8and50.9
monthsforserousandendometrioidhistology,respectively[IntJGynecolCancer20:945,2010].Inorder
todefinethebestchemotherapyregimen,alargeJapanesestudyrandomized652patientswithstageIIV
clearcellovariancancertoreceive6cyclesofcarboplatin,AUC6andpaclitaxel,175mg/monD1every
3 weeks versus cisplatin, 60 mg/m on D1 and irinotecan, 60 mg/m IV on D1, D8, and D15 every 28
days. After 2 years, there was no difference in PFS (77.6% versus 73% HR=1.17 95% CI: 0.861.58
p=0.3) or OS (87.4% versus 85.5% HR=1.13 95% CI: 0.791.61 p=0.48). Hematologic toxicity and
peripheral neuropathy were more frequent in the paclitaxel arm, while gastrointestinal symptoms and
febrile neutropenia were more common with irinotecan [J Clin Oncol 32:abstr 5507, 2014]. Therefore,
evenhavingworseprognosisandpoorresponsetochemotherapy,carboplatinandpaclitaxelremainthe
standardforclearcellhistology.CA125>12U/mLaftercompletionofadjuvanttherapyisassociatedwith
greater recurrence risk with PFS in 5 years of only 37.5% [Gynecol Oncol 116:57, 2010]. On the other
hand,inadvanceddisease,nadirvaluesinferiorthan510U/mLareassociatedwithgreaterPFSandOS
[GynecolOncol119:265,2010JSurgOncol100:244,2009AnnOncol19:327,2008 ].
Practicaltip.CisplatiniswellabsorbedwhenadministeredviaIP,thusrequiringthesameprecautionsasIV
cisplatin,suchashydrationandantiemeticuse.Thepatientspositionshouldbechangedevery15minfor2h
(right and left lateral decubitus, supine, and Trendelenburg positions). The temperature of the solution
administered via IP should be between 40C and 42C (104F and 108F). Peritoneal catheters with
fenestrationsandDraconcuffsshouldbeavoidedintheadministrationofIPchemotherapyinviewofthehigher
rates of obstruction and infection. A fully implantable singlelumen venous silicone catheter of large size is
recommended [J Clin Oncol 24:988, 2006]. Based on retrospective data and a systematic analysis
demonstratingacorrelationbetweenmetformin use and greater OS in ovarian cancer patients [J Clin Oncol
31:abstr 5522, 2013 Cancer 119:555, 2013 Int J Gynecol Cancer 23:1544, 2013], we recommend the
preferreduseofmetforminindiabeticpatients.
PatientswithclinicallyhighdiseaseburdeninstageIIIorIVorthosewithsuboptimalcytoreduction
duetolimitingcomorbidities,prolongedoperativetimeorlimitedsurgeonexperience
Definition.PatientswithclinicalascitesorperitonealinvolvementidentifiedbyCToftheabdomenandpelvis
and those in whom optimal cytoreduction would probably not be possible or would likely cause high surgical
morbidityinordertobeachieved.
Recommendation. Neoadjuvant chemotherapy with carboplatin, AUC 6 IV over 30 min on D1 with
paclitaxel, 80 mg/m IV over 1 hour on D1, D8 and D15 every 3 weeks for a total of 3 cycles or,
alternatively,inpatientswithlimitedperformancestatusand/ormultiplecomorbidities,carboplatin,AUC2
IV with paclitaxel, 60 mg/m IV, both on D1, D8 and D15 every 3 weeks for a total of 3 cycles, both
regimensfollowedbycytoreductivesurgery.Werecommendtheregimenwithcarboplatin,AUC56IVon
D1 with paclitaxel, 175 mg/m IV on D1 every 3 weeks for those with logistical difficulties to arrange
weeklytherapy.Werecommend3morecyclesofthesamechemotherapyregimenaftersurgeryincaseof
response. Consider IP chemotherapy, as described above, in selected cases in which optimal
cytoreductionisachievedwithintervalcytoreduction.Treatmentrecommendationsforpatientssubjectedto
primary cytoreduction despite high disease burden are similar to those of postoperative therapy for
patientswithlowdiseaseburdendependingonanoptimalorsuboptimalcytoreduction.
Note. The recommendation for neoadjuvant chemotherapy for 3 cycles followed by surgical
cytoreductionisbasedonalargephaseIIItrialconductedbytheEuropeanOrganizationforResearchand
TreatmentofCancerGynecologicalCancerGroup(EORTCGCG55971)inassociationwiththeNational
Cancer Institute of Canada (NCIC). A total of 670 patients with stages IIIC and IV were randomized to
initial cytoreductive surgery followed by 6 cycles of platinumbased chemotherapy (generally
carboplatin/paclitaxel)versus3cyclesofneoadjuvantchemotherapyfollowedbyintervalsurgeryand3
cyclesofchemotherapy.Inamedianfollowupof4.7years,thetrialdidnotshowanydifferenceinPFS(12
months for both) or OS (29 versus 30 months) between the arms. However, the rate of surgical
complicationswaslowerinpatientswhoreceivedneoadjuvantchemotherapyfollowedbyintervalsurgery,
including lower postoperative mortality (0.7% versus 2.5%), infection (1.7% versus 8.1%), and grade 34
hemorrhage (4.1% versus 7.4%) [N Engl J Med 363:943, 2010 ]. An exploratory analysis of this study
demonstratedthatpatientswithstageIVdiseaseandmetastasis>45mmarethosewhobenefittedmost
fromthisstrategy[EurJCancer49:3191,2013].Corroboratingthedataabove,twostudies(CHORUSand
JCOG0602) demonstrated similar findings. CHORUS (with similar design) with 552 stage III/IV ovarian
cancerpatientsalsodemonstratedlesstoxicityintheneoadjuvantchemotherapyarmwithoutlossinOS
(24.5 versus 22.8 months) or PFS (11.7 versus 10.3 months) in comparison to surgery followed by
adjuvantchemotherapy,respectively[JClinOncol31:abstr5500,2013].JCOG0602isarandomizedstudy
with 301 stage III or IV ovarian, fallopian tube or peritoneum cancer patients that compared surgery
followedby8cyclesofchemotherapyversus4cyclesofchemotherapyfollowedbysurgeryfollowedby4
cyclesofchemotherapy.Chemotherapyconsistedofcarboplatin,AUC6andpaclitaxel,175mg/mevery
3 weeks. Although data on clinical outcomes (PFS and OS) are not yet available, this study at least
confirmspreviousfindingsthatneoadjuvantchemotherapyisassociatedwithlessextensivesurgeriesand
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confirmspreviousfindingsthatneoadjuvantchemotherapyisassociatedwithlessextensivesurgeriesand
fewerperioperativecomplications[JClinOncol32:abstr5508,2014].Themajorcriticismstothesestudies
were the low rates of optimal cytoreduction, surgical variability between centers, selection of older
populationwithmoreadvanceddisease,aswellasinferiorOScomparedtootherstudies.Therefore,we
recommend this approach only for patients with high disease burden who are not candidates for optimal
cytoreductionand/orhavehighriskofsurgicalmorbidity.Theidealistotrytooperateapatientafter34
cyclesofneoadjuvantchemotherapy,sincearetrospectiveanalysisdemonstratedthatlongercoursesare
associated with worse prognosis [J Clin Oncol 32:abstr 5572, 2014]. We favor the combination of
carboplatinevery3weeksandweeklypaclitaxelasdescribedabove[LancetOncol14:1020,2013], or,
alternatively, both agents weekly [Lancet Oncol 15:396, 2014]. In addition, we suggest that IP
chemotherapybecontemplatedforyoungmotivatedpatientswhohavehadoptimalcytoreduction(residual
disease1cm).ThisextrapolationisbasedonfavorabledatafromIPchemotherapyanddatafromphase
II and retrospective studies that suggest a potential benefit for this strategy [Gynecol Oncol 112:444,
2009 IntJGynecolCancer24:43,2014],eventhoughothercomparativeretrospectivestudiesquestion
thebenefit[GynecolOncol121:451,2011].PhaseIIItrialsareunderwaytoanswerthisimportantquestion.
Anothernotuncommonsituationreferstopatientssubjectedtosuboptimalcytoreduction.Itisimportantto
differentiate in this scenario whether suboptimal cytoreduction occurred despite maximum attempt to
cytoreducebyasurgeonwithgreatexperienceorduetopatientsstatusand/orsurgeonslimitedskills.In
thefirstscenario,theGOG152studydidnotdemonstrateafavorableimpactfromintervalcytoreduction,
despiteamaximumattemptofoptimalcytoreductionbyoncologicalgynecologists[NEnglJMed351:2544,
2004]. This study randomized 550 patients with epithelial ovarian cancer with stage III or IV and with
residualdisease>1cmafterprimarycytoreductionbetweentreatmentwithcisplatinandpaclitaxelfor6
cycles versus the same regimen for 3 cycles followed by interval cytoreduction followed by 3 additional
cycles.Incontrast,therandomizedstudyconductedbyEORTCdemonstratedthatthestrategyofinterval
cytoreductioninpatientssubjectedtosuboptimalcytoreductionresultedinfavorableOSimpactaswellas
less surgical morbidity in those with high disease burden in comparison to those initially operated on [N
Engl J Med 332:629, 1995 Semin Oncol 27:31, 2000]. An attempt at maximum cytoreduction during
initialsurgerywasnotpartoftheinclusioncriteriainthisstudy,besidesthefactthatmanywomenwerenot
operatedonbyoncologicalgynecologists.Therefore,wefavornotproceedingwithintervalcytoreductionin
situations in which neither a maximum attempt at cytoreduction nor the surgeons experience are
questioned as possible causes for suboptimal cytoreduction. Systemic treatment as described above for
patients with suboptimal resection should be utilized. However, neoadjuvant systemic therapy based on
carboplatin and paclitaxel according to the discussion above followed by surgery and adjuvant
chemotherapy should be utilized when maximum cytoreduction was not the primary objective and/or the
initial surgery was performed by an inexperienced surgeon. Additionally, treatment with intraperitoneal
chemotherapy or continuation of the same systemic treatment utilized as neoadjuvant therapy should be
considered and discussed in relatively young and motivated patients who were subjected to optimal
intervalcytoreduction(residualdisease1cm).
Practical tip. Confirmation of histology prior to initiation of neoadjuvant therapy is important to rule out
tumorsofgastrointestinalorigin,lymphoma,orbreastcancermetastasis.CTorultrasoundguidedbiopsyofthe
peritoneumisanoption,inadditiontolaparoscopy,whichisabletoconfirmtheprimarysiteinmorethan90%
ofthecases[BJOG114:46,2007 ].
FollowupafterinitialtreatmentforstagesItoIV
Clinicalfollowupevery3monthsforthefirst2years,every6monthsinthefollowing3years,thenannually.
TheutilizationofCA125aspartofthefollowupshouldbediscussedbetweenphysicianandpatients,sincethe
treatmentofrelapseattheriseofCA125hasnotshownbenefitsintermsofOSwhencomparedtotreatment
at clinical progression [Lancet 376:1155, 2010 ]. Based on these data, we recommend treatment at
recurrence,basedonthepresenceofsymptomsand/orradiologicalprogression.ImagingstudiesincludingCT
andmagneticresonanceimaging(MRI)shouldbeperformedwhenrecurrenceissuspected.
SALVAGETREATMENT
Diseasesensitivetoplatinum(interval>6monthssincelastplatinumbased
treatment)
Recommendation. Start treatment at clinical relapse (symptoms and/or radiological progression). We
favor the combination of carboplatin, AUC 5 IV over 30 min with PLD, 30 mg/m IV over 3 h every 4
weeksfor6cycles,orthecombinationofcarboplatin,AUC4IVonD1,gemcitabine,1,000mg/mIVon
D1 and D8 and bevacizumab, 15 mg/kg IV on D1 every 3 weeks for 6 cycles followed by maintenance
with bevacizumab until progression or toxicity. In patients with significant comorbidities, singleagent
carboplatin, AUC 5 to 6 IV every 3 weeks for 6 cycles should be considered. In patients with
contraindication to platinum, consider trabectedin, 1.1 mg/m IV on D1 with PLD, 30 mg/m IV on D1
every3weeks.Considersalvageintervalcytoreductionpriortosystemictherapyaspreviouslysuggested
for patients who had complete resection on initial surgery, have good PS and absence of ascites whose
preoperative evaluation (including positron emitted tomography with computed tomography PET/CT, if
available)suggeststhatcompletecytoreductionispossible.
Note. The justification to start therapy at clinical relapse (not according to CA 125) is based on the
phase III MRC OV05 and EORTC 55955 trials, which evaluated the best moment to start systemic
treatmentatrecurrence.Fromatotalof1,442patientswithepithelialcarcinomaoftheovaryincomplete
remission after platinumbased chemotherapy who were randomized to early treatment (patient and
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remission after platinumbased chemotherapy who were randomized to early treatment (patient and
physicianawareofCA125levels)versuslatetreatmentwhenclinicallyindicated(patientandphysician
notawareofCA125levels),529presentedCA125twiceashighastheupperlimitofnormal.Themedian
timetotherapywas0.8and5.6monthsforearlyandlatetreatment,respectively(p<0.00001).However,
OSratesweresimilarinbotharms(p=0.98),althoughpatientstreatedatexclusiveprogressionofCA125
experienced higher toxicity and worse quality of life (p=0.001) [Lancet 376:1155, 2010 ]. Based on this
trial,patientswithdiseaseeitherresistantorsensitivetoplatinumshouldonlystarttherapywhenclinically
indicatedandnotsolelybasedonCA125recurrence.Numerousstudieshavesuggestedthatthegreater
the interval free of a platinum agent, the greater the response rate at reintroduction of carboplatin. For
instance, in the classical study from Markman et al., response rate was 27% in 26 patients with interval
freeofplatinumof512months,33%in23patientswithanintervalof1324months,and59%forthe33
patients with interval >24 months [J Clin Oncol 9:389, 1991]. Although retreatment with carboplatin and
paclitaxel is a valid option, the randomized CALYPSO trial conducted by the Gynecologic Cancer
IntergroupvalidatedtheuseofPLDinthiscontext.Atotalof976patientswithepithelialcarcinomaofthe
ovarywhorelapsed6monthsafterthelastplatinumtreatmentandwerepreviouslytreatedwithataxane
(at first or second recurrence) were randomized to 6 cycles of carboplatin, AUC 5 IV on D1 with
paclitaxel, 175 mg/m IV every 3 weeks versus carboplatin, AUC 5 IV on D1 with PLD, 30 mg/m IV
every4weeks.Progressionfreesurvival(primaryendpoint)was11.3monthsinthePLDarmcomparedto
9.4monthsinthepaclitaxelarm(HR=0.82,95%CI:0.720.94,p=0.005),withnodifferenceinOS[JClin
Oncol 28:3323, 2010 Br J Cancer 107:588, 2012 ]. Toxicity was very distinct between both arms.
There was more mucositis and handfoot syndrome in the PLD arm, while the paclitaxel arm had more
alopecia and neuropathy. The discontinuation rate due to toxicity was higher in thepaclitaxel arm (15%
versus 6%, p<0.001). Various antiangiogenic agents have been evaluated in combination with firstline
chemotherapyinpatientssensitivetoplatinum.TheOCEANStrialevaluatedtheroleofbevacizumab in
thetreatmentofrecurrentdisease[JClinOncol30:2039,2012 ].Atotalof484patientswithpreviously
treated platinum sensitive recurrent epithelial carcinoma of the ovary were randomized to 6 cycles of
carboplatinandgemcitabinecombinedwithbevacizumabversusplacebo,whichweremaintaineduntil
progression.Progressionfreesurvivalwas12.4monthsand8.4monthsinthebevacizumabandplacebo
arms,respectively(HR=0.4895%CI:0.380.60p<0.0001).Theresponseratewas78.5%versus57.4%,
respectively (p<0.0001). Other phase III studies have demonstrated benefit from the addition of new
antiangiogenics, such as cediranib [Eur J Cancer 49 (suppl 3):abstr LBA 10, 2013] and trebananib
[Lancet15:799,2014],tochemotherapyfortreatmentofplatinumsensitiveovariancancer.However,these
drugsarenotcommerciallyavailable.Somestudieshaveevaluatedregimenswithoutplatinum.AphaseIII
studyincluding672patientswithplatinumsensitiveorresistantdiseasedemonstratedthatthecombination
oftrabectedin,1.1mg/mIVonD1withPLD,30mg/mIVonD1every3weekspresentedsuperiorPFS
(9.2versus7.5monthsHR=0.7395%CI:0.560.95p=0.017)andresponserate(35.3%versus 22.6%)
compared to singleagent PLD, 50 mg/m IV on D1 every 4 weeks in patients with platinum sensitive
recurrent ovarian cancer. This benefit was not observed in the subgroup with platinumresistant disease.
Furthermore, there was no OS difference between groups [J Clin Oncol 28:3107, 2010 Eur J Cancer
48:2361,2012 ].ThiscombinationhasbeenapprovedbytheEMAandinCanada,butnotbytheFDA.
The role of hyperthermic intraperitoneal chemotherapy as treatment of recurrent ovarian cancer has not
beenestablishedandrequiresprospectiverandomizedstudiestodemonstrateitsrealefficacy[AnnSurg
Oncol 19:2352, 2012 BJOG 119:800, 2012 Gynecol Oncol 122:221, 2011Eur J Gynaecol Oncol
31:256,2010].Singleagentcarboplatinisagoodoptionforpatientswhohavesignificantcomorbiditiesor
have contraindication for polychemotherapy in view of its superior toxicity profile when compared to
combination regimens. The role of salvage cytoreduction remains controversial, although we favor this
strategyinpatientswithfavorableconditionsforacompletecytoreduction.Salvagecytoreductionseemsto
beassociatedwithasurvivaladvantage,althoughthebenefitisalmostrestrictedtopatientswithcomplete
resectionoftherecurrenttumor[GynecolOncol112:265,2009AnnSurgOncol19:597,2012Cochrane
DatabaseSystRev2:CD008765,2013].DESKTOPIIwasaprospectivestudyforthevalidationofthree
predictivefactorsofoperabilityofrecurrentovariancancercompleteresectionatinitialsurgery,goodPS,
andabsenceofascites.Thepresenceofthethreefactorswasassociatedwithcompleteresectionin76%
of the 129 operated patients [Int J Gynecol Cancer 21:289, 2011]. The use of platinumbased
postoperativechemotherapywasassociatedwithsuperiorOS(p=0.01)[AnnSurgOncol13:1702,2006],
andconsequentlyshouldbepartofthepostoperativetherapy.Patientswhopresentsomebutnotallofthe
favorablepredictivefactorscanproceedwithstaginglaparoscopytoevaluatethepossibilityofdebulking,
aiming for complete macroscopic resection. Retrospective analyses have suggested there may be a
benefit for second salvage surgery in selected cases [Eur J Surg Oncol 39:786, 2013 Ann Surg Oncol
20:1348, 2013]. PET/CT seems to be useful for the staging of possible candidates for salvage
cytoreduction with evaluation of resectability. For example, in a retrospective study of 90 patients with
recurrent disease by CA 125, PET/CT detected additional sites of disease in 68% of the patients when
compared to conventional imaging, most of whom with disease below the diaphragm (particularly
peritoneum and lymph nodes). Disease management was changed in 60% of the cases [Gynecol Oncol
112:462, 2009]. PET/CT is also capable of detecting other disease sites in 69% of the cases of solitary
recurrencedetectedbyUSand42%ofthecaseswithsolitarytumorsonCT[IntJGynecolCancer19:600,
2009].
Practical tip. Hypersensitivity to carboplatin is relatively common in patients who are retreated with the
agentandmayoccuratanymomentofretreatment.Thereappearstobearelationshipbetweenplatinumfree
interval and hypersensitivity to carboplatin. A study demonstrated that interval < 12 months was associated
with an incidence of 56.5% versus 26% when the interval was > 12 months [Gynecol Oncol 105:81, 2007].
Another also retrospective study demonstrated that the likelihood of hypersensitivity is 44%, 36%, and 27%
whentheintervalfromthelastplatinumdoseare612months,1224months,or>24months,respectively[J
Clin Oncol 32:abstr 5538, 2014]. There are two options to treat these patients: substitute carboplatin with
anotherplatinumcompoundsuchascisplatin(oroxaliplatin,whichislesswellestablished),ordesensitizethe
patient.Inastudywith64patientswhopresentedahypersensitivityreactiontocarboplatin,51weretreated7/9
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patient.Inastudywith64patientswhopresentedahypersensitivityreactiontocarboplatin,51weretreated
with a platinum (carboplatin or cisplatin) utilizing a fast desensitization protocol (1.5 h). Of the 22 who
receivedcisplatin,only1presentedhypersensitivitywhencomparedto14of19retreatedwithcarboplatin[J
ClinOncol32:abstr5538,2014].Noallergicreactionwasobservedinacasereportof2patientswithsevere
hypersensitivitytocarboplatinwhoweretreatedwithoxaliplatin[JClinOncol20:353,2002 ].Nevertheless,
there should be significant precautions, and all necessary measures to decrease the risk of hypersensitivity
should be applied (steroids, combined H1 and H2 blockage), since severe reactions, even death, have been
reported in this scenario. Some carboplatin desensitization protocols are available. A study described
successfulretreatmentof20outof23patients(87%)withadesensitizationprotocoladministeredover6h.A
recentseriesfromtheDanaFarberCancerInstitutethatusedadesensitizingprotocolwith12stepshadsimilar
success rates, confirming the techniques usefulness [Gynecol Oncol 99:393, 2005]. A template with the
desensitizationprotocolusedinourpracticeisavailableintheMedicalFormulassectionontheMOCwebsite.
Diseaserefractoryorresistanttoplatinum(intervalfromlastplatinumbased
treatment6months)
Recommendation.Starttreatmentatclinicalrelapse.Optionsincludebevacizumab,10mg/kgIVevery2
weeksor15mg/kgIVevery3weeksinassociationwithweeklypaclitaxel,80mg/mIV,orPLD,40mg/m
IVevery4weeks,ortopotecan,4mg/mIVonD1,D8andD15every4weeks(1.25mg/mfromD1toD5
isanalternative).Patientswithcontraindicationtobevacizumab(seebelow)shouldbetreatedwithoneof
theoptionsofmonotherapy:PLD,30to40mg/mIVevery4weeksgemcitabine,1,000mg/mIVover30
min on D1, D8 and D15 every 4 weeks topotecan, 1.25 mg/m IV from D1 to D5 every 3 weeks or 4
mg/mIVonD1,D8andD15every4weeksweeklypaclitaxel,80mg/mIVonD1,D8andD15every4
weeks oral etoposide, 30 to 50 mg/m/day from D1 to D21 every 4 weeks vinorelbine, 25 mg/m IV
weeklyifosfamide,1.5g/mIVfromD1toD3(withmesna,750mg/mpriortoand4hafterifosfamide)
every 3 weeks pemetrexed, 500 mg/m IV on D1 every 3 weeks. For patients who are not very
symptomatic, consider hormonal therapy with tamoxifen, 20 mg twice a day, aromatase inhibitors, or
fulvestrant,250mgIMmonthly.Thechoiceoftherapyshouldbeindividualized(seeoptionsbelow).
Note. The response rates to cisplatin or carboplatin are very small in these patients. Consequently,
otherchemotherapyagentsandantiangiogenicagentsshouldbeconsidered.Ovariancancerpatientsmay
benefitfrommultiplesequentialtreatmentlines[AnnOncol23:2605,2012 ].Theroleofbevacizumabin
patientswhoareresistantorrefractorytoplatinumwasevaluatedintheAURELIAstudy.Inthistrial,361
patients were randomized to chemotherapy with paclitaxel, topotecan or PLD with or without
bevacizumab until progression or limiting toxicity [J Clin Oncol 32:1302, 2014]. Previous exposure to
bevacizumab prior to enrollment was allowed. The addition of bevacizumab led to improvement in the
responseratefrom12.6%to30.9%(p=0.001)andthedoublingoftheprogressionfreeinterval(PFI)(3.4
versus6.7monthsHR=0.4895%CI:0.380.60p<0.001)withoutimprovementinOS(13.3versus 16.6
months HR=0.85 95% CI: 0.661.08 p<0.174). However, 40% of the patients randomized to
chemotherapyalonereceivedbevacizumabsingleagentafterprogression[JClinOncol32:1302,2014 ].
Itisimportanttoemphasizethatpatientstreatedwithbevacizumab and chemotherapy presented better
qualityoflife[JClinOncol32:1309,2014].Womenwithhistoryofintestinalobstruction,abdominalfistula,
or clinical/radiological evidence of rectosigmoid involvement were excluded, which contributed to the low
incidenceofintestinalperforation(2.2%)orabdominalfistula(1.1%).PLDwasevaluatedinaphaseIIItrial
with474patientsrandomizedbetweenPLD,50mg/mIVevery4weeksversustopotecan,1.5mg/mIV
fromD1toD5every21days.Therewasan18%reductionintheriskofdeathwithPLD[Gynecol Oncol
95:1, 2004]. The PLD dose of 50 mg/m used in the phase III trial and in many phase II studies is
associated with a high incidence of handfoot syndrome. Since there is no established doseresponse
correlation for PLD, smaller doses are usually recommended (i.e., 30 to 40 mg/m every 4 weeks). A
characteristic of this agent is the longer time to clinical response compared to other cytotoxic agents.
Therefore,atleast3cyclesshouldbeperformedpriortoevaluationofresponse.Tworandomizedstudies
comparedPLDversusgemcitabineinsecondlinetreatmentanddemonstratedsimilarratesofPFSand
OS [J Clin Oncol 26:890, 2008 J Clin Oncol 25:2811, 2007 ]. Phase II studies suggest that oral
etoposideismoreefficaciousthantheintravenousformulation[JCancerResClinOncol119:55,1992].
The administration of oral etoposide is contraindicated in patients with significant gastrointestinal tract
involvement due to its erratic absorption. The dose of topotecan recommended in a phase II trial was
associatedwithahighincidenceofleukopenia,anemia,andthrombocytopenia.Sincenodoseresponse
relationshipwasestablished,therecommendeddosesare1.25mg/mIVfromD1toD5or1.5mg/mIV
from D1 to D4 every 3 weeks. A less toxic and slightly less efficacious option is the use of weekly
topotecan at the dose of 4 mg/m IV on D1, D8, and D15 every 4 weeks [J Clin Oncol 29:242, 2011
Gynecol Oncol 120:454, 2011]. In a series with 24 patients resistant to platinum, weekly singleagent
vinorelbine demonstrated 21% overall response [J Clin Oncol 14:2546, 1996]. Ifosfamide presented a
12% response at the expense of significant hematological and neurological toxicity in a study with 41
patients[JClinOncol10:243,1992].InaphaseIIstudywith51patientsresistant/refractorytoplatinum,a
21% overall response and PFS of 2.9 months were observed with pemetrexed [J Clin Oncol 27:2686,
2009 ]. A phase II study did not demonstrate any difference between the doses of 500 mg/m and 900
mg/m, except for an increased toxicity with the latter [Eur J Cancer 45:1415, 2009]. Sunitinib was
evaluatedinaphaseIItrialatthedoseof50mg/dayfor28daysevery6weekswithPFSof4.8months
and OS of 13.6 months [Ann Oncol 23:2265, 2012 ]. Hormonal therapy is another option for relapsed
patients.Ametaanalysisdemonstratedthatpatientswithhighexpressionofprogesteronereceptorhave
better prognosis [Int J Gynecol Cancer 23:25, 2013]. A randomized trial of 241 patients with disease
refractoryorresistanttoplatinumfoundanoverallresponserateof7%withtamoxifen,24%withweekly
paclitaxel,and15%withPLD.AlthoughthePFIwaslongerinthechemotherapyarms(62versus84and
99days,respectively),therewasnosignificantdifferenceinOSbetweenthearms[JClinOncol26:abstr
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99days,respectively),therewasnosignificantdifferenceinOSbetweenthearms[JClinOncol26:abstr
5508,2008].AphaseIItrialwith31patientsevaluatedfulvestrant,500mgIMonD1,followedby250mg
IM on D15 and D29, then once a month. Overall response and stable disease rates were 8% and 35%,
respectively [Gynecol Oncol 113:205, 2009]. Aromatase inhibitors have also demonstrated activity as a
single agent. A phase II trial evaluated letrozole in 42 patients and demonstrated partial response (PR)
andstablediseasein17%and26%ofthecases,respectively[ClinCancerRes13:3617,2007 ].Another
phaseIItrialthatincluded31patientswithdiseaseresistanttoplatinumandtaxanestreatedwithletrozole
reportedPRandstablediseasein3%and33%ofthecases,respectively[GynecolOncol110:56,2008].A
trialthatevaluatedexemestanein24patientsdemonstratedstablediseasein36%formorethan14weeks
[J Clin Oncol 24:abstr 5026, 2006]. Radiotherapy might be useful in patients with predominantly pelvic
recurrence[GynecolOncol69:36,1998GynecolOncol80:213,2001].
Practical tip. Prophylactic measures to decrease handfoot syndrome from PLD include the use of
comfortable shoes, avoiding contact with hot water, and the prophylactic use of hand and foot creams.
Whenever there are signs of the syndrome at the start of a cycle, administration is not recommended until
complete resolution. The following dose should be reduced and/or the interval between cycles should be
increased. Since PLD is associated with severe allergic reactions in 7% of the patients, premedication with
dexamethasone, 20 mg IV, cimetidine, 300 mg IV, and diphenhydramine, 50 mg IV is recommended. A
palliative strategy that may be useful in patients with intestinal obstruction is the use of octreotide acetate
analogues, which may even allow for the removal of nasogastric tube in a few cases [J Clin Oncol 30:4337,
2012 Bull Cancer 99:E1, 2012 ]. Another option to be considered if octreotide analogues are not
successfulisdecompressivegastrostomy[GynecolOncol129:103,2013].
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