卵巢癌内科治疗现状与进展

卵巢癌内科治疗现状与进展卵巢癌（Ovarian

Cancer）发病与预后75%

初诊为晚期（III-IV期）目前治疗>

90%

复发中位生存期

4-5

年晚期患者

5年生存率

30%*Surveillance,Epidemiology,andEndResultsprogramoftheNationalCancer

InstituteGLOBOCAN2012:

http://globocan.iarc.fr/Pages/fact_sheets_population.aspxIncidenceMortalityCancerNumber(%)ASR

(W)Number(%)ASR

(W)Ovary2387193.66.11519174.33.8Ovarian

CancerincludingFallopianTubeCancerandPrimaryPeritoneal

Cancer演示者2016-05-19

08:01:01TheNationalCancerInstituteestimates

thatmorethan22,000

womenwillbediagnosedwithovariancancersintheUnitedStatesin2007andmorethan15,000

womenwilldieofthedisease.Atotalof75%ofnewcasesarediagnosedinadvancedstage,whichisdifferentfromothercancers,particularlybreastcancer.Screeninganddetectionmethodsforthisdiseasearelimited.Thereisamorethan90%recurrenceratewithcurrenttherapies,andmediansurvivalisbetween4and5years.Thesurvivalrateafter5yearsforadvanceddiseaseis

30%.卵巢癌分期Stage

IVStageIIIStageIIStage

IAJCCFIGOOvarian

CancerincludingFallopianTubeCancerandPrimaryPeritoneal

Cancer演示者2016-05-19

08:01:01StageIovariancanceris

confinedto1orbothovaries.InstageII,thecancerhasspreadtootherpelvicorgans,suchastheuterusandfallopiantubes,butnottootherabdominalorgans.Stage

IIIovariancancerinvolvescancermetastasistoabdominalorgans,suchasabdominallymphnodes,liver,andbowel.InstageIV,thecancerhasspreadtootherdistantsites,suchaslung,brain,andlymphnodesinthe

neck.Thesurvivalrateforovarian

cancerisstronglyassociatedwithdiseasestageatdiagnosis.TheSurveillance,Epidemiology,andEndResults(SEER)surveyreportedrelativesurvivalrates

bystageatdiagnosisfrom1988to2003.Thesurvivalrateforovary-confinedstageIdiseaseisverygood,butdramaticallydecreasesforstageIIIandIVdisease.Amongthedifferenthistologicaltypesofovariancancer,whichincludeserous,mucinous,endometrioid,andclearcell,70%ofserous-typetumorsarediagnosedinadvancedstagewhereas50%ofmucinousandclearcelltypesarediagnosedinstage

I.JelicS,etal.2002CongressoftheEuropeanSocietyforMedicalOncology.MocharnukR.Availableat:

/viewarticle/444134.StageIIIIIIIVDescriptionConfined

toovariesConfinedto

pelvisConfinedtoabdomen/lymphnodesDistant

metastases比例20%5%58%17%5年生存率73%45%21%<

5%80706050403020100IIIIIIIV卵巢癌初诊时分期与预后诊断时分期根据组织学类型GilksCB,etal.ModPathol.2009;22(suppl1s):215A(abstract

979)分期透明细胞癌内膜样癌粘液性癌低级别浆液性癌高级别浆液性癌癌NOSI-II26.2%29.4%8.5%1.9%30%4.0%III-IV4.9%3.5%1.1%4.9%84.2%1.4%All10.4%10.3%3.6%3.5%70%2.1%NCCN指南

Completion

surgery/surgical

stagingNCCN指南 化疗方案5-year

survivalratelog-rank:

p<0.0001ThreeRandomizedPhaseIIITrialswith3126

Patients75%100%0TTiimmee,(mMoonntthhs)s0mmHR(95%CI)2.70 (2.37,

3.07)1.34 (1.21,

1.49)手术残留肿瘤（RT）对预后的影响OverallSurvival,

%1mm–10mmvs0

mm>10mmvs1mm–10

mmLog-rank:

P<.0011mm–10

mm>10mm12 24 36 48 60 72 84 96 108 120 132 144duBoisA,etal.Cancer.

2009;115(6):1234-1244.50%25%0%duBoisA,etal.Cancer.

2009;15(6):1234-1244.A0.37(0.30;

0.47)0.36(0.31;

0.42)0.49(0.34;

0.70)nyresidual

tumor”完全切除是肿瘤分期独立的预后因素InitialFIGO

Stage无残留病灶 有残留病灶HR(95%

CI)中位生存期,月+60.3

months+46.9

months+30.0

monthsFIGO

IIB-IIIBFIGO

IIICFIGO

IV108.6 48.381.1 34.254.6 24.6HR=Hazardratio,referenceclassforHRis

“NCCN指南EORTC55955:

复发 早期治疗与延时治疗Ovariancancerincompleteremissionafterfirst-lineplatinum-based

chemotherapyandanormal

CA125CA125>2xupperlimitof

normalRANDOMIZEDEarlytreatmentClinicianandpatient

informedDelayedtreatmentCliniciannotinformed,treatmentdelayeduntilclinically

indicatedREGISTERBlindedCA125measuredevery3

monthsRustinGJS,etal.Lancet.

2010;376(9747):1155-1163.计划入组:

1400目标:

OS,

TFS,

QoL00.500.250.751.00ProportionAliveNotStarted

Second-LineChemotherapyEarly265231614111110109Delayed264177116916956494233PatientsatRisk,

n036 9 12

15

18

21

24MosSince

Randomization何时化疗？Median,

MosEarlyDelayed0.85.6HR:0.29(95%CI:0.24-0.35;P<

.00001)RustinG,etal.ASCO2009.

Abstract1.随机到二线治疗时间RustinGJS,etal.Lancet.

2010;376(9747):1155-1163.RustinG,etal.ASCO2009.

Abstract1.Early265247211165131947251383122Delayed2642362031671291036953383119PatientsatRisk,

nProportion

SurvivingHR:1.00(95%CI:0.82-1.22;P=

.98)6 12

18

24

30

36

42

48

54

60MosSince

RandomizationAbsdiffat2yrs:

-0.1%(95%CIdiff:-6.8,

6.3%)EarlyDelayed00.750.500.251.000生存期注意：需由外科医师判断有否二次减瘤指证RustinGJS,etal.Lancet.

2010;376(9747):1155-1163.I/II期经手术+化疗

几乎所有患者可获临床CR– 20%-25%

复发理想减瘤

III期>

90%

获得临床

CR– 75%

复发次理想减瘤

III-IV期50%

获得临床

CR– >

90%

复发复发性卵巢癌: 临床问题EndofFrontlineTherapy0

Mos 6Mos 12

MosPrimaryTreatmentRefractoryResistantSensitive复发：铂敏感与铂耐药Partiallyplatinum-sensitiveFullyplatinum-sensitive复发卵巢癌:

无铂间期与生存期0-3

Prog0-3

Non-PD3-12

Mos12-18

Mos18+

MosPFS,

days90176174275339OS,

days217375375657957Response,

%924355262DaysPercentagePujade-LauraineE,etal.ASCO2002.Abstract

829.100090080070060050040030020010001009080706050403020100Months基于PFS1复发后生存期差异(到复发/进展

0-6月

vs

6-12月 vs

12+

月)0-6months(558patients/511

deaths)medianOS8.1

months6-12months(641/567)medianOS14.5

months12+months(889/528)medianOS24.8

monthslogrank

P<.0001AndreasduBois

20078+6+10

month复发后治疗的选择Fullyplatinum-sensitive>12

MonthsCarboplatincombination

(PLD,Gemcitabine,or

Paclitaxel)Platinum-resistant<6

MonthsNon-platinumsingle

agentPartiallyplatinum-sensitive6–12

MonthsOptions:PLD+CarboplatinPLD+

TrabectedinPLD,pegylatedliposomal

doxorubicinNCCN指南DiesisteineÜberschriftÜber

maximalzwei

ZeilenDr.Max

Müller-Mustermann

+

©

AdB2016卵巢癌复发患者个体化治疗时代-治疗路线图DiesisteineÜberschriftÜber

maximalzwei

ZeilenDr.Max

Müller-MustermannPFS-奥拉帕尼

治疗BRCA1/2

突变

*ThegreatestPFSbenefitwasobservedinpatientswitha

BRCA1/2mutation

(BRCAm)

which

was

present

in

136

of

the

265

enrolled

pts.*Includes

patients

with

germline

and/or

somatic

mutations;

†patients

were

treated

until

disease

progressionLedermannetal.LancetOncol.

2014;15(8):852–861©

AdB2016DiesisteineÜberschriftÜber

maximalzwei

ZeilenDr.Max

Müller-MustermannPLD

+CarboplatinGemcitabine

+Carboplatin

+BevacizumabPaclitaxel

+Carboplatin

+BevacizumabPlatinum

regimefollowed

byOlaparibPFSCC>

TCOSCC=

TCPFSCGB>

CGOSCGB=

CGPFSTCB>

TCOSTCB=

TCPFSPt.+Ola>

Pt.OS

n.s.Schedule:d1

q4

wSchedule:d1+8

q3

w→d1

q3Schedule:d1q

3w+

maintenanceSchedule:d1q3

w+

maintenanceSkin/mucosaHematotoxicityInfection

G3JointpainAlopeciaNeurotoxicityofPt.

Regime+Fatigue

NauseaAnemiaAlopecia

7%Hypertension

20%QoL

identicalQoL

?QoL

identicalQoL

identicalsuperiorsuperiorsuperiorsuperior©

AdB2016Paclitaxel

+CarboplatinGemcitabine

+CarboplatinPLD

+CarboplatinGemcitabine

+Carboplatin

+BevacizumabPaclitaxel

+Carboplatin

+BevacizumabPlatinum

regimefollowed

byOlaparibPFSTC>

COSTC>

CPFSCG>COS

?PFSCC>

TCOSCC=

TCPFSCGB>

CGOSCGB=

CGPFSTCB>

TCOSTCB=

TCPFSPt.+Ola>

Pt.OS

n.s.Schedule:

d1q3

wSchedule:

d1+8q3

wSchedule:

d1q4

wSchedule:

d1+8q3

w→d1

q3Schedule:

d1q3

w+

maintenanceSchedule:

d1q3

w+

maintenanceNeurotoxicityHematotoxicitySkin/mucosaHematotoxicityInfection

G3JointpainAlopeciaNeurotoxicityofPt.

Regime+Fatigue

NauseaAnemiaAlopecia

86%Alopecia

15%Alopecia

7%Hypertension

20%QoL

identicalQoL

identicalQoL

identicalQoL

?QoL

identicalQoL

identical复发性卵巢癌 铂类方案

比较DiesisteineÜberschriftÜber

maximalzwei

ZeilenDr.Max

Müller-Mustermann化疗联合贝伐单抗可增加有效率的症状控制耐药复发和敏感复发卵巢癌©

AdB2016卵巢癌的分子分型LGSOCKRASBRAFMucinousKRASType

IIHGSOCTP53/RB

pathwayBRCA1/2ChromosomalinstabilityDISTINCT

DISEASES WITHDIFFERENTDRIVER

ALTERATIONSPatientselectionbasedonrobustpredictive

biomarkers=keyto

success!!!!!LGSOC,lowgradeserousovariancarcinoma;HGSOC,highgradeserousovarian

carcinomaDespierreE,etal.IntJGynecolCancer.

2014;24:468-477.Type

IEndometrioidPTENPIK3CACTNNBClearCellPIK3CA

ARID1A卵巢癌常见5种类型High-GradeSerousMucinousLow-GradeSerousUsualstage

atdiagnosisAdvancedClear

Cell

EndometrioidEarly EarlyEarlyEarlyoradvancedPresumedtissueoforigin/precursorlesionFallopiantubeor

tubalmetaplasiaininclusionsof

OSEEndometriosis,adenofibromaEndometriosis,adenofibromaAdenoma-borderline-carcinomasequence;teratomaSerousborderlinetumorGenetic

riskSignificantmolecularBRCA

1/2?HNPCCPTEN,??p53and

pRbHNF-1ββ-Catenin,KRASBRAF

orabnormalities pathwayARID1AKRAS

MI,ARID1AKRASProliferation HighLowLowIntermediateLowResponsetoprimary 80%15%?15%26-28%chemotherapyPrognosis PoorIntermediateFavorableFavorableFavorable卵巢癌靶向治疗研究Angiogenesis(novalidated

predictors)PARPinhibitors(high-gradeserous-

HRD)RAS-MEKpathway(low-grade

serous)ADC(Folatereceptor,

NaPib2,

..) (allepithelialov

ca)EGFR(erlotinibnegativeinfirst

line)ErbB3(eg,pertuzumab,...)(LowHER3mRNA

expression)PI3K/AKT/mTOR(PI3K:Clear

cell)P53(high-grade

serous)Targetingcell

cycleImmuno-oncology,eg,

anti-PD-1/PD-L1VariationoftheSumoftheLongestDiameter,

%120100806040200-20-40-60-80-100CR,completeresponse;PR,partial

responseDisisML,etal.JClinOncol.2015;33(Suppl):Abstract.5509.VargaA,etal.JClinOncol.2015;33(Suppl):Abstract

5510.PR

(RECIST)PR

(irRC)Clear

cellAtumorsizedecrease

≥30%hasbeenobservedin

11/75patients(14.7%)PhaseIbTrial

ofAvelumab(anti-PD-L1)KEYNOTE-028:MulticohortPhaseIbTrialofPembrolizumab(a