卵巢癌內(nèi)科治療現(xiàn)狀與進(jìn)展

卵巢癌內(nèi)科治療現(xiàn)狀與進(jìn)展卵巢癌（Ovarian

Cancer）發(fā)病與預(yù)后75%

初診為晚期（III-IV期）目前治療>

90%

復(fù)發(fā)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卵巢癌初診時(shí)分期與預(yù)后診斷時(shí)分期根據(jù)組織學(xué)類型GilksCB,etal.ModPathol.2009;22(suppl1s):215A(abstract

979)分期透明細(xì)胞癌內(nèi)膜樣癌粘液性癌低級(jí)別漿液性癌高級(jí)別漿液性癌癌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 化療方案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)手術(shù)殘留腫瘤（RT）對(duì)預(yù)后的影響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”完全切除是腫瘤分期獨(dú)立的預(yù)后因素InitialFIGO

Stage無殘留病灶 有殘留病灶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:

復(fù)發(fā) 早期治療與延時(shí)治療Ovariancancerincompleteremissionafterfirst-lineplatinum-based

chemotherapyandanormal

CA125CA125>2xupperlimitof

normalRANDOMIZEDEarlytreatmentClinicianandpatient

informedDelayedtreatmentCliniciannotinformed,treatmentdelayeduntilclinically

indicatedREGISTERBlindedCA125measuredevery3

monthsRustinGJS,etal.Lancet.

2010;376(9747):1155-1163.計(jì)劃入組:

1400目標(biāo):

OS,

TFS,

QoL00.500.250.751.00ProportionAliveNotStarted

Second-LineChemotherapyEarly265231614111110109Delayed264177116916956494233PatientsatRisk,

n036 9 12

15

18

21

24MosSince

Randomization何時(shí)化療？Median,

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

.00001)RustinG,etal.ASCO2009.

Abstract1.隨機(jī)到二線治療時(shí)間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：需由外科醫(yī)師判斷有否二次減瘤指證RustinGJS,etal.Lancet.

2010;376(9747):1155-1163.I/II期經(jīng)手術(shù)+化療

幾乎所有患者可獲臨床CR– 20%-25%

復(fù)發(fā)理想減瘤

III期>

90%

獲得臨床

CR– 75%

復(fù)發(fā)次理想減瘤

III-IV期50%

獲得臨床

CR– >

90%

復(fù)發(fā)復(fù)發(fā)性卵巢癌: 臨床問題EndofFrontlineTherapy0

Mos 6Mos 12

MosPrimaryTreatmentRefractoryResistantSensitive復(fù)發(fā)：鉑敏感與鉑耐藥Partiallyplatinum-sensitiveFullyplatinum-sensitive復(fù)發(fā)卵巢癌:

無鉑間期與生存期0-3

Prog0-3

Non-PD3-12

Mos12-18

Mos18+

MosPFS,

days90176174275339OS,

days217375375657957Response,

%924355262DaysPercentagePujade-LauraineE,etal.ASCO2002.Abstract

829.100090080070060050040030020010001009080706050403020100Months基于PFS1復(fù)發(fā)后生存期差異(到復(fù)發(fā)/進(jìn)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復(fù)發(fā)后治療的選擇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卵巢癌復(fù)發(fā)患者個(gè)體化治療時(shí)代-治療路線圖Diesisteineüberschriftüber

maximalzwei

ZeilenDr.Max

Müller-MustermannPFS-奧拉帕尼

治療BRCA1/2

突變

*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復(fù)發(fā)性卵巢癌 鉑類方案

比較Diesisteineüberschriftüber

maximalzwei

ZeilenDr.Max

Müller-Mustermann化療聯(lián)合貝伐單抗可增加有效率的癥狀控制耐藥復(fù)發(fā)和敏感復(fù)發(fā)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卵巢癌常見5種類型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卵巢癌靶向治療研究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