卵巢癌化療進(jìn)展

1、會計學(xué)1卵巢癌化療進(jìn)展卵巢癌化療進(jìn)展Cervical470,000230,000Endometrial189,00045,000Ovarian192,000114, 牛牛文庫文檔分享 牛牛文庫文檔分享Women發(fā)病率發(fā)病率32%Breast12%Lung & bronchus11%Colon & rectum6%Uterine corpus4%Ovary 4%Non-Hodgkin lymphoma 3%Melanomaof skin3%Thyroid2%Pancreas2%Urinary bladder20%All Other Sites死亡率死亡率25%Lung &

2、 bronchus15%Breast11%Colon & rectum6%Pancreas5%Ovary4%Non-Hodgkinlymphoma4%Leukemia3%Uterine corpus2%Brain/ONS2%Multiple myeloma23%All other sitesCancer Facts & Figures,ACSO, 牛牛文庫文檔分享Incidences of Gynecological Cancers in Shanghai Citizens(1974-2000)4.86.510.5051

3、0152025301974199419972000YearIncidences ( /100,000)Ovarian CancerCervical Cacner Endometrial Cancer上海市居民卵巢癌、宮頸癌、宮體癌發(fā)病率上海市居民卵巢癌、宮頸癌、宮體癌發(fā)病率（1974-2000，SCDC） 牛牛文庫文檔分享 牛牛文庫文檔分享(3040% 復(fù)發(fā)率)Grade 1 (or 2)Grade 3Clear cell cancer結(jié)果6個療程進(jìn)展危險性降低了33% 生存率無改善隨機(jī)臨床試驗無立即化療 vs 立即化療結(jié)果立即化療 生存率提高8% vs復(fù)發(fā)時化療(82% vs 74%) 牛牛

4、文庫文檔分享準(zhǔn)確全面分期依據(jù)手術(shù)探查和 病理組織學(xué)、細(xì)胞學(xué)檢查根據(jù)腹腔內(nèi)轉(zhuǎn)移灶的大小對III期再分為IIIa、IIIb、IIIc腹膜后淋巴結(jié)轉(zhuǎn)移影響分期肝表面和肝實質(zhì)轉(zhuǎn)移分屬III期和IV期 Stage I: 局限于卵巢 Stage II: 局限于盆腔 Stage III: 局限于腹腔 Stage IV: 遠(yuǎn)處轉(zhuǎn)移 牛牛文庫文檔分享Armstrong D, et al. N Engl J Med 2006;354:34-43 .Isonishi S, et al. the Lancet 2009; 374:1331-3819GOG111(N=410)-期環(huán)磷酰胺環(huán)磷酰胺750mg/m2順鉑順鉑

5、75mg/m2泰素泰素35mg/m2(24h)順鉑順鉑75mg/m2VSORR: 73% 60% p=0.01CR: 51% 31% p=0.01PFS: 18mo 13mo p=0.001OS: 38mo 24mo p=0.001毒性毒性: 泰素泰素/順鉑組有較多的血液學(xué)順鉑組有較多的血液學(xué)毒性和神經(jīng)毒性，但毒性可控毒性和神經(jīng)毒性，但毒性可控OV10(N=688)-期環(huán)磷酰胺環(huán)磷酰胺750mg/m2順鉑順鉑75mg/m2泰素泰素175mg/m2(3h)順鉑順鉑75mg/m2ORR: 77% 66% p=0.01CR: 50% 36% p=0.01PFS: 16.6mo 12mo p=0.00

6、05OS: 35mo 25mo p=0.0016毒性毒性: 泰素泰素/順鉑組有較多的血液學(xué)毒順鉑組有較多的血液學(xué)毒性和神經(jīng)毒性，但毒性可控性和神經(jīng)毒性，但毒性可控VSJ Natl Cancer Inst 2000;92:699708McGuire, et al. N Engl J Med 1996 334:1-6Epithelial Ovarian Cancer Optimal Stage III No prior therapy Elective Second-Look Non-Inferiority Design56.7 vs 48.8 m = 7.9 mOptimalStage IIIN

7、A50%21 months59 monthsSuboptimalIII & IV75%25%18 months30 months25Michael A Bookman, MDFox Chase Cancer CenterPhiladelphia, PAProc ASCO 2005:Abstract 500226R A N D O M I Z ECarboplatin AUC 5 (d1)Paclitaxel 175 mg/m2 (d1)Doxil 30 mg/m2 (d1, every other cycle)Carboplatin AUC 6 (d1)Paclitaxel 175 m

8、g/m2 (d1)Carboplatin AUC 6 (d1)Paclitaxel 175 mg/m2 (d1)Carboplatin AUC 6 (d8)Gemcitabine 1 g/m2 (d1,8)Carboplatin AUC 5 (d3)Topotecan 1.25 mg/m2 (d1-3)Carboplatin AUC 5 (d1)Paclitaxel 175 mg/m2 (d1)Gemcitabine 800 mg/m2 (d1,8)Median PFS and HR (95% CI)16.1 1.00016.4 0.990 (0.884-1.107)16.4 0.998 (0

9、.891-1.117)15.3 1.094 (0.979-1.224)15.4 1.052 (0.940-1.176)Median OS and HR (95% CI)40.0 1.00040.4 0.978 (0.838-1.141)42.8 0.972 (0.832-1.136)39.1 1.068 (0.918-1.244)40.2 1.035 (0.888-1.206)29Proc ASCO 2005:Abstract 500231Cisplatin 75 mg/m2Paclitaxel 135 mg/m2 (24 h)Cisplatin 100 mg/m2 IP d1Paclitax

10、el 135 mg/m2 (24 h) IV d1Paclitaxel 60 mg/m2 IP d8Armstrong, et al. NEJM 354:34-43, 200633Arm 1Arm 1（ IV IV組）組）Arm 2Arm 2（ IP IP組）組）中位中位PFS PFS （p=0.05p=0.05）18.318.3月月23.823.8月月中位中位OSOS（p=0.03p=0.03）49.749.7月月65.665.6月月毒副反應(yīng)（毒副反應(yīng)（p0.001p12個月復(fù)發(fā)個月復(fù)發(fā)0 67 1213 18 18020406080100距前次治療的時間（月）距前次治療的時間（月）有效率有

11、效率 (%)Blackledge, et al. Br J Cancer. 1989;59:650-653. 分類分類 目標(biāo)目標(biāo) 治療無效治療無效 緩解緩解( 6, 12 個月個月) 治愈治愈?單藥治療單藥治療鉑類鉑類79834.531 38紫杉醇類紫杉醇類1,31632.530 35聯(lián)合治療聯(lián)合治療紫杉醇類為主或有鉑類紫杉醇類為主或有鉑類31548.947 55鉑類為主鉑類為主91453.650 57紫杉醇類和鉑類紫杉醇類和鉑類21155.648 62無紫杉醇類和鉑類無紫杉醇類和鉑類39922.819 27但是但是, 這個問題在一個這個問題在一個RCT即可解決即可解決!Pfisterer e

12、t al. J Clin Oncol 2006;24(29):4699-4707.隨隨機(jī)機(jī)健擇 1000 mg/m2 d1,8 + 卡鉑 AUC 4 d1, 每3周方案卡鉑 AUC=5 d1, 每3周方案356例對鉑類敏感復(fù)發(fā)的卵巢癌患者根據(jù)以下因素分層：最后一次含鉑治療間隔 (6-12 或12 月)含鉑一線方案( 紫杉醇)有可測量病灶月無疾病進(jìn)展生存概率0.01.00612182430364248Log-rank p-value = .0031卡鉑組：中位卡鉑組：中位 5.8月月95%CI, 5.27.1月月健擇健擇 /卡鉑卡鉑組：中位組

13、：中位 8.6月月 95%CI, 7.99.7月月 卡鉑組178例162例進(jìn)展事件；健擇/卡鉑組178例163例進(jìn)展事件Pfisterer et al. J Clin Oncol 2006;24(29):4699-4707.1Pfisterer et al. J Clin Oncol 2006;24(29):4699.2Pfisterer et al. Int J Gynecol Cancer 2005;15(Suppl 1):36-41.健擇健擇/卡鉑治療復(fù)發(fā)卵巢癌的卡鉑治療復(fù)發(fā)卵巢癌的III期臨床試驗期臨床試驗各個方案的毒副作用不同：各個方案的毒副作用不同：卡鉑卡鉑- -紫杉醇：神經(jīng)毒性紫

14、杉醇：神經(jīng)毒性卡鉑卡鉑- -多西紫杉醇：血液性毒性多西紫杉醇：血液性毒性卡鉑卡鉑- -吉西他濱：血液性毒性吉西他濱：血液性毒性順鉑順鉑- -吉西他濱：血液性毒性吉西他濱：血液性毒性手術(shù)手術(shù)手術(shù)few selected pts. few selected pts. few selected pts. (e.g. bowel obstruction)(e.g. bowel obstruction)(e.g. bowel obstruction)內(nèi)分泌內(nèi)分泌內(nèi)分泌 TX TX TXSelected pts.,Selected pts.,Selected pts.,rather 3rd/4th lin

15、e ? rather 3rd/4th line ? rather 3rd/4th line ? 支持治療支持治療支持治療every pt. as neededevery pt. as neededevery pt. as needed放療放療放療few selected pts.few selected pts.few selected pts.心理心理心理- - -社會支持社會支持社會支持every pt. as neededevery pt. as neededevery pt. as needed“ “ “新藥新藥新藥“ “ “only in clinical trialsonly in

16、 clinical trialsonly in clinical trials鉑類為主治療鉑類為主治療鉑類為主治療mainly pt-sensitive ROCmainly pt-sensitive ROCmainly pt-sensitive ROCFrom Dr. Andreas du Bois有效率有效率 隨機(jī)臨床試驗，隨機(jī)臨床試驗，0 6個月個月紫杉醇紫杉醇 1,4 n = 90拓泊替康拓泊替康 1,2,4 n = 259 楷萊楷萊 3n = 130奧沙利鉑奧沙利鉑 4 n = 1321 ten Bokkel JCO 1997 2 Gore EJC 2002 3 GordonJCO 2

17、001 4 Piccart JCO 2000%有效率有效率 隨機(jī)臨床試驗，隨機(jī)臨床試驗， 6個月個月紫杉醇紫杉醇 1,4 n = 90拓泊替康拓泊替康 1,2,4 n = 259楷萊楷萊 3 n = 109奧沙利鉑奧沙利鉑 4 n = 1321 ten Bokkel JCO 1997 2 Gore EJC 2002 3 GordonJCO 2001 4 Piccart JCO 2000%Randomised Studies in Recurrent OC: Studies Pts. mono- vs. mono chemotherapy 10 2.195 mono: schedule/dose

18、/application 7 1.614 mono- vs. endocrine therapy 2 303 endocrine vs. endocrine therapy 2 106 combination vs. combination 2 107 mono vs. combination* 14 3.499 all: 37 7.924* Including 1 trial with multiple regimens according to testing; most other trials in pts. with platinum sensitive relapseRPaclit

19、axel 175 mg/m 3h q21Paclitaxel 175 mg/mEpirubicin 80 mg/m q21Buda A 2004, Br J Cancer106 pts. 12 mos.106 pts.results: OR 47% vs. 37% (combi), PFS 6 vs. 6 mos. OS 14 vs. 12 mos. (n.s.)RTopotecan 1.25 mg/m d1-5 q21Topotecan 1.0 mg/m d1-5 Etoposid 50 mg po d 6-12 q21Sehouli J 2008, JCO178 pts.177 pts.r

20、esults: OR 36% (TE) vs. 32% (TG) vs. 28 % (Topo) mean PFS 15 vs. 13 vs. 13 months (n.s.)mean OS 23 vs. 18 vs. 24 months (n.s.)Topotecan 0.5 - 0.75 mg/m d1-5 Gemcitabine 800 mg/m d1 + 600 mg/m d8 q21app. 20% refractory41% 12 Mon.147 pts.mono vs. combination chemotherapy in refractory recurrent OCTrab

21、ectedin+PLD4.0 mosPLD3.7 mosPFS events: 163HR: 0.95 (0.70-1.30)P = 0.7540 by courtesy of BJ Monk et al (Email: )mono vs. combination chemotherapy in refractory recurrent OCRDoxil/Caelyx (PLD) 50 mg/m q28Trabectedin 1.1 mg/m q 21 +Doxil/Caelyx (PLD) 30 mg/m q28BJ Monk et all , ESMO 20081

22、18 pts.113 pts.results: OR 12,2% vs 13,4% (combi; n.s.), PFS/OS n.s.手術(shù)手術(shù)手術(shù)few selected pts. few selected pts. few selected pts. (e.g. bowel obstruction)(e.g. bowel obstruction)(e.g. bowel obstruction)內(nèi)分泌內(nèi)分泌內(nèi)分泌 TX TX TXSelected pts.,Selected pts.,Selected pts.,rather 3rd/4th line ? rather 3rd/4th lin

23、e ? rather 3rd/4th line ? 支持治療支持治療支持治療every pt. as neededevery pt. as neededevery pt. as needed放療放療放療few selected pts.few selected pts.few selected pts.心理心理心理- - -社會支持社會支持社會支持every pt. as neededevery pt. as neededevery pt. as needed“ “ “新藥新藥新藥“ “ “only in clinical trialsonly in clinical trialsonly i

24、n clinical trials目前尚無足夠證據(jù)支持鉑類為主治療鉑類為主治療鉑類為主治療mainly pt-sensitive ROCmainly pt-sensitive ROCmainly pt-sensitive ROCFrom Dr. Andreas du BoisRandomised Studies in Recurrent OC: Studies Pts. mono- vs. mono chemotherapy 10 2.195 mono: schedule/dose/application 7 1.614 mono- vs. endocrine therapy 2 303 en

25、docrine vs. endocrine therapy 2 106 combination vs. combination 2 107 mono vs. combination* 14 3.499 all: 37 7.924* Including 1 trial with multiple regimens according to testing; most other trials in pts. with platinum sensitive relapse65復(fù)復(fù)發(fā)發(fā)或或耐耐藥藥的的卵卵巢巢癌癌癌癌患患者者泰素泰素80mg/m2, 每周給藥，連續(xù)每周給藥，連續(xù)3周，周，休息一周，至

26、少兩休息一周，至少兩周期。周期。66RTopotecan 1,5 mg/m iv d1-5 q21Caelyx 50 mg/m iv q28Gordon 2001, J Clin Oncol 2004, Gynecol Oncol235 pts.55% Pt.-refractory, 70% prior taxans239 pts.Results platinum refractory subgroup:Caelyx (130)Topotecan (124) p-valuePFS (weeks, median) 9,1 13,1 0.733OS (weeks, median) 36 41 0.

27、455 G3/4 toxicity (all pts.;%) Neutropenia 12 77 0.001Anemia 5 28 0.001Thrombocytopenia 1 34 0.001Leukopenia 10 50 0.001Treatment-related sepsis 0 4 0.001Alopecia (all grades) 16 49 0.007Hand-Foot-Syndrom 23 0 0.001Stomatitis 8 0.4 0.001mono vs. mono chemotherapy in recurrent (mostly) refractory OC

28、- RCTsRGemcitabine 1000 mg/m d1+8 q21Caelyx 50 mg/m d1 q28Mutch, JCO 200799 pts.96 pts.Results:mono vs. mono chemotherapy in recurrent (mostly) refractory OC - RCTs66 pts.64 pts.ParameterCAELYX(n=96)Gemcitabine (n=99)ORR (pts w/ measurable disease) median PFSmedian OS8%3.1 mos.13.5 mos.6%3.6 mos.12.

29、7 mos.Toxicity Neutropenia, grade 3/4 Constipation, grade 2-4 N/V, grade 2-4 HFS, grade 2/3 Mucositis, grade 2/318%9%12%19%*15%*38%*25%*28%*-3%*Statistically significant.Mutch DG, et al. J Clin Oncol 2007;25(19):2811-2819.Results:OR 16% vs. 18% (Gem), OR duration 18 vs. 17 (Gem) weeks ; n.s.QoL adva

30、ntage for caelyx in 2 of 4 time points (p 0.05)RGemcitabine 1000 mg/m d1,8, 15 q28Caelyx 40 mg/m d1 q28Mito-3G Ferrandina et al JCO 200877 pts.100% platinum-taxan, TFI 12 mos. (57% 6 mos.)76 pts.mono vs. mono chemotherapy in recurrent (mostly) refractory OC - RCTs手術(shù)手術(shù)手術(shù)few selected pts. few selected

31、 pts. few selected pts. (e.g. bowel obstruction)(e.g. bowel obstruction)(e.g. bowel obstruction)內(nèi)分泌內(nèi)分泌內(nèi)分泌 TX TX TXSelected pts.,Selected pts.,Selected pts.,rather 3rd/4th line ? rather 3rd/4th line ? rather 3rd/4th line ? 支持治療支持治療支持治療every pt. as neededevery pt. as neededevery pt. as needed放療放療放療few

32、 selected pts.few selected pts.few selected pts.心理心理心理- - -社會支持社會支持社會支持every pt. as neededevery pt. as neededevery pt. as needed“ “ “新藥新藥新藥“ “ “only in clinical trialsonly in clinical trialsonly in clinical trials目前尚無足夠證據(jù)支持鉑類為主治療鉑類為主治療鉑類為主治療mainly pt-sensitive ROCmainly pt-sensitive ROCmainly pt-sensitive ROCFrom Dr. Andreas du Bois二線治療二線治療一線治療一線治療一線治療一線治療三線治療三線治療12 個月個月3 個月個月3 個月個月STOPSTOP二線治療二線治療3 個月個月3 個月個月 牛牛文庫文檔分享Scarfone et al 2002,Milan, Italy; n=1631III-