卵巢癌化疗新进展-中山大学肿瘤医院

1、卵巢癌化疗新进展卵巢癌化疗新进展The state of the art in chemotherapy for ovarian cancers复旦大学附属肿瘤医院妇瘤科复旦大学附属肿瘤医院妇瘤科 Cervical470,000230,000Endometrial189,00045,000Ovarian192,000114,000Women发病率发病率32%Breast12%Lung & bronchus11%Colon & rectum6%Uterine corpus4%Ovary 4%Non-Hodgkin lymphoma 3%Melanomaof skin3%Thyro

2、id2%Pancreas2%Urinary bladder20%All Other Sites死亡率死亡率25%Lung & bronchus15%Breast11%Colon & rectum6%Pancreas5%Ovary4%Non-Hodgkinlymphoma4%Leukemia3%Uterine corpus2%Brain/ONS2%Multiple myeloma23%All other sitesCancer Facts & Figures,ACSO,2003美国卵巢癌流行病学特征美国卵巢癌流行病学特征Incidences of Gynecologica

3、l Cancers in Shanghai Citizens(1974-2000)4.86.510.50510152025301974199419972000YearIncidences ( /100,000)Ovarian CancerCervical Cacner Endometrial Cancer上海市居民卵巢癌、宫颈癌、宫体癌发病率上海市居民卵巢癌、宫颈癌、宫体癌发病率（1974-2000，SCDC）1.1. 早期卵巢癌化疗早期卵巢癌化疗2.2. 中晚期卵巢癌化疗中晚期卵巢癌化疗3.3. 新辅助化疗新辅助化疗/ /中间手术中间

4、手术4.4. 复发性卵巢癌化疗复发性卵巢癌化疗5.5. 维持维持 巩固治疗巩固治疗6. Ca125升高处理升高处理l 未治患者未治患者主要目的是治愈主要目的是治愈手术分期和细胞减灭术，继而紫杉醇手术分期和细胞减灭术，继而紫杉醇/ /铂类联合化疗铂类联合化疗l 复发患者复发患者主要目的是减轻症状和提高生活质量主要目的是减轻症状和提高生活质量化疗可以延长生存时间化疗可以延长生存时间l 最终结果最终结果长期存活长期存活: 25-30%: 25-30%5-5-年年 生存率从生存率从 30% (1970s) 30% (1970s) 提高至提高至 50%50%l 全面的分期剖腹探查术全面的分期剖腹探查术经

5、腹全子宫经腹全子宫/ /双侧卵巢输卵管切除双侧卵巢输卵管切除 (TAH/BSO) (TAH/BSO)大网膜切除大网膜切除淋巴结切除术（淋巴结切除术（dissectiondissection）腹膜和膈膜活检（腹膜和膈膜活检（ biopsies biopsies）细胞学检查细胞学检查l 高危高危 vsvs 低危早期卵巢癌低危早期卵巢癌(510% 复发率复发率)(3040% 复发率复发率)Grade 1 (or 2)Grade 3Clear cell cancer辅助化疗的随机临床试验辅助化疗的随机临床试验:3 vs 6 疗程疗程紫杉醇紫杉醇 + 卡铂卡铂结果结果6个疗程个疗程进展危险性降低了进展危

6、险性降低了33% 33% 生存率无改善生存率无改善随机临床试验随机临床试验无立即化疗无立即化疗 vs 立即化疗立即化疗结果结果立即化疗立即化疗 生存率提高生存率提高8%8% vs复发时化疗复发时化疗(82% vs 74%)III盆腔外腹膜种植和盆腔外腹膜种植和/ /或外阳性腹膜后或腹股沟淋巴或外阳性腹膜后或腹股沟淋巴结结A A 病灶大致局限于真骨盆病灶大致局限于真骨盆; ; 淋巴结阴性淋巴结阴性; ;镜下腹腔种植镜下腹腔种植B B 腹腔种植灶腹腔种植灶 2 cm; 2 cm; 淋巴结阴性淋巴结阴性C C 腹腔种植灶腹腔种植灶 2 cm 2 cm 和和/ /或或阳性腹膜后淋巴结或腹股沟阳性腹膜后

7、淋巴结或腹股沟IVIV远处转移远处转移准确全面分期依据手术探查和准确全面分期依据手术探查和 病理组织学、细胞学检查病理组织学、细胞学检查根据腹腔内转移灶的大小对根据腹腔内转移灶的大小对III期再分为期再分为IIIa、IIIb、IIIc腹膜后淋巴结转移影响分期腹膜后淋巴结转移影响分期肝表面和肝实质转移分属肝表面和肝实质转移分属III期期和和IV期期 Stage I: 局限于卵巢局限于卵巢 Stage II: 局限于盆腔局限于盆腔 Stage III: 局限于腹腔局限于腹腔 Stage IV: 远处转移远处转移l GOG 1111 and OV-102 Cisplatin + paclitaxel

8、 vs cisplatin + cyclophosphamide Improved survival and progression-free survival withcisplatin + paclitaxel l GOG 1323 Cisplatin vs paclitaxel vs cisplatin + paclitaxel No statistaical difference in overall survivall ICON-34 Carboplatin + paclitaxel vs carboplatin or CAP(cyclophosphamide + doxorubic

9、in + cisplatin) No statistical difference in survivall GOG 1585; AGO-OVAR6 Carboplatin + paclitaxel preferred combination overcisplatin + paclitaxell ICON-5-GOG182 （2006） Carboplatin + paclitaxel vs Gemcitabin triplet vs Doxil Triplet vs Topotecan duble + TP vs Gemcitabin dublet + TP(cyclophosphamid

10、e + doxorubicin + cisplatin) No statistical difference in survivall GOG 172 （2006） cisplatin + paclitaxel iv/ip preferred combination overcisplatin + paclitaxel ivl JGOG （2009） Carboplatin （d1）+ paclitaxel 80mg weekly perferred Carboplatin + paclitaxel Armstrong D, et al. N Engl J Med 2006;354:34-43

11、 .Isonishi S, et al. the Lancet 2009; 374:1331-3819GOG111(N=410)-期期环磷酰胺环磷酰胺750mg/m2顺铂顺铂75mg/m2泰素泰素35mg/m2(24h)顺铂顺铂75mg/m2VSORR: 73% 60% p=0.01CR: 51% 31% p=0.01PFS: 18mo 13mo p=0.001OS: 38mo 24mo 50%l 长期生存率长期生存率 20 25%OptimalStage IIINA50%21 months59 monthsSuboptimalIII & IV75%25%18 months30 mon

12、thsl 引入更有效的方案引入更有效的方案紫杉醇紫杉醇 / / 卡铂卡铂 + + 新药新药腹腔化疗腹腔化疗增加剂量强度增加剂量强度新的细胞毒性药物新的细胞毒性药物分子靶向治疗分子靶向治疗l 对复发癌更有效的治疗对复发癌更有效的治疗l 发明有效的维持治疗发明有效的维持治疗l 标准治疗标准治疗PC + X比较五种方案治疗晚期卵巢上皮癌或原比较五种方案治疗晚期卵巢上皮癌或原发性腹膜癌的发性腹膜癌的III期随机临床试验期随机临床试验25Michael A Bookman, MDFox Chase Cancer CenterPhiladelphia, PAProc ASCO 2005:Abstract

13、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 mg/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)Ca

14、rboplatin 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 (0.891-1.117)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 (

15、0.918-1.244)40.2 1.035 (0.888-1.206) 加入第三种细胞毒性药物增加了血液学毒性，但加入第三种细胞毒性药物增加了血液学毒性，但是这种毒性是可控制的是这种毒性是可控制的 在所有评价的方案中，加入第三种细胞毒药物不在所有评价的方案中，加入第三种细胞毒药物不能改善患者预后（包括无进展生存和总生存）能改善患者预后（包括无进展生存和总生存）29Proc ASCO 2005:Abstract 5002lIV IP31Cisplatin 75 mg/m2Paclitaxel 135 mg/m2 (24 h)Cisplatin 100 mg/m2 IP d1Paclitaxel

16、 135 mg/m2 (24 h) IV d1Paclitaxel 60 mg/m2 IP d8Armstrong, et al. NEJM 354:34-43, 2006结论：静脉内紫杉醇联合腹腔内顺铂和紫杉醇可改善理想减灭术后结论：静脉内紫杉醇联合腹腔内顺铂和紫杉醇可改善理想减灭术后 III期卵巢癌患者的生存率期卵巢癌患者的生存率33Arm 1Arm 1（ IV IV组）组）Arm 2Arm 2（ IP IP组）组）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

17、毒副反应（毒副反应（p0.001p12个月复发个月复发0 67 1213 18 18020406080100距前次治疗的时间（月）距前次治疗的时间（月）有效率有效率 (%)Blackledge, et al. Br J Cancer. 1989;59:650-653. 分类分类 目标目标 治疗无效治疗无效 缓解缓解( 6, 12 个月个月) 治愈治愈?单药治疗单药治疗铂类铂类79834.531 38紫杉醇类紫杉醇类1,31632.530 35联合治疗联合治疗紫杉醇类为主或有铂类紫杉醇类为主或有铂类31548.947 55铂类为主铂类为主91453.650 57紫杉醇类和铂类紫杉醇类和铂类211

18、55.648 62无紫杉醇类和铂类无紫杉醇类和铂类39922.819 27但是但是, 这个问题在一个这个问题在一个RCT即可解决即可解决!Pfisterer et al. J Clin Oncol 2006;24(29):4699-4707.随随机机健择健择 1000 mg/m2 d1,8 + 卡铂卡铂 AUC 4 d1, 每每3周方周方案案卡铂卡铂 AUC=5 d1, 每每3周方案周方案356例对铂类敏感复发例对铂类敏感复发的卵巢癌患者的卵巢癌患者根据以下因素分层：根据以下因素分层：最后一次含铂治疗间隔最后一次含铂治疗间隔 (6-12 或或12 月月)含铂一线方案含铂一线方案( 紫杉醇紫杉醇

19、)有可测量病灶有可测量病灶月月无疾病进展生存概率无疾病进展生存概率0.01.00612182430364248Log-rank p-value = .0031卡铂组：卡铂组：中位中位 5.8月月95%CI, 5.27.1月月健择健择 /卡铂卡铂组：组：中位中位 8.6月月 95%CI, 7.99.7月月 卡铂组卡铂组178例例162例进展事件；例进展事件；健择健择/卡铂组卡铂组178例例163例进展事件例进展事件Pfisterer et al. J Clin Oncol 2006;24(29):4699-4707.l 铂类敏感的复发卵巢癌患

20、者铂类敏感的复发卵巢癌患者健择健择联合卡铂方案显著延长联合卡铂方案显著延长PFS，提高缓解率，且未，提高缓解率，且未降低生活质量降低生活质量1健择健择联合卡铂快速缓解症状，并明显改善生活质量联合卡铂快速缓解症状，并明显改善生活质量21Pfisterer et al. J Clin Oncol 2006;24(29):4699.2Pfisterer et al. Int J Gynecol Cancer 2005;15(Suppl 1):36-41.健择健择/卡铂治疗复发卵巢癌的卡铂治疗复发卵巢癌的III期临床试验期临床试验各个方案的毒副作用不同：各个方案的毒副作用不同：卡铂卡铂- -紫杉醇：神

21、经毒性紫杉醇：神经毒性卡铂卡铂- -多西紫杉醇：血液性毒性多西紫杉醇：血液性毒性卡铂卡铂- -吉西他滨：血液性毒性吉西他滨：血液性毒性顺铂顺铂- -吉西他滨：血液性毒性吉西他滨：血液性毒性手术手术手术手术手术手术few selected pts. few selected pts. few selected pts. (e.g. bowel obstruction)(e.g. bowel obstruction)(e.g. bowel obstruction)内分泌内分泌内分泌内分泌内分泌内分泌 TX TX TXSelected pts.,Selected pts.,Selected pts.

22、,rather 3rd/4th line ? rather 3rd/4th line ? rather 3rd/4th line ? 支持治疗支持治疗支持治疗支持治疗支持治疗支持治疗every pt. as neededevery pt. as neededevery pt. as needed放疗放疗放疗放疗放疗放疗few selected pts.few selected pts.few selected pts.心理心理心理心理心理心理- - -社会支持社会支持社会支持社会支持社会支持社会支持every pt. as neededevery pt. as neededevery pt.

23、as needed“ “ “新药新药新药新药新药新药“ “ “only in clinical trialsonly in clinical trialsonly in clinical trials铂类为主治疗铂类为主治疗铂类为主治疗铂类为主治疗铂类为主治疗铂类为主治疗mainly pt-sensitive ROCmainly pt-sensitive ROCmainly pt-sensitive ROCFrom Dr. Andreas du Bois有效率有效率 随机临床试验，随机临床试验，0 6个月个月紫杉醇紫杉醇 1,4 n = 90拓泊替康拓泊替康 1,2,4 n = 259 楷莱楷

24、莱 3n = 130奥沙利铂奥沙利铂 4 n = 1321 ten Bokkel JCO 1997 2 Gore EJC 2002 3 GordonJCO 2001 4 Piccart JCO 2000%有效率有效率 随机临床试验，随机临床试验， 6个月个月紫杉醇紫杉醇 1,4 n = 90拓泊替康拓泊替康 1,2,4 n = 259楷莱楷莱 3 n = 109奥沙利铂奥沙利铂 4 n = 1321 ten Bokkel JCO 1997 2 Gore EJC 2002 3 GordonJCO 2001 4 Piccart JCO 2000%Randomised Studies in Recu

25、rrent OC: Studies Pts. mono- vs. mono chemotherapy 10 2.195 mono: schedule/dose/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 accordi

26、ng to testing; most other trials in pts. with platinum sensitive relapseRPaclitaxel 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

27、 1.0 mg/m d1-5 Etoposid 50 mg po d 6-12 q21Sehouli J 2008, JCO178 pts.177 pts.results: 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%

28、12 Mon.147 pts.mono vs. combination chemotherapy in refractory recurrent OCTrabectedin+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 q28Trabe

29、ctedin 1.1 mg/m q 21 +Doxil/Caelyx (PLD) 30 mg/m q28BJ Monk et all , ESMO 2008118 pts.113 pts.results: OR 12,2% vs 13,4% (combi; n.s.), PFS/OS n.s.手术手术手术手术手术手术few selected pts. few selected pts. few selected pts. (e.g. bowel obstruction)(e.g. bowel obstruction)(e.g. bowel obstruction)内分泌内分泌内分泌内分泌内分泌

30、内分泌 TX TX TXSelected pts.,Selected pts.,Selected pts.,rather 3rd/4th line ? rather 3rd/4th line ? rather 3rd/4th line ? 支持治疗支持治疗支持治疗支持治疗支持治疗支持治疗every pt. as neededevery pt. as neededevery pt. as needed放疗放疗放疗放疗放疗放疗few selected pts.few selected pts.few selected pts.心理心理心理心理心理心理- - -社会支持社会支持社会支持社会支持社会支

31、持社会支持every pt. as neededevery pt. as neededevery pt. as needed“ “ “新药新药新药新药新药新药“ “ “only in clinical trialsonly in clinical trialsonly in clinical trials目前尚无足够证据支持目前尚无足够证据支持铂类为主治疗铂类为主治疗铂类为主治疗铂类为主治疗铂类为主治疗铂类为主治疗mainly pt-sensitive ROCmainly pt-sensitive ROCmainly pt-sensitive ROCFrom Dr. Andreas du Bo

32、isRandomised 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 endocrine vs. endocrine therapy 2 106 combination vs. combination 2 107 mono vs. combination* 14 3.499 all: 37 7.924* Including 1 trial wi

33、th multiple regimens according to testing; most other trials in pts. with platinum sensitive relapse65复复发发或或耐耐药药的的卵卵巢巢癌癌癌癌患患者者泰素泰素80mg/m2, 每周给药，连续每周给药，连续3周，周，休息一周，至少两休息一周，至少两周期。周期。 用于对用于对TP方案无反应或耐药的病例方案无反应或耐药的病例 RRMarkman25%Kaern 56%Kita25-56% 毒性主要为可耐受的神经毒性毒性主要为可耐受的神经毒性_J Clin Oncol 20:2365, 2002Eur

34、 J Gynecol Oncol 23:383, 2002Gynecol Oncol 92:813, 200466RTopotecan 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,

35、1 13,1 0.733OS (weeks, median) 36 41 0.455 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 chemothera

36、py in recurrent (mostly) refractory OC - 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 PFSme

37、dian OS8%3.1 mos.13.5 mos.6%3.6 mos.12.7 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.l 研究结论：研究结论：健择健择可替代聚乙二醇脂质体阿霉素治疗铂类耐药的卵可替代聚乙二醇脂质体阿霉素治疗铂类耐药的卵巢癌患者巢癌患者Mutch DG, et al. J Clin O

38、ncol 2007;25(19):2811-2819.Results:OR 16% vs. 18% (Gem), OR duration 18 vs. 17 (Gem) weeks ; n.s.QoL advantage 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.

39、mono vs. mono chemotherapy in recurrent (mostly) refractory OC - RCTs手术手术手术手术手术手术few selected pts. few selected pts. few selected pts. (e.g. bowel obstruction)(e.g. bowel obstruction)(e.g. bowel obstruction)内分泌内分泌内分泌内分泌内分泌内分泌 TX TX TXSelected pts.,Selected pts.,Selected pts.,rather 3rd/4th line ? ra

40、ther 3rd/4th line ? rather 3rd/4th line ? 支持治疗支持治疗支持治疗支持治疗支持治疗支持治疗every pt. as neededevery pt. as neededevery pt. as needed放疗放疗放疗放疗放疗放疗few selected pts.few selected pts.few selected pts.心理心理心理心理心理心理- - -社会支持社会支持社会支持社会支持社会支持社会支持every pt. as neededevery pt. as neededevery pt. as needed“ “ “新药新药新药新药新药新

41、药“ “ “only in clinical trialsonly in clinical trialsonly in clinical trials目前尚无足够证据支持目前尚无足够证据支持铂类为主治疗铂类为主治疗铂类为主治疗铂类为主治疗铂类为主治疗铂类为主治疗mainly pt-sensitive ROCmainly pt-sensitive ROCmainly pt-sensitive ROCFrom Dr. Andreas du Bois二线治疗二线治疗一线治疗一线治疗一线治疗一线治疗三线治疗三线治疗12 个月个月3 个月个月3 个月个月STOPSTOP二线治疗二线治疗3 个月个月3 个

42、月个月Maintenance（维持）（维持） l Prolonged administration of treatment延长治疗延长治疗l Treatment until progression治疗至进展治疗至进展Consolidation（巩固）（巩固）l A defined therapy following a responseto initial treatment首次治疗有效后，接着同样的治疗首次治疗有效后，接着同样的治疗Scarfone et al 2002,Milan, Italy; n=1631III-IV, SLL, pCRPaclitaxel-platinumEpiru

43、bicin x 4vs observationOSNSShroeder et al 2004,AGO, GINECO; n=1,3082IIb IVPaclitaxel + carboTopotecan x 4vs observationPFSNSOS DePlacido et al 2004, MITO, Italy; n=2733III IVPaclitaxel + carbocCR, cPRTopotecan x 4 vs observationPFSNSCure et al 2004,GINECO; n=1104III IVPlatinum based CTSLL, pCR, 2 cm

44、HDCT (Carbo + cyclo) vs conventionalCT x 3 PFSNSOSNSMarkmann et al 2003, SWOG, n=2775 III IVPaclitaxel + platinumcCRPaclitaxel3 or 12 cyclesq 28PFS 21 vs 28, p 0.005l Markman的的期临床研究：期临床研究：两组两组PFS相差相差7个月，个月，OS无差异无差异277 例卵巢癌例卵巢癌患者经过手术患者经过手术后及后及TP 联合联合化疗达到完全化疗达到完全缓解缓解RTaxol 175 mg/ m2 3小时滴小时滴注，每月注，每月1

45、次，共次，共3个月个月Taxol 175 mg/ m2 3 小时小时滴滴注，每月注，每月1 次，共次，共12个月个月Markman M et al. Gynecol Oncol 2002; 84(3):79 l 独特腹腔上皮和独特腹腔上皮和MllerianMllerian上皮上皮 Specialized relationship; spread via implantation Frequent production of ascites, associated with VEGF Negative immunoregulation ( VEGF, IL-10, IL-6, IL-12, APC)l 生长因子受体生长因子受体 EGF-R frequently expressed, mutations uncommon, frequency of overexpression variable HER2/neu frequently expressed, high-level overexpression 15%, gene amplification uncommon ER/PR