卵巢癌化疗进展

1、.,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,.,女性生殖道肿瘤: 全世界统计1,Ferlay et al. GLOBOCAN 2000 IARC, WHO 2001 (www.dep.iarc.fr),.,.,Women,发病率 32% Breast 12% Lung 2001/, 2004.,卵巢癌可认为是一种 慢性疾病,早期卵巢癌: FIGO I and II,全面的分期剖腹探查术 经腹全子宫/双侧卵巢输卵管切除 (TAH/BSO) 大网膜切除 淋巴结切除术（dissec

2、tion） 腹膜和膈膜活检（ biopsies） 细胞学检查 高危 vs 低危早期卵巢癌,Staging classifications and clinical practice guidelines of gynaecologic cancers. ,早期卵巢癌,Medical Oncology: A comprehensive review. textbook,低危,高危,(510% 复发率),(3040% 复发率),Stage IA or IB,Stage IC,Grade 1 (or 2),Grade 3 Clear cell cancer,高危早期卵巢癌,Y

3、oung SGO 2003 2. Young RC. Semin Oncol 27 (3):8-10., 2000 3. ICON-1, EORTC-ACTION: J Natnl Can Inst. Vol. 95, No. 2, January 15, 2003 4. Mannel et al. GOG-175 protocol, ,GOG1571,2,辅助化疗的随机临床试验: 3 vs 6 疗程 紫杉醇 + 卡铂,结果 6个疗程 进展危险性降低了33% 生存率无改善,Action 淋巴结阴性; 镜下腹腔种植 B 腹腔种植灶 2 cm; 淋

4、巴结阴性 C 腹腔种植灶 2 cm 和/或阳性腹膜后淋巴结或腹股沟 IV 远处转移,Medical Oncology: A comprehensive review. textbook,准确全面分期依据手术探查和 病理组织学、细胞学检查 根据腹腔内转移灶的大小对III期再分为IIIa、IIIb、IIIc 腹膜后淋巴结转移影响分期 肝表面和肝实质转移分属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: 远处转移,.,晚期卵巢癌：关键临床实验1,GOG 1111 and OV-102 Cisplatin + pac

5、litaxel vs cisplatin + cyclophosphamide Improved survival and progression-free survival with cisplatin + paclitaxel GOG 1323 Cisplatin vs paclitaxel vs cisplatin + paclitaxel No statistaical difference in overall survival ICON-34 Carboplatin + paclitaxel vs carboplatin or CAP (cyclophosphamide + dox

6、orubicin + cisplatin) No statistical difference in survival GOG 1585; AGO-OVAR6 Carboplatin + paclitaxel preferred combination over cisplatin + paclitaxel,1. McGuire WP et al. N Engl J Med 1996, 334:1-8 4. ICON Group. Lancet 2002, 360:505-515 2. Piccart M et al. Int J Gyn Cancer 2003, 13 (suppl 2),

7、144-148 5. Ozols RF et al. J Clin Oncol 2003; 21:3194-3200 3. Muggia F et al. J Clin Oncol 2000, 18:106-115 6. du Bois et al. J Natl Cancer Inst. 2003 Sep 3;95(17):1320-9,晚期卵巢癌: 关键临床实验2,ICON-5-GOG182 （2006） Carboplatin + paclitaxel vs Gemcitabin triplet vs Doxil Triplet vs Topotecan duble + TP vs Ge

8、mcitabin dublet + TP (cyclophosphamide + doxorubicin + cisplatin) No statistical difference in survival GOG 172 （2006） cisplatin + paclitaxel iv/ip preferred combination over cisplatin + paclitaxel iv JGOG （2009） Carboplatin （d1）+ paclitaxel 80mg weekly perferred Carboplatin + paclitaxel,Armstrong D

9、, et al. N Engl J Med 2006;354:34-43 .Isonishi S, et al. the Lancet 2009; 374:1331-38,TP方案成为晚期卵巢癌一线化疗的“标准”,19,1996,2000,GOG111 (N=410)-期,环磷酰胺750mg/m2 顺铂75mg/m2,泰素35mg/m2(24h) 顺铂75mg/m2,VS,ORR: 73% 60% p=0.01,CR: 51% 31% p=0.01,PFS: 18mo 13mo 12个月复发,存在的相关问题 大多数(55%) 晚期患者将会出现铂类敏感性复发,无治疗间期,0 6,7 12,13

10、18, 18,0,20,40,60,80,100,距前次治疗的时间（月）,有效率 (%),Blackledge, et al. Br J Cancer. 1989;59:650-653.,二线化疗的目标,分类 目标 治疗无效 缓解 ( 6, 12 个月) 治愈?,对铂类敏感的卵巢癌,两药联合化疗能否成为对铂类敏感的复发性卵巢癌患者的治疗标准？,对铂类敏感的复发性卵巢癌 单药有效率 累积总有效率（OR）,du Bois A et al. 2000 Geburtsh Frauenheilk 2000; 60:41-58,但是, 这个问题在一个RCT即可解决!,Pfisterer et al. J

11、Clin Oncol 2006;24(29):4699-4707.,健择/卡铂治疗复发卵巢癌的III期临床试验,健择/卡铂治疗复发卵巢癌的III期临床试验: PFS,卡铂组178例162例进展事件；健择/卡铂组178例163例进展事件,Pfisterer et al. J Clin Oncol 2006;24(29):4699-4707.,铂类敏感的复发卵巢癌患者 健择联合卡铂方案显著延长PFS，提高缓解率，且未降低生活质量1 健择联合卡铂快速缓解症状，并明显改善生活质量2,1Pfisterer et al. J Clin Oncol 2006;24(29):4699. 2Pfisterer

12、et al. Int J Gynecol Cancer 2005;15(Suppl 1):36-41.,健择/卡铂治疗复发卵巢癌的III期临床试验,各个方案的毒副作用不同： 卡铂-紫杉醇：神经毒性 卡铂-多西紫杉醇：血液性毒性 卡铂-吉西他滨：血液性毒性 顺铂-吉西他滨：血液性毒性,铂类耐药复发性卵巢癌治疗模式:,手术 few selected pts. (e.g. bowel obstruction),内分泌 TX Selected pts., rather 3rd/4th line ?,支持治疗 every pt. as needed,放疗 few selected pts.,心理-社会支

13、持 every pt. as needed,“新药“ only in clinical trials,非铂单药 Tx,非铂联合 Tx,铂类为主治疗 mainly pt-sensitive ROC,From Dr. Andreas du Bois,对铂类耐药卵巢癌,选择哪种非铂类？ 单药 联合 或改变用药途径？ 或改变用药方案？,有效率 随机临床试验，0 6个月,紫杉醇 1,4 n = 90,拓泊替康 1,2,4 n = 259,楷莱 3 n = 130,奥沙利铂 4 n = 132,1 ten Bokkel JCO 1997 2 Gore EJC 2002 3 Gordon JCO 2001

14、4 Piccart JCO 2000,%,有效率 随机临床试验， 6个月,紫杉醇 1,4 n = 90,拓泊替康 1,2,4 n = 259,楷莱 3 n = 109,奥沙利铂 4 n = 132,1 ten Bokkel JCO 1997 2 Gore EJC 2002 3 Gordon JCO 2001 4 Piccart JCO 2000,%,What is the Evidence?,Randomised Studies in Recurrent OC: Studies Pts. mono- vs. mono chemotherapy 10 2.195 mono: schedule/d

15、ose/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 relapse,R,

16、Paclitaxel 175 mg/m 3h q21,Paclitaxel 175 mg/m Epirubicin 80 mg/m q21,Buda A 2004, Br J Cancer,106 pts. 12 mos.,106 pts.,results: OR 47% vs. 37% (combi), PFS 6 vs. 6 mos. OS 14 vs. 12 mos. (n.s.),R,Topotecan 1.25 mg/m d1-5 q21,Topotecan 1.0 mg/m d1-5 Etoposid 50 mg po d 6-12 q21,Sehouli J 2008, JCO,

17、178 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 q21,app. 20% refractory 41% 12 Mon.,147 pts.,mono vs. combination chemotherapy in re

18、fractory recurrent OC,Trabectedin+PLD 4.0 mos,PLD 3.7 mos,PFS events: 163 HR: 0.95 (0.70-1.30) P = 0.7540 by courtesy of BJ Monk et al (Email: ),mono vs. combination chemotherapy in refractory recurrent OC,R,Doxil/Caelyx (PLD) 50 mg/m q28,Trabectedin 1.1 mg/m q 21 + Doxil/Caelyx (PLD) 3

19、0 mg/m q28,BJ Monk et all , ESMO 2008,118 pts.,113 pts.,results: OR 12,2% vs 13,4% (combi; n.s.), PFS/OS n.s.,铂类耐药复发性卵巢癌治疗模式:,手术 few selected pts. (e.g. bowel obstruction),内分泌 TX Selected pts., rather 3rd/4th line ?,支持治疗 every pt. as needed,放疗 few selected pts.,心理-社会支持 every pt. as needed,“新药“ only

20、in clinical trials,非铂单药 Tx,目前尚无足够证据支持 非铂联合 Tx,铂类为主治疗 mainly pt-sensitive ROC,From Dr. Andreas du Bois,What is the Evidence?,Randomised 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. en

21、docrine 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 relapse,Weekly Paclitaxel,65,复发或耐药的卵巢癌癌患者,泰素80mg/m2, 每周给药，连续3周，休息一周，至少两周期。,Weekly Pa

22、clitaxel （80 mg/m2/周）,用于对TP方案无反应或耐药的病例 RR Markman 25% Kaern 56% Kita 25-56% 毒性主要为可耐受的神经毒性 _ J Clin Oncol 20:2365, 2002 Eur J Gynecol Oncol 23:383, 2002 Gynecol Oncol 92:813, 2004,66,R,Topotecan 1,5 mg/m iv d1-5 q21,Caelyx 50 mg/m iv q28,Gordon 2001, J Clin Oncol 2004, Gynecol Oncol,235 pts. 55% Pt.-

23、refractory, 70% prior taxans,239 pts.,Results platinum refractory subgroup: Caelyx (130) Topotecan (124) p-value PFS (weeks, median) 9,1 13,1 0.733 OS (weeks, median) 36 41 0.455 G3/4 toxicity (all pts.;%) Neutropenia 12 77 0.001 Anemia 5 28 0.001 Thrombocytopenia 1 34 0.001 Leukopenia 10 50 0.001 T

24、reatment-related sepsis 0 4 0.001 Alopecia (all grades) 16 49 0.007 Hand-Foot-Syndrom 23 0 0.001 Stomatitis 8 0.4 0.001,mono vs. mono chemotherapy in recurrent (mostly) refractory OC - RCTs,R,Gemcitabine 1000 mg/m d1+8 q21,Caelyx 50 mg/m d1 q28,Mutch, JCO 2007,99 pts.,96 pts.,Results:,mono vs. mono

25、chemotherapy in recurrent (mostly) refractory OC - RCTs,66 pts.,64 pts.,*Statistically significant.,健择vs.聚乙二醇脂质体阿霉素治疗铂类耐药的卵巢癌的III期临床试验,研究结论： 健择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,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 ad

26、vantage for caelyx in 2 of 4 time points (p 0.05),R,Gemcitabine 1000 mg/m d1,8, 15 q28,Caelyx 40 mg/m d1 q28,Mito-3 G Ferrandina et al JCO 2008,77 pts. 100% platinum-taxan, TFI 12 mos. (57% 6 mos.),76 pts.,mono vs. mono chemotherapy in recurrent (mostly) refractory OC - RCTs,铂类耐药复发性卵巢癌治疗模式:,手术 few s

27、elected pts. (e.g. bowel obstruction),内分泌 TX Selected pts., rather 3rd/4th line ?,支持治疗 every pt. as needed,放疗 few selected pts.,心理-社会支持 every pt. as needed,“新药“ only in clinical trials,首选 非铂单药： Caelyx Topotecan Gemcitabine,目前尚无足够证据支持 非铂联合 Tx,铂类为主治疗 mainly pt-sensitive ROC,From Dr. Andreas du Bois,二线

28、治疗,一线治疗,一线治疗,三线治疗,12 个月,3 个月,3 个月,STOP,STOP,二线治疗,3 个月,3 个月,卵巢癌终止治疗： London Royal Marsden Hospital 指南,.,Maintenance（维持） Prolonged administration of treatment 延长治疗 Treatment until progression 治疗至进展 Consolidation（巩固） A defined therapy following a response to initial treatment 首次治疗有效后，接着同样的治疗,定义：Definit

29、ions,巩固/维持治疗 随机临床试验（RCT） （i.v. ）,1. Scarfone ASCO 2002 abstract book: 2. Shroeder IGCS 2004 Abstr 567: 3. MITO-1 J Clin Oncol. 2004 Jul 1; 22(13):263542: 4. Cure J of Clin Oncol, 2004 ASCO Vol 22, No 14S (July 15 Supplement), 2004; 5006: 5. Markman JCO, Vol 21, No 13 (July 1) 2003; 24602465,巩固化疗,Mar

30、kman的期临床研究： 两组PFS相差7个月，OS无差异,277 例卵巢癌患者经过手术后及TP 联合化疗达到完全缓解,R,Taxol 175 mg/ m2 3小时滴 注，每月1 次，共3个月,Taxol 175 mg/ m2 3 小时滴 注，每月1 次，共12个月,Markman M et al. Gynecol Oncol 2002; 84(3):79,卵巢癌: 生物靶向治疗,独特腹腔上皮和Mllerian上皮 Specialized relationship; spread via implantation Frequent production of ascites, associated with VEGF Negative immunoregulation (VEGF, IL-10, IL-6, IL-12, APC) 生长因子