卵巢癌化疗进展.ppt

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（dissection） 腹膜和膈膜活

2、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,Young SGO 200

3、3 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; 淋巴结阴性 C腹腔种植灶 2 cm

4、 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 + paclitaxel vs cisplatin

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

6、No statistical difference in survival GOG 1585; AGO-OVAR6 Carboplatin + paclitaxel preferred combination overcisplatin + paclitaxel,1.McGuire WP et al. N Engl J Med 1996, 334:1-84.ICON Group. Lancet 2002, 360:505-515 2.Piccart M et al. Int J Gyn Cancer 2003, 13 (suppl 2), 144-1485. Ozols RF et al. J

7、 Clin Oncol 2003; 21:3194-3200 3.Muggia F et al. J Clin Oncol 2000, 18:106-1156.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 Gemcitabin dublet + TP(cyclophosp

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

9、-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 p=0.001,OS: 38mo 24mo p=0.001,毒性: 泰素/顺铂组有较多的血液学毒性和神经毒性，但毒性可控,OV10 (N=688)-期,环磷酰胺750mg/m2 顺铂

10、75mg/m2,泰素175mg/m2(3h) 顺铂75mg/m2,ORR: 77% 66% p=0.01,CR: 50% 36% p=0.01,PFS: 16.6mo 12mo p=0.0005,OS: 35mo 25mo p=0.0016,毒性: 泰素/顺铂组有较多的血液学毒性和神经毒性，但毒性可控,VS,J Natl Cancer Inst 2000;92:699708,McGuire, et al. N Engl J Med 1996 334:1-6,GOG158: Ovarian (optimal III),Cisplatin 75 mg/m2 Paclitaxel 135 mg/m2

11、 (24 h),Carboplatin AUC 7.5 Paclitaxel 175 mg/m2 (3 h),Epithelial Ovarian Cancer Optimal Stage III No prior therapy Elective Second-Look Non-Inferiority Design,Open:03-Apr-95 Closed:26-Jan-98 Accrual:792 pts (evaluable),I,II,Ozols, et al. Proc J Clin Oncol 21:3194, 2003,GOG158: Ovarian (optimal III)

12、,CDDP-Paclitaxel (24-h) (n = 400) median 48.8 m,Carbo-Paclitaxel (3-h) (n = 392) median 56.7 m,Adjusted Cox analysis HR 0.86 (95% CI 0.71 1.04),Ozols, et al. Proc J Clin Oncol 21:3194, 2003,56.7 vs 48.8 m = 7.9 m,晚期卵巢癌的化疗,总之: 手术和化疗后约 75% 患者临床完全缓解（CCR）， 但复发率 50% 长期生存率 20 25%,提高疗效的可能对策,引入更有效的方案 紫杉醇 /

13、卡铂 + 新药 腹腔化疗 增加剂量强度 新的细胞毒性药物 分子靶向治疗 对复发癌更有效的治疗 发明有效的维持治疗,Ozols, Seminars in Oncology, vol 29; Suppl 1 (Feb) 2002: 32-42.,提高初治卵巢癌化疗疗效：三药联合化疗,标准治疗PC + X,GOG0182-ICON5,比较五种方案治疗晚期卵巢上皮癌或原发性腹膜癌的III期随机临床试验,25,Michael A Bookman, MD Fox Chase Cancer Center Philadelphia, PA,Proc ASCO 2005:Abstract 5002,GOG018

14、2-ICON5,26,GOG0182-ICON5: 无进展生存,Median PFS and HR (95% CI) 16.1 1.000 16.4 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),GOG0182-ICON5: 总生存,Median OS and HR (95% CI) 40.0 1.000 40.4 0.978 (0.838-1.141) 42.8 0.972 (0.832-1.136) 39.1 1.068 (0.918-1.244)

15、 40.2 1.035 (0.888-1.206),GOG0182-ICON5： 结论,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 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）,29,Proc ASCO 2005:Abstract 5002,IV IP,提高初治卵巢癌化疗疗效：改变用途径,GOG172,31,Cisplatin 75 mg/m2 Paclitaxel 135 mg/m2 (24 h),Cisplatin 100 mg/m2 IP d1 Paclitaxel 135 mg/m2 (24 h) IV d1 Paclitaxe

16、l 60 mg/m2 IP d8,上皮性卵巢癌 III期 满意减灭术 术前无治疗 选择性二探,Open:23-Mar-98 Closed:29-Jan-01 Accrual:415 例 (可评价),I,II,Armstrong, et al. NEJM 354:34-43, 2006,GOG172: Ovarian (optimal III) IP vs. IV,CDDP (IV) Paclitaxel (IV) (n = 210),CDDP (IP) Paclitaxel (IP+IV) (n = 206),Armstrong, et al. NEJM 354:34-43, 2006,GOG

17、 172,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,33,3周疗周疗,提高初治卵巢癌化疗疗效：增加用药频率,PC紫杉醇周疗 vs 标准PT3周疗 (JGOG ，2009),每周疗：Paclitaxel 80mg d1, 8,15 Carboplatin AUC 6 d1 3周疗：Paclitaxel 180mg d1 Carboplatin AUC 6 d1,Isonishi S, et al. the Lancet 2009; 374:1331-38,晚期卵巢癌化疗,卡铂和紫杉醇：卡铂（AUC=56）紫杉醇(175mg/m2) 滴注 3小时，每3

18、周重复，共68个疗程(catrgory 1) 顺铂和紫杉醇：紫杉醇(135mg/m2) iv d1，DDP 100mg/m2 ip d2,紫杉醇(60mg/m2) ip d8,每3周重复，共68个疗程(catrgory 1) 卡铂和多西紫杉醇：卡铂（AUC=56）多西紫杉醇(60-75mg/m2) 滴注 1小时，每3周重复，共68个疗程(catrgory 1) 如对泰素过敏，可改用其他替代药物（如：泰素帝，topotecan，健择，或脂质体阿霉素）。 不能耐受静脉化疗者，可选用口服化疗药，如：VP-16。,举例：Case 1,53岁，女性 表现为腹胀 无腹腔外肿瘤生长证据 肿瘤中等度大 实施活

19、检后患者被转至妇科肿瘤医师,举例：Case 1,对此患者实施了满意的细胞减灭术. 残留肿瘤最大直径：1cm. 1枚腹主动脉旁淋巴结累及 病理：中分化浆液性乳头状癌 转至寻求化疗,举例：Case 1,我们的患者选择腹腔化疗 2个周期化疗后她的CA125水平自122降至10 患者无症状，继续接受了4个周期的化疗 盆腔检查、CT扫描、CA125结果均正常,新辅助化疗与中间性细胞减灭术,Neoadjuvant Chemotherapy Interval Cytoreduction,中间性细胞减灭术（12th IGCS曼谷，2008）,随机非劣性实验：718例IIIc-IV期卵巢癌 初次细胞减灭术化疗6

20、程 Vs 化疗3程细胞减灭术化疗3程 总生存率：29 m vs 30 m PFS: 12 m vs 12 m,Vergote et al. 12th biennial meeting of IGCS, Bangkok, Thailand,2008,肠系膜根部转移 肝实质多发转移,上皮性卵巢癌：Epithelial Ovarian Cancer (EOC)100例患者的典型“结局”,Early stage (I-II),Advanced stage (III-IV),Clinical partial response(cPR), Stable disease(SD), Progression,R

21、elapse / Progression,Clinical complete response (cCR),25,75,8,40,35,Pathologic partial Response(pPR),Pathologic complete Response(pCR),16,24,Relapse,2nd3rd line therapy,8,73,FIGO annual report on treatments of gynecological cancers Editor: Pecorelli S. Intern J Gynecol 95:132030,约 25% 患者于一线TC(paclit

22、axel+Carb.)治疗后 6-12个月复发,约 50% 患者于一线TC治疗后 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 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）,

23、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 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

24、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 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)

25、,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,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

26、,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 GordonJCO 2001 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 GordonJCO 2001 4 Piccart JCO 2000,%,What is the Evidence?,Randomi

27、sed 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 with multi

28、ple regimens according to testing; most other trials in pts. with platinum sensitive relapse,R,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,Topotec

29、an 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,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 + 6

30、00 mg/m d8 q21,app. 20% refractory 41% 12 Mon.,147 pts.,mono vs. combination chemotherapy in refractory 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

31、 recurrent OC,R,Doxil/Caelyx (PLD) 50 mg/m q28,Trabectedin 1.1 mg/m q 21 + Doxil/Caelyx (PLD) 30 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/

32、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,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

33、.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 according to testing; most other trials in pts. with platinum

34、 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 Paclitaxel （80 mg/m2/周）,用于对TP方案无反应或耐药的病例 RR Markman25% Kaern 56% Kita25-56% 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 d

35、1-5 q21,Caelyx 50 mg/m iv q28,Gordon 2001, J Clin Oncol 2004, Gynecol Oncol,235 pts. 55% Pt.-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.;%) Neu

36、tropenia 12 77 0.001 Anemia 5 28 0.001 Thrombocytopenia 1 34 0.001 Leukopenia 10 50 0.001 Treatment-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

37、mg/m d1+8 q21,Caelyx 50 mg/m d1 q28,Mutch, JCO 2007,99 pts.,96 pts.,Results:,mono vs. mono 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

38、):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),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.,mon

39、o 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 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 in clinical trials,首选 非铂单药： Caelyx Topoteca

40、n 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

41、固） A defined therapy following a responseto initial treatment 首次治疗有效后，接着同样的治疗,定义：Definitions,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

42、 Supplement), 2004; 5006: 5. Markman JCO, Vol 21, No 13 (July 1) 2003; 24602465,巩固化疗,Markman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, associat