卵巢癌化疗进展

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,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%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25%Lung & bronchus15%Breast11%Colon & rectum6%Pancreas5%Ovary4%Non-Hodgkinlymphoma4%Leukemia3%Uterine corpus2%Brain/ONS2%Multiple myeloma23%All other sites,Cancer Facts & Figures,ACSO,2003,上海市居民卵巢癌、宫颈癌、宫体癌发病率（1974-2000，SCDC）,内容简介,早期卵巢癌化疗中晚期卵巢癌化疗新辅助化疗/中间手术复发性卵巢癌化疗维持巩固治疗Ca125升高处理,卵巢癌的治疗,未治患者主要目的是治愈手术分期和细胞减灭术，继而紫杉醇/铂类联合化疗复发患者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最终结果长期存活: 25-30%5-年 生存率从 30% (1970s) 提高至 50%,Ries LAG et al. SEER Cancer Statistics Review, 1975-2001, National Cancer Institute. Bethesda, MD, /csr/1975; 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 3Clear cell cancer,高危早期卵巢癌,Young 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, 20034. 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 & Icon3,随机临床试验无立即化疗 vs 立即化疗,结果立即化疗 生存率提高8% vs复发时化疗(82% vs 74%),FIGO Stage III and IV定义,III盆腔外腹膜种植和/或外阳性腹膜后或腹股沟淋巴结A病灶大致局限于真骨盆; 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 和/或阳性腹膜后淋巴结或腹股沟IV远处转移,Medical Oncology: A comprehensive 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-102Cisplatin + paclitaxel vs cisplatin + cyclophosphamideImproved survival and progression-free survival withcisplatin + paclitaxel GOG 1323Cisplatin vs paclitaxel vs cisplatin + paclitaxelNo statistaical difference in overall survivalICON-34Carboplatin + paclitaxel vs carboplatin or CAP(cyclophosphamide + doxorubicin + cisplatin)No statistical difference in survivalGOG 1585; AGO-OVAR6Carboplatin + paclitaxel preferred combination overcisplatin + paclitaxel,1.McGuire WP et al. N Engl J Med 1996, 334:1-84.ICON Group. Lancet 2002, 360:505-5152.Piccart M et al. Int J Gyn Cancer 2003, 13 (suppl 2), 144-1485. Ozols RF et al. J Clin Oncol 2003; 21:3194-32003.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(cyclophosphamide + doxorubicin + cisplatin)No statistical difference in survivalGOG 172 （2006）cisplatin + paclitaxel iv/ip preferred combination overcisplatin + paclitaxel ivJGOG （2009）Carboplatin （d1）+ paclitaxel 80mg weekly perferred Carboplatin + paclitaxel,Armstrong D, 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 p=0.001,OS: 38mo 24mo 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 / 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, MDFox Chase Cancer CenterPhiladelphia, PA,Proc ASCO 2005:Abstract 5002,GOG0182-ICON5,26,GOG0182-ICON5: 无进展生存,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),GOG0182-ICON5: 总生存,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),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/m2Paclitaxel 135 mg/m2 (24 h),Cisplatin 100 mg/m2 IP d1Paclitaxel 135 mg/m2 (24 h) IV d1Paclitaxel 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-98Closed:29-Jan-01Accrual: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 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 d13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 ChemotherapyInterval 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程Vs化疗3程细胞减灭术化疗3程总生存率：29 m vs 30 mPFS: 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,Relapse / Progression,Clinical complete response(cCR),25,75,8,40,35,Pathologic partialResponse(pPR),Pathologic completeResponse(pCR),16,24,Relapse,2nd3rd line therapy,8,73,FIGO annual report on treatments of gynecological cancers Editor: Pecorelli S. Intern J Gynecol & Obstet, Nov 2003 supplement,复发性卵巢癌目前的治疗,Current Management of Recurrent Ovarian Cancer,0.00,0.25,0.50,0.75,1.00,0,12,24,36,48,60,72,84,Time (Months),Probability PFS,AGO OVAR-3: du Bois A et al. J Natl Cancer Inst 2003; 95:132030,约 25% 患者于一线TC(paclitaxel+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）,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),内分泌 TXSelected 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 1,2,4 n = 259,楷莱 3n = 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?,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. 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,Paclitaxel 175 mg/m 3h q21,Paclitaxel 175 mg/mEpirubicin 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,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% refractory41% 12 Mon.,147 pts.,mono vs. combination chemotherapy in refractory recurrent OC,Trabectedin+PLD4.0 mos,PLD3.7 mos,PFS 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 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 TXSelected 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,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. 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,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 RRMarkman25%Kaern 56%Kita25-56% 毒性主要为可耐受的神经毒性_J Clin Oncol 20:2365, 2002Eur J Gynecol Oncol 23:383, 2002Gynecol 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.-refractory, 70% prior taxans,239 pts.,Results platinum refractory subgroup:Caelyx (130)Topotecan (124) p-valuePFS (weeks, median) 9,1 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 0.001,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 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 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-3G 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 selected pts. (e.g. bowel obstruction),内分泌 TXSelected 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 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 Supplement), 2004; 5006: 5. Markman JCO, Vol 21, No 13 (July 1) 200