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 & bronchus 11% Colon & rectum 6% Uterine corpus 4% Ovary 4% Non-Hodgkin lymphoma 3% Melanoma of skin 3% Thyroid 2
2、% Pancreas 2% Urinary bladder 20% All Other Sites,死亡率 25% Lung & bronchus 15% Breast 11% Colon & rectum 6% Pancreas 5% Ovary 4% Non-Hodgkin lymphoma 4% Leukemia 3% Uterine corpus 2% Brain/ONS 2% Multiple myeloma 23% All other sites,Cancer Facts & Figures,ACSO,2003,美国卵巢癌流行病学特征,上海市居民卵巢癌、宫颈癌、宫体癌发病率（197
3、4-2000，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, http:
4、/seer.cancer.gov/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. www.figo.org,早期卵巢癌,Medical Oncology: A co
5、mprehensive 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 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
6、, www.cancernet.nci.nih.gov,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
7、 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 + cyclophosphamide
8、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 + doxorubicin + cisplatin) No statistical dif
9、ference 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), 144-148 5. Ozols RF et al. J Clin Oncol
10、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 Gemcitabin dublet + TP (cyclophosphamide +
11、 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, et al. N Engl J Med 2006;354:34-43 .Is
12、onishi 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75mg/m2
13、,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 (24 h)
14、,Carboplatin AUC 7.5 Paclitaxel 175 mg/m2 (3 h),Epithelial Ovarian CancerOptimal Stage IIINo prior therapyElective Second-LookNon-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),CDDP-Pa
15、clitaxel (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 / 卡铂 + 新药
16、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,GOG0182-ICON5,
17、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) 40.2 1.
18、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 Paclitaxel 60 mg/
19、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 172,结论：
20、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, 8,15Carboplatin AUC 6 d1 3周疗：Paclitaxel 180mg d1Carboplatin 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(
21、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
22、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程 Vs 化疗3程细
23、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,Relapse /
24、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 & Obstet, Nov 2003 supplement,复发性卵巢癌目前的
25、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
26、 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
27、 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. 2
28、Pfisterer 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 p
29、ts.,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 3 n = 130,奥沙利铂 4 n = 132,1 ten Bokkel JCO 1997 2 Gore EJC 2002 3 Gordon
30、 JCO 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 Gordon JCO 2001 4 Piccart JCO 2000,%,What is the Evidence?,Randomised Studies in Recurrent OC:Studies Pts.mono- vs. mono chemotherapy 10 2.195mono: sch
31、edule/dose/application 7 1.614mono- vs. endocrine therapy 2 303endocrine vs. endocrine therapy 2 106combination vs. combination 2 107mono vs. combination* 14 3.499all: 37 7.924 * Including 1 trial with multiple regimens according to testing; most other trialsin pts. with platinum sensitive relapse,R
32、,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,
33、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 refr
34、actory 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: bjmonkuci.edu),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
35、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 in
36、 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 2.195mono: schedule/dose/application 7 1.614mono- vs. endocrine therapy 2 303endocrine vs. endocrine
37、 therapy 2 106combination vs. combination 2 107mono vs. combination* 14 3.499all: 37 7.924 * Including 1 trial with multiple regimens according to testing; most other trialsin 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 （8
38、0 mg/m2/周）,用于对TP方案无反应或耐药的病例RRMarkman 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 Oncol2004, Gynecol Oncol,235 pts.55% Pt.-refractory, 70% pri
39、or 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 Treatment-related se
40、psis 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 chemotherapy in rec
41、urrent (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 i
42、n 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 selected pts. (e.g. bo
43、wel 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,二线治疗,一线治疗,一线治疗,三线治疗,12 个
44、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：Definitions,巩固/维持治疗 随机临床试验（RCT）
45、 （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,Markman的期临床研究：两组PFS相差7个月，OS
46、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 immu
47、noregulation (VEGF, IL-10, IL-6, IL-12, APC) 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/AR frequently expressed, variable functionality Other receptors less well characterized 生长因子产物 Frequent high-level expression of VEGF Increased expression of IL10, IL6, TNF, TGF,
