卵巢癌化疗新进展和治疗Thestateoftheartinchemotherapyforovariancancers

1、卵巢癌化疗新进展和治疗The state of the art in chemotherapy for ovarian cancers 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%Ova

2、ry4%Non-Hodgkinlymphoma4%Leukemia3%Uterine corpus2%Brain/ONS2%Multiple myeloma23%All other sitesCancer 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: 25-3

3、0%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, ; 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 cl

4、inical practice guidelines of gynaecologic cancers. 早期卵巢癌(510% 复发率)Medical Oncology: A comprehensive review. textbook低危高危(3040% 复发率)Stage IA or IBStage ICGrade 1 (or 2)Grade 3Clear cell cancer高危早期卵巢癌辅助化疗的随机临床试验:3 vs 6 疗程紫杉醇 + 卡铂 Young SGO 2003 2. Young RC. Semin Oncol 27 (3):8-10., 2000 3. ICON-1, E

5、ORTC-ACTION: J Natnl Can Inst. Vol. 95, No. 2, January 15, 20034. Mannel et al. GOG-175 protocol, GOG1571,2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 c

6、m 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1GOG 1111 and OV-102Cisplatin + paclitaxel vs cisplatin + cyclo

7、phosphamideImproved 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

8、 difference in survivalGOG 1585; AGO-OVAR6Carboplatin + paclitaxel preferred combination overcisplatin + paclitaxel1.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;

9、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2ICON-5-GOG182 （2006）Carboplatin + paclitaxel vs Gemcitabin triplet vs Doxil Triplet vs Topotecan duble + TP vs Gemcitabin dublet + TP(cyclophosphamide + doxorubicin

10、+ 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. th

11、e Lancet 2009; 374:1331-38TP方案成为晚期卵巢癌一线化疗的“标准”1719962000GOG111(N=410)-期环磷酰胺750mg/m2顺铂75mg/m2泰素35mg/m2(24h)顺铂75mg/m2VSORR: 73%CR: 51%PFS: 18mo OS: 38mo 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泰素175mg/m2(3h)顺铂75mg/m2ORR: 77%CR: 50%PFS: 16.6mo OS: 35mo 毒性: 泰素/顺铂组有较多的血液学毒性和神经毒性，但

12、毒性可控VSJ Natl Cancer Inst 2000;92:699708McGuire, et al. N Engl J Med 1996 334:1-6GOG158: Ovarian (optimal III)Cisplatin 75 mg/m2Paclitaxel 135 mg/m2 (24 h)Paclitaxel 175 mg/m2 (3 h) Epithelial Ovarian Cancer Optimal Stage III No prior therapy Elective Second-Look Non-Inferiority DesignOpen:03-Apr-95C

13、losed:26-Jan-98Accrual:792 pts (evaluable)IIIOzols, et al. Proc J Clin Oncol 21:3194, 2003GOG158: Ovarian (optimal III)CDDP-Paclitaxel (24-h)(n = 400) median 48.8 mCarbo-Paclitaxel (3-h)(n = 392) median 56.7 mAdjusted Cox analysisHR 0.86 (95% CI 0.71 1.04)Ozols, et al. Proc J Clin Oncol 21:3194, 200

14、356.7 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 + XGOG0182-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23Michael

15、 A Bookman, MDFox Chase Cancer CenterPhiladelphia, PAProc ASCO 2005:Abstract 5002GOG0182-ICON524R A N D O M I Z Ex8Carboplatin AUC 5 (d1)Paclitaxel 175 mg/m2 (d1)Doxil 30 mg/m2 (d1, every other cycle)IIIx8Carboplatin AUC 6 (d1)Paclitaxel 175 mg/m2 (d1)ICarboplatin AUC 6 (d1)Paclitaxel 175 mg/m2 (d1)

16、x4x4Carboplatin AUC 6 (d8)Gemcitabine 1 g/m2 (d1,8)Vx4Carboplatin AUC 5 (d3)Topotecan 1.25 mg/m2 (d1-3)IVx8Carboplatin AUC 5 (d1)Paclitaxel 175 mg/m2 (d1)Gemcitabine 800 mg/m2 (d1,8)IIGOG0182-ICON5: 无进展生存Median PFS and HR (95% CI)16.4 0.990 (0.884-1.107)16.4 0.998 (0.891-1.117)15.3 1.094 (0.979-1.22

17、4)15.4 1.052 (0.940-1.176)GOG0182-ICON5: 总生存Median OS and HR (95% CI)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 1.035 (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）27Proc ASCO 2005:Abstract 5002IV IP提高初治卵巢癌化疗疗效

18、：改变用途径GOG17229Cisplatin 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)IIIArmstrong, et al. NEJM 354:34-43, 2006GOG172: Ovarian (optimal III) IP vs.

19、IVCDDP (IV) Paclitaxel (IV)(n = 210)CDDP (IP) Paclitaxel (IP+IV)(n = 206)Armstrong, et al. NEJM 354:34-43, 2006GOG 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313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 Carboplati

20、n AUC 6 d1Isonishi 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（

21、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 153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

22、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 mVergote 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), ProgressionRelap

23、se / ProgressionClinical complete response(cCR)257584035Pathologic partialResponse(pPR)Pathologic completeResponse(pCR)1624Relapse2nd3rd line therapy873FIGO 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 Mana

24、gement of Recurrent Ovarian Cancer012243648607284Time (Months)Probability PFSAGO 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 67 1213 18 18020406080100距前次治疗的时间（月）有效率 (%)Blackledge, et

25、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.随机健择 1000 mg/m2 d1,8 + 卡铂 AUC 4 d1,

26、每3周方案卡铂 AUC=5 d1, 每3周方案356例对铂类敏感复发的卵巢癌患者根据以下因素分层：最后一次含铂治疗间隔 (6-12 或12 月)含铂一线方案( 紫杉醇)有可测量病灶健择/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月无疾病进展生存概率0.00.10.20.30.40.50.60.70.80.91.00612182430364248Log-rank p-value = .0031卡铂组：中位 5.8月95%CI, 5.27.1月健择 /卡铂组：中位 8.6月 95%CI, 7.99.7月卡铂组178例162例进展事件；健择/卡铂组178

27、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/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

28、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 ROCFrom Dr. Andreas du Bois对铂类耐药卵巢癌选择哪种非铂类？

29、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 = 1321 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 = 1321 ten Bokkel JCO 1997 2 Gore EJC 2002 3 GordonJCO 2001 4 Pi

30、ccart JCO 2000%What is the Evidence?Randomised Studies in Recurrent OC: Studies Pts. mono- vs. endocrine therapy 2 303 endocrine vs. endocrine therapy 2 106 combination vs. combination 2 107* Including 1 trial with multiple regimens according to testing; most other trials in pts. with platinum sensi

31、tive 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 1.0 mg/m d1-5 Etoposid 50 mg po d 6-12 q21Sehouli J 2008, J

32、CO178 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% 12 Mon.147 pts.mono vs. combination chemotherapy in refracto

33、ry 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 q28Trabectedin 1.1 mg/m q 21 +Doxil/Caelyx (PLD) 30 mg/m q28BJ Monk et all , ESMO

34、 2008118 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

35、mainly pt-sensitive ROCFrom Dr. Andreas du BoisWhat is the Evidence?Randomised Studies in Recurrent OC: Studies Pts. mono- vs. endocrine therapy 2 303 endocrine vs. endocrine therapy 2 106 combination vs. combination 2 107* Including 1 trial with multiple regimens according to testing; most other tr

36、ials in pts. with platinum sensitive relapse Weekly Paclitaxel 61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, 200462RTopotecan

37、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-valueOS (weeks, median) 36 41 0.455 G3/4 toxicity (all pts.;%) Neutropenia Alopecia (all grades

38、) 16 49 0.007mono vs. mono chemotherapy 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.*Statistically significant.健择vs.聚乙二醇脂质体阿霉素治疗铂类

39、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)RGemcitabine 1000 mg/m d1,8, 15 q28Caelyx 40 mg/m d1 q28Mito-3G Ferrandina e

40、t al JCO 200877 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.

41、 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 ROCFrom 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STOPSTOP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

42、 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) 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RTaxol 175 mg/ m2 3小时滴注，每月1 次，共3个月Taxol 175 mg/