1、卵巢癌化療新進展 The state of the art in chemotherapy for ovarian cancers,復旦大學附屬腫瘤醫(yī)院婦瘤科,1,女性生殖道腫瘤: 全世界統(tǒng)計1,Ferlay et al. GLOBOCAN 2000 IARC, WHO 2001 (www.dep.iarc.fr),2,3,Women,發(fā)病率 32% Breast 12% Lung 2001/, 2004.,卵巢癌可認為是一種 慢性疾病,早期卵巢癌: FIGO I and II,全面的分期剖腹探查術 經(jīng)腹全子宮/雙側卵巢輸卵管切除 (TAH/BSO) 大網(wǎng)膜切除 淋巴結切除術（dissecti

2、on） 腹膜和膈膜活檢（ biopsies） 細胞學檢查 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% 復發(fā)率),(3040% 復發(fā)率),Stage IA or IB,Stage IC,Grade 1 (or 2),Grade 3 Clear cell cancer,高危早期卵巢癌,You

3、ng 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,輔助化療的隨機臨床試驗: 3 vs 6 療程 紫杉醇 + 卡鉑,結果 6個療程 進展危險性降低了33% 生存率無改善,Action 淋巴結陰性; 鏡下腹腔種植 B 腹腔種植灶 2 cm; 淋巴結

4、陰性 C 腹腔種植灶 2 cm 和/或陽性腹膜后淋巴結或腹股溝 IV 遠處轉移,Medical Oncology: A comprehensive review. textbook,準確全面分期依據(jù)手術探查和 病理組織學、細胞學檢查 根據(jù)腹腔內轉移灶的大小對III期再分為IIIa、IIIb、IIIc 腹膜后淋巴結轉移影響分期 肝表面和肝實質轉移分屬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: 遠處轉移,16,晚期卵巢癌：關鍵臨床實驗1,GOG 1111 and OV-102 Cisplatin + pacl

5、itaxel 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 + doxo

6、rubicin + 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), 1

7、44-148 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: 關鍵臨床實驗2,ICON-5-GOG182 （2006） Carboplatin + paclitaxel vs Gemcitabin triplet vs Doxil Triplet vs Topotecan duble + TP vs Gem

8、citabin 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方案成為晚期卵巢癌一線化療的“標準”,19,1996,2000,GOG111 (N=410)-期,環(huán)磷酰胺750mg/m2 順鉑75mg/m2,泰素35mg/m2(24h) 順鉑75mg/m2,VS,ORR: 73% 60% p=0.01,CR: 51% 31% p=0.01,PFS: 18mo 13mo 12個月復發(fā),存在的相關問題 大多數(shù)(55%) 晚期患者將會出現(xiàn)鉑類敏感性復發(fā),無治療間期,0 6,7 12,13 1

10、8, 18,0,20,40,60,80,100,距前次治療的時間（月）,有效率 (%),Blackledge, et al. Br J Cancer. 1989;59:650-653.,二線化療的目標,分類 目標 治療無效 緩解 ( 6, 12 個月) 治愈?,對鉑類敏感的卵巢癌,兩藥聯(lián)合化療能否成為對鉑類敏感的復發(fā)性卵巢癌患者的治療標準？,對鉑類敏感的復發(fā)性卵巢癌 單藥有效率 累積總有效率（OR）,du Bois A et al. 2000 Geburtsh Frauenheilk 2000; 60:41-58,但是, 這個問題在一個RCT即可解決!,Pfisterer et al. J C

11、lin Oncol 2006;24(29):4699-4707.,健擇/卡鉑治療復發(fā)卵巢癌的III期臨床試驗,健擇/卡鉑治療復發(fā)卵巢癌的III期臨床試驗: PFS,卡鉑組178例162例進展事件；健擇/卡鉑組178例163例進展事件,Pfisterer et al. J Clin Oncol 2006;24(29):4699-4707.,鉑類敏感的復發(fā)卵巢癌患者 健擇聯(lián)合卡鉑方案顯著延長PFS，提高緩解率，且未降低生活質量1 健擇聯(lián)合卡鉑快速緩解癥狀，并明顯改善生活質量2,1Pfisterer et al. J Clin Oncol 2006;24(29):4699. 2Pfisterer e

12、t al. Int J Gynecol Cancer 2005;15(Suppl 1):36-41.,健擇/卡鉑治療復發(fā)卵巢癌的III期臨床試驗,各個方案的毒副作用不同： 卡鉑-紫杉醇：神經(jīng)毒性 卡鉑-多西紫杉醇：血液性毒性 卡鉑-吉西他濱：血液性毒性 順鉑-吉西他濱：血液性毒性,鉑類耐藥復發(fā)性卵巢癌治療模式:,手術 few selected pts. (e.g. bowel obstruction),內分泌 TX Selected pts., rather 3rd/4th line ?,支持治療 every pt. as needed,放療 few selected pts.,心理-社會支持

13、 every pt. as needed,“新藥“ only in clinical trials,非鉑單藥 Tx,非鉑聯(lián)合 Tx,鉑類為主治療 mainly pt-sensitive ROC,From Dr. Andreas du Bois,對鉑類耐藥卵巢癌,選擇哪種非鉑類？ 單藥 聯(lián)合 或改變用藥途徑？ 或改變用藥方案？,有效率 隨機臨床試驗，0 6個月,紫杉醇 1,4 n = 90,拓泊替康 1,2,4 n = 259,楷萊 3 n = 130,奧沙利鉑 4 n = 132,1 ten Bokkel JCO 1997 2 Gore EJC 2002 3 Gordon JCO 2001 4

14、 Piccart JCO 2000,%,有效率 隨機臨床試驗， 6個月,紫杉醇 1,4 n = 90,拓泊替康 1,2,4 n = 259,楷萊 3 n = 109,奧沙利鉑 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/do

15、se/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,P

16、aclitaxel 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,1

17、78 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 ref

18、ractory 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) 30

19、 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.,鉑類耐藥復發(fā)性卵巢癌治療模式:,手術 few selected pts. (e.g. bowel obstruction),內分泌 TX Selected pts., rather 3rd/4th line ?,支持治療 every pt. as needed,放療 few selected pts.,心理-社會支持 every pt. as needed,“新藥“ only i

20、n clinical trials,非鉑單藥 Tx,目前尚無足夠證據(jù)支持 非鉑聯(lián)合 Tx,鉑類為主治療 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. end

21、ocrine 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,復發(fā)或耐藥的卵巢癌癌患者,泰素80mg/m2, 每周給藥，連續(xù)3周，休息一周，至少兩周期。,Weekly Pac

22、litaxel （80 mg/m2/周）,用于對TP方案無反應或耐藥的病例 RR Markman 25% Kaern 56% Kita 25-56% 毒性主要為可耐受的神經(jīng)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.-r

23、efractory, 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 Tr

24、eatment-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 c

25、hemotherapy in recurrent (mostly) refractory OC - RCTs,66 pts.,64 pts.,*Statistically significant.,健擇vs.聚乙二醇脂質體阿霉素治療鉑類耐藥的卵巢癌的III期臨床試驗,研究結論： 健擇可替代聚乙二醇脂質體阿霉素治療鉑類耐藥的卵巢癌患者,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 adv

26、antage 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,鉑類耐藥復發(fā)性卵巢癌治療模式:,手術 few se

27、lected pts. (e.g. bowel obstruction),內分泌 TX Selected pts., rather 3rd/4th line ?,支持治療 every pt. as needed,放療 few selected pts.,心理-社會支持 every pt. as needed,“新藥“ only in clinical trials,首選 非鉑單藥： Caelyx Topotecan Gemcitabine,目前尚無足夠證據(jù)支持 非鉑聯(lián)合 Tx,鉑類為主治療 mainly pt-sensitive ROC,From Dr. Andreas du Bois,二線治

28、療,一線治療,一線治療,三線治療,12 個月,3 個月,3 個月,STOP,STOP,二線治療,3 個月,3 個月,卵巢癌終止治療： London Royal Marsden Hospital 指南,74,Maintenance（維持） Prolonged administration of treatment 延長治療 Treatment until progression 治療至進展 Consolidation（鞏固） A defined therapy following a response to initial treatment 首次治療有效后，接著同樣的治療,定義：Definit

29、ions,鞏固/維持治療 隨機臨床試驗（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,鞏固化療,Mar

30、kman的期臨床研究： 兩組PFS相差7個月，OS無差異,277 例卵巢癌患者經(jīng)過手術后及TP 聯(lián)合化療達到完全緩解,R,Taxol 175 mg/ m2 3小時滴 注，每月1 次，共3個月,Taxol 175 mg/ m2 3 小時滴 注，每月1 次，共12個月,Markman M et al. Gynecol Oncol 2002; 84(3):79,卵巢癌: 生物靶向治療,獨特腹腔上皮和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) 生長因子