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1、卵巢癌化療新進展The state of the art in chemotherapy for ovarian cancers,復(fù)旦大學(xué)附屬腫瘤醫(yī)院婦瘤科,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),Women,發(fā)病率32%Breast12%Lung & bronchus11%Colon & rectum6%Uterine corpus4%Ovary 4%Non-Hodgkin lymphoma 3%Melanomaof skin3%Thyroid2%Pancreas2%Urinar

2、y 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、宮頸癌、宮體癌發(fā)病率（1974-2000，SCDC）,內(nèi)容簡介,早期卵巢癌化療中晚期卵巢癌化療新輔助化療/中間手術(shù)復(fù)發(fā)性卵巢癌化療維持鞏固治療

3、Ca125升高處理,卵巢癌的治療,未治患者主要目的是治愈手術(shù)分期和細胞減滅術(shù)，繼而紫杉醇/鉑類聯(lián)合化療復(fù)發(fā)患者主要目的是減輕癥狀和提高生活質(zhì)量化療可以延長生存時間最終結(jié)果長期存活: 25-30%5-年 生存率從 30% (1970s) 提高至 50%,Ries LAG et al. SEER Cancer Statistics Review, 1975-2001, National Cancer Institute. Bethesda, MD, http:/seer.cancer.gov/csr/1975; 2001/, 2004.,卵巢癌可認為是一種慢性疾病,早期卵巢癌: FIGO I an

4、d II,全面的分期剖腹探查術(shù)經(jīng)腹全子宮/雙側(cè)卵巢輸卵管切除 (TAH/BSO)大網(wǎng)膜切除淋巴結(jié)切除術(shù)（dissection）腹膜和膈膜活檢（ biopsies）細胞學(xué)檢查高危 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 comprehensive review. textbook,低危,高危,(510% 復(fù)發(fā)率),(3040% 復(fù)發(fā)率),Stage IA or IB,Stag

5、e 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, www.cancernet.nci.nih.gov,GOG1571,2,輔助化療的隨機臨床試驗:3 vs 6 療程紫杉醇 + 卡鉑,結(jié)果6個療程進展危險性降

6、低了33% 生存率無改善,Action & Icon3,隨機臨床試驗無立即化療 vs 立即化療,結(jié)果立即化療 生存率提高8% vs復(fù)發(fā)時化療(82% vs 74%),FIGO Stage III and IV定義,III盆腔外腹膜種植和/或外陽性腹膜后或腹股溝淋巴結(jié)A病灶大致局限于真骨盆; 淋巴結(jié)陰性;鏡下腹腔種植B腹腔種植灶 2 cm; 淋巴結(jié)陰性C腹腔種植灶 2 cm 和/或陽性腹膜后淋巴結(jié)或腹股溝IV遠處轉(zhuǎn)移,Medical Oncology: A comprehensive textbook,準(zhǔn)確全面分期依據(jù)手術(shù)探查和 病理組織學(xué)、細胞學(xué)檢查根據(jù)腹腔內(nèi)轉(zhuǎn)移灶的大小對III期再分為III

7、a、IIIb、IIIc腹膜后淋巴結(jié)轉(zhuǎn)移影響分期肝表面和肝實質(zhì)轉(zhuǎn)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(zhuǎn)移,晚期卵巢癌：關(guān)鍵臨床實驗1,GOG 1111 and OV-102Cisplatin + paclitaxel vs cisplatin + cyclophosphamideImproved survival and progression-free survival withcisplatin + paclitaxel GOG 1323Cisplatin vs paclitaxel

8、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.

9、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):132

10、0-9,晚期卵巢癌: 關(guān)鍵臨床實驗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 ov

11、ercisplatin + 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方案成為晚期卵巢癌一線化療的“標(biāo)準(zhǔn)”,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7

12、5mg/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/順鉑組有較多的血液學(xué)毒性和神經(jīng)毒性，但毒性可控,OV10(N=688)-期,環(huán)磷酰胺750mg/m2順鉑75mg/m2,泰素175mg/m2(3h)順鉑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/順鉑組有較多的血液學(xué)毒性和神經(jīng)毒性，但毒

13、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/m2Paclitaxel 135 mg/m2 (24 h),Carboplatin AUC 7.5Paclitaxel 175 mg/m2 (3 h),Epithelial Ovarian Cancer Optimal Stage III No prior therapy Elective Second-Look Non-Inferiori

14、ty Design,Open:03-Apr-95Closed:26-Jan-98Accrual:792 pts (evaluable),I,II,Ozols, et al. Proc J Clin Oncol 21:3194, 2003,GOG158: Ovarian (optimal III),CDDP-Paclitaxel (24-h)(n = 400) median 48.8 m,Carbo-Paclitaxel (3-h)(n = 392) median 56.7 m,Adjusted Cox analysisHR 0.86 (95% CI 0.71 1.04),Ozols, et a

15、l. Proc J Clin Oncol 21:3194, 2003,56.7 vs 48.8 m = 7.9 m,晚期卵巢癌的化療,總之:手術(shù)和化療后約 75% 患者臨床完全緩解（CCR）， 但復(fù)發(fā)率 50%長期生存率 20 25%,提高療效的可能對策,引入更有效的方案紫杉醇 / 卡鉑 + 新藥腹腔化療增加劑量強度新的細胞毒性藥物分子靶向治療對復(fù)發(fā)癌更有效的治療發(fā)明有效的維持治療,Ozols, Seminars in Oncology, vol 29; Suppl 1 (Feb) 2002: 32-42.,提高初治卵巢癌化療療效：三藥聯(lián)合化療,標(biāo)準(zhǔn)治療PC + X,GOG0182-ICON5

16、,比較五種方案治療晚期卵巢上皮癌或原發(fā)性腹膜癌的III期隨機臨床試驗,25,Michael A Bookman, MDFox Chase Cancer CenterPhiladelphia, PA,Proc ASCO 2005:Abstract 5002,GOG0182-ICON5,26,GOG0182-ICON5: 無進展生存,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),G

17、OG0182-ICON5: 總生存,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： 結(jié)論,加入第三種細胞毒性藥物增加了血液學(xué)毒性，但是這種毒性是可控制的在所有評價的方案中，加入第三種細胞毒藥物不能改善患者預(yù)后（包括無進展生存和總生存）,29,Proc ASCO 2005:Abstract 5002,IV IP,提高初治卵巢癌化療療效：改變用途徑,GOG

18、172,31,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 滿意減滅術(shù) 術(shù)前無治療 選擇性二探,Open:23-Mar-98Closed:29-Jan-01Accrual:415 例 (可評價),I,II,Armstrong, et al. NEJM 354:34-43, 2006,GOG172: Ovarian (optimal III) IP vs. IV

19、,CDDP (IV) Paclitaxel (IV)(n = 210),CDDP (IP) Paclitaxel (IP+IV)(n = 206),Armstrong, et al. NEJM 354:34-43, 2006,GOG 172,結(jié)論：靜脈內(nèi)紫杉醇聯(lián)合腹腔內(nèi)順鉑和紫杉醇可改善理想減滅術(shù)后 III期卵巢癌患者的生存率,33,3周療周療,提高初治卵巢癌化療療效：增加用藥頻率,PC紫杉醇周療 vs 標(biāo)準(zhǔn)PT3周療 (JGOG ，2009),每周療：Paclitaxel 80mg d1, 8,15 Carboplatin AUC 6 d13周療：Paclitaxel 180mg d1 Ca

20、rboplatin AUC 6 d1,Isonishi S, et al. the Lancet 2009; 374:1331-38,晚期卵巢癌化療,卡鉑和紫杉醇：卡鉑（AUC=56）紫杉醇(175mg/m2) 滴注 3小時，每3周重復(fù)，共68個療程(catrgory 1)順鉑和紫杉醇：紫杉醇(135mg/m2) iv d1，DDP 100mg/m2 ip d2,紫杉醇(60mg/m2) ip d8,每3周重復(fù)，共68個療程(catrgory 1)卡鉑和多西紫杉醇：卡鉑（AUC=56）多西紫杉醇(60-75mg/m2) 滴注 1小時，每3周重復(fù)，共68個療程(catrgory 1)如對泰素過敏

21、，可改用其他替代藥物（如：泰素帝，topotecan，健擇，或脂質(zhì)體阿霉素）。不能耐受靜脈化療者，可選用口服化療藥，如：VP-16。,舉例：Case 1,53歲，女性表現(xiàn)為腹脹無腹腔外腫瘤生長證據(jù)腫瘤中等度大實施活檢后患者被轉(zhuǎn)至婦科腫瘤醫(yī)師,舉例：Case 1,對此患者實施了滿意的細胞減滅術(shù).殘留腫瘤最大直徑：1cm. 1枚腹主動脈旁淋巴結(jié)累及病理：中分化漿液性乳頭狀癌轉(zhuǎn)至尋求化療,舉例：Case 1,我們的患者選擇腹腔化療2個周期化療后她的CA125水平自122降至10患者無癥狀，繼續(xù)接受了4個周期的化療盆腔檢查、CT掃描、CA125結(jié)果均正常,新輔助化療與中間性細胞減滅術(shù),Neoadjuv

22、ant ChemotherapyInterval Cytoreduction,中間性細胞減滅術(shù)（12th IGCS曼谷，2008）,隨機非劣性實驗：718例IIIc-IV期卵巢癌初次細胞減滅術(shù)化療6程Vs化療3程細胞減滅術(shù)化療3程總生存率：29 m vs 30 mPFS: 12 m vs 12 m,Vergote et al. 12th biennial meeting of IGCS, Bangkok, Thailand,2008,腸系膜根部轉(zhuǎn)移肝實質(zhì)多發(fā)轉(zhuǎn)移,上皮性卵巢癌：Epithelial Ovarian Cancer (EOC)100例患者的典型“結(jié)局”,Early stage (I

23、-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

24、 gynecological cancers Editor: Pecorelli S. Intern J Gynecol & Obstet, Nov 2003 supplement,復(fù)發(fā)性卵巢癌目前的治療,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,約 25% 患者

25、于一線TC(paclitaxel+Carb.)治療后6-12個月復(fù)發(fā),約 50% 患者于一線TC治療后12個月復(fù)發(fā),存在的相關(guān)問題大多數(shù)(55%) 晚期患者將會出現(xiàn)鉑類敏感性復(fù)發(fā),無治療間期,0 6,7 12,13 18, 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(biāo),分類 目標(biāo) 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(fù)發(fā)性卵巢癌患者的治療標(biāo)準(zhǔn)？,對鉑類敏感的復(fù)發(fā)性卵巢癌單藥有效率 累積

26、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 Clin Oncol 2006;24(29):4699-4707.,健擇/卡鉑治療復(fù)發(fā)卵巢癌的III期臨床試驗,健擇/卡鉑治療復(fù)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(fù)發(fā)卵巢癌患者健擇聯(lián)合卡鉑方案顯著延

27、長PFS，提高緩解率，且未降低生活質(zhì)量1健擇聯(lián)合卡鉑快速緩解癥狀，并明顯改善生活質(zhì)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.,健擇/卡鉑治療復(fù)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(fù)發(fā)性卵巢癌治療模式:,手術(shù)few selected pts. (e.g. bowel obstruction

28、),內(nèi)分泌 TXSelected 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,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 = 2

29、59,楷萊 3n = 130,奧沙利鉑 4 n = 132,1 ten Bokkel JCO 1997 2 Gore EJC 2002 3 GordonJCO 2001 4 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 GordonJCO 2001 4 Piccart JCO 2000,%,What is the Evidence?,Randomised Studies

30、 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

31、 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

32、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

33、,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: 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 mg/m q28,BJ Monk et all