晚期胃癌化疗策略

晚期胃癌化疗策略 晚期胃癌治疗现状 n局部进展期治愈：手术与化疗的结合 n复发或转移不能治愈：化疗为主的综合治 疗，但手术或其它局部治疗手段的作用加强 n化疗：新药、新方案高效低毒，近期疗效增加 而生存期延长不满意，但近3年进展迅速 胃癌化疗 n新辅助化疗 n辅助化疗 n晚期胃癌的化疗 生存目标 新辅化辅化 根治、延长PFS 手术 姑息化疗 手 术 化 疗 化 疗 延长生存期 改善生活质量 化疗 手术 局部治疗 晚期胃癌化疗临床问题 n药物、方案的选择 n疗程及后续治疗 n化疗与手术或局部治疗的合理应用（新辅 助化疗） n手术后辅助化疗 药物、方案的选择 所有的选择: 5FU/CAPE/S-1 DDP+5FU ECF/LFEP 多西紫杉醇/紫杉醇CAPE/DDP+5FU OXA+CAPE/5FU CPT-11+5FU/CAPE/S-1 分子靶点药物 Randomized Phase III Study : 1990-2000 StudyRegimenNRR (%) p- value MSTp- value EORTC 1991 FAM FAMTX 103 105 9 41 5%) in Prior 3 Months Centers Response assessment every 8 weeks independent of treatment schedule Cisplatin 100 mg/m2 IV D1 Cycles repeated every 4 weeks Docetaxel 75 mg/m2 IV D1 Cisplatin 75 mg/m2 IV D1 5-FU 750 mg/m2 CIV D1-5 Cycles repeated every 3 weeks 5-FU 1000 mg/m2 CIV D1-5 vs 胃癌III期临床-TAX 325随 访结果 n TCF vs CF p N 227 230 RR 37% 25% 0.0106 TTP 5.6m 3.7m 0.0004 2Y 18% 9% 0.0201 G3/4 81% 75% 2005 ASCO，abs 4002 TAX325: increased febrile neutropenia with TCF % patients with grade 3/4 Neutropenia Anemia Platelets Febrile neutro- penia, infection 0 20 40 60 80 100 TCF FP Moiseyenko VM et al. Proc Am Soc Clin Oncol 2005;(Abst 4002). 82 57 30 14 TAX 325 研究结果 nTCF(多西紫杉醇、顺铂、5FU)是用于预后较好的患者 的一项新的治疗选择 Moiseyenko et al, ASCO 2005, Abstract 4002 例数总总体缓缓解 疾病进进展时间时间 （月） 总总生存期（ 月） 34级级毒性 TCF221/22737%5.69.2 腹泻，感染， 中性粒细细胞减 少症* p=0.01p=0.0004p=0.02 CF 224/23025%3.78.6胃炎，肾肾毒性 *34级毒性包括：81的非血液学毒性反应， 75的血液学毒性反应中30伴有中性粒细胞减少性发热 CPT-11 for AGC期多中心 临床研究 （2003 ASCO）FFCD 9803 法国 Bouche O et al. J Clin Oncol2004;22:431927 例 数RRmTTPmOS LV5FU2 4513%3.2m6.8m LV5FU2- DDP 4427%4.9m9.5m LV5FU2- CPT-11 4540%6.7m11.3m CPT-11联合5-FU治疗AGC -III期临床试验（2005 ASCO） N=170 CPT-11 80mg/m2 CF 500mg/m2 5FU 2000mg/m2 civ 1/W x 6w N=163 CDDP 100mg/m2 d1 5FU 1000mg/m2/d d1-5 Q4W N=333 AGC RR 5454（31.8%31.8%） 4242（25.8%25.8%） TTP 5.0m 4.2m (p=0.088) TTF 4.0m 3.4m (p=0.002) OS 9.0m 8.7m p0.53 M. Dank 2005 ASCO abs 4003 新世纪初的选择：问题！ n多西紫杉醇（Docetaxel）联合DDP/5-FU： 高效！生存期延长！不良反应性大！ nCPT-11联合5-FU/CF: RR改善、安全性提高、TTF延长, OS无延长 n如何改变？更合理的选择？ 新的探索和循证医学证据 nOXA DDP nCAPE5-FU n重新设定剂量强度或改变剂量密度 n增、减药物联合 n续惯。 REAL 2 randomised multicentre phase III study comparing capecitabine with 5-FU and oxaliplatin with cisplatin in patients with advanced oesophagogastric cancer D Cunningham et al. 2006 ASCO Abstract LBA 4017 REAL-2: randomized, phase III trial in gastric and GEJ cancer Epirubicin Cisplatin 5-FU Epirubicin Cisplatin Xeloda Epirubicin Eloxatin 5-FU Epirubicin Eloxatin Xeloda 21-day cycle Planned duration of treatment: 24 weeks (8 cycles) Target randomization n=600 Eloxatin 130mg/m 2 day 1 CAPE 625 mg/m2 twice daily days 121 Eprirubucin 50mg/m2 day 1; Cisplatin 60 mg/m2 day1; 5-FU 200 mg/m2/day REAL 2: 研究目标 nPrimary endpoint of non-inferiority in overall survival nXeloda vs. 5-FU noxaliplatin vs. cisplatin nSecondary endpoints nORR and response duration nPFS nsafety nQoL Sumpter K et al. Br J Cancer 2005;92:197683. REAL 2 interim analysis: good response with oxali- vs. cisplatin % Cisplatin arms ECF 92:164449. 2. Al-Batran et al. J Clin Oncol 2004;22:65863. 3. Al-Batram et al, ASCO 2005, Abstract 4014. 方案例数缓缓解率 疾病进进展 时间时间 /总总 生存期 3-4度的 神经经病 变变 FOLFOX416138%7.1/11.25% FOLFOX624143%-/9.60 改良的FOLFOX6 vs 5-Fu(AIO) 顺铂顺铂 3 105 （80例可评评价 ） 39.1% 24.2% - 54.5% 19.4% Oxaliplatin/CF/5-FU vs paclitaxel/CF/5-FU in pats with advanced gastric cancer A phase II clinical trial T. Lin ASCO2006 Abstr 14014 armA FOLFOX6armB FOLFPa PTX 80 mg/m2 病例数 4643 CR+PR37.0%47.2% CR+PR+SD76.1%69.4% TTP6.0 m3.2 m? OS13.4 m13.8 m Phase II multicenter trial of docetaxel + oxaliplatin in stage IV gastroesophageal and/or stomach cancer PATIENT PROFILE: Median age=59.4 years 72% male patients, 76% white ECOG PS scores: 0 (45%); 1 ( 49%); 2 (6%) 32.8% of patients had distal gastric cancer N=71 Eligibility: Patients with metastatic (Stage IV) AGEJ/S ENDPOINTS: Primary: ORR, Secondary: time to response, duration of response, TTP, toxicity, 1- and 2-year survival Docetaxel 60 mg/m2 1h IV D1; q3w Oxaliplatin130 mg/m2 2h IV D1; q3w + Richards DA et al.2006 ASCO Abstract 4071 Results: efficacy N% Best response Partial response25 38 Stable disease (SD 6 months; 3 patients)3452 Progressive disease711 Clinical benefit rate2842 Time to response (months) Median 1.3 Range 1.14.4 Duration of response (months) Median 4.6 Range 2.718.3 Estimated overall survival rate Media survival time 95% CI 9.2 months 6.511.2 RR of 38% similar to TAX 325; OS of 9.2 months similar to TAX 325 Adverse events (Grade 3/4)Total (%) Haematological Leukopenia Neutropenia Thrombocytopenia Febrile neutropenia 17 70 7 7 Non-haematological Dehydration Diarrhoea Fatigue Nausea Vomiting 13 13 13 16 17 Results: toxicity ML17032 : CAPE vs 5-FU trial design FP Cisplatin 80 mg/m2 3-hour i.v. infusion 5-FU c.i. 800 mg/m2/day; d15 q3w XP Cisplatin 80 mg/m2 3-hour i.v. infusion Capecitabine 1000 mg/m2 twice daily; d114 q3w KPS 70% 1875 years Advanced and/or metastatic gastric cancer (AGC) 1 measurable lesion No prior treatment for AGC R A N D O M I Z A T I O N Superior response rate with XP vs. FP Confirmed response % (95% CI) XP (n=160) FP (n=156) p-value Overall response 41 (3349) 29 (2237) 0.030 Complete response 230.668 Partial response39260.019 Progressive disease 10180.041 ML17032 : XP vs FP progression-free survival HR 0.81 Estimated probability HR=0.81 (95% CI: 0.631.04) Compared to HR upper limit 1.25, p=0.0008 0 Months 2468101214161820222426 1.0 0.8 0.6 0.4 0.2 0.0 Per protocol analysis XP (n=139) FP (n=137) Median PFS months (95% CI) 5.6 (4.97.3) 5.0 (4.26.3) Similar all-grades hematologic adverse events: XP vs. FP % of patients XP (n=156) FP (n=155) Neutropenia3330 Leukopenia 1417 Anemia125 Thrombocytopenia66 A Phase II Trial of Capecitabine and DDP in AGCChina 2002.6-2003.5, N=145, Cape 1000mg/m2 Bid d1- 14 DDP 20mg/m2 iv d1-5 q3W 130pts evaluable : 98M/32F Age: 53.7ys Results CR 10 (8%) PR 48(37%) SD 51(39%) PD 21(16%) OS 12m Safety：grade 3-4 adverse event 5% -2005,2006 ASCO Summary of Combination Chemotherapy with CAPE in AGC Regimen X XP TX DX DX (weekly) ECX DXP N 44 42 45 42 55 54 40 RR(%) 34 55 49 60 40 59 68 TTP (mo) 3.2 6.3 5.7 5.2 4.5 6.0 7.8 OS (mo) 9.5 10.1 11.4 10.5 12.0 9.6 16.9 Neut(%) G3/4 0 32 47 15* 36 60 63 Neut Fever(%) 0 0 0 7 9 19 10 Tx Death - - - - - 1 1 X; Xeloda, P; Cisplatin, T; Taxol, D; Docetaxel, E; Epirubicin, C; Cisplatin * not based on weekly CBC CAPE vs 5-FU in doublet regimens for AGC StudiesnRR (%) PFS/TTP months OS months Oxaliplatin + 5-FU1 Oxaliplatin + X2 44 20 40 65 5.8 7.5 9.3 too early Irinotecan + 5-FU3 Irinotecan + X4 172 38 32 46 5.0 5.1 9.0 8.6 Paclitaxel + 5-FU5 Paclitaxel + X6 38 40 42 50 4.3 6.8 9.9 13.6 Docetaxel + 5-FU7 Docetaxel + X8 43 38 38 60 5.5 5.2 9.5 10.5 1. Al-Batran S Proc Am Soc Clin Oncol 2005;(Abst 4015); 2. Park Y Br J Cancer 2006;94:95963; 3. Dank M Proc Am Soc Clin Oncol 2005;(Abst 4003); 4. Baek J Br J Cancer 2006 Apr 25; 5. Park S. Anticancer Drugs 2006;17:2259;6. Kang. H. Proc Am Soc Clin Oncol 2004;(Abst 4051, poster update); 7. Thuss-Patience P J Clin Oncol 2005;23:494501; 8. Park Y Br J Cancer 2004;90:132933 新的探索和循证医学证据 nCAPE5-FU nOXA DDP n重新设定剂量强度或改变剂量密度 n增、减药物联合 n续惯。 伊立替康联合5-FU/LV、CDDP治疗 胃癌 方法nRR( %) 中位生 存期（ 月） 研究者 CPT-11:80mg/m2 , 5-FU:2000mg/m2 , FA： 500mg/m2 , CDDP：20-50mg/m2 每2周1次 1770NASchleucher et al（2003 ） 降低5FU剂量强度 改变给药间隔 增加DDP 伊立替康联合奥沙利铂治疗胃癌 CR(%)PR(%)RR(%)中位有效期 （月） 中位进进展期 （月） 中位存活时间时间 （月） 3.146.950.055.58.5 中性粒细 胞减少症 贫血 3级 腹泻 神经 毒性 3级 虚弱 发热性中 性粒细胞 减少症 不 良 反 应 发 生 率 Souglakos J, et al. Ann Oncol. 2004;15(8):1204-9 N=32 CPT: 200mg/m2 iv 30m d1, OXA: 85mg/m2 iv 2h d1 Q3WCPT: 200mg/m2 iv 30m d1, OXA: 85mg/m2 iv 2h d1 Q3W 有效率提高！ 生存期延长不满意！ irinotecan plus capecitabine in patients with AGC nN= 38/ 40 /41 ， nCape 1000 mg/m2 BID day 1- 14 irinotecan 100 mg/m2 d 1，8 Q3W nRR 46.3%. TTP 5.1 OS 8.6 m, n Grade 3/4 neutropenia in 4 pats grade 3 febrile neutropenia in 2 pats. grade 3 diarrhea grade 2 HFS in 6 patients J. Baek ASCO2006，ABSTR14037 nIri 80 mg/m2 on d1, 8, and 15 ncape 625 mg/m2 BID D1- 14; Q 4 w n29/31 pts were evaluable for response nPR 38.5% . SD29%, nTTP 5.8 months n OS 10.5 months nno grade III-IV toxicity F. Farhat ASCO2006 Abstr 14030 nS-1 80 mgm2 d1 - 14 q28d nCPT-11 70-100 mgm2 d1 , 8 nq 4 weeks, nphase I : nMTD : CPT-11 90 mg/m2 nRD 80 mg/m2. n phase II: 42 pats nThe median treatment course was 5 (range: 113). n RR 62% (95% confidence interval: 47.276.6%), n The median survival time was 444 days. ngrade 34haematological 19% ; nonhaematological toxicities 10%, 伊立替康联合S1治疗胃癌临床I/II 期试验 M Inokuch British J Cancer (2006) 94, 1130 1135 nN=45/48 irinotecan 150 mg/m2 d1 oxaliplatin 85 mg/m2 d1 lv 100 mg/m2/ d 5-FU 2000 mg/m2 48-h ci d1, Q 2 w nRR 73.3 % （2 CRs and 31 PR）. SD 9% PD 18% nestimated mOS 14.0 m estimated mTTP 8.9 m ngrade 3/4 toxicities were neutropenia (11% of all cycles) and emesis (12%) FOLFOXIRI combination chemotherapy in metastatic or recurrent gastric cancer J. Lee ASCO2006 Abstr 4076 Aphase I study of S-1 plus weekly docetaxel in patients with mGC nMTD for this regimen was S-1 90 mg/m2/d + docetaxel 35 mg/m2 d1,8 n RD was S-1 80 mg/m2/d (D1-14) + docetaxel 35 mg/m2 (D1, 8). nDLT : diarrhea and febrile neutropenia S. R. Park, H. K. Kim ASCO 2006Abst 14005； T. Ozaki, ASCO 2006Abst 14108 nMTD S1: 80 mg/m2 d1-21 + docetaxel 25mg/m2 D1,8,15 n RD S1 80 mg/m2 d1-21 and docetaxel : 20 mg/m2 day1, 8 and 15 nDLT : febrile neutropenia, Grade3 stomatitis and continuous Grade 4 neutropenia. 3 周 方 案 5 周 方 案 Capecitabine and docetaxel for advanced gastric cancer npart I ：Docetaxel 75 mg/m2 d1, capecitabine 2000 mg/m2 d1-14, q3w. CR 2.6%, PR 52.6%, NC 36.8%, PD 7.9%, RR: 55.3% nIn part II ： further improve tolerability ： reduced the dose of docetaxel to 60 mg/m2 and capecitabine to 1600 mg/m2 to P. C. Thuss-Patience, 2006ASCO Abstr: 4068 Taxanes+5-FU或CDDP二联治疗AGC 方法： PCT 175mg/m2/3w, DCT 75-85mg/m2/3w 5-FU 750mg/m2 civ , d1-5/3w或 200-300mg/m2/3w civ2w/3w CDDP 20mg/m2 I.V. d1-5/3w或75mg/m2 I.V. /d1/3w A phase I/II study of oxaliplatin, docetaxel, and capecitabine in advanced carcinoma of the esophagus and stomach. DLT： Grade 3/4 diarrhea, nausea, and febrile neutropenia RD：Oxaliplatin 50 mg/m2 and docetaxel 35 mg/m2 day 1 and 8 capecitabine 750mg/m2 BID 10 days Q21 day D. L. Evans ASCO2006 Abstr 14046 A phase II study of alternating chemotherapy with CDDP/ 5FU/ FA and epirubicin (E)/ docetaxel (T) (CF-ET regimen) as first line therapy for pts with MGC nN= 34 CDDP 35 mg/m2 d1, 2, 15 and 16, 5FU 2000 mg/m2 ci d 1, 8, 15 and 22, FA 200 mg/m2 iv d 1, 8, 15 and 22 E 60 mg/m2 d 29 and 43, T 60 mg/m2 d 29 and 43 q 8W n RR 64.5%. The median response duration was 6.1 months . OS 11.4 months 。 n Grade 3/4 toxicities： leukopenia 41/37.5%, neutropenia 16/82%, thrombocytopenia 23.2/0%, H. H. Kirchner ASCO2006 Abstr 14021 续贯 靶向治疗 靶点期 Her-2Herceptin VEGFBevacizumab(Avastin) EGFR西妥昔单单抗（C225） 多靶点Sutent(Sunitinib) EGFR nEGFR在66的胃癌中过表达（Roid 2001） n吉非替尼（酪氨酸激酶抑制剂） n胃癌：缓解率为1，N75（ASCO2003） n食管腺/鳞细胞癌：缓解率为1012，N=56（ ASCO 2004） nErlotinib（Tarceva） n食管腺/鳞细胞癌：缓解率为16，N=17（ASCO 2004） n胃或胃食管交接部癌：N2644，缓解率为0 12（1例完全缓解）（ASCO2005） VEGFR nBevacizumab抑制VEGFR n在转移性病变中顺铂和伊立替康（MSKCC ） n辅助ECF方案（MAGIC-2实验） 胃癌靶向治疗 Bevacizumab（BEV）联合PT-11+DDP 一线治疗AGC - II期临床试验（ASCO 2005） BEV 15mg/kg d1 CPT 65mg/m2 d1，8 DDP 30mg/m2 d1，8 q3w N=24 3m PFS 89% 6m PFS 76% 16例可评价近期疗效 PR （12/16）75% MR 3 ，SD 1 不良反应（24例）： 级白细胞减少、恶心呕吐、腹泻 8% 血栓（4肺和2深静脉）：6例（20%）； 2例胃穿孔，2例几近穿