2006ASCO 胃癌治疗 最新研究结果 北京大学临床肿瘤学院 消化内科 沈 琳 2006 － 7

现 状： ► 在转移性胃癌的治疗中没有公认的治疗 “ 金标 准 ” ► “ FP ， FLP, ECF …… 在晚期胃癌中不应该 被当作标准治疗方案 ” ，但是常用的试验对照 方案 Vanhoefer U, et al. J Clin Oncol. 2000;14:2648–57.

新世纪，新选择 … ► 紫杉烷类 ＋顺铂 /5-Fu ► EOX → ECF ► CAPE +DDP → 5-FU+DDP ► 伊立替康＋ 5-Fu ► OXA ＋ 5-Fu ► 其它： CAPE/S-1+DOC/PTX

Docetaxel, 5-FU and Cisplatin: V 325 Phase III R A N D O M I Z E Stratification Factors: Liver Involvement Prior Gastrectomy Measurable vs Evaluable Disease Weight Loss (>5%) in Prior 3 Months Centers Response assessment every 8 weeks independent of treatment schedule Cisplatin 100 mg/m 2 IV D1 Cycles repeated every 4 weeks Docetaxel 75 mg/m 2 IV D1 Cisplatin 75 mg/m 2 IV D1 5-FU 750 mg/m 2 CIV D1-5 Cycles repeated every 3 weeks 5-FU 1000 mg/m 2 CIV D1-5 vs

研究 V325 结果 ► TCF( 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 总体缓 解 疾病进展时 间（月） 总生存期 （月） 3 — 4 级毒性 TCF 221/ % 腹泻，感染， 中性粒细胞 减少症 * p=0.01p=0.0004p=0.02 CF # / % 胃炎，肾毒 性 *3 － 4 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 —— Ⅱ期多中心临 床研究 （ 2003 ASCO ） FFCD 9803 法国 例 数例 数例 数例 数RRmTTPmOS LV5FU24513%3.2m6.8m LV5FU2- DDP 4427%4.9m9.5m LV5FU2- CPT %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 31.8% 25.8% TTP 5.0m 4.2m (p=0.05) AEs 10.0% 21.5% (p=0.004) OS p> 0.05 M. Dank 2005 ASCO abs 4003

► N=45/48 irinotecan 150 mg/m2 d1 irinotecan 150 mg/m2 d1 oxaliplatin 85 mg/m2 d1 oxaliplatin 85 mg/m2 d1 lv 100 mg/m2/ d lv 100 mg/m2/ d 5-FU 2000 mg/m2 48-h ci d1, Q 2 w 5-FU 2000 mg/m2 48-h ci d1, Q 2 w ► RR 73.3 % （ 2 CRs and 31 PR ）. SD 9% PD 18% ► estimated mOS 14.0 m estimated mTTP 8.9 m ► grade 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

新世纪，新选择 … ► 紫杉烷类 ＋顺铂 /5-Fu ► EOX → ECF ► CAPE +DDP → 5-FU+DDP ► 伊立替康＋ 5-Fu ► OXA ＋ 5-Fu ► 其它： CAPE/S-1+DOC/PTX

REAL 2 phase III trial: study design Sumpter K et al. Br J Cancer 2005;92:1976–83. First-line advanced esophagogastric cancer R A N D O M I Z A T I O N Epirubicin Cisplatin 5-FU Epirubicin Oxaliplatin 5-FU Epirubicin Cisplatin Xeloda Epirubicin Oxaliplatin Xeloda  Primary endpoint: overall survival  2X2 design with ECF as standard arm n=1002

REAL-2: Efficacy Efficacy ECF N=249 ECX N=241 EOF N=235 EOX N=239 P: ECF vs EOX RR (%) PFS (mo) OS (mo) Cunningham et al. ASCO 2006

ECFEOFECXEOX Grade 3/4 non- haematological toxicity, % Grade 3/4 neutropenia, % p-value REAL 2: safety outcomes ► There was less neutropenia in the Eloxatin- containing arms compared with the cisplatin- containing arms

REAL 2: conclusions ► The primary objective of the trial was met:  Capecitabine is not inferior to 5-FU  Oxaliplatin is not inferior to cisplatin ► In these triplet regimens  Capecitabine could replace 5-FU  Oxaliplatin could replace cisplatin ► The use of EOX is associated with improved efficacy over ECF

ML17032 trial design FP Cisplatin 80 mg/m 2 3-hour i.v. infusion 5-FU c.i. 800 mg/m 2 /day; d1–5 q3w XP Cisplatin 80 mg/m 2 3-hour i.v. infusion Capecitabine 1000 mg/m 2 twice daily; d1–14 q3w KPS ≥70% 18–75 years Advanced and/or metastatic gastric cancer (AGC) ≥1 measurable lesion No prior treatment for AGC RANDOMIZATIONRANDOMIZATION

Primary endpoint met: progression-free survival HR 0.81 Estimated probability HR=0.81 (95% CI: 0.63–1.04) Compared to HR upper limit 1.25, p= Months Per protocol analysis XP (n=139) FP (n=137) Median PFS months (95% CI) 5.6 (4.9–7.3) 5.0 (4.2–6.3)

Superior response rate with XP vs. FP Confirmed response % (95% CI) XP (n=160) FP (n=156) p-value Overall response 41 (33 – 49) 29 (22 – 37) Complete response Partial response Progressive disease

Similar all-grades hematologic adverse events: XP vs. FP % of patients % of patients XP (n=156) FP (n=155) Neutropenia3330 Leukopenia1417 Anemia125 Thrombocytopenia66

first-line chemotherapy with fluorouracil, leucovorin and oxaliplatin (FLO) versus fluorouracil, leucovorin and cisplatin (FLP) FLO F 2600mg/m2 24h infusion, L 200mg/m2, oxaliplatin 85mg/m2 q2w FLP F 2000mg/m2 24h infusion, qw L 200mg/m2, qw cisplatin 50mg/m2, q2w. Total 220 pts Median age 64 yrs Advanced and/or metastatic gastric cancer (AGC) RANDOMIZATIONRANDOMIZATION S. Al-Batran, J. Hartmann, ASCO 2006

Superior Performance with FLO vs. FLP Confirmed response % (95% CI) FLO(N=98) FLP (n=102) p-value Overall response 34%27%0.012 TTP TTF S. Al-Batran, J. Hartmann, ASCO 2006

A phase I study of S-1 plus weekly docetaxel in patients with mGC ► MTD for this regimen was S-1 90 mg/m2/d + docetaxel 35 mg/m2 ► RD was S-1 80 mg/m2/d (D1-14) + docetaxel 35 mg/m2 (D1, 8). ► DLT : diarrhea and febrile neutropenia S. R. Park, H. K. Kim ASCO 2006Abst ； T. Ozaki, ASCO 2006Abst ► MTD Fixed full dose of S1: 80 mg/m2 daily was administrated orally for 3 weeks. + docetaxel 25mg/m2 D1,8,15 ► RD S1 80 mg/m2 for 3 weeks and TXT: 20 mg/m2 day1, 8 and 15 ► DLT : febrile neutropenia, Grade3 stomatitis and continuous Grade 4 neutropenia. 3周方案3周方案 5周方案5周方案

Capecitabine and docetaxel for advanced gastric cancer ► part 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% CR 2.6%, PR 52.6%, NC 36.8%, PD 7.9%, RR: 55.3% ► In 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

Replacing 5-FU in TCF with CAPE: high efficacy in first-line AGC 1. Moiseyenko V et al. Proc Am Soc Clin Oncol 2005;(Abst 4002); 2. Kang Y et al. J Clin Oncol 2004;22:329s (Abst 4066) poster update; 3. Kang Y et al. Personal communication. Efficacy TCF 1 (n=227) TCX 2,3 (n=40) ORR (%) 95% CI 37 30– –83 TTP/PFS (months) OS (months)

Grade 3/4 adverse events TCX vs TCF: less hematological toxicity with CAPE 1. Moiseyenko V et al. Proc Am Soc Clin Oncol 2005;(Abst 4002); 2. Kang YK et al. Personal communication; 3. Kang YK et al. J Clin Oncol 2004;22:329s (Abst 4066) poster update TCF (n=221) TCX (n=40) % patients Anemia Febrile neutropenia Lethargy Neuropathy Neutropenia Platelets Vomiting HFS

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

CAPE: an effective and safe oral therapy for gastric cancer ► 安全、有效，方便、灵活，可与下列药物联合 治疗胃癌 :  oxaliplatin  cisplatin  Docetaxel 、 paclitaxel  irinotecan ► 可以替代 5-FU ► 可以替代 5 － FU 作为三药联合之一

Taxanes 在胃癌中应用的关键 —— 减毒 —— 通过改变剂量或方案 ► 疗效不减低 ► 不良反应减少 ► 从三药联合改为两药：减去 DDP ► 5-FU→ CAPE/S-1 ► DDP → OXA ► DOC 改为周给药方法 ► DOC 降低剂量强度： 50 － 60mg/m2

CPT-11 在胃癌治疗中的关键 ► 进一步提高生存期，减少不良反应 ► FOLFIRI ， FOLFOXIRI? ► CPT-11+DDP/5-FU? ► S-I/CAPE+CPT-11? ► 靶向药物联合 CPT-11

结论 ► 目前，在转移性胃癌的治疗中没有一种方案明确 优于其他的治疗方案  有一些治疗方案可以获得极高的缓解率，但同时也被 证实存在难以耐受的毒性 ► 最近的资料显示 DOC/PTX/OXA/CPT- 11/CAPE/S-1 是有效的治疗药物 ► EOX, DOC/PTX/CPT/OXA+CAPE/S-1/FU ， 是最有前途的治疗方案 ► 需要更多的研究来证实和确认更为安全，且更为 有效的治疗方案和给药方法