胰腺国际论坛2014

同济大学附属东方医院高勇2014.11,晚期胰腺癌化疗选择的思考,Key Milestones in the Treatment of Pancreatic CancerFDA Approval for MPC1,1. DrugsFDA.gov. /scripts/cder/drugsatfda/index.cfm. Accessed June 20, 2012.,2,MPC, metastatic pancreatic cancer, PDAC, pancreatic ductal adenocarcinoma.,2014NCCN指南推荐：晚期胰腺癌一线治疗,分享内容,思考一、化疗方案，孰优孰劣思考二、预后因素深度分析思考三、支持治疗，被动？积极？,思考一、化疗方案，孰优孰劣？,生存期比较,晚期胰腺癌专家推荐或者NCCN指南：,a For fit patients defined as those with ECOG PS 0/1, 75 years old, no or limited comorbidities, serum bilirubin value 1.5 ULN who are not candidates for FOLFIRINOX or nab-paclitaxel.b For patients with poor performance status, elderly, and/or significant comorbidities.5-FU, 5-fluorouracil; CapeOx, capecitabine, oxaliplatin; ECOG, Eastern Cooperative Oncology Group; ESMO, European Society for Medical Oncology; FOLFIRINOX, 5-fluorouracil, leucovorin, irinotecan, oxaliplatin; NCCN, National Comprehensive Cancer Network; PC, pancreatic cancer; PS, performance status; pt, patient; ULN, upper limit of normal.,1. NCCN Clinical Practice Guidelines in Oncology: Pancreatic Adenocarcinoma. v1.2013. 2. Verslype C, et al. Ann Oncol. 2012;24:iv5-iv10.,6,研究方案,FOLFIRINOX,. . .,R,Conroy T. et al., N Engl J Med.2011 12;364(19):1817-25.,患者入组基线特征,Conroy T. et al., N Engl J Med.2011May 12;364(19):1817-25.Andrew H. Ko J Clin Oncol 2011; 29:3727-3729.,FOLFIRINOX组严重不良反应显著增加,Conroy T., et al., N Engl J Med. 2011; 364(19): 1817-25.,研究结论,FOLFIRINOX是转移性胰腺癌一线治疗的选择之一患者需76岁，PS 0/1，胆红素正常或接近正常水平,Conroy T. et al., N Engl J Med.2011 12;364(19):1817-25.,专家评论,该研究存在的问题：两组患者的基线特征并不完全平衡，吉西他滨组的肺部转移患者数显著高于试验组胆囊炎发生情况未提及，如胰头癌比例提高也许会增加胆道感染率。至少不推荐胆管支架患者接受该方案FOLFIRINOX的毒性反应堪忧：46%患者出现3/4级粒缺(5.4%伴发热),虽然研究结果为阳性，但副作用使其临床应用受阻,Tempero MA. 2010 ASCO Gastorintestinal (Noncolorectal) Cancer,主要终点: OS次要终点: 独立评审的 PFS 和 ORR (RECIST v1.0)根据 NCI CTCAE v 3.0 分级的安全性和耐受性治疗直至疾病进展每 8 周进行 CT 扫描这项国际性研究在北美、欧洲和澳大利亚的 151 家中心入组了 861 例患者,Goldstein D, El-Maraghi RH, Hammel P, et al. Updated survival from a randomized phase III trial (MPACT) of nab-paclitaxel plus gemcitabine versus gemcitabine alone for patients (pts) with metastatic adenocarcinoma of the pancreas abstract 178. Oral presentation at: Gastrointestinal Cancers Symposium; January 16-18, 2014; San Francisco, CA.,MPACT研究,Gem, gemcitabine; HR, hazard ratio; nab-P, nab-paclitaxel; OS, overall survival.Goldstein D, El-Maraghi RH, Hammel P, et al. Updated survival from a randomized phase III trial (MPACT) of nab-paclitaxel plus gemcitabine versus gemcitabine alone for patients (pts) with metastatic adenocarcinoma of the pancreas abstract 178. Oral presentation at: Gastrointestinal Cancers Symposium; January 16-18, 2014; San Francisco, CA.,2013 年 5 月 9 日更新的总生存,更长的随访期后，中位 OS 的差别为 2.1 个月，并且在白蛋白紫杉醇联合吉西他滨组出现了生存 3 年以上的患者,Goldstein D, El-Maraghi RH, Hammel P, et al. Updated survival from a randomized phase III trial (MPACT) of nab-paclitaxel plus gemcitabine versus gemcitabine alone for patients (pts) with metastatic adenocarcinoma of the pancreas abstract 178. Oral presentation at: Gastrointestinal Cancers Symposium; January 16-18, 2014; San Francisco, CA.,总生存率,Gem, gemcitabine; HR, hazard ratio; KPS, Karnofsky Performance Scale; nab-P, nab-paclitaxel; OS, overall survival.Goldstein D, El-Maraghi RH, Hammel P, et al. Updated survival from a randomized phase III trial (MPACT) of nab-paclitaxel plus gemcitabine versus gemcitabine alone for patients (pts) with metastatic adenocarcinoma of the pancreas abstract 178. Oral presentation at: Gastrointestinal Cancers Symposium; January 16-18, 2014; San Francisco, CA.,亚组的 OS 更新,S-1 的 GEST 研究:,分层因素: 转移性 vs. 局部晚期 研究中心,R,n=834,*根据体表面积（BSA）, BSA =1.5,Gem (n=277)1000 mg/m2 d1, 8, 154周重复,S-1 (n=280)80, 100, 120 mg*/body d1-286周重复,Gem + S-1 (n=277)GEM: 1000 mg/m2 d1, 8S-1: 60, 80, 100 mg*/body d1-143周重复,不可切除的晚期胰腺癌,优效性比较： GEM + S-1 vs GEM非劣效性比较：S-1 vs Gem主要终点： OS次要终点：PFS, ORR, 不良反应、生活质量,GEST 研究结果,RR：Gem vs. S-1：p=0.02Gem vs. GS: p0.001,Gem vs. S-1 : OS非劣效性HR=0.96 (97.5% CI:0.78-1.18)P0.001,Gem vs. GS : OS优效性HR=0.88 (97.5% CI:0.71-1.08)p=0.15,GEST 研究结论,主要终点总生存期无获益，仅局部晚期胰腺癌获益次要终点：延长PFS、提高ORR、改善生活质量,S-1单药总生存非劣效于GEM单药论证单药非劣效于GEM的首个III期临床试验S-1显示了良好疗效,GEM+S-1显著提高了无进展生存，但未提高总生存GEM+S-1可改善患者生活质量GEM+S-1可成为某些病例的治疗选择,思考二：预后因素深度分析,不考虑价格因素，AG方案是晚期胰腺癌，尤其是PS评分1-2分的首选,在更新的模型中，CA 19-9 是 OS 的显著预测因子，而转移灶数量不再是(P = 0.1046),Goldstein D, El-Maraghi RH, Hammel P, et al. Updated survival from a randomized phase III trial (MPACT) of nab-paclitaxel plus gemcitabine versus gemcitabine alone for patients (pts) with metastatic adenocarcinoma of the pancreas abstract 178. Oral presentation at: Gastrointestinal Cancers Symposium; January 16-18, 2014; San Francisco, CA.,MPACT研究OS 的多因素分析,1. Von Hoff DD, et al. N Engl J Med. 2013;369:1691-1703. 2. Goldstein D, El-Maraghi RH, Hammel P, et al. Updated survival from a randomized phase III trial (MPACT) of nab-paclitaxel plus gemcitabine versus gemcitabine alone for patients (pts) with metastatic adenocarcinoma of the pancreas abstract 178. Oral presentation at: Gastrointestinal Cancers Symposium; January 16-18, 2014; San Francisco, CA.,根据 OS 划分的基线特征,Chiorean EG, Von Hoff DD, Ervin TJ, et al. CA19-9 decrease at 8 weeks as a predictor of overall survival in a randomized phase III trial (MPACT) of weekly nab-paclitaxel plus gemcitabine vs gemcitabine alone in patients with metastatic pancreatic cancer abstract 4058. Poster presentation at: Annual Meeting of the American Society for Clinical Oncology 2013; May 31-June 4; Chicago, IL.,nab-P + Gem组CA199从基线水平下降的百分比均大于单药Gem,CA046深度解读：CA19-9 Kinetics During Treatment,Chiorean EG, Von Hoff DD, Ervin TJ, et al. CA19-9 decrease at 8 weeks as a predictor of overall survival in a randomized phase III trial (MPACT) of weekly nab-paclitaxel plus gemcitabine vs gemcitabine alone in patients with metastatic pancreatic cancer abstract 4058. Poster presentation at: Annual Meeting of the American Society for Clinical Oncology 2013; May 31-June 4; Chicago, IL.,CA046深度解读：Efficacy as a Function of CA19-9 Velocity During First 8 Weeks,所有进行了8周CA199检测的患者中，CA199降幅最大的1/3部分，平均降幅为17.7% per week两组CA199降幅超过17.7%/wk的患者分别为39% vs 26%(nab-P + Gem vs Gem)，差异非常显著比较CA199降幅最大的1/3部分患者，两组Median OS, PFS and ORR差异非常显著CA199降幅较小的那部分患者，两组中位生存期(nab-P + Gem vs Gem)10.4 vs 8.8 months (HR 0.78; P = 0.070),Chiorean EG, Von Hoff DD, Ervin TJ, et al. CA19-9 decrease at 8 weeks as a predictor of overall survival in a randomized phase III trial (MPACT) of weekly nab-paclitaxel plus gemcitabine vs gemcitabine alone in patients with metastatic pancreatic cancer abstract 4058. Poster presentation at: Annual Meeting of the American Society for Clinical Oncology 2013; May 31-June 4; Chicago, IL.,CA046深度解读：OS in Patients With a Decrease in CA19-9 Level 20% at Week 8,Chiorean EG, Von Hoff DD, Ervin TJ, et al. CA19-9 decrease at 8 weeks as a predictor of overall survival in a randomized phase III trial (MPACT) of weekly nab-paclitaxel plus gemcitabine vs gemcitabine alone in patients with metastatic pancreatic cancer abstract 4058. Poster presentation at: Annual Meeting of the American Society for Clinical Oncology 2013; May 31-June 4; Chicago, IL.,CA046深度解读：PFS in Patients With a Decrease in CA19-9 Level 20% at Week 8,Chiorean EG, Von Hoff DD, Ervin TJ, et al. CA19-9 decrease at 8 weeks as a predictor of overall survival in a randomized phase III trial (MPACT) of weekly nab-paclitaxel plus gemcitabine vs gemcitabine alone in patients with metastatic pancreatic cancer abstract 4058. Poster presentation at: Annual Meeting of the American Society for Clinical Oncology 2013; May 31-June 4; Chicago, IL.,CA046深度解读：OS in Patients With a Decrease in CA19-9 Level 90% at Week 8,Chiorean EG, Von Hoff DD, Ervin TJ, et al. CA19-9 decrease at 8 weeks as a predictor of overall survival in a randomized phase III trial (MPACT) of weekly nab-paclitaxel plus gemcitabine vs gemcitabine alone in patients with metastatic pancreatic cancer abstract 4058. Poster presentation at: Annual Meeting of the American Society for Clinical Oncology 2013; May 31-June 4; Chicago, IL.,CA046深度解读：PFS in Patients With a Decrease in CA19-9 Level 90% at Week 8,CA046深度解读：结论,与Gem组比较，nab-P + Gem组有更高的CA19-9反应率 (