胰腺國(guó)際論壇

1、同濟(jì)大學(xué)附屬東方醫(yī)院高勇2014.11,晚期胰腺癌化療選擇的思考,Key Milestones in the Treatment of Pancreatic CancerFDA Approval for MPC1,1. Drugs@FDA.gov. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed June 20, 2012.,2,

2、MPC, metastatic pancreatic cancer, PDAC, pancreatic ductal adenocarcinoma.,,2014NCCN指南推薦：晚期胰腺癌一線治療,分享內(nèi)容,思考一、化療方案，孰優(yōu)孰劣思考二、預(yù)后因素深度分析思考三、支持治療，被動(dòng)？積極？,思考一、化療方案，孰優(yōu)孰劣？,生存期比較,晚期胰腺癌專家推薦或者NCCN指南：,a For fit patients defined as th

3、ose 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/

4、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, irinot

5、ecan, 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 Adenoca

6、rcinoma. 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.,患者入組基線特征,Conroy T. et al., N Engl J Med. 2011

7、60;May 12;364(19):1817-25.Andrew H. Ko J Clin Oncol 2011; 29:3727-3729.,FOLFIRINOX組嚴(yán)重不良反應(yīng)顯著增加,Conroy T., et al., N Engl J Med. 2011; 364(19): 1817-25.,研究結(jié)論,FOLFIRINOX是轉(zhuǎn)移性胰腺癌一線治療的選擇之一患者需<76歲，PS 0/1，膽紅素正?；蚪咏Ｋ?Conro

8、y T. et al., N Engl J Med. 2011  12;364(19):1817-25.,專家評(píng)論,該研究存在的問(wèn)題：兩組患者的基線特征并不完全平衡，吉西他濱組的肺部轉(zhuǎn)移患者數(shù)顯著高于試驗(yàn)組膽囊炎發(fā)生情況未提及，如胰頭癌比例提高也許會(huì)增加膽道感染率。至少不推薦膽管支架患者接受該方案FOLFIRINOX的毒性反應(yīng)堪憂：46%患者出現(xiàn)3/4級(jí)粒缺(5.4%伴發(fā)熱),雖然研究結(jié)果為陽(yáng)性，但副作用使其臨

9、床應(yīng)用受阻,Tempero MA. 2010 ASCO Gastorintestinal (Noncolorectal) Cancer,,主要終點(diǎn): OS次要終點(diǎn): 獨(dú)立評(píng)審的 PFS 和 ORR (RECIST v1.0)根據(jù) NCI CTCAE v 3.0 分級(jí)的安全性和耐受性治療直至疾病進(jìn)展每 8 周進(jìn)行 CT 掃描這項(xiàng)國(guó)際性研究在北美、歐洲和澳大利亞的 151 家中心入組了 861 例患者,Goldstein D,

10、 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 [a

11、bstract 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-Mar

12、aghi 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

13、 178]. Oral presentation at: Gastrointestinal Cancers Symposium; January 16-18, 2014; San Francisco, CA.,2013 年 5 月 9 日更新的總生存,更長(zhǎng)的隨訪期后，中位 OS 的差別為 2.1 個(gè)月，并且在白蛋白紫杉醇聯(lián)合吉西他濱組出現(xiàn)了生存 3 年以上的患者,Goldstein D, El-Maraghi RH, Hammel P,

14、 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 presen

15、tation at: Gastrointestinal Cancers Symposium; January 16-18, 2014; San Francisco, CA.,總生存率,Gem, gemcitabine; HR, hazard ratio; KPS, Karnofsky Performance Scale; nab-P, nab-paclitaxel; OS, overall survival.Goldstein D,

16、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 [ab

17、stract 178]. Oral presentation at: Gastrointestinal Cancers Symposium; January 16-18, 2014; San Francisco, CA.,亞組的 OS 更新,,S-1 的 GEST 研究:,分層因素: ?轉(zhuǎn)移性 vs. 局部晚期 ?研究中心,R,n=834,*根據(jù)體表面積（BSA）, BSA =1.5,Gem (n=277)1000 mg/m2

18、 d1, 8, 154周重復(fù),S-1 (n=280)80, 100, 120 mg*/body d1-286周重復(fù),Gem + S-1 (n=277)GEM: 1000 mg/m2 d1, 8S-1: 60, 80, 100 mg*/body d1-143周重復(fù),,不可切除的晚期胰腺癌,優(yōu)效性比較： GEM + S-1 vs GEM非劣效性比較：S-1 vs Gem主要終點(diǎn)： OS次要終點(diǎn)：PFS, ORR, 不良反

19、應(yīng)、生活質(zhì)量,,GEST 研究結(jié)果,RR：Gem vs. S-1：p=0.02Gem vs. GS: p<0.001,Gem vs. S-1 : OS非劣效性HR=0.96 (97.5% CI:0.78-1.18)P<0.001,Gem vs. GS : OS優(yōu)效性HR=0.88 (97.5% CI:0.71-1.08)p=0.15,,GEST 研究結(jié)論,主要終點(diǎn)總生存期無(wú)獲益，僅局部晚期胰腺癌獲益次要終點(diǎn)

20、：延長(zhǎng)PFS、提高ORR、改善生活質(zhì)量,S-1單藥總生存非劣效于GEM單藥論證單藥非劣效于GEM的首個(gè)III期臨床試驗(yàn)S-1顯示了良好療效,GEM+S-1顯著提高了無(wú)進(jìn)展生存，但未提高總生存GEM+S-1可改善患者生活質(zhì)量GEM+S-1可成為某些病例的治療選擇,思考二：預(yù)后因素深度分析,不考慮價(jià)格因素，AG方案是晚期胰腺癌，尤其是PS評(píng)分1-2分的首選,在更新的模型中，CA 19-9 是 OS 的顯著預(yù)測(cè)因子，而轉(zhuǎn)移灶數(shù)量不再是

21、(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 adenocar

22、cinoma 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. Gold

23、stein 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 pan

24、creas [abstract 178]. Oral presentation at: Gastrointestinal Cancers Symposium; January 16-18, 2014; San Francisco, CA.,根據(jù) OS 劃分的基線特征,Chiorean EG, Von Hoff DD, Ervin TJ, et al. CA19-9 decrease at 8 weeks as a predictor o

25、f 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 Meet

26、ing of the American Society for Clinical Oncology 2013; May 31-June 4; Chicago, IL.,,nab-P + Gem組CA199從基線水平下降的百分比均大于單藥Gem,CA046深度解讀：CA19-9 Kinetics During Treatment,Chiorean EG, Von Hoff DD, Ervin TJ, et al. CA19-9 decr

27、ease 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]. Pos

28、ter presentation at: Annual Meeting of the American Society for Clinical Oncology 2013; May 31-June 4; Chicago, IL.,CA046深度解讀：Efficacy as a Function of CA19-9 Velocity During First 8 Weeks,所有進(jìn)行了8周CA199檢測(cè)的患者中，CA199降幅最大的1

29、/3部分，平均降幅為17.7% per week兩組CA199降幅超過(guò)17.7%/wk的患者分別為39% vs 26%(nab-P + Gem vs Gem)，差異非常顯著比較CA199降幅最大的1/3部分患者，兩組Median OS, PFS and ORR差異非常顯著CA199降幅較小的那部分患者，兩組中位生存期(nab-P + Gem vs Gem)10.4 vs 8.8 months (HR 0.78; P = 0.070

30、),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 patient

31、s 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深度解讀：OS in Patients With a Decrease in CA1

32、9-9 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 gemc

33、itabine 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深度解讀：PFS in Patien

34、ts 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

35、 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.

36、,CA046深度解讀：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)

37、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

38、 31-June 4; Chicago, IL.,CA046深度解讀：PFS in Patients With a Decrease in CA19-9 Level ≥ 90% at Week 8,,CA046深度解讀：結(jié)論,與Gem組比較，nab-P + Gem組有更高的CA19-9反應(yīng)率 (best decreases of ≥ 20% or ≥ 90%) nab-P + Gem組與Gem組比較，在8周CA199下降到特定水平

39、患者具有更好的OS, PFS, 和 ORRCA199在治療前8周迅速下降的患者提示預(yù)后較好 研究結(jié)果表明CA199是胰腺癌治療有效的早期血清標(biāo)志物,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)

40、 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; Ma

41、y 31-June 4; Chicago, IL.,CA19-9, carbohydrate antigen 19-9; Gem, gemcitabine; nab-P, nab-paclitaxel; ORR, overall response rate; OS, overall survival; PFS, progression-free survival.,思考三、支持治療，被動(dòng)？積極？,晚期胰腺癌患者負(fù)面因素：疼痛，中重度痛