The landscape of systemic treatment

The landscape of systemic treatment in metastatic pancreatic cancer has changed significantly since 2011. Conroy et al[29] have shown FOLFIRINOX (5-fluorouracil plus leucovorin, irinotecan and oxaliplatin) delivered significant improvement of median overall survival when compared to gemcitabine alone in a randomized phase Ⅲ study enrolling 342 patients [11.1 mo vs 6.8 mo (P < 0.001)]. Of note, this study excluded patients
3WJCO |www.wjgnet.com February 0, 206|Volume 7|Issue |
Trial/reference published year
Trial phase/patient number
Treatment regimen Primary endpoint Result
NCT00335543/205[63] Ⅱ, randomized/66 (254 planned)
Upfront surgery vs chemoradiation with gemcitabine/cisplatin and radiotherapy of 55.8 Gy
Median survival Median survival: 4.4 mo vs 7.4 mo (P = 0.96). Overall R0: 48% vs 52% (P = 0.8)
NCT00536874/204[64] Ⅱ/38 Gemcitabine and oxaliplatin 8-mo overall survival
8-mo overall survival: 63%. Median overall survival: 27.2 mo. Resection rate was 7%, and 74% of resection was R0
NCT00490360/2008[20,65] Ⅱ/28 Gemcitabine and cisplatin Resectability rate ≥ 70%
Resection rate was 89%, and 80% of resection was R0. Overall survival was 26.5 mo
Evans et al[2] Ⅱ/86 Chemoradiation with gemcitabine and radiotherapy of 30 Gy (in 0 fractions) for pancreatic head cancer
Clinical outcome Overall R0: 74%. Median overall survival was 22.7 mo with a 5-yr survival of 27% (36% in R0)
Varadhachary[22] Ⅱ/90 Gemcitabine and cisplatin followed by chemoradiation with gemcitabine and radiotherapy of 30 Gy for pancreatic head cancer
Clinical outcome Overall R0 was 58%. Additional chemotherapy did not improve clinical outcome
Palmer et al[66] Ⅱ, randomized/50 Gemcitabine vs gemcitabine and cisplatin Resection rate Resection rate was 54%: 9 (38%) in the gemcitabine arm and 8 (70%) in the combination arm
Table 1 Selected published neoadjuvant phase Ⅱ trials in resectable pancreatic adenocarcinoma between 2006-2015
Wong J et al . Neoadjuvant treatment for resectable pancreatic adenocarcinoma
ized phase Ⅱ/Ⅲ trial conducted in Japan since January 2013 (clinical trial information: UMIN000009634)[35]. This study plans to enroll 360 patients with resectable pancreatic cancer, and randomizes them to either surgery followed by adjuvant chemotherapy with S1 for 6 mo or 2 mo of neoadjuvant chemotherapy with gemcitabine and S1 followed by surgery then 6 mo of adjuvant chemotherapy with S1. The primary study endpoint is resection rate for phase Ⅱ and overall survival for phase Ⅲ. This study plans to have 40 patients in each arm of the phase Ⅱ part, and moves on to phase Ⅲ if there are no more than 14 cases of nonresection in each arm of phase Ⅱ study. S-1 is an oral fluorinated pyrimidine, containing tegafur, 5-chloro-2,4dihydroxypyridine and potassium oxonate at a molar ratio of 1:0.4:1[36]. Tegafur is a pro-drug of 5-fluorouracil, and S1 has been shown to deliver higher 5-fluorouracil levels in the plasma and the tumor tissue. The safety and efficacy of combination chemotherapy with gemcitabine and S1 for resectable pancreatic cancer have been reported in pilot study[37]. The UVA-PC-PD101 study (NCT02305186; Safety and Immunological Effect of Pembrolizumab in Resectable or Borderline Resectable Pancreatic Cancer) is a phase Ⅰb/Ⅱ multicenter study in patients with resectable or borderline resectable pancreatic cancer. This study will randomize 56 subjects in 2:1 to the experimental arm with pembrolizumab given concurrently with chemoradiation or control arm receiving chemoradiation only. Patients in both arms will receive surgery and adjuvant chemotherapy with gemcitabine. The primary outcome measures are to determine the safety of neoadjuvant chemoradiation with capecitabine in combination with pembrolizumab, and to examine and compare the difference in the number of tumor infiltrating lymphocytes (TILs) in resected pancreatic tissue between experimental and control arms[38]. The investigators hypothesize chemoradiation recruits TILs to the microenvironment of pancreatic cancer causing overexpression of programmed death-ligand 1 (PD-L1). PD-L1 binds to PD-1 on T-cells, and suppress cytotoxic T-cells. Pembrolizumab is a monoclonal antibody that targets the PD-1, and release the inhibition on cytotoxic T-cells. Therefore, it is expected that there are more immune effects at tumor tissues in the experimental arm than control arm. It will be interesting to see if this will
with suboptimal performance status (ECOG 2 and beyond) or ages older than 76 years old. Von Hoff and colleagues[30] reported increased median overall survival with nab-paclitaxel plus gemcitabine compared to gemcitabine alone in a randomized phase Ⅲ study with 861 patients [8.5 mo vs 6.7 mo (P < 0.001)]. Therefore both FOLFIRINOX and nab-paclitaxel/gemcitabine have become preferred regimens in advanced pancreatic cancer, and are currently explored in the neoadjuvant setting (Table 2).

結果 (中文) 1:

自 2011 年以来，全身治疗转移性胰腺癌组织中的景观有显著的改变。康罗伊 et al [29] 有显示 FOLFIRINOX （5-氟尿嘧啶加亚叶酸钙、 伊立替康和奥沙利铂） 交付的中位总生存期时相比，吉西他滨单独招收 342 病人随机的相位 ⅲ 研究重大改进 [11.1 vs 6.8 钼 (P < 0.001)]。值得注意的是，这项研究排除患者3WJCO | www.wjgnet.com 2 月 0、 20 6 |第 7 卷 |问题 |审判/参考出版的年审判阶段/病人数治疗方案主要终点结果NCT00335543/20 5 [63] 第二，随机/66 (254 计划)与吉西他滨/顺铂和放疗 55.8 Gy vs 接受同步放化疗前期手术中位生存期中位数生存︰ 4.4 墨玉 vs 7.4 (P = 0.96)。整体 R0: 48%和 52%(P = 0.8)NCT00536874/20 4 [64] ⅱ/38 吉西他滨和奥沙利铂 8-钼总生存率8 莫总体生存率︰ 63%。中位总生存期︰ 27.2 密苏里手术切除率为 7%和 74%的切除是 R0NCT00490360/2008 [20,65] ⅱ/28 吉西他滨与顺铂可切除率 ≥ 70%手术切除率为 89%和 80%的切除是 R0。总体生存率 26.5 莫埃文斯 et al [2] ⅱ/86 同步放化疗与吉西他滨和 30 Gy （在 0 的分数） 为胰头癌的放射治疗临床结果总体 R0: 74%。中位总生存期是 22.7 莫与 5 年生存的 27%（R0 36%)Varadhachary [22] ⅱ/90 吉西他滨联合顺铂跟着同步放化疗与吉西他滨和 30 Gy 为胰头癌的放射治疗临床结果总体 R0 为 58%。加辅助化疗并不能改善临床结果帕默 et al [66] 二、 随机/50 vs 吉西他滨吉西他滨和顺铂切除术切除率为 54%︰ 吉西他滨手臂及 8 （70%) 在组合臂 9 （38%)表 1 选定在切除胰腺癌 2006年-2015年年间发表新辅助期 ⅱ 试验黄 J et al。可切除的胰腺癌的新辅助治疗ized phase Ⅱ/Ⅲ trial conducted in Japan since January 2013 (clinical trial information: UMIN000009634)[35]. This study plans to enroll 360 patients with resectable pancreatic cancer, and randomizes them to either surgery followed by adjuvant chemotherapy with S1 for 6 mo or 2 mo of neoadjuvant chemotherapy with gemcitabine and S1 followed by surgery then 6 mo of adjuvant chemotherapy with S1. The primary study endpoint is resection rate for phase Ⅱ and overall survival for phase Ⅲ. This study plans to have 40 patients in each arm of the phase Ⅱ part, and moves on to phase Ⅲ if there are no more than 14 cases of nonresection in each arm of phase Ⅱ study. S-1 is an oral fluorinated pyrimidine, containing tegafur, 5-chloro-2,4dihydroxypyridine and potassium oxonate at a molar ratio of 1:0.4:1[36]. Tegafur is a pro-drug of 5-fluorouracil, and S1 has been shown to deliver higher 5-fluorouracil levels in the plasma and the tumor tissue. The safety and efficacy of combination chemotherapy with gemcitabine and S1 for resectable pancreatic cancer have been reported in pilot study[37]. The UVA-PC-PD101 study (NCT02305186; Safety and Immunological Effect of Pembrolizumab in Resectable or Borderline Resectable Pancreatic Cancer) is a phase Ⅰb/Ⅱ multicenter study in patients with resectable or borderline resectable pancreatic cancer. This study will randomize 56 subjects in 2:1 to the experimental arm with pembrolizumab given concurrently with chemoradiation or control arm receiving chemoradiation only. Patients in both arms will receive surgery and adjuvant chemotherapy with gemcitabine. The primary outcome measures are to determine the safety of neoadjuvant chemoradiation with capecitabine in combination with pembrolizumab, and to examine and compare the difference in the number of tumor infiltrating lymphocytes (TILs) in resected pancreatic tissue between experimental and control arms[38]. The investigators hypothesize chemoradiation recruits TILs to the microenvironment of pancreatic cancer causing overexpression of programmed death-ligand 1 (PD-L1). PD-L1 binds to PD-1 on T-cells, and suppress cytotoxic T-cells. Pembrolizumab is a monoclonal antibody that targets the PD-1, and release the inhibition on cytotoxic T-cells. Therefore, it is expected that there are more immune effects at tumor tissues in the experimental arm than control arm. It will be interesting to see if this will with suboptimal performance status (ECOG 2 and beyond) or ages older than 76 years old. Von Hoff and colleagues[30] reported increased median overall survival with nab-paclitaxel plus gemcitabine compared to gemcitabine alone in a randomized phase Ⅲ study with 861 patients [8.5 mo vs 6.7 mo (P < 0.001)]. Therefore both FOLFIRINOX and nab-paclitaxel/gemcitabine have become preferred regimens in advanced pancreatic cancer, and are currently explored in the neoadjuvant setting (Table 2).

結果 (中文) 3:

全身治疗转移性胰腺癌的景观自2011以来发生了明显的变化。康罗伊等[ 29 ]发现FOLFIRINOX（5-氟尿嘧啶+亚叶酸钙和奥沙利铂，伊立替康）交付的中位总生存期显着的改善相比，吉西他滨单药Ⅲ期随机研究纳入342例[ 11.1个月vs 6.8钼（P＜0.001）]。值得注意的是，这项研究排除了患者3wjco | www.wjgnet.com 0二月，206卷7期| | |试用/参考发表的一年试用期/病人数治疗方案主要终点结果nct00335543 / 205 [ 63 ]Ⅱ，随机/ 66（254计划）前期手术与放化疗联合吉西他滨/顺铂和放疗55.8 Gy中位生存中位生存期：4.4个月和7.4个月（P = 0.96）。总体：48% vs 52% R0（P = 0.8）nct00536874 / 204 [ 64 ] 38Ⅱ/吉西他滨和奥沙利铂8-mo生存8-mo总生存率：63%。中位总生存期：27.2个月，手术切除率为7%，与74%的切除R0nct00490360 / 2008 / 28 ] [ 20,65Ⅱ吉西他滨和顺铂的切除率≥70%手术切除率为89%，与80%的切除R0。总生存期为26.5个月伊万斯等人[ 2 ]Ⅱ/ 86放化疗与吉西他滨联合30 Gy放疗（0次）治疗胰头癌临床疗效：74%整体R0。中位总生存期为22.7莫与27%的5年生存率（36%在R0）varadhachary [ 22 ]Ⅱ/ 90吉西他滨和顺铂与吉西他滨和随后30 Gy治疗胰头癌放疗化疗临床结果总体R0为58%。额外的化疗并没有改善临床结果帕尔默等人[ 66 ]Ⅱ，随机/ 50吉西他滨与吉西他滨联合顺铂的手术切除率，手术切除率为54%：9（38%）在吉西他滨治疗组和8（70%）在联合组表1选择发表新辅助相Ⅱ试验在胰腺腺癌之间2006-2015黄等。可切除胰腺癌的新辅助治疗化相Ⅱ/Ⅲ自一月2013在日本进行的试验（临床试验信息：umin000009634）[ 35 ]。这项研究计划招收360名患者可切除胰腺癌患者，并随机为手术后辅助化疗与S1 6莫或与吉西他滨化疗2个月S1后手术6莫与S1的辅助化疗。主要研究终点为第一期的切除率和第一期的总生存期。本研究拟在相Ⅱ部分每一组40例，并移动到相Ⅲ如果没有超过14相Ⅱ每组研究活检病例。S-1是一种口服的氟嘧啶、替加氟、5-chloro-2,4dihydroxypyridine和氧嗪酸钾在摩尔比为1:0.4:1 [ 36 ]。替加氟是一种前药5-氟脲嘧啶，和S1已被证明在提供更高水平的血浆和肿瘤组织中5-氟尿嘧啶。安全与可切除胰腺癌吉西他滨和S1联合化疗疗效已在初步研究[ 37 ]报道。研究的uva-pc-pd101（nct02305186；安全和可切除或边缘可切除胰腺癌的免疫效应是pembrolizumab）相ⅠB /Ⅱ多中心研究可切除或可能切除的胰腺癌患者。本研究将随机56例在2:1与pembrolizumab实验组同时给予放化疗或放化疗只接收控制臂。在这两个武器的患者将接受手术和辅助化疗与吉西他滨。主要成果的措施是与卡培他滨联合pembrolizumab确定新辅助放化疗的安全性，并探讨和比较肿瘤浸润淋巴细胞（TIL）数的差异，在切除胰腺组织实验组和对照组[ 38 ]之间。研究人员推测，放化疗对胰腺癌引起新兵细胞程序性死亡配体（PD-L1）1表达的微环境。PD-L1与PD-1对T细胞，抑制细胞毒性T细胞。Pembrolizumab是单克隆抗体靶向PD-1，和细胞毒性T细胞释放的抑制作用。因此，预期在实验组的肿瘤组织中，有更多的免疫效应比对照组。这将是有趣的，看看这是否会不理想的性能状态（ECOG 2及以上）或年龄超过76岁。霍夫和他的同事们[ 30 ]报告增加中位总生存期与紫杉醇联合吉西他滨与吉西他滨单Ⅲ期随机研究861例[ 8.5个月vs 6.7钼（P＜0.001）]。因此，FOLFIRINOX和结合型紫杉醇联合吉西他滨已成为首选的方案在晚期胰腺癌，目前正在探索的新辅助治疗（表2）。