Background

The optimal preoperative treatment for locally advanced pancreatic cancer is unknown. We aimed to compare the efficacy and safety of nab-paclitaxel plus gemcitabine with nab-paclitaxel plus gemcitabine followed by fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) as multidrug induction chemotherapy regimens in locally advanced pancreatic cancer.

Methods

In this open-label, multicentre, randomised phase 2 study, done at 28 centres in Germany, eligible patients were adults (aged 18–75 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1 and histologically or cytologically confirmed, treatment-naive locally advanced pancreatic adenocarcinoma, as determined by local multidisciplinary team review. After two cycles of nab-paclitaxel 125 mg/m² plus gemcitabine 1000 mg/m² (administered intravenously on days 1, 8, and 15 of each 28-day cycle), patients without progressive disease or unacceptable adverse events were randomly assigned (1:1) to receive either two additional cycles of nab-paclitaxel plus gemcitabine (nab-paclitaxel plus gemcitabine group) or four cycles of sequential FOLFIRINOX (oxaliplatin 85 mg/m², leucovorin 400 mg/m², irinotecan 180 mg/m², fluorouracil 400 mg/m² by intravenous bolus followed by a continuous intravenous infusion of 2400 mg/m² for 46 h on day 1 of each 14-day cycle; sequential FOLFIRINOX group). Randomisation was done by the clinical research organisation on request of the trial centre using a permuted block design (block size 2 and 4). Patients, investigators, and study team members were not masked to treatment allocation. The primary endpoint was surgical conversion rate (complete macroscopic tumour resection) in the randomised population by intention-to-treat analysis, which was assessed by surgical exploration in all patients with at least stable disease after completion of induction chemotherapy. This trial is registered with ClinicalTrials.gov, NCT02125136.

Findings

Between Nov 18, 2014, and April 27, 2018, 168 patients were registered and 130 were randomly assigned to either the nab-paclitaxel plus gemcitabine group (64 patients) or the sequential FOLFIRINOX group (66 patients). Surgical exploration after completed induction chemotherapy was done in 40 (63%) of 64 patients in the nab-paclitaxel plus gemcitabine group and 42 (64%) of 66 patients in the sequential FOLFIRINOX group. 23 patients in the nab-paclitaxel plus gemcitabine group and 29 in the sequential FOLFIRINOX group had complete macroscopic tumour resection, yielding a surgical conversion rate of 35·9% (95% CI 24·3–48·9) in the nab-paclitaxel plus gemcitabine group and 43·9% (31·7–56·7) in the sequential FOLFIRINOX group (odds ratio 0·72 [95% CI 0·35–1·45]; p=0·38). At a median follow-up of 24·9 months (95% CI 21·8–27·6), median overall survival was 18·5 months (95% CI 14·4–21·5) in the nab-paclitaxel plus gemcitabine group and 20·7 months (13·9–28·7) in the sequential FOLFIRINOX group (hazard ratio 0·86 [95% CI 0·55–1·36]; p=0·53). All other secondary efficacy endpoints, such as investigator-assessed progression-free survival, radiographic response rate, CA 19-9 response rate, and R0 resection rate, were not significantly different between the two treatment groups except for improved histopathological downstaging in evaluable resection specimens from the sequential FOLFIRINOX group (ypT1/2 stage: 20 [69%] of 29 patients in the sequential FOLFIRINOX group vs four [17%] of 23 patients in the nab-paclitaxel plus gemcitabine group, p=0·0003; ypN0 stage: 15 [52%] of 29 patients in the sequential FOLFIRINOX group vs four [17%] of 23 patients in the nab-paclitaxel plus gemcitabine group, p=0·02). Grade 3 or higher treatment-emergent adverse events during induction chemotherapy occurred in 35 (55%) of 64 patients in nab-paclitaxel plus gemcitabine group and in 35 (53%) of 66 patients in the sequential FOLFIRINOX group. The most common of which were neutropenia (18 [28%] in nab-paclitaxel plus gemcitabine group, 16 [24%] in the sequential FOLFIRINOX group), nausea and vomiting (two [3%] in nab-paclitaxel plus gemcitabine group, eight [12%] in the sequential FOLFIRINOX group), and bile duct obstruction with cholangitis (six [9%] in nab-paclitaxel plus gemcitabine group, seven [11%] in the sequential FOLFIRINOX group). No deaths were caused by treatment-related adverse events during the induction chemotherapy phase.

Interpretation

Our findings suggest that nab-paclitaxel plus gemcitabine is similarly active and safe as nab-paclitaxel plus gemcitabine followed by FOLFIRINOX as multidrug induction chemotherapy regimens for locally advanced pancreatic cancer. Although conversion to resectability was achieved in about a third of patients, additional evidence is required to determine whether this translates into improved overall survival.

Funding

Celgene.

中文翻译：

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纳布紫杉醇联合吉西他滨与纳布紫杉醇联合吉西他滨联合FOLFIRINOX诱导化疗治疗局部晚期胰腺癌（NEOLAP-AIO-PAK-0113）：一项多中心，随机，2期试验

背景

局部晚期胰腺癌的最佳术前治疗尚不清楚。我们旨在比较nab-紫杉醇加吉西他滨与nab-紫杉醇加吉西他滨，氟尿嘧啶，亚叶酸，伊立替康和奥沙利铂（FOLFIRINOX）作为局部晚期胰腺癌多药诱导化疗方案的有效性和安全性。

方法

在这项开放性，多中心，随机的2期研究中，在德国的28个中心进行了研究，合格的患者是东部合作肿瘤小组的表现状态为0或1且经组织学或细胞学确认的成人（18-75岁）局部多学科小组审查确定为初次就诊的局部晚期胰腺癌。两次nab-紫杉醇125 mg / m ²加吉西他滨1000 mg / m ²周期（在每个28天周期的第1、8和15天静脉注射）后，将无进展性疾病或不良反应不可接受的患者随机分配（ 1：1）接受另外两个周期的nab-紫杉醇联合吉西他滨（nab-paclitaxel联合吉西他滨组）或四个周期的连续FOLFIRINOX（奥沙利铂85 mg / m²，静脉推注亚叶酸400 mg / m ²，伊立替康180 mg / m ²，氟尿嘧啶400 mg / m ²，然后连续静脉输注2400 mg / m ²每个14天周期的第1天持续46小时；顺序FOLFIRINOX组）。临床研究组织根据试验中心的要求，使用置换块设计（块大小2和4）进行了随机分组。患者，研究人员和研究小组成员并未隐瞒治疗分配。主要终点是通过意向性治疗分析的随机人群中的手术转化率（完全宏观肿瘤切除术），这通过在诱导化疗后至少具有稳定疾病的所有患者中的手术探查进行评估。该试验已在ClinicalTrials.gov（NCT02125136）上注册。

发现

在2014年11月18日至2018年4月27日之间，登记了168例患者，其中130例被随机分配至nab-紫杉醇联合吉西他滨组（64例）或连续FOLFIRINOX组（66例）。纳布-紫杉醇联合吉西他滨组的40例患者中有40（63％）位，而连续FOLFIRINOX组的66例患者中有42位（64％）患者完成了诱导化疗后的手术探查。纳布-紫杉醇联合吉西他滨组的23例患者和连续FOLFIRINOX组的29例患者已完成宏观肿瘤切除，纳布-紫杉醇的手术转化率为35·9％（95％CI 24·3–48·9）加吉西他滨组和连续FOLFIRINOX组的43·9％（31·7–56·7）（赔率0·72 [95％CI 0·35-1·45]； p = 0·38）。在平均随访24·9个月（95％CI 21·8–27·6）中，纳布-紫杉醇联合吉西他滨组的中位总生存期为18·5个月（95％CI 14·4–21·5），连续FOLFIRINOX组的中位总生存期为20·7个月（13·9–28·7）（危险比0·86 [95％CI 0·55-1·36]； p = 0·53）。除可评估的切除标本中改善的组织病理学分期有所改善外，两个治疗组之间的所有其他次要功效终点，如研究者评估的无进展生存期，影像学缓解率，CA 19-9缓解率和R0切除率均无显着差异。来自顺序FOLFIRINOX组（ypT1 / 2分期：顺序FOLFIRINOX组中的29位患者中的20 [69％]VS 4 [17％]的23例患者中的白蛋白结合型紫杉醇+吉西他滨组中，P = 0·0003; ypN0分期：连续FOLFIRINOX组29例患者中有15例[52％]与纳布-紫杉醇联合吉西他滨组23例患者中有4例[17％]，p = 0·02）。纳布-紫杉醇联合吉西他滨组的64例患者中有35（55％）发生在诱导化疗过程中的3级或更高级别的治疗不良事件，而连续FOLFIRINOX组的66例患者中有35（53％）发生。其中最常见的是中性粒细胞减少症（nab-紫杉醇联合吉西他滨组为18 [28％]，连续FOLFIRINOX组为16 [24％]），恶心和呕吐（nab-紫杉醇联合吉西他滨组为2 [3％]）， FOLFIRINOX序贯组中有8例[12％]，胆管炎伴胆管阻塞（nab-紫杉醇加吉西他滨组6例[9％]，FOLFIRINOX序贯组7例[11％]）。在诱导化疗阶段，没有与治疗相关的不良事件引起死亡。

解释

我们的研究结果表明，nab-紫杉醇联合吉西他滨的活性和安全性与nab-紫杉醇联合吉西他滨以及随后的FOLFIRINOX作为局部晚期胰腺癌的多药诱导化疗方案相似。尽管在大约三分之一的患者中实现了可切除性的转换，但是还需要其他证据来确定这是否可以改善总生存期。

资金

Celgene。