Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Department of Pancreatic Surgery, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Lancet Gastroenterol Hepatol. 2018 Jun;3(6):413-423. doi: 10.1016/S2468-1253(18)30081-5. Epub 2018 Apr 4.
Pancreatic ductal adenocarcinoma are known to metastasise early and a rationale exists for the investigation of preoperative chemotherapy in patients with resectable disease. We aimed to assess the role of combination chemotherapy in this setting in the PACT-15 trial.
We did this randomised, open-label, phase 2-3 trial in ten hospitals in Italy. We report the phase 2 part here. Patients aged 18-75 years who were previously untreated for pancreatic ductal adenocarcinoma, with Karnofsky performance status of more than 60, and pathologically confirmed stage I-II resectable disease were enrolled. Patients were randomly assigned (1:1:1), with a minimisation algorithm that stratified treatment allocation by centre and concentrations of carbohydrate antigen 19-9 (CA19-9 ≤5 × upper limit of normal [ULN] vs >5 × ULN), to receive surgery followed by adjuvant gemcitabine 1000 mg/m on days 1, 8, 15 every 4 weeks for six cycles (arm A), surgery followed by six cycles of adjuvant PEXG (cisplatin 30 mg/m, epirubicin 30 mg/m, and gemcitabine 800 mg/m on days 1 and 15 every 4 weeks and capecitabine 1250 mg/m on days 1-28; arm B), or three cycles of PEXG before and three cycles after surgery (arm C). Patients and investigators who gave treatments or assessed outcomes were not masked to treatment allocation. The primary endpoint was the proportion of patients who were event-free at 1 year. The primary endpoint was analysed in the per-protocol population. Safety analysis was done for all patients receiving at least one dose of study treatment. The trial is registered with ClinicalTrials.gov, number NCT01150630.
Between Oct 5, 2010, and May 30, 2015, 93 patients were randomly allocated to treatment. One centre was found to be non-compliant with the protocol, and all five patients at this centre were excluded from the study. Thus, 88 patients were included in the final study population: 26 in group A, 30 in group B, and 32 in group C. In the per-protocol population, six (23%, 95% CI 7-39) of 30 patients in group A were event-free at 1 year, as were 15 (50%, 32-68) of 30 in group B and 19 (66%, 49-83) of 29 in group C. The main grade 3 toxicities were neutropenia (five [28%] of 18 in group A, eight [38%] of 21 in group B, eight [28%] of 29 in group C before surgery, and ten [48%] of 21 in group C after surgery), anaemia (one [6%] in group A, four [19%] in group B, eight [28%] in group C before surgery, and five [24%] in group C after surgery), and fatigue (one [6%] in group A, three [14%] in group B, two [7%] in group C before surgery, and one [5%] in group C after surgery). The main grade 4 toxicity reported was neutropenia (two [11%] in group A, four [19%] in group B, none in group C). Febrile neutropenia was observed in one patient (3%) before surgery in group C. No treatment-related deaths were observed.
Our results provide evidence of the efficacy of neoadjuvant chemotherapy in resectable pancreatic ductal adenocarcinoma. Since the trial began, the standard of care for adjuvant therapy has altered, and other chemotherapy regimens developed. Thus, we decided to not continue with the phase 3 part of the PACT-15. We are planning a phase 3 trial of this approach with different chemotherapy regimens.
PERLAVITA ONLUS and MyEverest ONLUS.
胰腺导管腺癌已知早期转移，因此对于可切除疾病的患者，术前化疗的研究具有合理依据。我们旨在评估 PACT-15 试验中这种联合化疗的作用。
我们在意大利的十家医院进行了这项随机、开放标签、2-3 期试验。我们在此报告 2 期部分。招募了年龄在 18-75 岁之间、无胰腺导管腺癌既往治疗史、卡氏功能状态评分超过 60 分且病理证实为 I-II 期可切除疾病的患者。患者按 1:1:1 的比例随机分配（1:1:1），采用最小化算法，根据中心和碳水化合物抗原 19-9（CA19-9≤5×正常值上限[ULN]与>5×ULN）的浓度分层治疗分配，接受手术加术后每 4 周接受 6 个周期的吉西他滨 1000 mg/m（组 A）、手术加术后 6 个周期的 PEXG（顺铂 30 mg/m、表柔比星 30 mg/m 和吉西他滨 800 mg/m，第 1 和 15 天每 4 周，卡培他滨 1250 mg/m，第 1-28 天；组 B）或手术前 3 个周期和手术后 3 个周期的 PEXG（组 C）。给予治疗或评估结果的患者和研究者不知道治疗分配。主要终点是 1 年时无事件患者的比例。主要终点在方案人群中进行分析。对至少接受一剂研究治疗的所有患者进行安全性分析。该试验在 ClinicalTrials.gov 上注册，编号为 NCT01150630。
2010 年 10 月 5 日至 2015 年 5 月 30 日期间，共有 93 名患者随机分配至治疗组。发现有一家中心不符合方案，该中心的所有 5 名患者均被排除在研究之外。因此，最终研究人群包括 88 名患者：26 名在组 A，30 名在组 B，32 名在组 C。在方案人群中，组 A 中有 6 名（23%，95%CI 7-39）患者在 1 年内无事件，组 B 中有 15 名（50%，32-68）患者，组 C 中有 19 名（66%，49-83）患者。主要的 3 级毒性反应是中性粒细胞减少症（组 A 中 18 例中有 5 例[28%]，组 B 中 21 例中有 8 例[38%]，组 C 中 29 例中有 8 例术前，组 C 中 21 例中有 10 例[48%]术后）、贫血（组 A 中 1 例[6%]，组 B 中 4 例[19%]，组 C 中 29 例术前，组 C 中 21 例术后）和疲劳（组 A 中 1 例[6%]，组 B 中 3 例[14%]，组 C 中 29 例术前，组 C 中 1 例[5%]术后）。主要的 4 级毒性反应是中性粒细胞减少症（组 A 中 2 例[11%]，组 B 中 4 例[19%]，组 C 中无）。组 C 中有 1 例患者（3%）术前出现发热性中性粒细胞减少症。未观察到与治疗相关的死亡。
我们的结果提供了在可切除胰腺导管腺癌中使用新辅助化疗的疗效证据。自试验开始以来，辅助治疗的标准已发生改变，并且开发了其他化疗方案。因此，我们决定不继续进行 PACT-15 的 3 期部分。我们正在计划一项新的 3 期试验，采用不同的化疗方案。
PERLAVITA ONLUS 和 MyEverest ONLUS。
