Supplementary Material for: Sequence Therapy with FOLFIRINOX and Gemcitabine/Nab-Paclitaxel for Patients with Advanced Pancreatic Cancer – a Monocenter Retrospective Cohort Study

Background & aims: While irresectable pancreatic cancer has still a dismal overall prognosis, evidence about the optimal chemotherapy sequence is scarce. After treatment with FOLFIRINOX in first-line, Gemcitabine-monotherapy was established for years. As a potential treatment alternative after failure of FOLFIRINOX therapy, combination of Gemcitabine and Nab-Paclitaxel is used. However, this combination has formally not yet been approved for second-line treatment and investigation of efficiency and treatment tolerance is the aim of this trial. Methods: Therefore, we investigated 225 patients with histologically confirmed local advanced or metastatic pancreatic cancer in this retrospective mono-centre study (November 2010 – July 2019). Of this, 44 patients received FOLFIRINOX therapy and outcome was further analysed. The primary end point of this cohort was overall survival, secondary end points included progression free survival, response rate, and safety. Results: In most of the patients FOLFIRINOX as first-line treatment of irresectable pancreatic cancer resulted in temporary cancer control (partial response (PR): 50% and stable disease (SD): 18%), whereas tumor progression was observed in 23% of the patients. The median progression-free survival (PFS) time for FOLFIRINOX treatment was 7.3 months and median overall survival 10.3 months. Seven (16%) patients received additional local radio chemotherapy of the pancreatic tumor. During first-line therapy 8 (18%) patients had laparotomy for proof of resectability. Hereby, in three patients R0-, in three patients R1 resection, and irresectability in another 2 patients were achieved. Twenty-five of the 44 patients (57%) received second line therapy, namely 24 patients Gemcitabine/ Nab-Paclitaxel and 1 patient Gemcitabine and Erlotinib. Hereby, Gemcitabine/ Nab-Paclitaxel led again to temporary tumor control in 46% of the patients (PR: 21%, SD: 25%), while in 29% of the patient’s disease progression was observed. Corresponding median PFS for Gemcitabine and Nab-Paclitaxel treatment was 3.5 months. Patients who received second-line treatment with Nab-Paclitaxel and Gemcitabine had a more favorable prognosis (median OS: 17.4 versus 9.2 months; HR 0.32 [0.14 – 0.70], p<0.001) than patients who were not eligible for second-line treatment. Moreover, in multivariate analyses association with patients’ survival and tumor response to chemotherapy in both therapeutic lines and µGT below 100 IU/L in first-line FOLFIRINOX chemotherapy were observed. Conclusion: These real-world data suggest that Gemcitabine / Nab-Paclitaxel may be feasible after FOLFIRINOX therapy in patients with irresectable pancreatic cancer. However, prospective randomized data about the superiority to Gemcitabine monotherapy are needed.

背景与目的：尽管不可切除胰腺癌的总体预后仍然极差，但关于最优化疗序列的研究证据仍较为匮乏。一线采用FOLFIRINOX方案（FOLFIRINOX）治疗后，吉西他滨（Gemcitabine）单药治疗已沿用多年。作为FOLFIRINOX方案治疗失败后的潜在治疗替代方案，吉西他滨联合纳米白蛋白结合型紫杉醇（Nab-Paclitaxel）的方案已被临床应用，但该联合方案尚未正式获批用于二线治疗，因此本试验旨在探究其疗效与治疗耐受性。

方法：为此，本回顾性单中心研究纳入了2010年11月至2019年7月间经组织学确诊的225例局部晚期或转移性胰腺癌患者。其中44例患者接受了FOLFIRINOX方案治疗，并对其结局进行了进一步分析。本队列的主要终点为总生存期（overall survival, OS），次要终点包括无进展生存期（progression free survival, PFS）、客观缓解率以及安全性。

结果：多数接受FOLFIRINOX方案作为不可切除胰腺癌一线治疗的患者实现了暂时性肿瘤控制（部分缓解（partial response, PR）：50%，疾病稳定（stable disease, SD）：18%），而23%的患者出现了肿瘤进展。FOLFIRINOX方案治疗的中位无进展生存期为7.3个月，中位总生存期为10.3个月。7例（16%）患者接受了胰腺肿瘤的额外局部放化疗。一线治疗期间，8例（18%）患者接受了剖腹手术以评估可切除性，其中3例实现了R0切除、3例实现了R1切除，另有2例仍为不可切除状态。44例患者中25例（57%）接受了二线治疗，其中24例采用吉西他滨联合纳米白蛋白结合型紫杉醇方案，1例采用吉西他滨联合厄洛替尼（Erlotinib）方案。吉西他滨联合纳米白蛋白结合型紫杉醇方案再次使46%的患者实现了暂时性肿瘤控制（PR：21%，SD：25%），而29%的患者出现了疾病进展。该方案对应的中位无进展生存期为3.5个月。接受吉西他滨联合纳米白蛋白结合型紫杉醇二线治疗的患者预后更优（中位总生存期：17.4个月 vs 9.2个月；风险比（HR）0.32 [0.14–0.70]，p<0.001），优于未符合二线治疗指征的患者。此外，多变量分析显示，在两条治疗线中，患者生存与肿瘤对化疗的应答情况，以及一线FOLFIRINOX化疗时µGT（γ-谷氨酰转移酶）低于100 IU/L均存在相关性。

结论：本真实世界数据表明，对于不可切除胰腺癌患者，在FOLFIRINOX方案治疗后采用吉西他滨联合纳米白蛋白结合型紫杉醇方案可能具有可行性。但仍需开展前瞻性随机对照研究，以验证该方案相较于吉西他滨单药治疗的优越性。