Supplementary Material for: Comparative Safety and Efficacy of Therapeutic Options in Resectable and Advanced/Metastatic Pancreatic Cancer: A Systematic Review and Indirect Comparison

<b><i>Objectives:</i></b> FOLFIRINOX, gemcitabine/nab-paclitaxel (gem-nab/P), and gemcitabine-capecitabine (gem-cap) demonstrated superiority over gemcitabine monotherapy for pancreatic cancer (PC). It is still unclear which chemotherapy regimen is the most optimal. This study aimed to conduct a systematic review (SR) and indirect comparison to compare safety and efficacy of FOLFIRINOX versus gem-nab/P and gem-cap in PC. <b><i>Methods:</i></b> An SR was conducted in several databases from inception to November 2020. RCTs investigating resectable or advanced PC were included. Primary outcomes including overall survival (OS), disease-free survival (DFS)/progression-free survival (PFS)/relapse-free survival (RFS), and grade 3/4 adverse events (AEs) were pooled using a random effects model. Indirect comparisons were done to compare FOLFIRINOX versus gem-cap and gem-nab/P. Heterogeneity was evaluated using Cochran’s Q test and <i>I</i>² statistics. <b><i>Results:</i></b> Nine studies were identified involving 6,564 patients. Indirect comparisons showed FOLFIRINOX had significantly better OS (resectable: HR 0.78 [0.61–0.99]; advanced: HR 0.71 [0.60–0.85]) and RFS/DFS/PFS (resectable: HR 0.67 [0.55–0.82]; advanced: HR 0.65 [0.57–0.74]) compared to gem-cap as well as OS (resectable: HR 0.78 [0.61–1.00]; advanced: HR 0.73 [0.54–0.98]) and DFS/PFS (resectable: HR 0.66 [0.53–0.82]; advanced: HR 0.64 [0.49–0.83]) compared to gem-nab/P. FOLFIRINOX increased grade 3/4 AE risk compared to gem-cap and gem-nab/P. <b><i>Conclusions:</i></b> FOLFIRINOX is associated with significant survival benefits compared to gem-nab/P and gem-cap. However, it is important to consider the increased grade 3/4 AE risk associated with FOLFIRINOX.

**<i>研究目的</i>**：FOLFIRINOX方案、吉西他滨/nab-紫杉醇（gemcitabine/nab-paclitaxel, gem-nab/P）以及吉西他滨-卡培他滨（gemcitabine-capecitabine, gem-cap）在胰腺癌（pancreatic cancer, PC）治疗中均被证实优于吉西他滨单药治疗，但目前仍未明确何种化疗方案为最优选择。本研究旨在开展系统评价（systematic review, SR）与间接比较分析，对比FOLFIRINOX方案分别与gem-nab/P、gem-cap用于胰腺癌患者的安全性与有效性。

**<i>研究方法</i>**：本研究检索了多个数据库自建库至2020年11月的文献，纳入针对可切除或晚期胰腺癌的随机对照试验（randomized controlled trial, RCT）。采用随机效应模型合并分析主要结局指标，包括总生存期（overall survival, OS）、无病生存期（disease-free survival, DFS）/无进展生存期（progression-free survival, PFS）/无复发生存期（relapse-free survival, RFS）以及3/4级不良事件（adverse event, AE）。通过间接比较分析FOLFIRINOX方案与gem-cap、gem-nab/P的疗效差异，采用Cochran Q检验及I²统计量评估研究间异质性。

**<i>研究结果</i>**：本研究共纳入9项研究，涉及6564例患者。间接比较结果显示，相较于gem-cap，FOLFIRINOX方案可显著改善总生存期（可切除患者：风险比HR 0.78 [95%置信区间0.61–0.99]；晚期患者：HR 0.71 [0.60–0.85]）及无复发生存期/无病生存期/无进展生存期（可切除患者：HR 0.67 [0.55–0.82]；晚期患者：HR 0.65 [0.57–0.74]）；相较于gem-nab/P，FOLFIRINOX方案亦可显著改善总生存期（可切除患者：HR 0.78 [0.61–1.00]；晚期患者：HR 0.73 [0.54–0.98]）及无病生存期/无进展生存期（可切除患者：HR 0.66 [0.53–0.82]；晚期患者：HR 0.64 [0.49–0.83]）。此外，FOLFIRINOX方案的3/4级不良事件发生风险高于gem-cap与gem-nab/P。

**<i>研究结论</i>**：相较于gem-nab/P与gem-cap，FOLFIRINOX方案可带来显著的生存获益，但临床应用中需注意其伴随的3/4级不良事件风险升高的问题。