由于缺乏头对头的 III 期随机试验，因此对于晚期胰腺癌的最佳治疗顺序尚无明确的指南。我们通过模拟假设的随机试验来评估三种常见序贯治疗策略的现实有效性。该分析包括来自前瞻性临床队列研究《肿瘤登记胰腺癌》的 1551 名晚期胰腺癌患者，这些患者接受 FOLFIRINOX (n = 613) 或吉西他滨/白蛋白结合型紫杉醇 (GEMNAB; n = 938) 作为一线姑息治疗。我们使用边际结构模型来比较三种常见一线至二线治疗序列之间的总生存期 (OS) 和健康相关生活质量 (HRQoL) 恶化时间 (TTD)，并针对随时间变化的潜在混杂因素进行调整。序列为：FOLFIRINOX→GEMNAB、GEMNAB→FOLFOX/OFF 和 GEMNAB→纳米脂质体伊立替康 (NALIRI)  5-氟尿嘧啶。结果还根据胰腺癌评分按患者的预后风险分层计算。与风险无关的 HRQoL 中位 OS 和 TTD 分别为 FOLFIRINOX→GEMNAB 的 10.7 [8.9, 11.9] 和 6.4 [4.8, 7.7] 个月，GEMNAB→FOLFOX/OFF 的中位 OS 和 TTD 为 8.4 [7.4, 9.7] 和 5.8 [4.6, 7.1] 个月， GEMNAB→NALIRI 5-氟尿嘧啶为 8.9 [7.8, 10.4] 和 4.6 [4.1, 6.1] 个月。与 FOLFIRINOX→GEMNAB 相比，GEMNAB→FOLFOX/OFF 的低危患者的 OS 和 TTD 较差（OS：HR 2.09 [1.47, 2.98]；TTD：HR 1.97 [1.19, 3.27]）和 GEMNAB→NALIRI 5 的患者-氟尿嘧啶（OS：HR 1.35，[0.76，2.39]；TTD：HR 2.62 [1.56，4.42]）。括号表示 95% 置信区间。所评估的三种治疗序列的估计实际效果在很大程度上具有可比性。 就临床和患者报告的结果而言，低风险患者可能会受益于 FOLFIRINOX→GEMNAB 的强化治疗。未来有必要对晚期胰腺癌序贯治疗进行随机试验。© 2024 作者。约翰·威利出版的《国际癌症杂志》

There are no clear guidelines regarding the optimal treatment sequence for advanced pancreatic cancer, as head-to-head phase III randomised trials are missing. We assess real-world effectiveness of three common sequential treatment strategies by emulating a hypothetical randomised trial. This analysis included 1551 patients with advanced pancreatic cancer from the prospective, clinical cohort study Tumour Registry Pancreatic Cancer receiving FOLFIRINOX (n = 613) or gemcitabine/nab-paclitaxel (GEMNAB; n = 938) as palliative first-line treatment. We used marginal structural modelling to compare overall survival (OS) and time to deterioration (TTD) of health-related quality of life (HRQoL) between three common first- to second-line treatment sequences, adjusting for time-varying potential confounding. The sequences were: FOLFIRINOX→GEMNAB, GEMNAB→FOLFOX/OFF and GEMNAB→nanoliposomal irinotecan (NALIRI) + 5-fluorouracil. Outcome was also calculated stratified by patients' prognostic risk according to the Pancreatic Cancer Score. Median OS and TTD of HRQoL independent of risk were 10.7 [8.9, 11.9] and 6.4 [4.8, 7.7] months for FOLFIRINOX→GEMNAB, 8.4 [7.4, 9.7] and 5.8 [4.6, 7.1] months for GEMNAB→FOLFOX/OFF and 8.9 [7.8, 10.4] and 4.6 [4.1, 6.1] months for GEMNAB→NALIRI+5-fluorouracil. Compared to FOLFIRINOX→GEMNAB, OS and TTD were worse for poor-risk patients with GEMNAB→FOLFOX/OFF (OS: HR 2.09 [1.47, 2.98]; TTD: HR 1.97 [1.19, 3.27]) and those with GEMNAB→NALIRI+5-fluorouracil (OS: HR 1.35, [0.76, 2.39]; TTD: HR 2.62 [1.56, 4.42]). Brackets denote 95%-confidence intervals. The estimated real-world effectiveness of the three treatment sequences evaluated were largely comparable. Poor-risk patients might benefit from intensified treatment with FOLFIRINOX→GEMNAB in terms of clinical and patient-reported outcomes. Future randomised trials on sequential treatments in advanced pancreatic cancer are warranted.© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.