Supplementary Material for: Real World Advances in Metastatic Pancreatic Cancer Treatment in the Pre-Molecular Era: A retrospective single-center analysis 2010 - 2018

Introduction: Despite decades of extensive research, treatment options for pancreatic adenocarcinoma (PAC) patients kept limited, and prognosis remains dismal. For patients with metastatic PAC (mPAC), palliative combination chemotherapy remains the mainstay of treatment. Current treatment standards for mPAC have evolved from 2010 onwards with the introduction of combination chemotherapy protocols, the development of new chemotherapeutic agents, and the establishment of treatment sequences. Within our cohort, we analyzed the impact of different treatment options and sequences over time for mPAC patients in a Swiss academic center in the pre-molecular era between 2010 and 2018.
Methods: This retrospective analysis included 97 patients who received palliative chemotherapy for mPAC between 2010 and 2018 at our institution. Outcome parameters, including median overall survival (mOS) and median progression-free survival (mPFS), were analyzed in the context of chemotherapy regimens and the number of treatment lines received. For comparative analyses, patients were separated into two groups, advancing to stage IV (metastatic) between 2010 - 2012, and between 2013 - 2018, respectively. Univariate analyses were performed via the log-rank test.
Results: For the entire cohort, mOS and first-line mPFS were 8.2 months (95% confidence interval (95% CI) 6.3 - 8.6 months) and 4.8 months (95% CI 3.4 - 5.8 months), respectively. When comparing between patients advancing to stage IV (metastatic) 2010 - 2012 and 2013 - 2018, the most frequent choice of systemic first-line therapy evolved from single agent gemcitabine (GEM) towards the combination protocols FOLFIRINOX (FFX) and gemcitabine/nab-paclitaxel (GEM/nab-PTX). Moreover, the proportion of patients receiving further-line chemotherapies increased significantly between 2010 - 2012 to 2013 - 2018 (20% vs. 49% second-line treatment; p-value (P) = 0.0035). Finally, a significant improvement in overall survival (OS) was observed for patients advancing to metastatic disease 2013 - 2018 compared to 2010 - 2012 (mOS 8.6 months vs. 6.1 months; hazard ratio (HR) = 1.82, 95% CI = 1.10 - 3.02, P = 0.0068). The use of combination regimens (FFX or GEM/nab-PTX) instead of GEM monotherapy as first-line systemic treatment was associated with a significantly improved OS (mOS 9.0 vs. 5.1 months; HR = 0.39, 95% CI = 0.19 - 0.77, P = 0.0001) and first-line progression-free survival (PFS) (mPFS 5.0 vs. 4.7 months; HR = 0.57, 95% CI = 0.32 - 1.03, P = 0.0213).
Conclusions: In summary, systemic treatment of mPAC intensified during the study period with the availability of new first-line combination chemotherapy options and more lines of therapy. In parallel, patient survival improved, suggesting a causal relationship between more effective chemotherapy and improved outcome. Combination chemotherapy is standard-of-care for mPAC, while the future impact of molecular profiling and precision oncology on real-world patient outcome remains to be determined.

引言：尽管经过数十年的广泛研究，胰腺腺癌（PAC）患者的治疗选择仍然有限，预后依旧不佳。对于转移性胰腺腺癌（mPAC）患者，姑息性联合化疗仍是主要治疗手段。自2010年起，随着联合化疗方案的引入、新型化疗药物的开发以及治疗序列的建立，mPAC的当前治疗标准已逐步发展。在本队列中，我们分析了2010年至2018年前分子时代期间，瑞士某学术中心mPAC患者不同治疗选择及序列随时间的影响。
方法：本回顾性分析纳入2010年至2018年间在我院接受mPAC姑息性化疗的97例患者。我们结合化疗方案及接受的治疗线数，分析了包括中位总生存期（mOS）和中位无进展生存期（mPFS）在内的结局参数。为进行比较分析，患者被分为两组：2010-2012年进展至IV期（转移性）的患者，以及2013-2018年进展至IV期（转移性）的患者。采用对数秩检验进行单因素分析。
结果：整个队列的mOS为8.2个月（95%置信区间（95% CI）6.3-8.6个月），一线mPFS为4.8个月（95% CI 3.4-5.8个月）。对比2010-2012年与2013-2018年进展至IV期（转移性）的患者，系统性一线治疗的最常见选择从单药吉西他滨（GEM）转变为联合方案FOLFIRINOX（FFX）和吉西他滨/白蛋白结合型紫杉醇（GEM/nab-PTX）。此外，接受后续线化疗的患者比例在2010-2012年至2013-2018年间显著增加（二线治疗：20% vs. 49%；p值（P）=0.0035）。最后，与2010-2012年进展为转移性疾病的患者相比，2013-2018年进展的患者总生存期（OS）显著改善（mOS：8.6个月vs.6.1个月；风险比（HR）=1.82，95% CI=1.10-3.02，P=0.0068）。使用联合方案（FFX或GEM/nab-PTX）而非GEM单药作为一线系统性治疗，与OS显著改善（mOS：9.0个月vs.5.1个月；HR=0.39，95% CI=0.19-0.77，P=0.0001）及一线无进展生存期（PFS）改善（mPFS：5.0个月vs.4.7个月；HR=0.57，95% CI=0.32-1.03，P=0.0213）相关。
结论：综上，在研究期间，随着新型一线联合化疗方案的出现及更多治疗线数的应用，mPAC的系统性治疗强度有所增加。与此同时，患者生存期得到改善，提示更有效的化疗与更好的结局之间存在因果关系。联合化疗是mPAC的标准治疗，而分子谱分析和精准肿瘤学对真实世界患者结局的未来影响仍有待确定。