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.