Chemotherapy sequence in advanced pancreatic cancer – still a matter of debate?

Abstract

Background: Managing advanced pancreatic ductal adenocarcinoma (aPDAC) is challenging, particularly in determining the optimal sequence of chemotherapy protocols. Despite a 5-year survival rate of only 3%, recent data from the US National Cancer Database indicate significant improvements in median overall survival (OS) for patients with metastatic pancreatic cancer over the past decade. This progress is attributed to enhanced chemotherapy regimens, the introduction of (new)-adjuvant chemotherapy, improved surgical techniques, and centralized treatment in high-volume centers. Methods: We conducted a retrospective cohort study at three Austrian academic centers, including patients with histologically confirmed primary locally advanced or metastatic PDAC who received first-line chemotherapy with either FOLFIRINOX (FFX) or gemcitabine + nab-paclitaxel (GN), followed by second-line treatments with GN or nanoliposomal irinotecan with fluorouracil + leucovorin (nal-IRI/5-FU) after progression. The study's primary endpoints were second progression-free survival (PFS2) and OS. Statistical analyses employed propensity score matching and inverse probability of treatment weighting (IPTW) to balance the groups and estimate the impact of the treatment sequences on outcomes. Results: Among 455 screened patients, 118 met the inclusion criteria, with 73 receiving FFX followed by GN and 45 receiving GN followed by nal-IRI/5-FU. The median OS was 15.4 months, and PFS2 was 11.5 months for the entire cohort. The GN-nal-IRI/5-FU sequence showed a trend toward improved OS compared to the FFX-GN sequence (HR = 0.57, p = 0.07), with comparable PFS2 between the two regimens (HR = 0.87, p = 0.58). Baseline characteristics differed significantly between the groups, necessitating the use of IPTW to ensure comparability. Discussion: This study is the largest to date comparing the efficacy of FFX followed by GN versus GN followed by nal-IRI/5-FU in aPDAC. The GN-nal-IRI/5-FU sequence demonstrated a potential survival benefit, although not statistically significant. The results suggest that both treatment sequences are viable, particularly where access to newer agents is limited. The study's retrospective nature and baseline differences between groups are acknowledged limitations. Conclusion: For patients suitable for triplet therapies, starting with NALIRIFOX or mFOLFIRINOX is supported by recent phase 3 trials. For those not fit for such intensive regimens, GN followed by nal-IRI/5-FU remains a valid strategy. Further prospective studies are needed to confirm these findings.