Abstract / Summary
Abstract Background Pancreatic cancer is associated with high morbidity and mortality. Gemcitabine plus nab-paclitaxel (GA), along with FOLFIRINOX and NALIRIFOX, is a standard first-line treatment for advanced/metastatic pancreatic ductal adenocarcinoma (mPDAC). However, the standard GA schedule (days 1, 8, and 15 of a 28-day cycle) is associated with significant cumulative toxicity, leading to frequent dose reductions and treatment discontinuation in real-world practice. A biweekly GA regimen, consisting in administering chemotherapy on days 1 and 15 of a 28-day cycle, has been explored as an alternative to improve tolerability while maintaining efficacy. This systematic review evaluates the real-world efficacy and safety of biweekly GA for advanced or mPDAC. Methods A comprehensive search of PubMed, Embase, Web of Science, Scopus, and Cochrane databases was performed from inception through February 2026 following PRISMA guidelines. Retrospective and prospective studies comparing biweekly GA to the standard schedule were included. Two reviewers independently performed study selection, data extraction, and risk of bias assessment. Primary outcomes were overall survival (OS) and toxicity, secondary outcome was progression-free survival (PFS). Risk of bias was assessed using the ROBINS-I tool. Meta-analysis could not be performed due to data heterogeneity, therefore findings were summarized descriptively. Results Five retrospective studies met inclusion criteria. In studies evaluating standard-dose biweekly GA (gemcitabine 1000 mg/m² and nab-paclitaxel 125 mg/m²), median OS ranged from 9.1-10 months and median PFS from 4.8-5.4 months, comparable to historical data from the phase III MPACT trial and the control arm of the NAPOLI 3 trial. A large population-based study of elderly patients (n=1,303) reported shorter OS (7.6 months) with modified schedules, due to lower baseline performance status. Across studies, biweekly GA showed a favorable safety profile, with lower rates of grade ≥3 neutropenia, febrile neutropenia, and peripheral neuropathy compared to standard dosing. Conclusion Biweekly GA appears to be a feasible and well-tolerated dosing strategy, with survival outcomes overlapping historical weekly GA cohorts in advanced or mPDAC. While prospective randomized trials are needed, the reproducibility of efficacy and tolerability findings across real-world cohorts supports biweekly GA as a viable alternative.