Network Meta-Analysis: Triplet and Quadruplet Chemotherapy Regimens for Advanced Pancreatic Cancer
22 Dec, 2024 | 17:38h | UTCBackground: Advanced pancreatic ductal adenocarcinoma (PDAC) is associated with poor survival, as most patients present with metastatic or unresectable disease. While gemcitabine monotherapy was the mainstay for decades, subsequent trials found survival gains with multi-agent regimens such as FOLFIRINOX and gemcitabine plus nab-paclitaxel. However, head-to-head data comparing these regimens are limited. This systematic review and Bayesian network meta-analysis aimed to consolidate available evidence on first-line treatment options, focusing on both efficacy and safety outcomes.
Objective: To compare different chemotherapy regimens for unresectable locally advanced or metastatic PDAC, determining which options confer the greatest benefit in progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and toxicity profiles.
Methods: Phase 2–3 randomized controlled trials published since 2000 were searched in PubMed, Cochrane Central, and Embase, and from oncology conference proceedings. Eligible studies enrolled previously untreated patients with advanced PDAC, examining at least one regimen containing gemcitabine, fluorouracil, oxaliplatin, irinotecan, nab-paclitaxel, or liposomal irinotecan. Hazard ratios (HRs) and odds ratios (ORs) were computed within a Bayesian framework, ranking therapies using surface under the cumulative ranking curves. Risk of bias was assessed with Cochrane’s RoB 2 tool; evidence certainty was appraised using GRADE.
Results: Seventy-nine trials (22,168 patients) were included. PFS analysis showed gemcitabine plus nab-paclitaxel alternating FOLFOX (HR 0.32), PAXG (0.35), and NALIRIFOX (0.43) offered the highest benefit versus gemcitabine alone, followed by FOLFIRINOX (0.55) and gemcitabine plus nab-paclitaxel (0.62). For OS, the top three regimens were PAXG (HR 0.40), gemcitabine plus nab-paclitaxel alternating FOLFOX (0.46), and NALIRIFOX (0.56), with FOLFIRINOX (0.66) and gemcitabine plus nab-paclitaxel (0.67) close behind. NALIRIFOX demonstrated relatively lower rates of hematologic toxicity compared with FOLFIRINOX and gemcitabine plus nab-paclitaxel, although diarrhea and neuropathy remained frequent across most multi-drug regimens. Overall, the certainty of evidence was low, largely because of indirect comparisons and high heterogeneity among trials.
Conclusions: Among triplet options, NALIRIFOX and FOLFIRINOX appear most favorable for patients who can tolerate intensified therapy, with gemcitabine plus nab-paclitaxel remaining a viable option for less fit patients. Quadruplet regimens, either administered concurrently or sequentially, show promising efficacy but warrant validation in phase 3 trials.
Implications for Practice: Clinical decision-making should balance potential survival benefits with toxicity, patient performance status, and cost-effectiveness considerations. While more intensive combinations can prolong survival, adverse effects and patient quality of life must be carefully monitored.
Study Strengths and Limitations: This is the largest systematic review and network meta-analysis to date in this setting, synthesizing 79 trials. Nevertheless, the evidence base is limited by phase 2 studies, inconsistent reporting of toxicities, and relatively few direct head-to-head comparisons. Most trials lacked central radiographic review.
Future Research: Prospective phase 3 trials evaluating quadruplet or sequential regimens are needed. Additional biomarker-driven strategies, personalized chemotherapy scheduling, and earlier integration of palliative care may also help enhance survival and preserve quality of life in this population.