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Comparison of First-Line Chemotherapy Regimens in Unresectable Locally Advanced or Metastatic Pancreatic Cancer
TAKE-HOME MESSAGE
- The authors present a systematic review and meta-analysis of 79 randomized trials (N = 22,168 patients) assessing the safety and efficacy of first-line chemotherapy regimens in patients with advanced pancreatic ductal adenocarcinoma. The most effective regimens in terms of progression-free survival were gemcitabine plus nab-paclitaxel alternating with FOLFOX (HR, 0.32), PAXG (HR, 0.35), and NALIRIFOX (HR, 0.43), followed by FOLFIRINOX (HR, 0.55). Similar rankings were observed for overall survival, with PAXG associated with the greatest benefit (HR, 0.40; 95% CI, 0.25–0.65).
- The findings provide evidence for using triplet or quadruplet regimens as preferred first-line treatments in patients with good performance status, with gemcitabine plus nab-paclitaxel being a viable option for patients who are frailer.
abstract
This abstract is available on the publisher's site.
Access this abstract now Full Text Available for ClinicalKey SubscribersBACKGROUND
In advanced pancreatic ductal adenocarcinoma (PDAC), first-line chemotherapy is the standard of care. Due to the absence of head-to-head comparisons in clinical trials, we performed this systematic review and network meta-analysis to compare treatment options for PDAC in terms of their efficacy and toxicity.
METHODS
PubMed, the Cochrane Central Register of Controlled Trials, Embase, and oncological meetings websites were searched until Nov 15, 2023. We included phase 2-3 randomised controlled trials published after Jan 1, 2000, evaluating first-line treatments in patients with previously untreated, unresectable, locally advanced or metastatic PDAC. Primary endpoints assessed were progression-free survival and overall survival. Summary data were extracted from published reports. The deviance information criterion was used to choose between a random-effects or fixed-effects model. Hazard ratios (HRs) with 95% credible intervals were estimated using a Bayesian approach. The risk of bias was evaluated using the Cochrane Risk of Bias 2 (RoB 2) tool and studies were graded as low, some concerns, or high risk of bias. The quality of evidence was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation approach. This systematic review and network meta-analysis is registered with PROSPERO, CRD42023450330.
FINDINGS
6050 records were screened and 79 randomised controlled trials (22 168 patients) were included in the analysis. Gemcitabine was the most frequent comparator (in 50 [63%] of 79 trials) and was considered as the reference treatment. A fixed-effect model was used to analyse the primary outcomes. Regarding progression-free survival (71 trials, 19 479 patients), the most effective treatments were gemcitabine plus nab-paclitaxel alternating folinic acid, fluorouracil, and oxaliplatin ([FOLFOX] HR 0·32, 95% credible interval 0·22-0·47), cisplatin, nab-paclitaxel, capecitabine, and gemcitabine ([PAXG] 0·35, 0·22-0·55), and liposomal irinotecan in combination with fluorouracil, leucovorin, and oxaliplatin ([NALIRIFOX] 0·43, 0·34-0·54), followed by fluorouracil, leucovorin, irinotecan, and oxaliplatin ([FOLFIRINOX] 0·55, 0·47-0·65) and gemcitabine plus nab-paclitaxel (0·62, 0·54-0·72). Similar results were observed for overall survival (79 trials, 22 104 patients): PAXG (HR 0·40, 95% credible interval 0·25-0·65), gemcitabine plus nab-paclitaxel alternating FOLFOX (0·46, 0·32-0·66), and NALIRIFOX (0·56, 0·45-0·70) had the highest benefit, followed by FOLFIRINOX (0·66, 0·56-0·78) and gemcitabine plus nab-paclitaxel (0·67, 0·59-0·77). The overall risk of bias was low to some concerns. Certainty of evidence was low.
INTERPRETATION
Our findings suggest that NALIRIFOX and FOLFIRINOX should be the preferred options for patients who can tolerate these regimens, with gemcitabine plus nab-paclitaxel remaining a viable alternative, particularly in patients unfit for triplet therapy. Phase 3 randomised controlled trials investigating concomitant or sequential quadruplets are warranted.
FUNDING
None.
Additional Info
Disclosure statements are available on the authors' profiles:
Comparison of first-line chemotherapy regimens in unresectable locally advanced or metastatic pancreatic cancer: a systematic review and Bayesian network meta-analysis
Lancet Oncol 2024 Nov 11;[EPub Ahead of Print], L Mastrantoni, M Chiaravalli, A Spring, V Beccia, A Di Bello, C Bagalà, M Bensi, D Barone, G Trovato, G Caira, G Giordano, E Bria, G Tortora, L SalvatoreFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Treatment of metastatic pancreatic cancer is evolving, and genomic-based therapies are anticipated to be a major part of future therapy assignment, given both the ubiquity of KRAS mutations and emerging therapies targeted to KRAS. Nonetheless, today, combination cytotoxic therapy remains the mainstay of therapy for advanced disease, with much discussion focused on whether a gemcitabine-based two-drug or oxaliplatin/fluoropyrimidine/irinotecan (FOLFIRINOX or NALIRIFOX)-based four-drug combinations are preferable as the initial therapy choice in the front-line treatment of advanced pancreatic cancer. For now, targeted therapy remains a choice for a small but growing subset of patients. The detailed systematic review and Bayesian network meta-analysis of more than 22,000 patients over the last 25 years by Mastrantoni et al represents the most comprehensive and up-to-date examination of the data, and the key conclusion is that the totality of the data supports that a quadruplet combination is preferred for those with a good functional status.
These results need to be placed in the context of data on transcriptomic subtypes of pancreatic cancer. Specifically, about 70% to 80% of pancreatic cancers have a so-called "classical" subtype and about 20% to 30% a "basal-like" subtype. The basal type is associated with a poor prognosis and inherent treatment resistance. Preliminary data from the PASS-01 (Pancreatic Adenocarcinoma Signature Stratification for treatment) randomized phase II trial suggest that patients with a basal signature have a higher likelihood of treatment resistance to FOLFIRINOX and may benefit more from gemcitabine and nab-paclitaxel.1 Nonetheless, mature results are awaited, along with detailed correlative analyses, which may provide further insight.
Irrespective of individual trial results, it is clear that both two- and four-drug regimens are acceptable for most patients, and, as we enter 2025, both FOLFIRINOX and gemcitabine/nab-paclitaxel regimens are choices to which novel therapeutics can be added. We look forward to the day when dependency on cytotoxic therapy in this disease is less and we have increased opportunity for therapy selection refinement.
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