A Bayesian meta-analysis of multiple treatment comparisons of systemic regimens for advanced pancreatic cancer

Abstract

Background: For advanced pancreatic cancer, many regimens have been compared with gemcitabine (G) as the standard arm in randomized controlled trials. Few regimens have been directly compared with each other in randomized controlled trials and the relative efficacy and safety among them remains unclear.

Methods: A systematic review was performed through MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and ASCO meeting abstracts up to May 2013 to identify randomized controlled trials that included advanced pancreatic cancer comparing the following regimens: G, G+5-fluorouracil, G+ capecitabine, G+S1, G+ cisplatin, G+ oxaliplatin, G+ erlotinib, G+ nab-paclitaxel, and FOLFIRINOX. Overall survival and progression-free survival with 95% credible regions were extracted using the Parmar method. A Bayesian multiple treatment comparisons was performed to compare all regimens simultaneously.

Results: Twenty-two studies were identified and 16 were included in the meta-analysis. Median overall survival, progression free survival, and response rates for G arms from all trials were similar, suggesting no significant clinical heterogeneity. For overall survival, the mixed treatment comparisons found that the probability that FOLFIRINOX was the best regimen was 83%, while it was 11% for G+ nab-paclitaxel and 3% for G+ S1 and G+ erlotinib, respectively. The overall survival hazard ratio for FOLFIRINOX versus G+ nab-paclitaxel was 0.79 [0.50-1.24], with no obvious difference in toxicities. The hazard ratios from direct pairwise comparisons were consistent with the mixed treatment comparisons results.

Conclusions: FOLFIRINOX appeared to be the best regimen for advanced pancreatic cancer probabilistically, with a trend towards improvement in survival when compared with other regimens by indirect comparisons.

Figure 1. PRISMA Flow diagram of included and excluded trials identified from the literature search.

There were 13 studies that were excluded after full text review for “other” reasons. The reasons are as follows: 4 were secondary analyses, 2 were quality of life studies, 2 were pooled analyses, 1 study was not randomized, 1 was a review, 1 was a tumour marker study, 1 was a safety analysis, and 1 study was excluded because it was retrospective.

Figure 2. Treatment strategy network.

Numbers represent the number of studies comparing the linked regimens; brackets represent the number included in the quantitative analysis.

Figure 3. Forest plot of direct comparisons between the regimens.

Forest plot showing hazard ratio comparisons with 95% CI for overall survival (OS) from meta-analyses of direct comparisons between different combinations of gemcitabine (GEM), gemcitabine + fluorouracil (GF), gemcitabine + nab-paclitaxel (GnP), gemcitabine + capecitabine (GCap), gemcitabine + cisplatin (GCis), gemcitabine + erlotinib (GE), FOLFIRINOX, gemcitabine + oxaliplatin (GOx), and G + S1 (GS). I² values indicate statistical heterogeneity, where 0% indicates no observed heterogeneity and larger values show increasing heterogeneity (17).

Figure 4. Hazard ratio comparisons of overall survival (OS) from mixed treatment comparisons.

Median values given with 95% credible regions. Hazard ratios (HRs) expressed as experimental vs. control. G, gemcitabine; GF, gemcitabine + fluorouracil; GCap, gemcitabine + capecitabine; GOx, gemcitabine + oxaliplatin; GCis, gemcitabine + cisplatin; FOLFIRINOX; GE, gemcitabine + erlotinib; GS, gemcitabine + S1; GnP, gemcitabine + nab-paclitaxel.

Figure 5. Probabilities that each treatment regimen is the best based on overall survival (OS).

G, gemcitabine; GF, gemcitabine + fluorouracil; GCap, gemcitabine + capecitabine; GOx, gemcitabine + oxaliplatin; GCis, gemcitabine + cisplatin; FOLFIRINOX; GE, gemcitabine + erlotinib; GS, gemcitabine + S1; GnP, gemcitabine + nab-paclitaxel.