Abstract
BackgroundAdvanced pancreatic cancer confers poor prognosis and treatment advancement has been slow. Recent randomized clinical trials (RCTs) have demonstrated survival benefits for combination therapy compared to gemcitabine alone. However, the comparative benefits and harms of available combination chemotherapy treatments are not clear. We therefore conducted a systematic review and Bayesian network meta-analysis to assess the comparative safety and efficacy of chemotherapy regimens for the treatment of advanced pancreatic cancer.MethodsMEDLINE, PubMed, EMBASE, Cochrane Central Registry of Clinical trials and abstracts from major scientific meetings were searched for RCTs published from 2002 to 2013. Key outcomes were overall survival (OS), progression free survival (PFS), and safety including grade 3–4 febrile neutropenia, neutropenia, vomiting, diarrhea, fatigue and sensory neuropathy. Bayesian network meta-analyses were conducted to calculate survival and safety outcomes using gemcitabine (GEM) as the reference comparator. Effect estimates and 95% credible intervals were calculated for each comparison. Mean ranks and the probability of being best were obtained for each treatment analyzed in the network meta-analysis.ResultsThe search identified 23 studies involving 19 different treatment regimens and 9,989 patients. FOLFIRINOX, GEM/cisplatin/epirubicin/5FU (PEFG), GEM/NAB-paclitaxel (NAB-P), GEM/erlotinib+/-bevacizumab, GEM/capecitabine, and GEM/oxaliplatin were associated with statistically significant improvements in OS and PFS relative to gemcitabine alone and several other treatments. They were amongst the top ranked for survival outcomes amongst other treatments included. No significant differences were found for other combination chemotherapy treatments. Effect estimates from indirect comparisons matched closely to estimates derived from pairwise comparisons. Overall, combination therapies had greater risk for evaluated grade 3–4 toxicities over gemcitabine alone.ConclusionsIn the absence of head-to-head comparisons, we performed a mixed-treatment analysis to achieve high-quality information on the effectiveness and safety of each treatment. This study suggests that some combination therapies may offer greater benefits in the treatment of advanced pancreatic cancer than others. To more fully elucidate the comparative benefits and harms of different combination chemotherapy regimens, rigorously conducted comparative studies, or network meta-analysis of patient-level data are required.
Highlights
Advanced pancreatic cancer confers poor prognosis and treatment advancement has been slow
The combination of GEM/capecitabine, GEM/oxaliplatin, PEFG, GEM plus NAB-paclitaxel (NAB-P), GEM/erlotinib+/−bevacizumab and FOLFIRINOX were associated with statistically significant hazard ratios for overall survival (OS) over GEM alone (Additional file 1: Figure S1)
Our study found that in comparison to GEM alone, there was statistically significant improved survival associated with FOLFIRINOX, PEFG, GEM/NABP, GEM/capecitabine, GEM/erlotinib with or without bevacizumab and GEM/oxaliplatin
Summary
Advanced pancreatic cancer confers poor prognosis and treatment advancement has been slow. We conducted a systematic review and Bayesian network meta-analysis to assess the comparative safety and efficacy of chemotherapy regimens for the treatment of advanced pancreatic cancer. In 2011, a four drug regimen, which included folinic acid, 5-fluorouacil, irinotecan and oxaliplatin (FOLFIRINOX), was shown to have significantly superior survival outcomes compared to GEM alone [29]. This resulted in the adoption of FOLFIRINOX as the preferred option for patients with good performance status (ECOG 0-1/KPS > 70). A trial comparing GEM/NAB-P versus GEM alone demonstrated a statistically significant survival benefit for this new doublet, introducing another option for the management of advanced pancreatic cancer [28]. With the introduction of these therapeutic options, and the lack of randomized trials that directly compare all available treatments, it was of interest to indirectly compare the relative efficacy and safety of these treatments using a network meta-analysis
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