During the past decades, GEM radiosensitization has been used in some studies because of its systemic activity in pancreatic cancer and its potent radiosensitizing properties.7–10 In addition, a recent meta-analysis based on three small randomized controlled trials (RCTs) and one retrospective study suggested a survival benefit of GEM compared with 5-fluorouracil-based CRT,11 but at the cost of greater toxicity. Therefore, the optimal regimen for CRT remains elusive. Recently, two novel oral FU drugs, capecitabine and S-1, have been widely used in conjunction with radiotherapy for LAPC patients due to their improved therapeutic index, more favorable pharmacokinetics (similar to those of protracted infusion of 5-fluorouracil), and their convenient oral administration without the need for central venous access and an ambulatory infusion pump. However, whether oral FU-based CRT is better than GEM-based CRT for LAPC remains uncertain. Due to the controversy of the effect of oral FU-based CRT in LAPC, we conducted the present systematic review and meta-analysis to evaluate the efficacy and toxicities of oral FU-based CRT compared with GEM-based CRT for the treatment of LAPC.
MATERIALS AND METHODS
We developed a protocol that defined inclusion criteria, search strategy, outcomes of interest, and analysis plan. The reporting of the current systematic review adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statements.12
Identification and selection of studies
To identify studies for inclusion in our current systematic review and meta-analysis, we did a broad search of four databases, including Embase, Medline, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews, from the date of inception of every database to August 2014. The search included the following terms: “pancreatic neoplasms”, “pancreatic cancer”, “pancreatic carcinoma”, “pancreatic adenocarcinoma”, “gemcitabine”, “gemzar”, “oral fluoropyrimidines”, “capecitabine”, “xeloda”, “S-1”, “radiotherapy”, and “chemotherapy”. Additional references were searched through manual searches of the reference lists and specialist journals. No language restrictions were applied.
To be eligible for inclusion in our present systematic review and meta-analysis, study populations (referred to hereafter as cohorts) had to meet all the following criteria: 1) patients with LAPC; 2) treatment with GEM-based CRT, capecitabine-based CRT, or S-1 based CRT, while combined chemotherapy plus RT were excluded for analysis in our current study; 3) reported outcomes of interest (ie, objective response rate, survival, and complications); and 4) from an original study (ie, RCT, non-randomized clinical trial, observational studies, or case series).
Two investigators screened the titles and abstracts of potentially relevant studies. We retrieved the full text of relevant studies for further review by the same two reviewers. A third senior investigator resolved any discrepancies between reviewers. If reviewers suspected an overlap of cohorts in a report, they contacted the corresponding author for clarification; we excluded studies with a clear overlap.
The same pair of reviewers extracted study details independently, using a standardized pilot-tested form. A third investigator reviewed all data entries. We extracted the following data: author, study design, study period, median age, interventions (concurrent chemotherapy, radiation dose, and fractionation schedule), sample size, and outcomes of interest. We defined outcomes of interest as overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and toxic effects. We assessed survival outcomes at 1 and 5 years, while we also assessed 1-year PFS, ORR, and toxicities.
To assess quality, since we included non-comparative (uncontrolled) studies in our current systematic review and meta-analysis, we used the Newcastle–Ottawa quality assessment scale.13 We selected items that focused on representativeness of study patients, demonstration that the outcome of interest was not present at the start of the study, adequate assessment of outcome, sufficient length of follow-up to allow outcomes to arise, and adequacy of follow-up (Table S1, Supplementary Material).
We pre-specified the analysis plan in the protocol. We analyzed all patients who started GEM or oral FU-based CRT, regardless of their adherence to treatment. We calculated event rates of outcome (the proportion of patients who developed outcomes of interest) from the included cohorts for both GEM and oral FU-based CRT. We pooled log-transformed event rates with DerSimonian and Laird random-effect models and assessed heterogeneity using the Mantel–Haenszel test.14 We used the test of interaction proposed by Altman to compare log-transformed rates of outcomes between GEM and oral FU-based CRT.15 A statistical test with a P-value <0.05 was considered significant. To account for the potential effect of publication bias, we used the Duval and Tweedie non-parametric trim-and-fill method.16 To measure overall heterogeneity across the included cohorts, we calculated the I2 statistic, with I2>50% indicating high heterogeneity. We assessed potential publication bias by visual inspection of the symmetry of funnel plots and with the Egger regression asymmetry test. We did all statistical analyses with Stata version 12.1 (StataCorp LP, College Station, TX, USA) and comprehensive meta-analysis software version 2.0 (Biostat Inc, Englewood, NJ, USA).