This review found that S-1-based therapy was associated with improved overall survival and an equivalent overall response rate and largely similar safety profile compared with 5-FU-based therapy in patients with advanced gastric cancer. Lack of information about follow-up of patients meant that the results of the review should be interpreted with some caution.

To evaluate the efficacy and safety of S-1-based therapy compared with fluorouracil (5-FU)-based therapy for the treatment of advanced gastric cancer.

PubMed, EMBASE and The Cochrane Library were searched to December 2009 for relevant studies; search terms were reported. The abstracts and virtual meeting presentations from the American Society of Clinical Oncology conferences from 2000-2009 were also searched for additional studies. There were no language restrictions.

Randomised controlled trials (RCTs) and Phase II studies that compared S-1-based therapy with 5-FU-based therapy in patients with advanced gastric cancer at baseline were eligible for inclusion. Where combination chemotherapy was administered the control and intervention arms had to differ only by the S-1 and 5-FU therapies with no confounding by additional agents or interventions.

Three of the four included studies were conducted in Japan and China; the fourth trial was conducted in the United States. Both treatments were administered at various doses (where reported). In some studies, the treatments were given in combination with cisplatin therapy. Where reported, the patient age range was 56.5 to 64 years. The endpoints used for this review were overall survival, overall response rate (defined as the sum of partial and complete responses) and toxicity associated with treatment, measured as the incidence of grade three or grade four adverse events.

Two reviewers independently performed the study selection.

The methodological quality of the RCTs was evaluated with the critical review checklist of the Dutch Cochrane Centre in terms of treatment assignment, allocation concealment, blinding, accounting of withdrawals and drop-outs and similarity of treatment groups at baseline. The abstracts were assessed using a format presented by CONSORT (Consolidated Standards of Reporting Trials) in terms of trial design, participants, interventions, conclusions, registration of the trial and source of funding.

Two independent reviewers assessed study quality.

Two independent reviewers extracted data on an intention-to-treat basis to calculate hazard ratios (HR) for overall survival, and odds ratios (OR) for the other outcomes with 95% confidence intervals (CI) for each estimate. The authors stated that the reviewers reached consensus on all items.

Pooled hazard ratios, odds ratios and 95% confidence intervals for each summary estimate were calculated using a fixed-effect model. Statistical heterogeneity was evaluated using the Q-statistic and Ι². Where heterogeneity was present, the results were evaluated using subgroup and sensitivity analyses or were pooled using a random-effects model. The authors examined the potential for publication bias using the Begg and Egger tests.

Four RCTs (n=2,115) were included in the review. Sample sizes ranged from 150 to 1,029 patients. Three of the included trials were published as abstracts and one trial was published in a peer-reviewed journal. The overall risk of bias was unclear in the fully reported trial. The abstracts appeared to meet some of the inclusion criteria but none of them reported allocation concealment, blinding or source of funding.

There were benefits observed in overall survival with S-1-based group to with the 5-FU-based therapy (HR 0.87, 95% CI 0.79 to 0.96, three trials Ι²=0%), although there were no significant differences between treatment groups in overall response rate (OR 1.25, 95% CI 0.31 to 5.09, two trials; random-effects model). For this latter finding there was significant statistical heterogeneity observed across the trials (Ι²=90.5%).

Grade 3 to 4 neutropenia (three trials) was more likely to occur in patients treated with 5-FU-based therapy compared with the patients treated with S-1-based therapy, although statistically significant heterogeneity was observed, (OR 0.37, 95% CI 0.29 to 0.48, Ι²=70.2%). With the omission of one trial, heterogeneity was no longer statistically significant. There were no statistically significant differences observed between the treatment groups in grade 3-4 anaemia, leucopenia, nausea, diarrhoea in non-haematological toxicity (Ι²=88.9%), stomatitis (Ι²=90.8%) and treatment-related deaths.

The results of the Begg and Egger tests did not show any evidence of publication bias.

The meta-analysis indicated that S-1-based therapy was associated with improved overall survival and an equivalent overall response rate and largely similar safety profile compared with 5-FU-based therapy in patients with advanced gastric cancer.

The review addressed a clearly defined question and criteria for the inclusion of studies were stipulated, although not all outcomes were stipulated a priori. Appropriate databases were searched without language restriction and attempts were made to identify unpublished studies. Steps were taken at each stage of the review process to minimise errors and bias. Methodological quality results were reported briefly, although three of the included trials were published as abstracts only. The length of follow-up was not clear across the studies, which meant the pooling of survival data from varying follow-up points may not have been appropriate. In addition, there was little information provided on the patients in the trials. The authors combined the results in a meta-analysis and explored potential sources of heterogeneity using appropriate and validated methods. In general, the authors conclusions reflect the evidence presented, but the lack of information on follow-up (particularly for survival data) meant that the results should be interpreted with some caution.

Practice: The authors stated that given the convenience of oral administration, S-1-based therapy could be used as standard chemotherapeutic treatment for patients with advanced gastric cancer, particularly in Asia.

Research: The authors stated that further research was required to confirm these results in high quality trials, particularly in the West. Most of the results in the review were drawn from studies in Asia and there may be some differences in the side-effect profile of patients in the West.

None stated.

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.