RESUMO
Mechanisms accounting for sex differences in the incidence of adverse events caused by fluoropyrimidine treatments, and histologic differences in efficacy are insufficiently understood. We determined differences between the sexes in terms of the safety of S-1 plus oxaliplatin (SOX)/bevacizumab-versus-l-leucovorin, 5-fluorouracil (5-FU) and oxaliplatin (FOLFOX)/bevacizumab, and the impact of histology on their therapeutic effects, in 512 unresectable metastatic colorectal cancer patients from the SOFT phase III study. Nausea (OR: 2.88, P < 0.001) and vomiting (OR: 3.04, P = 0.005) occurred more frequently in females than males treated with SOX/bevacizumab, while nausea (OR: 2.12, P = 0.006), vomiting (OR: 3.26, P = 0.004), leukopenia (OR: 2.61, P < 0.001), neutropenia (OR: 2.92, P < 0.001), and alopecia (OR: 4.13, P < 0.001) were higher in females on FOLFOX/bevacizumab. Mean relative dose intensities (RDIs) of S-1 during all cycles of SOX/bevacizumab were significantly lower in females (73.9%) than males (81.5%) (P < 0.001), while RDIs of continuous infusion of 5-FU in the FOLFOX/bevacizumab regimen were 75.0% in females and 80.5% in males (P = 0.005). No significant differences in efficacy with regard to overall survival (OS) and progression-free survival (PFS) were identified between the sexes for either SOX/bevacizumab or FOLFOX/bevacizumab treatment. Patients with poorly-differentiated adenocarcinoma had significantly worse OS (HR: 2.72, 95% CI: 1.67-4.44, P < 0.0001) and PFS (HR: 1.89, 95% CI: 1.18-3.02, P = 0.0079) than patients with well- or moderately-differentiated adenocarcinoma. Female patients experienced more frequent and severe adverse reactions to SOX/bevacizumab and FOLFOX/bevacizumab and a worse prognosis for poorly-differentiated adenocarcinoma were confirmed in this phase III study. This warrants further translational research to identify the responsible mechanisms.
RESUMO
OBJECTIVES: In a literature-based meta-analysis for time-to-event data, the hazard ratio in each trial is often estimated from the summary statistics described in the article. Several methods have been proposed: the direct method (Peto method); the indirect method using a p-value by the log-rank test and the number of total events; and the survival curve method using the Kaplan-Meier estimate. However, there has been no published report on a detailed investigation of these methods. We evaluated the performance of these methods by simulation. METHODS: In a set of simulation experiments, performance of five methods was evaluated by the bias of estimated log hazard ratio and coverage probability of the confidence interval. The methods evaluated were: 1) Cox regression analysis, 2) direct method, 3) indirect method, 4) survival curve method, and 5) modified survival curve method with an alternative weighting scheme. RESULTS: The direct method was confirmed to have a high degree of accuracy. Although the indirect method was also highly accurate, it tended to underestimate effect size when there was a strong effect. The survival curve method tended to underestimate effect size when event numbers were small and effect size was large. The modified survival curve method could alleviate this tendency toward underestimation of effect size found with the original survival curve method. CONCLUSIONS: When the Kaplan-Meier curve is used to estimate hazard ratios in trials with small sample size in the literature-based meta-analysis, we should check critically whether those trials' hazard ratios and overall hazard ratio are underestimated or not.
