Ias test of PFS. The two oblique lines indicate the pseudo 95 confidence limits. doi:10.1371/journal.pone.0050925.gAntiEGFR MAbs and Oxaliplatin in Colorectal CancerFigure 9. Funnel plot for publication bias test of ORR. The two oblique lines indicate the pseudo 95 confidence limits. doi:10.1371/journal.pone.0050925.gpositive result cannot be interpreted into the benefit in the total outcome. The improvement in OPUS and PRIME studies are significant but not enough to change the total outcome. Although there seems to be a difference between A 196 cost panitumumab and cetuximab, the result of the test for heterogeneity of PFS was not significant (p = 0.13) and therefore the synthesis of the data is appropriate. The pooled analysis doesn’t show the improvement of overall response rate when adding cetuximab or panitumumab in the total outcome, while the ORR in PRIME study appear significantly higher in the panitumumab arm, and this should be confirmed in more RCTs as well. The comparison of R0 resection rate was not performed since there’s no report of R0 resection rate in KRAS wild type patients in OPUS study, but the response rate can infer the limitation of anti-EGFR MAbs in the neoadjuvant therapy when combined with oxaliplatin-based chemotherapy, whereas the efficacy of panitumumab needs more evidence to be verified. No available data were found that fatal AEs were related to cetuximab or panitumumab, though significantly purchase Pluripotin increased cutaneous toxicity were observed in the combined therapies arms, attributing to heavily expressed EGFR in the skin, which may correlate to the efficacy of anti-EGFR therapy. Other increased but manageable adverse events, like diarrhea, were also reported in all trials. Considering the data of adverse events refer to intention-to-treat (ITT) population (defined as randomly assigned patients who received at least one dose of study treatment), instead of KRAS wild type patients, we did not perform a statistical analysis. In ITT population, the main AEs of anti-EGFR agents are skin toxicity and the additional biotherapy were well tolerated. It seems that the combination of oxaliplatin and cetuximab or panitumumab didn’t show the efficacy in first-line treatment of mCRC. The result suggests that combined therapies are not just the simple addition. Each drug might have interaction with another in combination somehow by affecting the efficacy and/or toxicity. For combined therapies, drugs selection is as important as biomarker selection. Much more preclinical and clinical trials arerequired for combined therapies, especially the rigorous and prospective assessment. Since only one trial regarding panitumumab was included, the interpretation of efficacy of panitumumab should be more careful and more RCTs are needed to verify the conclusion. Although this meta-analysis was based on high-quality RCTs and was properly conducted, there are some typical limitations of our study. Our findings and interpretations were limited by the quality and quantity of data available. One major limitation is the number of trials is quite small and that possibly could not unveil the real situation, but the number of patients sample is amounted to 1270. Another, all of the data were extracted from abstracted data (AD) instead of individual patient data (IPD), which would be less powerful to confirm our findings. However, a correlation analysis shows AD meta-analysis is strongly correlated with IPD meta-analysis [24], indicating AD as a kind of acc.Ias test of PFS. The two oblique lines indicate the pseudo 95 confidence limits. doi:10.1371/journal.pone.0050925.gAntiEGFR MAbs and Oxaliplatin in Colorectal CancerFigure 9. Funnel plot for publication bias test of ORR. The two oblique lines indicate the pseudo 95 confidence limits. doi:10.1371/journal.pone.0050925.gpositive result cannot be interpreted into the benefit in the total outcome. The improvement in OPUS and PRIME studies are significant but not enough to change the total outcome. Although there seems to be a difference between panitumumab and cetuximab, the result of the test for heterogeneity of PFS was not significant (p = 0.13) and therefore the synthesis of the data is appropriate. The pooled analysis doesn’t show the improvement of overall response rate when adding cetuximab or panitumumab in the total outcome, while the ORR in PRIME study appear significantly higher in the panitumumab arm, and this should be confirmed in more RCTs as well. The comparison of R0 resection rate was not performed since there’s no report of R0 resection rate in KRAS wild type patients in OPUS study, but the response rate can infer the limitation of anti-EGFR MAbs in the neoadjuvant therapy when combined with oxaliplatin-based chemotherapy, whereas the efficacy of panitumumab needs more evidence to be verified. No available data were found that fatal AEs were related to cetuximab or panitumumab, though significantly increased cutaneous toxicity were observed in the combined therapies arms, attributing to heavily expressed EGFR in the skin, which may correlate to the efficacy of anti-EGFR therapy. Other increased but manageable adverse events, like diarrhea, were also reported in all trials. Considering the data of adverse events refer to intention-to-treat (ITT) population (defined as randomly assigned patients who received at least one dose of study treatment), instead of KRAS wild type patients, we did not perform a statistical analysis. In ITT population, the main AEs of anti-EGFR agents are skin toxicity and the additional biotherapy were well tolerated. It seems that the combination of oxaliplatin and cetuximab or panitumumab didn’t show the efficacy in first-line treatment of mCRC. The result suggests that combined therapies are not just the simple addition. Each drug might have interaction with another in combination somehow by affecting the efficacy and/or toxicity. For combined therapies, drugs selection is as important as biomarker selection. Much more preclinical and clinical trials arerequired for combined therapies, especially the rigorous and prospective assessment. Since only one trial regarding panitumumab was included, the interpretation of efficacy of panitumumab should be more careful and more RCTs are needed to verify the conclusion. Although this meta-analysis was based on high-quality RCTs and was properly conducted, there are some typical limitations of our study. Our findings and interpretations were limited by the quality and quantity of data available. One major limitation is the number of trials is quite small and that possibly could not unveil the real situation, but the number of patients sample is amounted to 1270. Another, all of the data were extracted from abstracted data (AD) instead of individual patient data (IPD), which would be less powerful to confirm our findings. However, a correlation analysis shows AD meta-analysis is strongly correlated with IPD meta-analysis [24], indicating AD as a kind of acc.