N the MRC COIN trial [13] and the NORDIC VII trial [14]. The intermittent chemotherapy group was excluded considering the settings of same regular administration in Title Loaded From File control groups. The PRIME trial [15,16] is the only trial regarding panitumumab, which evaluatedTitle Loaded From File Figure 3. Randomized effect model on HR of PFS. The pooled HR of PFS is symbolized by a solid diamond at the bottom of the forest plot and the width of which represents the 95 CI. doi:10.1371/journal.pone.0050925.gAntiEGFR MAbs and Oxaliplatin in Colorectal CancerFigure 4. Randomized effect model on risk ratio of ORR. The pooled RR of ORR is symbolized by a solid diamond at the bottom of the forest plot and the width of which represents the 95 CI. doi:10.1371/journal.pone.0050925.gthe efficacy and safety of panitumumab plus FOLFOX4 versus FOLFOX4 alone as initial treatment for mCRC.Publication BiasThe Begg’s test and funnel plots were performed to assess the publication bias. Publication bias was defined as P-value,0.05 in Begg’s test. No evidence for publication bias was shown according to the shape of funnel plots (Fig.7, Fig 8 and Fig 9) or the Begg’s test in OS (z = 0.34, p = 0.734), PFS (z = 1.02, p = 0.308), and ORR (z = 0.34, p = 0.734).Meta-analysis ResultsOS, PFS and ORR. 1270 patients from 4 randomized trials, 646 in the chemotherapy group and 624 in the chemotherapy adding anti-EGFR MAbs group, were included in the metaanalysis. Though the result of the test for heterogeneity of the therapeutic effect of 4 trials was not significant (chi-square = 2.17, P = 0.54, I2 = 0 ), the random-effects model was used to analyze the pooled data to minimize random errors. The main result of our`meta-analysis is shown in Figure 2. Overall, no OS benefit was found from combined therapy compared to chemotherapy alone in the mCRC (HR = 1.00, 95 CI [0.88, 1.13], p = 0.95). Significant PFS benefit was not found in this study either (HR = 0.86, 95 CI [0.71, 1.04], p = 0.13). The result of PFS is presented in Figure 3. Figure 4 illustrates the results of ORR (Risk Ratio = 1.08, 95 CI [0.86, 1.36]). No significantly increasing response rate was found in the pooled analysis. Subgroup analysis. Figure 5 and figure 6 show the subgroup analysis in cetuximab combination. The results reveal no significant efficacy of cetuximab 1317923 combined with oxaliplatin in OS (HR = 1.02, 95 CI [0.89, 1.18], P = 0.75) and PFS (HR = 0.87, 95 CI [0.65, 1.17], P = 0.36). Toxicities and safety. Toxic effects of 4 trials are summarized in Table 2 (only Grade 3? toxic effects were presented). Some of grade 3/4 adverse events (AEs) like skin toxicity and diarrhea were increasing by the addition of cetuximab and panitumumab to chemotherapy.DiscussionThe main finding of the present analysis is the combination of oxaliplatin and EGFR MAbs did not prolong OS or PFS in patients with wild type KRAS mCRC, compared with oxaliplatinbased chemotherapy alone. The addition of cetuximab or panitumumab has no statistically significant survival advantage over the single chemotherapy (HR for OS = 1.00, 95 CI [0.88, 1.13], p = 0.95; HR for PFS = 0.86, 95 CI [0.71, 1.04], p = 0.13). Panitumumab is a fully human anti-EGFR MAb, whereas cetuximab is a chimeric Mab. They are similar in mechanism of action and resistance. However, in view of different nature between two MAbs, subgroup analysis of cetuximab was conducted to confirm the efficacy. No subgroup analysis of panitumumab was performed regarding only one RCT including panitumumab. The s.N the MRC COIN trial [13] and the NORDIC VII trial [14]. The intermittent chemotherapy group was excluded considering the settings of same regular administration in control groups. The PRIME trial [15,16] is the only trial regarding panitumumab, which evaluatedFigure 3. Randomized effect model on HR of PFS. The pooled HR of PFS is symbolized by a solid diamond at the bottom of the forest plot and the width of which represents the 95 CI. doi:10.1371/journal.pone.0050925.gAntiEGFR MAbs and Oxaliplatin in Colorectal CancerFigure 4. Randomized effect model on risk ratio of ORR. The pooled RR of ORR is symbolized by a solid diamond at the bottom of the forest plot and the width of which represents the 95 CI. doi:10.1371/journal.pone.0050925.gthe efficacy and safety of panitumumab plus FOLFOX4 versus FOLFOX4 alone as initial treatment for mCRC.Publication BiasThe Begg’s test and funnel plots were performed to assess the publication bias. Publication bias was defined as P-value,0.05 in Begg’s test. No evidence for publication bias was shown according to the shape of funnel plots (Fig.7, Fig 8 and Fig 9) or the Begg’s test in OS (z = 0.34, p = 0.734), PFS (z = 1.02, p = 0.308), and ORR (z = 0.34, p = 0.734).Meta-analysis ResultsOS, PFS and ORR. 1270 patients from 4 randomized trials, 646 in the chemotherapy group and 624 in the chemotherapy adding anti-EGFR MAbs group, were included in the metaanalysis. Though the result of the test for heterogeneity of the therapeutic effect of 4 trials was not significant (chi-square = 2.17, P = 0.54, I2 = 0 ), the random-effects model was used to analyze the pooled data to minimize random errors. The main result of our`meta-analysis is shown in Figure 2. Overall, no OS benefit was found from combined therapy compared to chemotherapy alone in the mCRC (HR = 1.00, 95 CI [0.88, 1.13], p = 0.95). Significant PFS benefit was not found in this study either (HR = 0.86, 95 CI [0.71, 1.04], p = 0.13). The result of PFS is presented in Figure 3. Figure 4 illustrates the results of ORR (Risk Ratio = 1.08, 95 CI [0.86, 1.36]). No significantly increasing response rate was found in the pooled analysis. Subgroup analysis. Figure 5 and figure 6 show the subgroup analysis in cetuximab combination. The results reveal no significant efficacy of cetuximab 1317923 combined with oxaliplatin in OS (HR = 1.02, 95 CI [0.89, 1.18], P = 0.75) and PFS (HR = 0.87, 95 CI [0.65, 1.17], P = 0.36). Toxicities and safety. Toxic effects of 4 trials are summarized in Table 2 (only Grade 3? toxic effects were presented). Some of grade 3/4 adverse events (AEs) like skin toxicity and diarrhea were increasing by the addition of cetuximab and panitumumab to chemotherapy.DiscussionThe main finding of the present analysis is the combination of oxaliplatin and EGFR MAbs did not prolong OS or PFS in patients with wild type KRAS mCRC, compared with oxaliplatinbased chemotherapy alone. The addition of cetuximab or panitumumab has no statistically significant survival advantage over the single chemotherapy (HR for OS = 1.00, 95 CI [0.88, 1.13], p = 0.95; HR for PFS = 0.86, 95 CI [0.71, 1.04], p = 0.13). Panitumumab is a fully human anti-EGFR MAb, whereas cetuximab is a chimeric Mab. They are similar in mechanism of action and resistance. However, in view of different nature between two MAbs, subgroup analysis of cetuximab was conducted to confirm the efficacy. No subgroup analysis of panitumumab was performed regarding only one RCT including panitumumab. The s.
