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as the AIs bevacizumab and aflibercept. The effect of type of FP, whether oral, infusional or bolus was also explored. Methods Search strategy Publication databases were searched and proceedings of major conferences were handsearched. This study was not prospectively registered with a central registry. Unpublished data was sought from authors. 2 / 17 Chemotherapy and Targeted Agents in mCRC Eligibility criteria Published randomized controlled trials of any language or year were eligible for inclusion. Participants included were patients with metastatic colorectal cancer. Interventions studied were EGFR-I or AIs. EGFR-I trials were BQ123 biological activity restricted to KRAS exon 2 wild-type populations. Eligible comparisons were 1) chemotherapy with biological agent versus chemotherapy alone or 2) different chemotherapy regimens with the same biological agent. Search results were evaluated independently by two authors, with disagreements in eligibility resolved by consensus after PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19722344 reference to the full text of the article. Data was extracted into piloted forms and double-checked by another author to ensure accuracy. Endpoints The primary endpoint was overall survival; secondary endpoints were progression free survival, overall response rate and toxicity. Quality of life data was extracted where available. Other data extracted included PICOS, the quality/description of randomization, and any relevant funding sources. Risk of bias was performed at the study level, using the Cochrane risk of bias PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19723429 tool, with summary risk of bias as per Cochrane recommendations. The principal summary measures were hazard ratio for OS/PFS and odds ratios for ORR and toxicity. Meta-analysis was carried out using the generic inverse variant method, with fixed-effects analysis and calculation of HR/OR as applicable with 95% confidence intervals. Trials were characterized by type of biologic and chemotherapy backbone. The two groups of biological therapy investigated were: 1. EGFR-I: with oxaliplatin backbone vs with irinotecan backbone. 2. AIs: with ox backbone vs with iri backbone vs FP alone. Subgroup analysis was performed by type of FP: capecitabine, infusional or bolus. The mIFL regimen was considered in the bolus group. Given the increasing literature on the improved efficacy of EGFR-I in extended RAS settings, we performed additional analysis for OS in trials that reported this outcome in extended RAS wildtype populations. Heterogeneity was explored when I2>50% and p<0.10. Sensitivity analyses and funnel plots were undertaken to investigate possible bias. Results Study selection The literature search identified 256 potentially eligible citations from 2827 search results. Thirty-nine papers representing 23 studies comprising 10478 patients were eligible for inclusion. The EPIC trial was excluded, as analysis by KRAS exon 2 status was available for only 300/1298 patients, with incomplete OS and PFS data. Upon clarification with the lead author, we confirmed that insufficient data was currently available to enable metaanalysis and that there were no active plans for this analysis to be undertaken in the future. The PEAK trial, comparing FOLFOX + cetuximab to FOLFOX + bevacizumab in the first-line setting, was not included in quantitative analysis because it did not investigate the activity of either cetuximab or bevacizumab alone in addition to chemotherapy but rather compared its effects. The Ye study met the set requirements, but was excluded from analysis as no results were availa