PMC:6909918 / 6460-11893 JSONTXT

{"project":"2_test","denotations":[{"id":"31790382-19631507-69134699","span":{"begin":910,"end":912},"obj":"19631507"},{"id":"31790382-19631507-69134700","span":{"begin":5179,"end":5181},"obj":"19631507"}],"text":"Material and Methods\n\nLiterature search\nA network meta-analysis was performed following a systematic literature review using the Medline, Embase, and the Cochrane library databases to identify published randomized controlled trials (RCTs) up to March 30th, 2019. The literature search terms included ‘regorafenib,’ ‘fruquintinib,’ ‘TAS-102,’ and ‘colorectal carcinoma.’ The search strategy used to search Medline was as follows: regorafenib OR fruquintinib OR TAS-102. The search procedure was limited to original, published, prospective, randomized, placebo-controlled clinical trials, which had been published in full in the English language. The network meta-analysis was conducted in compliance with the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions and was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [10].\n\nInclusion and exclusion criteria\nThe inclusion criteria were fully published, phase III, prospective, randomized, placebo-controlled clinical trials related to regorafenib, fruquintinib, or TAS-102 in patients with metastatic colorectal carcinoma (mCRC). The study participants were those who had been evaluated as having disease progression after receiving at least one previous treatment regimen, who were randomly assigned to receive one of the agents (regorafenib, fruquintinib, or TAS-102) compared with placebo treatment in the control group. The studies were required to report the outcomes of objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs).\nThe exclusion criteria included non-controlled or single-arm studies, ongoing clinical trials, meeting abstracts, review articles, letters, meta-analysis data, case reports, commentaries, or publications not in the English language. For repeat publications of the results of the same study reported at different times, the most complete and updated reported publication was selected.\n\nOutcome data extraction\nThe available data from the included studies were extracted independently by two investigators (Chen and Peng), with any differences resolved by consensus between the two reviewers. The essential information extracted from the enrolled studies included the names of the trials, the number of patients, gender, median age, racial distribution, the Eastern Cooperative Oncology Group (ECOG) performance status, the primary site of the tumor, the KRAS status, previous treatment, and whether the patient received anti-EGFR or anti-VEGFR treatment. The length of follow-up and the duration of drug exposure were also identified. The primary outcomes evaluated in the network meta-analysis were PFS (randomized to death, regardless of cause) and OS (randomized to progression to death, regardless of cause). Secondary endpoints included ORR, with patients evaluated as partial response (PR) or complete response (CR) according to the response evaluation criteria in solid tumors (RECIST) criteria version 1.1, DCR, with patients evaluated as PR or CR or stable disease (SD) according to RECIST version 1.1, AEs of any grade, including high grade (≥grade 3) serious adverse events (SAEs), and fatal adverse events (FAEs).\n\nQuality assessment of included studies\nThe quality of the included studies was evaluated using the criteria of the Cochrane Collaboration tool to assess the risk of bias of RCTs by the two reviewers (Chen and Peng). The following items were used for the assessment: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessments, incomplete outcome data, selective reporting and other bias, which were presented as a risk of bias graph and a risk of bias summary.\n\nSubgroup analysis\nBecause of the potential diverse racial distribution in the published RCTs, a network subgroup meta-analysis was performed to compare the efficacy of regorafenib, TAS-102, and fruquintinib in Asian patients with mCRC refractory to previous treatment.\n\nStatistical analysis\nData were analyzed with STATA version 13.0 software (StataCorp, College Station, Texas, USA). Three or more interventions were divided into all possible combinations of two intervention tests. Consistency or inconsistency testing was waived because of the absence of a closed-loop in the present network meta-analysis. The intergroup discrepancies for outcomes of PFS and OS were presented with hazard ratios (HRs), and the variance estimates were calculated from the reported confidence intervals (CIs). HRs of PFS and OS were used for indirect comparison with the random-effects model. The ORR, DCR, AEs, SAEs, and FAEs were calculated with the ORs. Indirect comparison of regorafenib, fruquintinib, TAS-102, and placebo, network meta-analysis methods (STATA network) were performed. Based on the surface under the cumulative ranking (SUCRA) curve, the efficacy and safety of the three drug treatments were ranked. Review Manager (RevMan) version 5.3 software (Nordic Cochrane Centre, The Cochrane Collaboration, 2014) was used for the description of the PRISMA flow diagram [10], risk of bias summary, and risk of bias graph, while the other figures in the present study were developed with STATA version 13.0 software (StataCorp, College Station, Texas, USA). Publication bias of the literature was evaluated using funnel plots."}