The Efficacy Of Adding Targeted Agents To Neoadjuvant Therapy For Locally Advanced Rectal Cancer Patients: A Meta-analysis

Objective:Rectal cancer is one of the most commonly diagnosed and deadliest cancers around the world.Patients with locally advanced rectal cancer(LARC)are at tremendous risk of metastatic diseases due to high rates of local and distant recurrence.In recent years,neoadjuvant chemoradiotherapy(nCRT)has proven its effcacy in tumor downstaging and local control,however,the prognoses of LARC patients are far from satisfying.To improve the prognoses of LARC patients,the efficacy of adding targeted agents to neoadjuvant therapy has been investigated by many researchers but remains controversial.Methods:A literature search of relevant databases was conducted through December2016,804 studies were identifed and 32 investigations were ultimately included.A total of 1196 patients from 31 cohorts of 29 studies were eligible for quantitative synthesis in this single-arm setting meta-analysis.As pathologic complete response(pCR)shows promise as a prognosis indicator,we focused on pCR rates to evaluate whether adding targeted agents to neoadjuvant therapies improves the outcome of LARC patients.Furthermore,the pooled estimate of preoperative Grade 3/4 toxicity was calculated to evaluate the safety of adding targeted agents to neoadjuvant therapy.To evaluate heterogeneity,the Cochrane‘s Q test and inconsistent index(I~2)were performed,with I~2<40%considered acceptable.Potential origins of heterogeneity were detected by performing sensitivity analysis.Publication biases were evaluated via funnel plots,Begg‘s funnel plot,and Egger linear regression test for further confrmation.All statistical analyses were performed using STATA version 12.0(STATA,College Station,TX).Results:The pooled estimate of pCR for bevacizumab-relevant cohorts was 27%(95%CI,21–34%)(Fig.2A).Meanwhile,the pooled estimate of preoperative Grade 3/4toxicity for bevacizumab-relevant cohorts was 36%(95%CI,20–63%).The pooled estimates of Grade 3/4 bleeding,Grade 3/4 gastrointestinal perforation,and Grade 3/4wound-healing complication were also calculated and the results were 2.1%(95%CI,1.0–4.7%)for Grade 3/4 bleeding,1.9%(95%CI,0.7–5.4%)for Grade 3/4gastrointestinal perforation and 2.4%(95%CI,1.0–6.2%)for Grade 3/4 wound-healing complication.The pooled estimate of pCR for cetuximab-relevant studies was 14%(95%CI,9–21%).The pooled estimate of preoperative Grade 3/4 toxicity for cetuximab-relevant cohorts was not calculated as most included studies did not report preoperative Grade 3/4 toxicity.Conclusion:Our study revealed that adding bevacizumab to the neoadjuvant therapy regimens provides an appreciable pCR and an acceptable safety for LARC patients.However,more RCTs are needed for further validation.Meanwhile,the efficacy of cetuximab remains inconclusive,RCTs with larger scale and better study design that stress more on mutational status are needed.Meanwhile,most of the anti-EGFR cohorts are small-scale and stress KRAS status only.To the best of our knowledge,however,anti-EGFR activity might be also strictly determined by the mutational statuses of NRAS and BRAF,the efficacy of cetuximab remains inconclusive.To better elucidate the efficacy of adding cetuximab to neoadjuvant therapy for LARC patients,RCTs with larger scale and better study design that stress more on mutational status are needed.Besides,researchers should pay more attention to studying and evaluating the safety of cetuximab.