Combining Correlated Outcomes and Surrogate Endpoints in a Network Meta-Analysis of Colorectal Cancer Treatments

Abstract

This study aimed to investigate the efficacy and safety of systemic therapies in the treatment of unresectable advanced or metastatic colorectal cancer. Predicted hazard ratios (HRs) and their 95% credible intervals (CrIs) for overall survival (OS) were calculated from the odds ratio (OR) for the overall response rate and/or HR for progression-free survival using multivariate random effects (MVRE) models. We performed a network meta-analysis (NMA) of 49 articles to compare the efficacy and safety of FOLFOX/FOLFIRI±bevacizumab (Bmab)/cetuximab (Cmab)/panitumumab (Pmab), and FOLFOXIRI/CAPEOX±Bmab. The NMA showed significant OS improvement with FOLFOX, FOLFOX+Cmab, and FOLFIRI+Cmab compared with that of FOLFIRI (HR = 0.84, 95% CrI = 0.73-0.98; HR = 0.76, 95% CrI = 0.62-0.94; HR = 0.80, 95% CrI = 0.66-0.96, respectively), as well as with FOLFOX+Cmab and FOLFIRI+Cmab compared with that of FOLFOXIRI (HR = 0.69, 95% CrI = 0.51-0.94 and HR = 0.73, 95% CrI = 0.54-0.97, respectively). The odds of adverse events grade ≥3 were significantly higher for FOLFOX+Cmab vs. FOLFIRI+Bmab (OR = 2.34, 95% CrI = 1.01-4.66). Higher odds of events were observed for FOLFIRI+Pmab in comparison with FOLFIRI (OR = 2.16, 95% CrI = 1.09-3.84) and FOLFIRI+Bmab (OR = 3.14, 95% CrI = 1.51-5.89). FOLFOX+Cmab and FOLFIRI+Bmab showed high probabilities of being first- and second-line treatments in terms of the efficacy and safety, respectively. The findings of the efficacy and safety comparisons may support the selection of appropriate treatments in clinical practice. PROSPERO registration: CRD42020153640.

Keywords: colorectal cancer; network meta-analysis; surrogate endpoints.

Figure 1

Network geometry of head-to-head trials. Data are presented as networks for comparison of (A) overall survival (observed values only), (B) overall survival (combining observed and predicted values), and (C) adverse events grade ≥3. The width of each line reflects the number of studies. The sizes of the circles are proportional to the number of study participants. FOLFOX (5-fluorouracil, folinic acid, and oxaliplatin), FOLFIRI (5-fluorouracil, folinic acid, and irinotecan), FOLFOXIRI (5-fluorouracil, folinic acid, oxaliplatin, and irinotecan), CAPEOX (capecitabine and oxaliplatin), Bmab (bevacizumab), Cmab (cetuximab), and Pmab (panitumumab).

Figure 2

Treatment ranking probability and SUCRA ranking plots. Data are presented as the probability of first- and second-line treatment ranking according to (A) overall survival and (B) adverse events grade ≥ 3. (C) Correlation and (D) k-means clustering analysis of SUCRA values. FOLFOX (5-fluorouracil, folinic acid, and oxaliplatin), FOLFIRI (5-fluorouracil, folinic acid, and irinotecan), FOLFOXIRI (5-fluorouracil, folinic acid, oxaliplatin, and irinotecan), CAPEOX (capecitabine and oxaliplatin), Bmab (bevacizumab), Cmab (cetuximab), Pmab (panitumumab), OS (overall survival), and AEs (adverse events).