The Role of Maintenance Strategies in Metastatic Colorectal Cancer: A Systematic Review and Network Meta-analysis of Randomized Clinical Trials

Abstract

Importance: In metastatic colorectal cancer, induction combination chemotherapy with a targeted agent is considered the mainstay of treatment. Multiple randomized clinical trials have examined different strategies of continuing cytotoxic therapy until progression compared with a period of either observation or the use of various maintenance agents. However, those randomized clinical trials have shown inconsistent efficacy results that make it challenging to draw any conclusion on which strategy is preferred. Therefore, a network meta-analysis is helpful to compare different agents across randomized clinical trials.

Objective: To evaluate the comparative effectiveness of different treatment strategies for patients with metastatic colorectal cancer.

Evidence review: MEDLINE, Embase, Scopus, Web of Science, and the Cochrane Central Register of Controlled Trials were searched for randomized clinical trials evaluating different strategies for patients with previously untreated metastatic colorectal cancer. Trials of interest included those including patients with metastatic colorectal cancer who were treated with an initial period of cytotoxic chemotherapy (with or without a biologic) and then switched to one of the following strategies: observation; maintenance with bevacizumab (Bev), fluoropyrimidine (FP), or both (FP + Bev); or continuing the induction regimen until progression. Outcomes of interest included overall survival (OS) and progression-free survival (PFS). The overall effect was pooled using the DerSimonian and Laird random-effects model. Network meta-analysis was conducted using a random-effects consistency model to pool evidence from direct and indirect comparisons. Agents were ranked using surface under the cumulative ranking (SUCRA) probabilities. Higher SUCRA scores correspond to greater efficacy. Initial analysis was performed on December 18, 2018. An updated search was performed in April 2019, and no additional studies were added.

Findings: Twelve trials at low risk of bias (5540 patients; age range, 23-85 years; 64.4 % male) were included. Network meta-analysis showed no benefit of continuing full cytotoxic chemotherapy until progression vs observation in terms of PFS (hazard ratio, 0.71; 95% CI, 0.46-1.09) and OS (hazard ratio, 0.95; 95% CI, 0.85-1.07). Compared with observation, maintenance therapy showed a PFS benefit (hazard ratio, 0.58; 95% CI, 0.43-0.77) but not an OS benefit (hazard ratio, 0.91; 95% CI, 0.83-1.01). All maintenance strategies (FP, FP + Bev, and Bev) showed significant improvement in PFS vs observation. On SUCRA analysis, maintenance treatment (FP or FP + Bev) had the highest likelihood of achieving improved PFS (67.1% for FP, 99.8% for FP + Bev, and 36.5% for Bev) and OS (81.3% for FP, 73.2% for FP + Bev, and 32.6% for Bev).

Conclusions and relevance: For patients with metastatic colorectal cancer, there is no benefit to continuing the full induction regimen until progression, without a period of either observation or maintenance treatment. A maintenance strategy with a fluoropyrimidine, with or without the addition of bevacizumab, is preferred. However, given the lack of a clear OS benefit, shared decision-making should include observation as an acceptable alternative.

Figure 1.. Hazard Ratios for the Pairwise Comparisons of the Network Meta-analysis

Direct and indirect comparisons should be read from left to right. Hazard ratios for comparisons are in the cell in common between the column-defining and row-defining treatment. For progression-free survival, a hazard ratio of less than 1 favors row-defining treatment. For overall survival, a hazard ratio of less than 1 favors column-defining treatment. Bev indicates bevacizumab; CTX, continuing induction regimen; FP, fluoropyrimidine; MTC, maintenance; and OBS, observation.

Figure 2.. Meta-analyses of the Included Studies Examining Progression-Free Survival and Overall Survival for Maintenance Treatment vs Observation

The marker size indicates the relative weight of the study as it contributes to the results of the overall comparison. IV indicates inverse-variance random-effect analysis. Percentages do not total 100 owing to rounding. HR indicates hazard ratio.

Figure 3.. Flow Diagram Showing Suggested Algorithm for Maintenance Strategies in Metastatic Colorectal Cancer

FPIRI indicates fluoropyrimidine with irinotecan; FPOX, fluoropyrimidine with oxaliplatin. ^aThe same recommendations could be considered for FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) with less supporting evidence. ^bMost of the maintenance trials used oxalipatin-based regimens. The fluoropyrimidine used can be either capecitabine or fluorouracil. ^cCan consider adding bevacizumab to the maintenance treatment with fluoropyrimidine if bevacizumab was added to the induction period.