Efficacy and toxicities of combination maintenance therapy in the treatment of advanced colorectal cancer: a meta-analysis of randomized controlled trials

: Purpose: We performed a systematic review and meta-analysis to investigate the efficacy and toxicities of combination maintenance therapy for the treatment of advanced colorectal cancer (CRC). Methods: Relevant trials were identified by searching electronic databases and conference meetings. Prospective randomized controlled trials (RCTs) assessing combination maintenance therapy in advanced CRC patients were included. Outcomes of interest included overall survival (OS), progression-free survival (PFS) and grade 3-4 toxicities. observation. Additionally, more incidences of any grade 3-4 toxicities (diarrhea, fatigue and hand-foot skin reaction) were observed in the combination maintenance therapy. Conclusions: The findings of this study show that the efficacy of combination maintenance therapy is comparable to that of bevacizumab alone in terms of PFS and OS for advanced CRC patients, but at the cost of increased grade 3-4 toxicities. Thus single agent bevacizumab remains the recommended maintenance treatment for advanced CRC patients.


Introduction
Colorectal cancer (CRC) is the fourth most commonly diagnosed cancer worldwide , with over 1.2 million new cancer cases and 608,700 deaths estimated to have occurred annually [1]. Nearly one fourth of patients are diagnosed with advanced/metastatic disease, with a 5-year survival of less than 10% [2]. For patients with advanced/metastatic CRC, the treatment goal is to prolong survival and improve quality of life. For patients with advanced CRC, chemotherapy alone yields median survival durations of approximately 20 months [3,4]. During the past decades, the introduction of novel targeted agents, such as bevacizumab, aflibercept and cetuximab, has modestly improved outcomes in treatment-naïve patients [5][6][7]. However, additional therapeutic options are needed.
In order to sustain a reduced tumor size and relieve tumor-related symptoms, maintenance therapy has emerged as a novel therapeutic strategy for advanced CRC [8]. Maintenance therapy can be classified into two types: switch maintenance therapy and continuous maintenance therapy. Continuation maintenance is defined as keeping ongoing administration one or more drugs (combination maintenance) used in first-line regimen; while switch maintenance generally introduces an additional agent immediately after completion of four to six cycles of first-line chemotherapy. A previously published meta-analysis has demonstrated that maintenance therapy with Downloaded from https://portlandpress.com/bioscirep/article-pdf/doi/10.1042/BSR20180641/855673/bsr-2018-0641.pdf" /><meta name="dc.identifier" content="10.1042/BSR20180641" /><meta property="og:updated_time" content="10/24/2018 by guest on 08 February 2020 either a continuation or a switch strategy significantly increased progression free survival (PFS, HR 0.56; CI 95% 0.44-0.71, p<0.00001) and time to failure strategies (TFS, HR 0.79; CI 95% 0.7-0.9, p=0.0005) in comparison to observation. Thus, the authors concluded that maintenance therapy should be considered the standard regimen in patients with stage IV colorectal cancer after first line induction therapy.
However, to our best knowledge, the role of combination maintenance therapy in the treatment of advanced CRC remains undetermined. As a result, we conduct this systematic review and meta-analysis to assess the overall efficacy and toxicities of combined maintenance therapy in advanced CRC patients.

Study Design
We performed this systematic review and meta-analysis according to the Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines 2009 [9].

Search strategy
We conducted a comprehensive literature search of public databases including PubMed, EMBASE, Web of Science and the Cochrane library (up to April 30, 2017).
Relevant search keywords including the followings: ''colorectal cancer,'' ''maintenance therapy,'' and ''randomized controlled trials.'' No language restriction was administered. An up-to-date search for relevant trials was performed on August 30, 2017. We also conducted a manual search of conference proceedings. All results were input into Endnote X7 reference software (Thomson Reuters, Stamford, CT, US) for duplication exclusion and further reference management.

Study Selection
Clinical trials that met the following criteria were included: (1) prospective phase II or III trials involving colorectal patients; (2) trials comparing combination maintenance therapy versus single agent maintenance therapy or observation; and (3) available survival data regarding advanced CRC patients. If multiple publications of the same trial were retrieved or if there was a case mix between publications, only the most recent publication (and the most informative) was included. Downloaded from https://portlandpress.com/bioscirep/article-pdf/doi/10.1042/BSR20180641/855673/bsr-2018-0641.pdf" /><meta name="dc.identifier" content="10.1042/BSR20180641" /><meta property="og:updated_time" content="10/24/2018 by guest on 08 February 2020

Data Extraction
Two independent investigators conducted the data abstraction, and any discrepancy between the reviewers was resolved by consensus. The following information was extracted for each study: first author's name, year of publication, trial phase, number of enrolled subjects, treatment arms, median age, median progression-free survival, and overall survival.

Outcome measures
A formal meta-analysis was conducted using Comprehensive Meta Analysis software (Version 2.0). The outcome data were pooled and reported as hazard ratio (HR). The primary outcome of interest was OS and secondary outcomes PFS and any grade 3-4 toxicities in advanced CRC patients.

Statistical Analysis
All statistical analyses were performed by using Version 2 of the Comprehensive MetaAnalysis program (Biostat, Englewood, NJ). Between-study heterogeneity was estimated using the χ 2 -based Q statistic [10]. The I 2 statistic was also calculated to evaluate the extent of variability attributable to statistical heterogeneity between trials.
A statistical test with a p-value less than 0.05 was considered significant. Study quality was assessed by using the Jadad scale based on the reporting of the studies' methods and results [11].

Results:
Search results: We initially found 160 relevant citations of maintenance therapy in CRC patients.
There was a significantly increased risk of developing severe non-hematologic toxicities (diarrhea, fatigue, and hand-foot reaction), but not for hypertension, bleeding and thrombosis (table 2).

Publication bias
Begg's funnel plot and Egger's test were performed to assess the publication bias of literatures. The Begg's funnel plots did not reveal any evidence of obvious asymmetry (PFS, p=0.85; OS, p=0.57, figure 5). Then, Egger's test was used to provide statistical evidence of funnel plot symmetry. The results still did not suggest any evidence of publication bias for PFS (p=0.74) and OS (p=0.77).

Discussion
Due to the addition of novel biological agents to first-line chemotherapy in advanced colorectal cancer patients, the prognosis of advanced CRC patients has been significantly improved [18][19][20]. However, the optimal duration of first-line treatment remains a controversial issue [21]. Continuous long-term chemotherapy would inevitably increase the side effects associated with chemotherapy and potentially induce the development of drug resistance. On the other hand, intermittent treatment is likely to adversely impact the chemotherapeutic efficacy and treatment outcomes.
Two previously meta-analyses have found that maintenance therapy in advanced CRC patients significantly improved PFS and OS in comparison with observation [22,23].
Before the present study, Dr. Xu et al [24] performed a meta-analysis of three randomized controlled trials to assess the overall efficacy and toxicities of bevacizumab in combination with erlotinib as maintenance therapy in advanced CRC patients, and found that the addition of erlotinib to bevacizumab as maintenance therapy significantly increased overall survival and progression-free survival with an increased but manageable toxicity in CRC patients. However, there is a major error in the meta-analysis analysis, thus the pooled results could be wrong. In fact, the trial

Conclusion
In conclusion, this is the most comprehensive meta-analysis specifically assessing the efficacy and toxicities of combination maintenance therapy in the treatment of advanced CRC patients. The results of our study suggest that efficacy of combination maintenance therapy is comparable to that of bevacizumab alone in advanced CRC patients who have not progressed after at least four cycles of platinum-based chemotherapy, but at the cost of increased grade 3-4 toxicities. Thus single agent bevacizumab remains the recommended maintenance treatment for advanced CRC patients.