Adjuvant Anti-Inflammatory Therapy in Postoperative Colorectal Cancer: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

Abstract

Colorectal cancer (CRC) recurrence remains a major challenge in postsurgery. Chronic inflammation driven by cyclooxygenase (COX-2) and prostaglandin pathways promotes tumor recurrence, encouraging interest in nonsteroidal anti-inflammatory drugs (NSAIDs) like aspirin (acetylsalicylic acid, ASA) and COX-2 inhibitors. While observational studies suggest a benefit in reducing recurrence, randomized controlled trial (RCT) evidence is controversial. This meta-analysis evaluates the efficacy and safety of adjuvant NSAIDs in nonmetastatic resected CRC. We systematically searched PubMed, Scopus, and Cochrane Central for RCTs comparing anti-inflammatory agents to placebo in postoperative CRC patients. Primary outcomes included overall survival (OS) and disease-free survival (DFS); secondary outcomes were time to recurrence (TTR), recurrence rate, and adverse events. Subgroup analyses focused on aspirin use and the presence of PI3K pathway mutations were performed. Five RCTs (7246 patients) were included. Anti-inflammatory therapy improved DFS (HR = 0.85; 95% CI: 0.76-0.96; P = .008) and TTR (HR = 0.61; 95% CI: 0.44-0.84; P = .003) but not OS (HR = 0.90; P = .07) or recurrence rates (RR = 0.90; P = .06). Aspirin demonstrated superior DFS benefit (HR = 0.70; P = .03) and patients with PI3K mutations had markedly reduced recurrence risk (HR = 0.56; P < .0001). Serious cardiac events, gastrointestinal bleeding, and infections showed no significant differences. Adjuvant anti-inflammatory therapy improves DFS and delays recurrence in postoperative CRC, with pronounced benefit in PIK3CA mutant tumors. These findings support biomarker-driven strategies and highlight the need for ongoing trials to validate long-term efficacy and safety.