Association between the antibiotics use and recurrence in patients with resected non-metastatic colorectal cancer: EVADER-1, a nation-wide pharmaco-epidemiologic study

Abstract

Importance: The impact of antibiotics (ATBs) on the risk of colorectal cancer (CRC) recurrence after curative resection remains unknown. Objective: We aimed to evaluate the effect of the type and the class of ATBs on recurrence in patients with resected non-metastatic CRC. Design: Our cohort study included patients between 01/2012 and 12/2014. Each CRC patient was followed up to 3 years after surgical resection. Setting: This study was conducted using extracted data from the French cancer cohort set up based on the National Health Data System by the French National Cancer Institute. Participants: All newly diagnosed non-metastatic CRC patients resected were included. We excluded patients not affiliated to the major health insurance scheme in France (n=16 857) and with immunosuppression (n=32,359). Exposures: The perioperative ATB intake (from 6 months before surgery until 1 year after) was classified according to the class, the period of use (pre- vs post-resection), the disease stage (localized and locally advanced), and the primary tumor location (colon and rectum/junction). Main Outcome and Measure: The primary endpoint was the 3-year disease-free survival (DFS). The impact of ATB was assessed using time-dependent multivariate Cox models. Results: A total of 35,496 CRC patients were included. Seventy-nine percent of patients had at least one ATB intake. Outpatient ATB intake after surgery was associated with unfavorable 3-year DFS mostly in patients with locally advanced stage and during chemotherapy (HR ranging from 1.22 to 1.41, P<0.0001), while no excess of mortality was observed in patients receiving ATBs as outpatient. The ATBs associated with decreased 3-year DFS were cephalosporins, streptogramins, quinolones, penicillin A with beta-lactamase inhibitors, and antifungals with differential effects according to the primary tumor location and disease stage. Conclusion and Relevance: These findings suggest that ATBs modulate the risk of recurrence after early CRC resection with a differential impact of the ATB classes depending on disease stage and tumor site. This study also gives important clues on how ATBs may modulate the efficacy of cancer treatments. Ultimately, EVADER-1 will pave the way for therapeutic interventions targeting the microbiome aiming to improve cancer outcome.