PREBICC - Prebiotic intervention in patients with advanced colorectal cancer treated with 5-FU-based chemotherapy: protocol of a double-blind randomized controlled trial

Background Standard systemic treatment for advanced colorectal cancer (CRC) often involves fluoropyrimidines, such as 5-fluorouracil (5-FU). Previous observational clinical studies, as well as pre-clinical research, demonstrated that chemotherapy affects the gut bacteria and its metabolites, potentially leading to microbial dysbiosis. Microbial dysbiosis might negatively influence anti-cancer efficacy and toxicity of the treatment. Therefore, targeted microbiota modulation using prebiotic fibers could potentially optimize 5-FU-based chemotherapy. This explorative intervention study aims to investigate the effects of daily administration of a prebiotic fiber mixture in a nutritionally complete oral nutritional supplement (ONS) on the intestinal microbiota composition in patients with advanced colorectal cancer treated with 5-FU-based chemotherapy. Moreover, the effect of the prebiotic fiber ONS intervention on fecal, blood, clinical, and tolerance parameters will be evaluated. Methods 62 CRC patients scheduled for 5-FU-based therapy (FOLFOX, CAPOX, or capecitabine monotherapy) with or without bevacizumab, panitumumab or cetuximab will be prospectively enrolled in a double-blinded randomized controlled study. After informed consent, patients will be randomized to receive either the prebiotic fiber mixture ONS or control ONS, starting at least three days prior to the start of the 5-FU-based treatment. They will continue to take it twice daily for the duration of either four cycles of FOLFOX (in total 8 weeks) or three cycles of CAPOX or capecitabine monotherapy (in total 9 weeks). At multiple timepoints throughout the intervention, patients will collect fecal samples and complete questionnaires on food habits, patient characteristics, chemotherapy side effects, quality of life, current nutritional status, and physical performance. Microbiota composition, SCFA levels, and other parameters will be measured in the fecal samples. In addition, blood samples will be collected and analyzed for various parameters. Body composition and tumor response will be evaluated based on imaging. Discussion In conclusion, this randomized exploratory clinical intervention study outlines a novel approach to enhance the efficacy and reduce the toxicity of 5-FU-based chemotherapy in patients with advanced CRC through gut microbiota modulation using prebiotics. The knowledge obtained holds the potential to significantly impact clinical practices, improve patient outcomes, and advance microbiome-targeting interventions. Trial registration This study is registered in the Dutch OMON database under NL86537.068.24