Understanding the mechanism behind preoperative exercise therapy in patients with gastrointestinal cancers: A prospective, randomized clinical trial.

Abstract

LBA4087 Background: Upwards of 50% of patients who undergo gastrointestinal (GI) cancer surgery will not receive any chemotherapy due to the failure to heal from the surgery or its associated complications. Pre-operative exercise therapy (PEx) aims to optimize the medical and physical state of high-risk patients prior to undergoing surgery. Our group has shown PEx to be protective against the inflammatory injury caused by surgical stress in mice through a metabolic reprogramming towards an anti-inflammatory profile. However, there is a gap in knowledge regarding the utility of PEx among GI cancer patients undergoing surgery and how PEx impacts surgical outcomes. This study seeks to evaluate the mechanism behind PEx among patients undergoing major abdominal surgery for GI cancer through a randomized controlled trial. Methods: Eligible patients diagnosed with GI cancers with planned abdominal surgery were randomized to receive PEx or no PEx between September 2020 and March 2022. PEx patients were evaluated by a physical therapist (PT) and prescribed a personalized training regimen based on objective assessments. Patient blood was drawn on the day of enrollment, day of surgery, then at 2 weeks and at 3 months following surgery. The primary endpoint is to investigate the mechanism behind the modulation of the inflammatory response of PEx among patients undergoing GI cancer surgery. Results: During an 18-month period, 30 patients were randomized to PEx and 35 randomized to non-PEx. Both cohorts were similar in age, gender, and comorbidity burden. Using patient serum samples, the secretome revealed a transcriptomic shift towards an anti-inflammatory and anti-tumorigenic phenotype in post-PEx patient blood samples when compared to pre-PEx and non-PEX patients. The secretome heatmap demonstrates significant changes post-PEX when compared to pre-PEx and non-PEX. Specifically, there was an upregulation of Esterase D protein (ESTD), Secreted Ly-6/uPAR-related protein 1 (SLUR1), tissue inhibitor of metalloproteinase (TIMP), and Phosphoinositide-3-kinase interacting protein 1 (P3IP1) which are associated with an anti-inflammatory and anti-tumorigenic phenotype. Moreover, there was a downregulation of pro-tumorigenic protein pathways including ankyrin 1 protein (ANK1), KIT protein, and Prolyl isomerase protein (PIN1). Additionally, gene ontology analysis used to evaluate differentially expressed proteins, revealed that proteins associated with lymphocyte mediated immunity were downregulated after PEx. Conclusion: Preoperative exercise may mitigate the pro-inflammatory and pro-tumorigenic state of cancer by the upregulation and downregulation of specific cellular pathways. Data obtained from this study can be used to create a new class of therapeutics, exercise mimetics. Clinical trial information: NCT04602026.