{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T10:10:09Z","timestamp":1788775809482,"version":"build-2803163510"},"reference-count":45,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T00:00:00Z","timestamp":1788652800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Although robust observational data have long associated physical activity with improved colon cancer survival, the lack of randomized evidence has perpetuated a \u201ccausality gap,\u201d confining exercise to supportive lifestyle advice and creating a clinical dilemma for surgeons. This paradigm has been fundamentally reshaped by the landmark phase III CHALLENGE trial. This review synthesizes the clinical, epidemiological, and translational evidence establishing exercise as a validated, disease-modifying intervention. In the CHALLENGE trial, a 3-year structured physical activity program significantly improved both disease-free survival (HR 0.72) and overall survival (HR 0.63) in patients with resected stage III or high-risk stage II colon cancer post-adjuvant chemotherapy, demonstrating a clinically meaningful additive benefit following completion of standard adjuvant chemotherapy. Mechanistically, exercise drives a multi-layered host\u2013tumor reprogramming. Each acute exercise bout triggers transient surges of muscle-derived myokines (e.g., IL-6, SPARC) and immune-cell mobilization, enhancing natural killer and CD8+ T cell tumor infiltration. Cumulatively, these repeated acute pulses drive chronic adaptations, including downregulation of the pro-proliferative insulin\/IGF-1 axis, attenuation of pro-tumor systemic inflammation, and microenvironmental remodeling at metastatic sites. To bridge the implementation gap, exercise oncology must transition from vague recommendations to structured, biomarker-driven clinical prescriptions defining type, dose, and duration. Mirroring the institutional success of Enhanced Recovery After Surgery (ERAS) protocols, physical activity should be systematically embedded into multidisciplinary, post-adjuvant oncologic care pathways. As the primary coordinators of colorectal cancer care, gastrointestinal surgeons must lead the transformation of exercise from optional supportive care into a validated, disease-modifying standard of care.<\/jats:p>","DOI":"10.3390\/cancers18172883","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T09:23:37Z","timestamp":1788773017000},"page":"2883","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Exercise as a Disease-Modifying Therapy in Colon Cancer: Practice-Changing Evidence from the CHALLENGE Trial"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3294-1924","authenticated-orcid":false,"given":"Dai","family":"Shida","sequence":"first","affiliation":[{"name":"Division of Frontier Surgery, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1620","DOI":"10.1016\/S1470-2045(20)30527-1","article-title":"Effect of duration of adjuvant chemotherapy for patients with stage III colon cancer (IDEA collaboration): Final results from a prospective, pooled analysis of six randomised, phase 3 trials","volume":"21","author":"Andre","year":"2020","journal-title":"Lancet Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1097\/CEJ.0000000000000511","article-title":"Physical activity and mortality in patients with colorectal cancer: A meta-analysis of prospective cohort studies","volume":"29","author":"Qiu","year":"2020","journal-title":"Eur. 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