Colorectal cancer is the second leading cause of cancer death, and it is increasingly diagnosed in people under 50. But treatment has advanced remarkably in the last two years. A randomized trial proved for the first time that exercise improves survival after cancer, immunotherapy can now eliminate some tumors before surgery, and a targeted combination doubled survival in one of the most aggressive forms. This article explains how colon cancer is treated in 2026 and why the cancer’s biology decides almost everything.
The Tests That Decide Treatment
Mismatch repair (MMR) or microsatellite instability (MSI). About 15 percent of colon cancers are mismatch repair-deficient, which makes them highly responsive to immunotherapy.
RAS and BRAF mutations decide whether drugs targeting the EGFR receptor can work and identify the aggressive BRAF V600E subtype.
HER2 and other targets open additional options, and the side of the colon where the tumor began also affects which drugs work best. See our article on tumor DNA and RNA sequencing.
Circulating tumor DNA after surgery shows who still has hidden cancer. In Australia’s DYNAMIC trials, it allowed many patients to safely avoid chemotherapy. See our article on ctDNA liquid biopsy.
Immunotherapy Before Surgery: The Dutch NICHE-2 Trial
At the Netherlands Cancer Institute in Amsterdam, patients with locally advanced mismatch repair-deficient colon cancer received just a short course of two immunotherapy drugs, nivolumab and ipilimumab, before surgery. In 95 percent, the tumor had largely disappeared by the time of surgery, and in about two-thirds no living cancer cells remained at all.1 For stage III mismatch repair-deficient colon cancer, the ATOMIC trial, presented in 2025, showed that adding the immunotherapy drug atezolizumab to standard chemotherapy after surgery reduced recurrence.
Exercise: The First Randomized Proof
For decades, observational studies suggested that physically active people survive colon cancer more often. The CHALLENGE trial, led by the Canadian Cancer Trials Group at 55 centers and published in the New England Journal of Medicine in June 2025, finally tested it. After chemotherapy, 889 patients with high-risk stage II or stage III colon cancer were randomly assigned to a three-year structured exercise program with a coach, or to health-education materials alone.
The exercise program reduced the risk of recurrence, new cancer or death by 28 percent. At eight years, 90.3 percent of the exercise group were alive, compared with 83.2 percent of the education group.2 Experts noted that the benefit was similar in size to adding the chemotherapy drug oxaliplatin, a cornerstone of colon cancer treatment. It is the strongest evidence ever produced that something a patient does for themselves improves survival from cancer.
Other Strategies After Surgery
Aspirin. In the 2025 Nordic ALASCCA trial, low-dose aspirin roughly halved recurrence in patients whose tumors carried PI3K pathway alterations, about a third of all patients.3 See our guide to repurposed drugs for cancer.
Mushroom extract. In Japanese randomized trials, the turkey tail extract PSK improved survival when added to chemotherapy after colorectal cancer surgery. See our article on medicinal mushrooms and cancer.
Vitamin D. See our article on vitamin D and cancer for what the trials in digestive cancers show.
Metastatic Colon Cancer: Treatment by Biology
Mismatch repair-deficient. In the CheckMate 8HW trial, led from Paris, first-line nivolumab plus ipilimumab dramatically extended progression-free survival compared with chemotherapy, and the combination is now approved as first treatment.4
BRAF V600E-mutated. This subtype has historically had the worst outlook. In the BREAKWATER trial, led from Vall d’Hebron in Barcelona and published in the New England Journal of Medicine in 2025, first-line encorafenib plus cetuximab with chemotherapy doubled median overall survival, to 30.3 months compared with 15.1 months.5
Other subtypes. RAS wild-type cancers, particularly on the left side of the colon, benefit from EGFR-targeted antibodies; HER2-amplified cancers respond to HER2-targeted drugs; KRAS G12C-mutated cancers have targeted combinations. Low-dose maintenance treatment after initial chemotherapy, studied in the Dutch CAIRO3 trial, is explained in our article on metronomic chemotherapy. In RAS-mutated cancers, a large Chinese trial suggested a benefit from high-dose IV vitamin C added to chemotherapy.
How Cancer Expert MD Helps
Cancer Expert MD specializes in education and consultation for people with Stage IV and metastatic cancer. When treatment stops working, our guide to what to do next explains the steps. Our book, The New Reality of Cancer, covers testing and treatment across all cancers.
Frequently Asked Questions
Does exercise improve colon cancer survival?
Yes. In the randomized CHALLENGE trial, a three-year structured exercise program after chemotherapy reduced recurrence, new cancer or death by 28 percent and improved eight-year survival.
What is mismatch repair-deficient colon cancer?
About 15 percent of colon cancers lack a DNA repair system, which gives them many mutations and makes them highly responsive to immunotherapy.
What is the newest treatment for BRAF-mutated colon cancer?
First-line encorafenib plus cetuximab with chemotherapy, which doubled median survival to 30.3 months in the 2025 BREAKWATER trial.
Can a blood test show if colon cancer is gone after surgery?
A circulating tumor DNA test can show whether cancer DNA remains, which strongly predicts recurrence and can guide whether chemotherapy is needed.
About the author. Dr. Silver, MD, graduated from Temple University School of Medicine, trained as an interventional cardiologist, and has practiced medicine for nearly fifty years. A lymphoma survivor of about twenty-five years, he is co-author, with Dr. Lindmeier, DHSc, of The New Reality of Cancer: The Science of Recovery. Read more about Dr. Silver, MD.
Research by Dr. Lindmeier, DHSc, cancer educator and co-author of The New Reality of Cancer.
More articles on cancer types and all articles.
References
- Chalabi M, Verschoor YL, Tan PB, et al. Neoadjuvant immunotherapy in locally advanced mismatch repair-deficient colon cancer (NICHE-2). New England Journal of Medicine. 2024;390(21):1949–1958.
- Courneya KS, Vardy JL, O’Callaghan CJ, et al. Structured exercise after adjuvant chemotherapy for colon cancer (CHALLENGE). New England Journal of Medicine. 2025.
- Martling A, et al. Low-dose aspirin for PI3K-altered localized colorectal cancer (ALASCCA). New England Journal of Medicine. 2025;393(11):1051–1064.
- André T, Elez E, Van Cutsem E, et al. Nivolumab plus ipilimumab in microsatellite-instability-high metastatic colorectal cancer (CheckMate 8HW). New England Journal of Medicine. 2024.
- Elez E, et al. Encorafenib, cetuximab, and mFOLFOX6 in BRAF-mutated colorectal cancer (BREAKWATER). New England Journal of Medicine. 2025.
This article is for education only. It is not medical advice and does not diagnose or treat any condition. Cancer Expert MD has no financial relationship with any laboratory, drug maker, supplement company, clinic or hospital.
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