Review Article
Vol. 5, Issue 2, 2025 · P1-9
Adjuvant Therapy for Patients with Localized Colon Cancer
Ronan W. Hsieh, MD, MS,Ibrahim H. Sahin, MD
Submission received: 2025-07-28 / Accepted: 2025-11-07 / Published: 2025-11-13
Abstract
Adjuvant treatment for patients with localized colon cancer is ever evolving, with more personalized approaches for both deficient mismatch repair (dMMR) and proficient mismatch repair (pMMR) colon cancer. Circulating tumor DNA (ctDNA) is being investigated to understand its role in the detection and elimination of minimal residual disease after surgical excision of the primary tumor to offer a more personalized treatment approach. Recently, adjuvant chemoimmunotherapy has become the new standard of care treatment for stage III dMMR colon cancer based on significantly improved disease-free survival outcomes reported in the ATOMIC trial. For stage II and III pMMR colon cancer, adjuvant chemotherapy remains the standard of care treatment. Whether ctDNA will provide further risk stratification and create opportunities for drug development for patients with stage II and III colon cancer remains to be seen. Emerging data for adjunct therapies such as aspirin, non-steroidal anti-inflammatory drugs, and structured exercise programs appear promising and may improve survival in select patients. Multidisciplinary discussion and molecular profile-driven management of localized colon cancer are paramount to a favorable patient outcome.
Take Home Messages
1. Adjuvant FOLFOX and atezolizumab for 3 – 6 months, followed by atezolizumab for 6 – 9 months, is the new standard of care for stage III dMMR colon cancer after surgery.
2. Neoadjuvant immunotherapy should be considered for patients with stage II and III dMMR colon cancer before surgery, particularly for patients with T4 or bulky disease where negative surgical margins are difficult to achieve.
3. ctDNA-guided decision for adjuvant treatment may be helpful in cases where the benefit of adjuvant treatment is equivocal to risk, such as low-risk stage II colon cancer.
4. Adjuvant aspirin or celecoxib for three years significantly improves disease-free survival for patients with localized PIK3CA-mutated colorectal cancer.
5. Structured exercise program significantly improves disease-free survival and overall survival for patients with localized colorectal cancer.
Introduction
Colorectal cancer (CRC) is the third most common cancer and the second most deadly cancer worldwide. While the incidence of CRC is decreasing by ~2% per year due to the adoption of screening colonoscopy in older patients, the incidence of early-onset CRC (age <50 at diagnosis) is increasing.1 Among patients with a new diagnosis of CRC, approximately 80% of patients present with localized cancer at diagnosis, for which the treatment intent is curative.2 While surgery alone is able to achieve a cure in 60% - 95% of localized colon cancer, depending on the disease stage at diagnosis, many patients with stage II or III colon cancer benefit from adjuvant systemic therapy after surgery. Recent studies indicate a multidisciplinary and biomarker-driven approach to localized colon cancer will significantly improve disease-free survival (DFS) and reduce unnecessary toxicity of adjuvant treatment.3
In this review, we aim to summarize the current evidence of adjuvant systemic therapy and propose treatment recommendations for localized colon cancer. Treatment for localized rectal cancer is out of scope of this review, as the standard of care treatment for localized rectal cancer is neoadjuvant chemotherapy with or without neoadjuvant radiation.4,5
Localized Colon Cancer with Deficient Mismatch Repair
Mismatch repair is one of the cell's DNA repair mechanisms to repair single-base insertions or deletions during DNA replication.6 Deficient mismatch repair (dMMR) results from highly heterogeneous genetic variants, including but not limited to germline molecular events, somatic missense mutations/deletions, and promoter hypermethylation. Because most of the DNA mismatches happen in short and repetitive DNA sequences called "microsatellites", deficient mismatch repair leads to DNA frameshift, which generates a significantly different sequence of amino acids.7 As the sequence of amino acids appears drastically different from the original copy, the abnormal protein serves as a "neoantigen" which could stimulate a strong CD8 T-cell-mediated immune response when the tumor is treated with immunotherapy.8 Many preclinical studies and clinical studies have shown that dMMR solid tumors are particularly responsive to immunotherapy.9 In 2023, the U.S. FDA granted full approval to pembrolizumab for unresectable or metastatic dMMR solid tumors where the tumors have progressed after previous treatments and there are no alternative treatment options, based on the KEYNOTE-158 study.10
Stage II dMMR Colon Cancer
Fluoropyrimidines are minimally effective and potentially harmful for patients with dMMR CRC. The resistance to fluoropyrimidines could be explained by the tumor's excessive production of the drug's targets, such as thymidylate synthase and dihydropyrimidine dehydrogenase.11 In the Phase III QUASAR study,12 218 patients had stage II dMMR CRC. In this subgroup of patients, adjuvant 5-fluorouracil (5-FU) did not significantly improve the risk of recurrence compared to observation (odds ratio [OR] for recurrence, 0.81; 95% CI 0.29, 2.22). An earlier pooled analysis of clinical trials even showed a significantly reduced overall survival in patients taking adjuvant 5-FU as compared to those observed without 5-FU, suggesting a detrimental effect of 5-FU monotherapy (hazard ratio [HR], 2.92; 95% CI, 1.02, 8.54)13. Given the favorable prognosis of the disease12 and limited evidence to support adjuvant chemotherapy, we recommend observation for patients with stage IIA dMMR colon cancer after surgical resection. At this time, the optimal adjuvant therapy for stage IIB/C is not well defined due to limited data. However, it is important to recognize that T4 disease inherently carries an increased risk of recurrence, and patients who are interested in adjuvant therapy could consider oxaliplatin-based adjuvant therapies such as FOLFOX or CAPOX. While stage III and IV dMMR colon cancers are responsive to immunotherapy,14,15 we currently do not have sufficient clinical evidence to suggest adjuvant immunotherapy for patients with stage II dMMR colon cancer, as these patients were not included in the ATOMIC trial. Nonetheless, patients with bulky stage II dMMR colon cancer can be treated with neoadjuvant immunotherapy based on the NICHE trial discussed in the next section.16
Stage III dMMR Colon Cancer
Clinical studies have established adjuvant chemotherapy and immunotherapy as the standard of care for stage III dMMR colon cancer after surgical resection. In the Phase III ATOMIC study,15 712 patients with stage III dMMR colon cancer were randomized to receive FOLFOX with atezolizumab for six months, followed by atezolizumab for six more months (FOLFOX-atezolizumab arm) or FOLFOX alone for six months (FOLFOX arm). The FOLFOX-atezolizumab arm had a significantly better three-year DFS than the FOLFOX arm (86.4% vs. 76.6%; HR 0.50; 95% CI, 0.34, 0.72). The clinical benefits remained significant across many subgroups, such as primary tumor location, T stage, N stage, etc. The overall survival data were immature as of June 2025. There were significantly more grade 3 or 4 adverse events in the FOLFOX-atezolizumab arm than in the FOLFOX arm, such as fatigue, nausea, peripheral sensory neuropathy, and decreased neutrophil and platelet counts. However, the rates of immune-mediated adverse events (imAE) were similar between the two arms, suggesting that the risk of imAE was small and that the manifestation of imAE overlapped with symptoms of chemotherapy-associated adverse events. Based on the ATOMIC data, we anticipate adjuvant FOLFOX-atezolizumab will become the new standard of care for stage III dMMR colon cancer once approved by the U.S. FDA. However, it is unclear if all patients with stage III dMMR colon cancer would need a six-month course of FOLFOX. In low-risk stage III colon cancer (T1-3 N1), three months of adjuvant CAPOX is non-inferior to six months of CAPOX, and three months of adjuvant FOLFOX appears similar to six months of FOLFOX (non-inferiority margin not met) based on the IDEA collaboration study.17 Given the long-term toxicity of oxaliplatin, earlier discontinuation of chemotherapy can be considered after a three-month course of adjuvant FOLFOX-atezolizumab for patients with low-risk stage III colon cancer who are experiencing significant neuropathy. It is also unclear if adjuvant atezolizumab for up to 12 months is necessary, but given the favorable safety profile of atezolizumab, we recommend continuation of atezolizumab up to a total of 12 months of adjuvant therapy for most patients with stage III colon cancer.
While the ATOMIC trial demonstrated clear benefit, several studies have also investigated the efficacy of neoadjuvant immunotherapy in localized colon cancer. In the phase II NICHE-2 study,16 113 patients with clinical stage II and III colon cancer were given neoadjuvant nivolumab every two weeks for two doses and ipilimumab one dose before surgical resection. The study showed that neoadjuvant immunotherapy achieved a pathologic complete response rate of 68% and a major pathologic response rate of 98%. With a median follow-up of 26 months, three-year DFS was 100%. This dual-immunotherapy regimen appeared tolerable. Grade 3 or 4 adverse events were 4%; only 2 patients (~2%) had surgery delayed by more than two weeks. This dramatic benefit seen with only 4 weeks of immunotherapy as opposed to 1 year of atezolizumab raises several questions regarding the utility of chemotherapy, choice of immunotherapeutic agents, and duration of adjuvant immunotherapy for patients with dMMR colon cancer.
Concerns for universal use of neoadjuvant dual immunotherapy for all stage II and III dMMR colon cancer include inaccurate clinical staging in early-stage colon cancer, over-treatment for low-risk stage II dMMR colon cancer, and no control arm using standard-of-care adjuvant chemotherapy/chemoimmunotherapy in the NICHE-2 study. Nevertheless, despite a single-arm design, the remarkable results of neoadjuvant dual immunotherapy shown in the NICHE-2 study suggest this strategy could be beneficial in select settings. As the dual immunotherapy led to a major pathologic response rate of 98%, we favor using neoadjuvant dual immunotherapy16 instead of adjuvant chemoimmunotherapy15 in T4 or bulky disease, where negative surgical margins are difficult to achieve. As dual immunotherapy has a favorable safety profile, we suggest neoadjuvant dual immunotherapy for less fit patients who might not tolerate adjuvant chemoimmunotherapy. Given 68% of patients achieved a complete pathologic response, dual immunotherapy followed by non-operative management in stage II/III colon cancer could be considered in patients who are not surgical candidates because of performance status or comorbidities. However, there are currently no data to support non-operative management as the standard of care, so careful selection of patients and physician-patient shared decision making are important if a patient is interested in non-operative management.
Localized Colon Cancer with Proficient Mismatch Repair
Stage II pMMR Colon Cancer
Clinical benefits of adjuvant chemotherapy in stage II colon cancer with proficient mismatch repair (pMMR) are minimal, which is approximately a 3 – 5% improvement of long-term (≥5 years) overall survival.18,19 Some studies suggested unselective use of adjuvant chemotherapy in every patient with stage II colon cancer could lead to reduced survival.20 Hence, the ASCO guidelines recommend selective use of adjuvant chemotherapy only in high-risk stage II disease.21 Definitions of "high risk" vary in different guidelines. The ASCO, NCCN, and ESMO guidelines recognize T4, inadequately sampled lymph nodes (<12), poorly differentiated or undifferentiated tumor, perforation, obstruction, lymphovascular invasion, and perineural invasion as risk factors associated with a poor prognosis. Some literature suggests tumor deposits, high tumor budding score (≥10), and elevated preoperative CEA are also risk factors.22 Adjuvant chemotherapy with 5-FU or capecitabine may be considered in this subgroup of high-risk stage II pMMR colon cancer. Furthermore, additional oxaliplatin to 5-FU or capecitabine could be considered for stage II pMMR colon cancer with T4 or multiple high-risk factors. In the Phase III MOSAIC trial23-25 which studied the benefits of additional oxaliplatin to adjuvant 5-FU (FOLFOX), patients with high-risk stage II colon cancer, such as T4, <10 sampled lymph nodes, perforation, obstruction, poorly-differentiated tumors, and venous invasion, had a numerically longer five-year DFS if adjuvant FOLFOX was given versus 5-FU, although the difference did not reach statistical significance. To this date, the available high-level evidence has not been definitive enough to suggest adjuvant chemotherapy doublets (FOLFOX or CAPOX), monotherapy (5-FU or capecitabine), or observation in stage II pMMR colon cancer. Treatment decision is often based on the number and type of risk factors, patient preference, and the physician's personal experience.
Stage III pMMR Colon Cancer
In contrast to stage II pMMR colon cancer, the clinical benefits of adjuvant chemotherapy in stage III pMMR colon cancer are well-established in several studies.23,26-28 The phase III MOSAIC study randomly assigned 2,246 patients with stage II and III colon cancer to receive adjuvant FOLFOX or 5-FU.23 In the subgroup of stage III colon cancer, the FOLFOX arm had a significantly longer six-year overall survival than the 5-FU arm (72.9% vs. 68.7%; HR, 0.80; 95% CI, 0.65, 0.97). Another phase III study randomized patients with stage III colon cancer to receive capecitabine and oxaliplatin (CAPOX) or capecitabine alone.29 Similar to the MOSAIC study, the CAPOX arm also demonstrated a significantly longer seven-year overall survival than the capecitabine arm (73% vs. 67%; HR = 0.83; 95% CI, 0.70, 0.99). Largely based on these studies, adjuvant CAPOX or FOLFOX is recommended as the standard of care for stage III pMMR colon cancer across major guidelines. Of note, adjuvant oxaliplatin may generate a lower survival benefit in older (age ≥70) or less fit patients28 and should be carefully considered under shared decision-making between providers and patients.
The optimal duration of adjuvant FOLFOX or CAPOX has been studied in the IDEA collaboration study,17 which pooled data from six randomized controlled trials of stage III CRC and compared three versus six months of adjuvant chemotherapy in a non-inferiority design. The primary endpoint was three-year DFS. The study results suggested three months of CAPOX were non-inferior to six months of CAPOX for patients with low-risk stage III colon cancer. Three months of FOLFOX had a similar three-year DFS to six months of FOLFOX, although it did not meet the prespecified statistical margin of non-inferiority. In contrast, for patients with high-risk stage III colon cancer, defined as T4 and/or N2 disease, six months of FOLFOX was superior to three months of FOLFOX, whereas three months of CAPOX was similar to six months of CAPOX (statistical margin not met). In summary, the IDEA study suggests a consideration for three months of adjuvant treatment for stage III pMMR colon cancer except T4 and/or N2 disease.
Alternative Approach: Circulating Tumor DNA-Guided Management
Circulating tumor DNA (ctDNA) is a type of cell-free DNA that is shed from tumor cells into the body circulation.30 It is sensitive (~90%) and highly specific (~100%) to detect residual tumor cells, which could lead to recurrent disease.31 Studies have shown that positive postoperative ctDNA is prognostic of poor outcomes, and clearance of ctDNA in subsequent blood draws after adjuvant therapy indicates improved outcomes.32,33 ctDNA may be most useful in treatment decision-making when the benefits of adjuvant chemotherapy are equivocal to the risks. For example, ctDNA could risk-stratify stage II colon cancer, where the benefit of adjuvant chemotherapy is overall minimal (3 – 5% in overall survival). In the phase II DYNAMIC study, patients with stage II colon cancer were randomly assigned to receive ctDNA-guided management of adjuvant chemotherapy or standard clinicopathologic feature-guided management at the treating physician's discretion. Patients in the ctDNA-guided management group were only given adjuvant chemotherapy if they were tested ctDNA positive after surgery. The results showed that ctDNA-guided management was non-inferior to standard clinicopathologic feature-guided management in five-year recurrence-free survival (88.3% vs. 87.2%) and five-year overall survival (93.8% vs. 93.3%; HR, 1.05; 95% CI, 0.47, 2.37).34,35 Because positive ctDNA has a high rule-in value for disease recurrence (specificity ~100%), adjuvant chemotherapy should be considered for patients tested ctDNA positive after surgery, regardless of the tumor's clinicopathologic risk factors. On the other hand, a negative ctDNA does not indicate no adjuvant chemotherapy in high-risk disease with one or several clinicopathologic risk factors. Among patients with stage II colon cancer tested ctDNA negative after surgery, those with high-risk disease had a significantly lower three-year DFS than those with low-risk disease (86.4% vs. 96.7%; HR 3.04; 95% CI, 1.26, 7.34).34 This suggests ctDNA should be an adjunct tool but not a replacement for the standard clinicopathologic risk factors in the decision-making process for adjuvant chemotherapy. Finally, there are insufficient data to support an escalation of adjuvant treatment to a more intensive regimen, such as FOLFOX to FOLFIRINOX, for patients with positive ctDNA after surgery. Several studies are being conducted to investigate intensive regimens in this setting, such as DYNAMIC-III,36 CIRCULATE-NORTH AMERICA (NRG-GI008, NCT05174169), and ALTAIR (NCT04457297).
Adjunct Therapies
Aspirin and non-steroidal anti-inflammatory drugs (NSAIDs)
The clinical benefits of adjuvant aspirin and NSAIDs are controversial in localized CRC. The drugs inhibit the cyclooxygenase (COX) pathway, which is overexpressed in approximately 80% of CRC.37,38 While several observational studies showed improved overall survival in patients taking adjuvant aspirin or NSAIDs,39 randomized controlled trials have failed to demonstrate a universal benefit of adjuvant aspirin or NSAIDs in patients with localized CRC. In the multi-national phase III ASCOLT study,40 1,550 patients with localized CRC who completed surgical resection and ≥3 months of adjuvant chemotherapy were randomized to receive aspirin 200 mg daily or placebo. At a median follow-up of 59.2 months, five-year DFS was numerically higher in the aspirin group than the placebo group, but the difference was not statistically significant (77.0% vs. 74.8%; HR, 0.91; 95% CI, 0.73, 1.13). In another phase III Alliance CALGB/SWOG 80702 study,41 2,526 patients with stage III colon cancer were randomized to receive adjuvant FOLFOX with or without celecoxib 400 mg daily for three years. The celecoxib group showed a numerically higher three-year DFS (76.3% vs. 73.4%) and five-year overall survival (84.3% vs. 81.6%), but the difference was not statistically significant either. Based on the available data, we do not suggest universal use of adjuvant aspirin or NSAIDs for patients with localized CRC. Adjuvant aspirin may still be considered if patients have cardiovascular comorbidities for secondary prevention of cardiac events.
Notably, localized CRC with somatic PIK3CA mutation (5 – 20% of CRC) may benefit from adjuvant aspirin or celecoxib. PIK3CA mutation enhances COX-2 activity and prostaglandin E2 synthesis, which in turn inhibits the apoptosis of CRC cells.42 By inhibiting COX-2 activity, adjuvant aspirin could induce apoptosis of micrometastatic CRC cells and improve DFS after surgery. In the phase III ALASCCA study,43 626 patients with stage I, II, and III PIK3CA-mutated CRC were randomized to receive adjuvant aspirin 160 mg daily or placebo for three years after surgical resection. In the cohort of PIK3CA exon 9 and/or exon 20 mutated CRC, three-year DFS was numerically higher for the aspirin group versus the placebo group (89% vs. 81%; HR, 0.61; 95% CI, 0.34, 1.08). In the other cohort of other PIK3CA mutations, three-year DFS was significantly higher for the aspirin group (89% vs. 79%; HR, 0.51; 95% CI, 0.29, 0.88). Similar to the ALASCCA study, the Alliance CALGB/SWOG 80702 study also reported a significantly improved DFS and OS in PIK3CA-mutated stage III colon cancer treated with adjuvant celecoxib versus placebo.44 Based on the available evidence, we recommend adjuvant aspirin or celecoxib for three years in PIK3CA-mutated stage I, II, and III CRC if no contraindication.
Structured Exercise Program
Higher physical activity before and after the diagnosis of CRC has been associated with reduced DFS and CRC-specific mortality (~35% reduction) in observational studies and post-hoc analyses of clinical trials.45,46 While most providers recommend exercise to patients with CRC, only 35% of CRC patients meet the recommended intensity of physical activity proposed by the American Cancer Society (≥150 minutes of moderate-to-strenuous or ≥60 minutes of strenuous physical activity per week),47 suggesting provider's verbal encouragement for exercise is not sufficient to help patients achieve desired physical activity. In a phase III randomized controlled trial (CHALLENGE),48 889 patients with stage III and high-risk stage II colon cancer who had completed surgical resection and adjuvant chemotherapy were randomized to participate in a structured exercise program for three years or to receive health education materials only. The structured exercise program included support from a certified physical activity consultant, behavior-support sessions, and supervised exercise sessions every two or four weeks for three years. The goal of the exercise program was to increase recreational aerobic exercise from baseline by ≥10 metabolic equivalent task–hours per week. The study showed that patients enrolled in the structured exercise program had a significantly improved five-year DFS (80% vs. 74%) and eight-year OS (90% vs. 83%) than those given education materials only. Based on the study results, all patients with localized CRC should be referred to a structured exercise program after surgery and adjuvant chemotherapy, if applicable.
Conclusion
Adjuvant chemotherapy and immunotherapy are the new standard of care for stage III dMMR colon cancer. Neoadjuvant immunotherapy could be considered in select cases of stage II and III dMMR colon cancer. ctDNA is helpful in cases where the benefit versus risk of adjuvant therapy is equivocal. For patients with PIK3CA-mutated CRC, adjuvant aspirin or celecoxib should be considered if no contraindications. A structured exercise program should be implemented for all patients with localized CRC.
Conflict(s) of Interest
R.W.H had honoria from Incyte, AstraZeneca, Curio Science, Guidepoint, GRG Health, and Doximity; speaker program with Incyte, AstraZeneca and BeOne Medicines; research funding from Bayer; advisory board with Bristol Myers Squibb.
I.H.S. received advisory board fees from Pfizer, Amgen, Seattle Genetics, GSK, Lumanity, and Clearview; research grants from Bayer; speaker for Pfizer and Amgen.
Funding Information
N/A
Ethical Statements
N/A
Informed Consent
N/A
Data Availability Statement
N/A
Acknowledgements
N/A
Declaration of AI Use in Scientific Writing
N/A
Author Contributions
Concept and design: RWH, IHS
Data acquisition: RWH, IHS
Data analysis and interpretation: RWH, IHS
Drafting of the manuscript: RWH, IHS
Critical revision of the manuscript: RWH, IHS
All authors (RWH, IHS) approved the final version of the manuscript and agree to be accountable for all aspects of the work, in accordance with the International Committee of Medical Journal Editors criteria.
Reference
1. Siegel RL, Wagle NS, Cercek A, et al. Colorectal cancer statistics, 2023. CA Cancer J Clin. 2023;73(3):233-254. doi:10.3322/caac.21772
2. Biller LH, Schrag D. Diagnosis and treatment of metastatic colorectal cancer: a review. JAMA. 2021;325(7):669-685. doi:10.1001/jama.2021.0106
3. Peng D, Cheng Y. Improved overall survival of colorectal cancer under multidisciplinary team: a meta-analysis. Biomed Res Int. 2021;2021:5541613. doi:10.1155/2021/5541613
4. Schrag D, Shi Q, Weiser MR, et al. Preoperative treatment of locally advanced rectal cancer. N Engl J Med. 2023;389(4):322-334. doi:10.1056/NEJMoa2303269
5. Verheij FS, Omer DM, Williams H, et al. Long-term results of organ preservation in patients with rectal adenocarcinoma treated with total neoadjuvant therapy: the randomized phase II OPRA trial. J Clin Oncol. 2024;42(5):500-506. doi:10.1200/JCO.23.01208
6. Chung DC, Rustgi AK. DNA mismatch repair and cancer. Gastroenterology. 1995;109(5):1685-1699. doi:10.1016/0016-5085(95)90660-6
7. Ionov Y, Peinado MA, Malkhosyan S, et al. Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature. 1993;363(6429):558-561. doi:10.1038/363558a0
8. Yarchoan M, Johnson BA 3rd, Lutz ER, et al. Targeting neoantigens to augment antitumour immunity. Nat Rev Cancer. 2017;17(4):209-222. doi:10.1038/nrc.2016.154
9. Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409-413. doi:10.1126/science.aan6733
10. Maio M, Ascierto PA, Manzyuk L, et al. Pembrolizumab in microsatellite instability high or mismatch repair deficient cancers: updated analysis from the phase II KEYNOTE-158 study. Ann Oncol. 2022;33(9):929-938. doi:10.1016/j.annonc.2022.05.519
11. Etienne-Grimaldi MC, Mahamat A, Chazal M, et al. Molecular patterns in deficient mismatch repair colorectal tumours: results from a French prospective multicentric biological and genetic study. Br J Cancer. 2014;110(11):2728-2737. doi:10.1038/bjc.2014.213
12. Hutchins G, Southward K, Handley K, et al. Value of mismatch repair, KRAS, and BRAF mutations in predicting recurrence and benefits from chemotherapy in colorectal cancer. J Clin Oncol. 2011;29(10):1261-1270. doi:10.1200/JCO.2010.30.1366
13. Sargent DJ, Marsoni S, Monges G, et al. Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol. 2010;28(20):3219-3226. doi:10.1200/JCO.2009.27.1825
14. Andre T, Elez E, Lenz HJ, et al. Nivolumab plus ipilimumab versus nivolumab in microsatellite instability-high metastatic colorectal cancer (CheckMate 8HW): a randomised, open-label, phase 3 trial. Lancet. 2025;405(10476):383-395. doi:10.1016/S0140-6736(24)02848-4
15. Sinicrope F, Arnold D, Peters W, et al. Randomized trial of standard chemotherapy alone or combined with atezolizumab as adjuvant therapy for patients with stage III deficient DNA mismatch repair (dMMR) colon cancer (Alliance A021502; ATOMIC). Presented at: ASCO Annual Meeting; 2025; Chicago, IL. doi:10.1200/JCO.2025.43.17_suppl.LBA1
16. Chalabi M, Verschoor YL, Tan PB, et al. Neoadjuvant immunotherapy in locally advanced mismatch repair-deficient colon cancer. N Engl J Med. 2024;390(21):1949-1958. doi:10.1056/NEJMoa2400634
17. Grothey A, Sobrero AF, Shields AF, et al. Duration of adjuvant chemotherapy for stage III colon cancer. N Engl J Med. 2018;378(13):1177-1188. doi:10.1056/NEJMoa1713709
18. QUASAR Collaborative Group, Gray R, Barnwell J, et al. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. Lancet. 2007;370(9604):2020-2029. doi:10.1016/S0140-6736(07)61866-2
19. Sargent D, Sobrero A, Grothey A, et al. Evidence for cure by adjuvant therapy in colon cancer: observations based on individual patient data from 20,898 patients on 18 randomized trials. J Clin Oncol. 2009;27(6):872-877. doi:10.1200/JCO.2008.19.5362
20. Bockelman C, Engelmann BE, Kaprio T, et al. Risk of recurrence in patients with colon cancer stage II and III: a systematic review and meta-analysis of recent literature. Acta Oncol. 2015;54(1):5-16. doi:10.3109/0284186X.2014.975839
21. Baxter NN, Kennedy EB, Bergsland E, et al. Adjuvant therapy for stage II colon cancer: ASCO guideline update. J Clin Oncol. 2022;40(8):892-910. doi:10.1200/JCO.21.02538
22. Niedzwiecki D, Bertagnolli MM, Warren RS, et al. Documenting the natural history of patients with resected stage II adenocarcinoma of the colon after random assignment to adjuvant treatment with edrecolomab or observation: results from CALGB 9581. J Clin Oncol. 2011;29(23):3146-3152. doi:10.1200/JCO.2010.32.5357
23. Andre T, Boni C, Navarro M, et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol. 2009;27(19):3109-3116. doi:10.1200/JCO.2008.20.6771
24. Andre T, de Gramont A, Vernerey D, et al. Adjuvant fluorouracil, leucovorin, and oxaliplatin in stage II to III colon cancer: updated 10-year survival and outcomes according to BRAF mutation and mismatch repair status of the MOSAIC study. J Clin Oncol. 2015;33(35):4176-4187. doi:10.1200/JCO.2015.63.4238
25. Tournigand C, Andre T, Bonnetain F, et al. Adjuvant therapy with fluorouracil and oxaliplatin in stage II and elderly patients (between ages 70 and 75 years) with colon cancer: subgroup analyses of the Multicenter International Study of Oxaliplatin, Fluorouracil, and Leucovorin in the Adjuvant Treatment of Colon Cancer trial. J Clin Oncol. 2012;30(27):3353-3360. doi:10.1200/JCO.2012.42.5645
26. Kuebler JP, Wieand HS, O'Connell MJ, et al. Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J Clin Oncol. 2007;25(16):2198-2204. doi:10.1200/JCO.2006.08.2974
27. Schmoll HJ, Twelves C, Sun W, et al. Effect of adjuvant capecitabine or fluorouracil, with or without oxaliplatin, on survival outcomes in stage III colon cancer and the effect of oxaliplatin on post-relapse survival: a pooled analysis of individual patient data from four randomised controlled trials. Lancet Oncol. 2014;15(13):1481-1492. doi:10.1016/S1470-2045(14)70486-3
28. Yothers G, O'Connell MJ, Allegra CJ, et al. Oxaliplatin as adjuvant therapy for colon cancer: updated results of NSABP C-07 trial, including survival and subset analyses. J Clin Oncol. 2011;29(28):3768-3774. doi:10.1200/JCO.2011.36.4539
29. Schmoll HJ, Tabernero J, Maroun J, et al. Capecitabine plus oxaliplatin compared with fluorouracil/folinic acid as adjuvant therapy for stage III colon cancer: final results of the NO16968 randomized controlled phase III trial. J Clin Oncol. 2015;33(32):3733-3740. doi:10.1200/JCO.2015.60.9107
30. Hsieh RW, Symonds LK, Siu J, et al. Identification of circulating tumor DNA as a biomarker for diagnosis and response to therapies in cancer patients. Int Rev Cell Mol Biol. 2025;391:43-93. doi:10.1016/bs.ircmb.2024.08.006
31. Coombes RC, Page K, Salari R, et al. Personalized detection of circulating tumor DNA antedates breast cancer metastatic recurrence. Clin Cancer Res. 2019;25(14):4255-4263. doi:10.1158/1078-0432.CCR-18-3663
32. Kotani D, Oki E, Nakamura Y, et al. Molecular residual disease and efficacy of adjuvant chemotherapy in patients with colorectal cancer. Nat Med. 2023;29(1):127-134. doi:10.1038/s41591-022-02115-4
33. Kasi PM, Ensor J, Langer N, et al. Circulating tumor DNA (ctDNA) for informing adjuvant chemotherapy (ACT) in stage II/III colorectal cancer (CRC): interim analysis of BESPOKE CRC study. Presented at: ASCO Gastrointestinal Cancers Symposium; 2024; San Francisco, CA.
34. Tie J, Cohen JD, Lahouel K, et al. Circulating tumor DNA analysis guiding adjuvant therapy in stage II colon cancer. N Engl J Med. 2022;386(24):2261-2272. doi:10.1056/NEJMoa2200075
35. Tie J, Wang Y, Lo SN, et al. Circulating tumor DNA analysis guiding adjuvant therapy in stage II colon cancer: 5-year outcomes of the randomized DYNAMIC trial. Nat Med. 2025;31(5):1509-1518. doi:10.1038/s41591-025-03579-w
36. Tie J, Wang Y, Loree JM, et al. Circulating tumor DNA-guided adjuvant therapy in locally advanced colon cancer: the randomized phase 2/3 DYNAMIC-III trial. Nat Med. 2025. doi:10.1038/s41591-025-04030-w
37. Sheng J, Sun H, Yu FB, et al. The role of cyclooxygenase-2 in colorectal cancer. Int J Med Sci. 2020;17(8):1095-1101. doi:10.7150/ijms.44439
38. Wu QB, Sun GP. Expression of COX-2 and HER-2 in colorectal cancer and their correlation. World J Gastroenterol. 2015;21(20):6206-6214. doi:10.3748/wjg.v21.i20.6206
39. Chan AT, Ogino S, Fuchs CS. Aspirin use and survival after diagnosis of colorectal cancer. JAMA. 2009;302(6):649-658. doi:10.1001/jama.2009.1112
40. Chia JWK, Segelov E, Deng Y, et al. Aspirin after completion of standard adjuvant therapy for colorectal cancer (ASCOLT): an international, multicentre, phase 3, randomised, double-blind, placebo-controlled trial. Lancet Gastroenterol Hepatol. 2025;10(3):198-209. doi:10.1016/S2468-1253(24)00387-X
41. Meyerhardt JA, Shi Q, Fuchs CS, et al. Effect of celecoxib vs placebo added to standard adjuvant therapy on disease-free survival among patients with stage III colon cancer: the CALGB/SWOG 80702 (Alliance) randomized clinical trial. JAMA. 2021;325(13):1277-1286. doi:10.1001/jama.2021.2454
42. Hall DCN, Benndorf RA. Aspirin sensitivity of PIK3CA-mutated colorectal cancer: potential mechanisms revisited. Cell Mol Life Sci. 2022;79(7):393. doi:10.1007/s00018-022-04430-y
43. Martling A, Hed Myrberg I, Nilbert M, et al. Low-dose aspirin for PI3K-altered localized colorectal cancer. N Engl J Med. 2025;393(11):1051-1064. doi:10.1056/NEJMoa2504650
44. Nowak JA, Twombly T, Ma C, et al. Improved survival with adjuvant cyclooxygenase 2 inhibition in PIK3CA-activated stage III colon cancer: CALGB/SWOG 80702 (Alliance). J Clin Oncol. 2024;42(24):2853-2859. doi:10.1200/JCO.23.01680
45. Ballard-Barbash R, Friedenreich CM, Courneya KS, et al. Physical activity, biomarkers, and disease outcomes in cancer survivors: a systematic review. J Natl Cancer Inst. 2012;104(11):815-840. doi:10.1093/jnci/djs207
46. Brown JC, Ma C, Shi Q, et al. Physical activity in stage III colon cancer: CALGB/SWOG 80702 (Alliance). J Clin Oncol. 2023;41(2):243-254. doi:10.1200/JCO.22.00171
47. Blanchard CM, Courneya KS, Stein K, et al. Cancer survivors' adherence to lifestyle behavior recommendations and associations with health-related quality of life: results from the American Cancer Society's SCS-II. J Clin Oncol. 2008;26(13):2198-2204. doi:10.1200/JCO.2007.14.6217
48. Courneya KS, Vardy JL, O'Callaghan CJ, et al. Structured exercise after adjuvant chemotherapy for colon cancer. N Engl J Med. 2025;393(1):13-25. doi:10.1056/NEJMoa2502760