Version July 2025
INTRODUCTION —
Surgical resection is the only curative treatment for locoregional colon cancer. Outcome is most closely related to the extent of disease at presentation. (See "Overview of the management of primary colon cancer", section on 'Prognosis' and "Overview of the management of rectal adenocarcinoma", section on 'Prognosis'.)
Among patients who have undergone potentially curative resection for colorectal cancer (CRC), disease recurrence is thought to arise from clinically occult micrometastases that are present at the time of surgery. The goal of adjuvant (ie, postoperative) therapy is to eradicate these micrometastases, thereby increasing the cure rate. (See "Adjuvant therapy for resected stage III (node-positive) colon cancer" and "Adjuvant therapy for resected stage II colon cancer".)
Patients with rectal cancer have a higher risk of local recurrence as compared with colon cancer. As a result, various neoadjuvant and adjuvant strategies are employed in the treatment of locally advanced rectal cancer. (See "Neoadjuvant therapy for rectal adenocarcinoma" and "Adjuvant therapy for resected rectal adenocarcinoma not treated with neoadjuvant therapy" and "Adjuvant therapy after neoadjuvant therapy for rectal cancer".)
Beyond the benefits of standard therapy, there is interest in evaluating the effect of several adjunctive factors on the outcomes of patients with treated non-metastatic CRC. These adjunctive therapies include interventions to achieve energy balance (ie, maintaining a healthy body weight, higher levels of physical activity), intake of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), vitamin D status, and coffee consumption.
The impact of these adjunctive treatments in patients with non-metastatic treated CRC are presented here. Further details on the roles of adjunctive treatments in metastatic CRC as well as the role of diet, physical activity, and body weight in cancer survivors are discussed separately. (See "Initial systemic therapy for metastatic colorectal cancer", section on 'What is the role of vitamin D?' and "The roles of diet, physical activity, and body weight in cancer survivors".)
DIET AND EXERCISE —
Given the mounting evidence that diet and exercise can modify prognosis, patients with CRC should be encouraged to maintain a healthy weight and exercise regularly. The role of a healthy diet, as well as the effect of specific dietary components including nuts, coffee, and fiber, is discussed in detail separately. (See "The roles of diet, physical activity, and body weight in cancer survivors".)
ASPIRIN AND OTHER NSAIDs —
We do not routinely administer daily aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) to patients with non-metastatic treated CRC. Although observational studies initially suggested clinical benefit, subsequent randomized trials evaluating these agents failed to demonstrate a disease-free or overall survival benefit. There is also a small but real risk for adverse treatment effects (eg, gastrointestinal bleeding, worsening of preexisting coagulopathy, gastritis, or peptic ulcer disease).
All patients — Studies have demonstrated the efficacy of aspirin in the prevention of colorectal adenomas and CRC through its actions as an inhibitor of the cyclooxygenase 2 (COX-2) pathway [1-4]. This pathway is overexpressed in 80 to 85 percent of CRCs. (See "NSAIDs (including aspirin): Role in prevention of colorectal cancer".)
In patients with non-metastatic CRC who are treated with curative intent, many observational studies [5-15] (but not all [16-18]) also suggested that aspirin and other NSAIDs are associated with improved overall survival. As an example, in an observational study of patients with CRC from the Nurses' Health Study and the Health Professionals Follow-up Study, aspirin users had a 29 percent lower cancer-specific mortality and a 21 percent lower overall mortality than nonusers [5]. The reduction in mortality was even greater among patients who initiated aspirin use after cancer diagnosis than among patients who used it before, and benefit was limited to those whose tumors overexpressed COX-2. Benefits were similar in patients who received standard adjuvant chemotherapy and those who did not and in those with stage I, II, and III disease at diagnosis. Very few of these studies addressed the potential for harm with aspirin use [13], and none addressed the appropriate dose.
Despite these initial observational studies, subsequent randomized trials evaluating aspirin or NSAID use in patients with non-metastatic CRC have failed to demonstrate a disease-free or overall survival benefit [19-21].
●In a placebo-controlled phase III trial (Alliance CALGB/SWOG 80702) of 2526 patients with stage III colon cancer, the addition of celecoxib to oxaliplatin-based adjuvant chemotherapy did not improve disease-free (hazard ratio [HR] 0.89, 0.76-1.03) or overall survival (HR 0.86, 0.72-1.04) [21]. Outcomes for patients with PIK3CA-activated tumors are discussed separately. (See 'Subgroups with molecular alterations' below.)
●In preliminary results from a placebo-controlled phase III trial (ASCOLT) of 1550 patients with Dukes' C and high-risk Dukes' B CRC who were treated with surgery and standard chemotherapy, the addition of aspirin failed to improve disease-free (HR 0.91, 0.73-1.13) or overall survival (HR 0.75, 95% CI 0.53-1.07) [22].
Subgroups with molecular alterations — Although there may be patients with specific molecular alterations who benefit from aspirin or NSAID use, it is premature to test individual patients for such molecular alterations (eg, PIK3CA gene) to make decisions about such adjunctive agents.
Data underscore the complexity of the interplay among aspirin and NSAIDs and various molecular alterations such as PIK3CA status, PTGS2 expression, BRAF mutations, expression of human leukocyte antigen (HLA) class I antigens, the programmed cell death 1 protein (PD-1) immune checkpoint pathway, and potentially, other factors that have not yet been determined. Further investigations are necessary to determine the clinical significance of these findings. Data are as follows:
●In a placebo-controlled phase III trial (Alliance CALGB/SWOG 80702), among a subgroup of 259 patients with stage III colon cancer with a PIK3CA gain-of-function mutation, the addition of celecoxib to adjuvant chemotherapy demonstrated improved overall survival (HR 0.44, 95% CI 0.22-0.85) compared with patients with PIK3CA wild-type tumors (HR 0.94, 95% CI 0.68-1.30), with a statistically significant test for interaction [23]. Although a similar disease-free survival benefit was also seen for the addition of celecoxib to adjuvant chemotherapy in PIK3CA mutated tumors relative to wild-type tumors, the test for interaction was not significant [23].
●In an observational study of 964 patients with CRC from the Nurses' Health Study and the Health Professionals Follow-up Study, postcancer aspirin use in patients whose tumors harbor mutations in the PIK3CA gene (17 percent of the total) was associated with marked reduction in CRC-specific death (HR 0.18, 95% CI 0.06-0.61), whereas in patients whose cancer was wild-type for PIK3CA, the HR for CRC death was not influenced by aspirin use (HR 0.96, 95% CI 0.69-1.32) [24].
A meta-analysis of five studies (including the above study) that compared postdiagnosis aspirin use in CRC patients identified by PIK3CA status found that the overall effect of aspirin on mortality was not statistically significant (HR for overall survival 0.82, 95% CI 0.63-1.08) but that aspirin use was associated with significantly reduced overall mortality in PIK3CA mutation carriers (HR 0.71, 95% CI 0.51-0.99) [25].
●A subsequent analysis of data from the Nurses' Health Study and the Health Professionals Follow-up Study suggested that regular aspirin use was associated with a lower risk of BRAF wild-type but not BRAF mutant CRC [26]. The reduced risk of BRAF wild-type cancer in aspirin users was seen primarily in tumors that overexpressed prostaglandin-endoperoxide synthase 2 (PTGS2, also known as COX-2). Furthermore, the association between regular aspirin use and a lower risk of BRAF wild-type CRC in this study appeared to be independent of PIK3CA status.
An association has also been reported between aspirin benefit and RAS mutation status, with benefit limited to those with RAS wild-type tumors [14].
●A meta-analysis of seven studies on postdiagnosis aspirin therapy and seven studies on prediagnosis aspirin use concluded that postdiagnosis (but not prediagnosis) use of aspirin significantly improved overall mortality (HR 0.84, 95% CI 0.75-0.94), although the difference in CRC-specific mortality did not reach the level of statistical significance (HR 0.77, 95% CI 0.52-1.14) [11]. The overall survival benefit appeared to be confined to those patients whose tumors overexpressed PTGS2 (HR 0.65, 95% CI 0.50-0.85) and to those with mutated PIK3CA (HR 0.58, 95% CI 0.37-0.90).
●Others report an association between aspirin benefit and tumor expression of HLA class I antigens but not overexpression of PTGS2 or mutated PIK3CA [8].
●Other data suggest a differential effect of aspirin according to immune checkpoint status, with lower levels of programmed cell death 1 ligand (PD-L1; resulting in lower signaling through the immune checkpoint pathway) being associated with a stronger protective effect [27]. (See "Principles of cancer immunotherapy", section on 'Tumor evasion of immune surveillance'.)
VITAMIN D STATUS —
In patients with non-metastatic treated CRC, vitamin D deficiency is associated with adverse outcomes. However, the evidence supporting vitamin D supplementation to improve overall survival is weak. Nevertheless, given the benefits of vitamin D repletion in terms of skeletal health and the possibility of better cancer-related outcomes, it is reasonable to test serum vitamin D levels in patients with newly diagnosed CRC and to replete those with low levels (serum 25-hydroxyvitamin D [25(OH) D] <20 ng/mL [50 nmol/L]).
The efficacy of vitamin D supplementation in metastatic CRC is discussed separately. (See "Initial systemic therapy for metastatic colorectal cancer", section on 'What is the role of vitamin D?'.)
In patients with nonmetastatic treated metastatic CRC, vitamin D deficiency is associated with a worse prognosis:
●In a subset of patients enrolled in the phase III Cancer and Leukemia Group B (CALGB) Alliance 89803 trial comparing adjuvant chemotherapy with weekly fluorouracil/leucovorin with or without irinotecan, those in the highest quintile of predicted vitamin D score (which was based on race, geographic area of residence, dietary and supplemental vitamin D intake from food frequency questionnaires, body mass index [BMI], and physical activity, a method previously validated in metastatic CRC [28]) had significantly improved recurrence-free and overall survival compared with those in the lowest quintile (adjusted hazard ratio [HR] for death or recurrence 0.62, 95% CI 0.44-0.86) [29].
●Another observational study suggests that low postoperative 25(OH) D levels may be associated with significantly worse survival, especially among patients with node-negative disease [30]. The adjusted HRs for CRC-specific and all-cause mortality were 0.68 (95% CI 0.50-0.90) and 0.70 (95% CI 0.55-0.89), respectively, for highest versus lowest 25(OH) D tertiles, and for stage II disease, the HR for CRC-specific mortality was 0.44.
A pooled analysis of data from seven randomized trials concluded that there was a clinically meaningful benefit of vitamin D supplementation on CRC survival outcomes (HR 0.70, 95% CI 0.48-0.93) [31]. While the inclusion criteria, intervention doses, and outcomes varied among the studies, a beneficial effect of vitamin D supplementation was seen in trials specifically undertaken in CRC patients (HR for progression-free survival 0.65, 95% CI 0.36-0.94) and there was also a suggestive effect in incident CRC cases from other population-based trials (HR for CRC-specific survival 0.76, 95% CI 0.39-1.13). (See "Vitamin D and extraskeletal health", section on 'Cancer' and "Vitamin D and extraskeletal health", section on 'Mortality'.)
However, it is not certain that this association between poor vitamin D status and elevated CRC mortality is causal. There may be confounding influences relating to this observation, such as patients with more advanced disease being more likely indoors and less exposed to sunlight, and thus less replete with vitamin D. In addition, higher vitamin D levels may be acting as a surrogate for other healthy behaviors or biologically more favorable disease. Furthermore, whether higher levels of vitamin D supplementation can improve prognosis in conjunction with adjuvant chemotherapy is not yet known.
The benefits of vitamin D repletion in terms of skeletal and extraskeletal health are discussed in detail separately. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment" and "Vitamin D and extraskeletal health".)
ISSUES FOR SURVIVORS —
Recommendations for post-treatment cancer surveillance and issues for long-term survivors of colon cancer are discussed in detail separately. (See "Post-treatment surveillance for colorectal cancer" and "Approach to the care of colorectal cancer survivors".)
INFORMATION FOR PATIENTS —
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Colon and rectal cancer (The Basics)")
●Beyond the Basics topics (see "Patient education: Colon and rectal cancer (Beyond the Basics)" and "Patient education: Treatment of metastatic colorectal cancer (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Adjunctive therapies – Beyond the benefits of standard therapy, there is interest in evaluating several adjunctive factors on the outcomes of patients with treated non-metastatic colorectal cancer (CRC). Such adjunctive factors include diet and exercise, aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs), and vitamin D. (See 'Introduction' above.)
●Diet and exercise – Given the mounting evidence that diet and exercise can modify prognosis, patients with CRC should be encouraged to maintain a healthy weight and exercise regularly. (See 'Diet and exercise' above and "The roles of diet, physical activity, and body weight in cancer survivors".)
●Aspirin and other NSAIDs
•We do not routinely administer daily aspirin and NSAIDs to patients with non-metastatic treated CRC. Although observational studies initially suggested clinical benefit, subsequent randomized trials evaluating these agents failed to demonstrate a disease-free or overall survival benefit. There is also a small but real risk for adverse treatment effects (eg, gastrointestinal bleeding, worsening of preexisting coagulopathy, gastritis, or peptic ulcer disease). (See 'Aspirin and other NSAIDs' above.)
•Although there may be patients with specific molecular alterations who benefit from aspirin or NSAID use, it is premature to test individual patients for such molecular alterations (eg, PIK3CA gene) to make decisions about adjunctive agents. (See 'Subgroups with molecular alterations' above.)
●Vitamin D status
•In patients with non-metastatic treated CRC, vitamin D deficiency is associated with adverse outcomes. However, the evidence supporting vitamin D supplementation to improve overall survival is weak. (See 'Vitamin D status' above.)
•Nevertheless, given the benefits of vitamin D repletion in terms of skeletal health and the possibility of better cancer-related outcomes, it is reasonable to test serum vitamin D levels in patients with newly diagnosed CRC and to replete those with low levels (serum 25-hydroxyvitamin D [25(OH) D] <20 ng/mL [50 nmol/L]).
