Version May 2024
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 postoperative (adjuvant) therapy is to eradicate these micrometastases, thereby increasing the cure rate. In colon cancer, the benefits of adjuvant chemotherapy have been most clearly demonstrated in stage III (node-positive (table 1)) colon cancer, whereas benefit in stage II disease remains controversial. (See "Adjuvant therapy for resected stage III (node-positive) colon cancer" and "Adjuvant therapy for resected stage II colon cancer" and "Adjuvant therapy for resected rectal adenocarcinoma in patients not receiving neoadjuvant therapy".)
Patients with rectal cancer have a higher risk of local recurrence as compared with colon cancer, and the adjuvant strategy often includes radiation therapy as well as chemotherapy for both stage II and III disease (table 1). Neoadjuvant or induction chemoradiotherapy is an increasingly used option for patients with locally advanced rectal adenocarcinomas, with additional chemotherapy to eradicate micrometastases administered postoperatively; however, in some cases, chemotherapy can also be given preoperatively. (See "Adjuvant therapy for resected rectal adenocarcinoma in patients not receiving neoadjuvant therapy", section on 'Stage II to III disease following transabdominal surgery' and "Adjuvant therapy after neoadjuvant therapy for rectal cancer", section on 'Benefit of postoperative chemotherapy' and "Neoadjuvant therapy for rectal adenocarcinoma", section on 'Total neoadjuvant therapy for locally advanced tumors'.)
Beyond the benefits of chemotherapy and radiation therapy, several adjunctive factors have been associated with improved outcomes after treatment of early stage CRC, including 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 data linking these adjunctive treatments to outcomes will be addressed here. A more in-depth discussion on the roles of diet, physical activity, and body weight in cancer survivors is provided elsewhere. (See "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 early stage 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 elsewhere. (See "The roles of diet, physical activity, and body weight in cancer survivors".)
ASPIRIN AND OTHER NSAIDS — Several observational studies suggest that use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) may improve survival among patients receiving treatment for early CRC, although it is not clear that all patients benefit. Many oncologists, including some of the authors and editors associated with this topic review, recommend a daily dose of aspirin to patients with resected early stage CRC unless they have a contraindication (preexisting coagulopathy, on anticoagulants, history of gastritis or peptic ulcer disease). The optimal dose is not established, although the most common range is 75 to 325 mg daily. It is premature to consider testing individual patients for mutations in the PIK3CA gene in order to make decisions about postcancer aspirin use.
Numerous observational studies and randomized trials [1-3] have demonstrated the efficacy of aspirin against the development of colorectal adenomas and CRC through its actions as an inhibitor of the cyclooxygenase 2 (COX-2) pathway. This pathway is overexpressed in 80 to 85 percent of CRCs. (See "NSAIDs (including aspirin): Role in prevention of colorectal cancer".)
Many (but not all [4-6]) observational studies also suggest that use of aspirin and other NSAIDs may also improve survival among patients receiving treatment for early CRC [7-17]. As an example, in a report of patients with CRC who were participating in the Nurses' Health Study and the Health Professionals Follow-up Study, aspirin users had a significant 29 percent lower cancer-specific mortality and a 21 percent lower overall mortality than nonusers [7]. 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 the studies addressed the potential for harm with aspirin use [15], and none addressed the appropriate dose.
These data suggest that aspirin may influence the biology of established CRCs after potentially curative resection. However, all of the available data are from observational studies, and prospective confirmation of the benefit of aspirin in a randomized trial is needed before routine use of aspirin or any other NSAID can be routinely recommended, given the potential for harm (eg, gastrointestinal bleeding). One prospective randomized trial (the ASPREE trial) showed that low-dose aspirin actually increased mortality from CRC (as well as other anatomic sites), although CRC mortality was not prespecified as an endpoint, follow-up was short (median 4.7 years), and the trial was stopped prematurely, increasing the likelihood of artifactual results [18,19].
There are two other ongoing trials with CRC mortality as a prespecified endpoint (the phase III Alliance 80702 trial and the Aspirin for Dukes C and High Risk Dukes B Colorectal Cancers study [ASCOLT]), and one of them, ALLIANCE, failed to find any benefit from the addition of celecoxib to oxaliplatin-based adjuvant chemotherapy in stage III colon cancer, either for disease-free or overall survival [20]. Results from the ASCOLT trial will not be available for several years.
Do all patients benefit? — Neither of these trials has selected patients according to molecular pathology, and it is not clear that all patients potentially benefit from NSAIDs:
●In a 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 (hazard ratio [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) [21].
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) [22].
●A later 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 [23]. 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 [16].
●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) [13]. 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 human leukocyte antigen (HLA) class I antigens but not overexpression of PTGS2 or mutated PIK3CA [10].
●Still 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 [24]. (See "Principles of cancer immunotherapy", section on 'Tumor evasion of immune surveillance'.)
These data underscore the complexity of the interplay among aspirin, PIK3CA status, PTGS2 expression, BRAF mutations, expression of 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. Given that these data are observational and derived from subset analysis, it is premature to consider testing individual patients for mutations in the PIK3CA gene or any other putative predictive factor in order to make decisions about postcancer aspirin use.
VITAMIN D STATUS — An association between higher vitamin D levels and prognosis of CRC has been suggested. Whether higher levels of vitamin D supplementation can improve prognosis in conjunction with adjuvant chemotherapy for those with early stage disease is not yet known. Nevertheless, given the benefits of vitamin D repletion in terms of skeletal health and the possibility of better cancer-related outcomes, it seems 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]).
An association between vitamin D levels and prognosis of metastatic CRC has been observed. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach", section on 'Issues related to vitamin D'.)
A similar relationship has been suggested in patients with earlier stage disease:
●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 [25]) 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) [26].
●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 [27]. 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 (p = 0.004).
In addition, 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) [28]. 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 elsewhere. (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 elsewhere. (See "Post-treatment surveillance after colorectal cancer treatment" and "Approach to the long-term survivor of colorectal cancer".)
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: Colorectal cancer treatment; metastatic cancer (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Benefits of adjunctive therapies – Beyond the benefits of chemotherapy and radiation therapy, several adjunctive factors have been associated with improved outcomes after treatment of early stage colorectal cancer (CRC), including 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. (See 'Introduction' above.)
●Diet and exercise – Given the mounting evidence that diet and exercise can modify prognosis, patients with early stage CRC should be encouraged to maintain a healthy weight and exercise regularly. (See 'Diet and exercise' above.)
●Aspirin and other NSAIDs
•Several observational studies suggest that use of aspirin and other NSAIDs may improve survival among patients receiving treatment for early CRC, although randomized trials are needed to confirm benefit. It is not clear that all patients benefit. (See 'Do all patients benefit?' above.)
•While awaiting the results of prospective randomized trials, many oncologists, including some of the authors, recommend a daily dose of aspirin to patients with resected early stage CRC unless they have a contraindication (preexisting coagulopathy, on anticoagulants, history of gastritis or peptic ulcer disease).
The optimal dose is not established, but the range is most commonly 75 to 325 mg daily. It is premature to consider testing individual patients for mutations in the PIK3CA gene in order to make decisions about postcancer aspirin use. (See 'Aspirin and other NSAIDs' above.)
●Vitamin D status
•An association between higher vitamin D levels and prognosis in early stage CRC has been suggested. Whether higher levels of vitamin D supplementation can improve prognosis in conjunction with adjuvant chemotherapy is not yet known.
•Nevertheless, given the benefits of vitamin D repletion in terms of skeletal health and the possibility of better cancer-related outcomes, it seems 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]). (See 'Vitamin D status' above.)
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