Colorectal cancer remains one of the most significant global health challenges, ranking as the third most common cancer worldwide. In 2020, there were an estimated 2 million new cases and nearly 1 million deaths from the disease. Despite advances in treatment, particularly the inclusion of oxaliplatin in chemotherapy regimens over the past two decades, significant improvements in survival rates and recurrence prevention have been limited. In this context, the exploration of inexpensive and widely available medications like aspirin for secondary prevention of colorectal cancer has attracted considerable attention.
Aspirin, a well-known COX-1 and COX-2 inhibitor, has long been studied for its potential to reduce cancer recurrence, particularly in hereditary colorectal cancer syndromes where polyp recurrence is a significant concern. Previous studies have shown promising results for aspirin in reducing colorectal cancer risk in these specific populations, leading researchers to investigate whether it could be beneficial for patients who have already completed primary treatment for colorectal cancer.
The ASCOLT trial, led by the National Cancer Center Singapore, is one of the most ambitious studies to date examining the potential of aspirin in preventing disease recurrence after standard adjuvant therapy for high-risk colorectal cancer. The trial’s findings, published in The Lancet Gastroenterology & Hepatology, suggest that while aspirin showed some potential, its role in preventing recurrence of high-risk Dukes’ B and C colorectal cancer remains uncertain.
The Design of the ASCOLT Trial
The ASCOLT trial (Aspirin after Completion of Standard Adjuvant Therapy for Colorectal Cancer) was an international, multicenter, phase 3 randomized, double-blind, placebo-controlled trial designed to provide robust evidence on the efficacy of aspirin in colorectal cancer recurrence prevention. The trial began in 2009 and enrolled 1,587 adult participants across 66 centers in 11 countries. To be eligible, participants had to have high-risk Dukes’ B or C colon cancer or Dukes’ B or C rectal cancer and had to have completed resection and at least three months of chemotherapy.
Participants were randomly assigned to one of two groups: one group received 200 mg of aspirin daily, while the other received a placebo. The treatment duration was three years, with regular follow-up visits that included clinical assessments, imaging, and colonoscopies. The primary goal of the trial was to assess disease-free survival, while secondary outcomes included overall survival and the prevention of cancer recurrence.
Results of the ASCOLT Trial
The findings from the ASCOLT trial, after five years of follow-up, revealed no significant difference between the aspirin and placebo groups in terms of disease recurrence prevention. The aspirin group had a disease-free survival rate of 77.0% at five years, compared to 74.8% in the placebo group. The hazard ratio for disease recurrence was 0.91 (95% confidence interval [CI]: 0.73–1.13), suggesting a slight advantage in favor of aspirin. However, the confidence intervals for the hazard ratio crossed 1, indicating that the observed difference was not statistically significant. This means that the potential benefit of aspirin could range from beneficial to negligible or, in rare cases, even slightly harmful.
Similarly, overall survival was slightly better in the aspirin group, with a five-year survival rate of 91.4% compared to 88.9% in the placebo group. The hazard ratio for overall survival was 0.75 (95% CI: 0.53–1.07), again suggesting a potential benefit of aspirin. However, the confidence intervals for the hazard ratio also crossed 1 in this case, rendering the observed difference statistically insignificant.
Subgroup Analysis and Potential Insights
Despite the lack of statistically significant findings in the primary and secondary outcomes, the ASCOLT trial’s results hinted at the possibility of aspirin benefiting certain patient subgroups. In particular, patients who had not been treated with oxaliplatin during their adjuvant chemotherapy seemed to experience a more favorable outcome with aspirin. However, after adjusting for multiple comparisons, this observation lost statistical significance. It suggests that while there may be trends indicating aspirin’s potential efficacy in specific subsets of patients, the evidence is not yet conclusive.
The study’s authors emphasize that the ASCOLT trial provides the first randomized evidence of aspirin’s role in secondary prevention of colorectal cancer recurrence. While the results effectively rule out any large, meaningful benefits, they leave the door open for the possibility of modest benefits, particularly in specific patient populations.
Ongoing Research and the Future of Aspirin in Cancer Prevention
The findings from the ASCOLT trial are unlikely to put an end to the investigation of aspirin’s role in colorectal cancer prevention, especially given the drug’s affordability and global accessibility. Ongoing biomarker studies within the ASCOLT cohort are working to identify subgroups of patients who may benefit from aspirin therapy. These studies focus on identifying genetic mutations or molecular markers that could predict a patient’s response to aspirin. For example, researchers are looking at whether certain mutations, such as those in the PIK3CA gene or overexpression of COX-2, might make certain patients more likely to benefit from aspirin.
The ASCOLT trial is not an isolated study in this area. Other ongoing trials are also investigating the role of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) in cancer prevention, particularly in the context of colorectal cancer. A planned meta-analysis that combines results from similar studies is expected to provide more definitive answers on whether aspirin can play a role in secondary prevention of colorectal cancer.
The Broader Context of Colorectal Cancer Treatment
Colorectal cancer is a major global health concern, and despite advances in treatment, survival rates remain relatively stagnant in recent decades. The introduction of oxaliplatin, a chemotherapy agent, has improved outcomes in high-risk patients, but researchers have been continually searching for new treatments to reduce recurrence and improve long-term survival. Aspirin, due to its widespread availability and low cost, has emerged as a potential adjunct therapy, but as the ASCOLT trial demonstrates, its benefits may be limited or more modest than previously hoped.
The results of the ASCOLT trial underscore the complexities of cancer treatment. While aspirin is known for its anti-inflammatory properties and its ability to reduce the recurrence of certain cancers, such as those related to hereditary syndromes, the effectiveness of aspirin in post-cancer treatment for high-risk patients is not yet fully understood. Given the mixed results from the ASCOLT trial, it’s clear that more research is needed to determine whether aspirin should be a standard part of colorectal cancer recovery or whether its use should be limited to specific patient populations.
Conclusion
The ASCOLT trial offers valuable insights into the role of aspirin in the secondary prevention of colorectal cancer recurrence. While the results did not show a statistically significant benefit, they open the door for further exploration, particularly in identifying patient subgroups that may derive more benefit from aspirin treatment. Ongoing studies will continue to investigate the molecular mechanisms that could guide the use of aspirin and other NSAIDs in cancer prevention. Ultimately, the ASCOLT trial highlights the complexity of cancer treatment and the need for personalized approaches to therapy. While aspirin may not yet offer a definitive solution for preventing colorectal cancer recurrence, its potential role in specific subsets of patients remains an area of active investigation.
References: John W K Chia et al, Aspirin after completion of standard adjuvant therapy for colorectal cancer (ASCOLT): an international, multicentre, phase 3, randomised, double-blind, placebo-controlled trial, The Lancet Gastroenterology & Hepatology (2025). DOI: 10.1016/S2468-1253(24)00387-X
Seohyuk Lee et al, Adjuvant aspirin therapy and colorectal cancer survival, The Lancet Gastroenterology & Hepatology (2025). DOI: 10.1016/S2468-1253(24)00393-5
