A new international clinical trial has found that three years of aspirin use after standard adjuvant therapy for high-risk Dukes’ B and C colorectal cancer did not significantly reduce disease recurrence. The trial, led by the National Cancer Center Singapore and published in The Lancet Gastroenterology & Hepatology, investigated the potential benefits of aspirin in preventing colorectal cancer recurrence. The study enrolled 1,587 participants from 66 centers in 11 countries and found that while there was a slight difference in the disease-free survival and overall survival rates between the aspirin group and the placebo group, the differences were not statistically significant. Subgroup analysis suggested a potential benefit for patients not treated with oxaliplatin, but this finding was also inconclusive after further adjustments. Ongoing biomarker studies are exploring potential subsets of patients who might benefit from aspirin therapy, and a meta-analysis of similar trials is planned for further clarity.

Background

Colorectal cancer (CRC) is the third most prevalent cancer globally, with an estimated 2 million new cases and 1 million deaths in 2020 alone. Despite advances in treatment, such as the addition of oxaliplatin to chemotherapy regimens over two decades ago, the cure rates for high-risk CRC patients have plateaued. This has spurred interest in repurposing inexpensive, widely available drugs like aspirin, which has been shown in previous studies to reduce the risk of colorectal cancer and polyp recurrence in patients with hereditary cancer syndromes.

The ASCOLT Trial

The ASCOLT trial, which started in 2009, enrolled 1,587 adults with high-risk colorectal cancer who had completed their initial surgery and at least three months of chemotherapy. The patients had either Dukes’ B or C colon cancer or Dukes’ B or C rectal cancer. These patients were randomized to receive either 200 mg of aspirin daily or a placebo for three years. Follow-up visits were conducted over five years, with regular clinical assessments, imaging, and colonoscopies to monitor for disease recurrence.

The primary endpoint of the trial was disease-free survival, which is defined as the time a patient remains free of cancer recurrence after completing treatment. The secondary endpoint was overall survival, which measures the length of time a patient survives after starting treatment. Both endpoints were assessed at the five-year follow-up.

Results

The results of the ASCOLT trial showed a modest difference between the aspirin and placebo groups, but the difference was not statistically significant. The aspirin group had a five-year disease-free survival rate of 77.0%, compared to 74.8% in the placebo group. The hazard ratio (HR) for disease recurrence was 0.91, with a 95% confidence interval (CI) ranging from 0.73 to 1.13. Similarly, the five-year overall survival rate was 91.4% for the aspirin group versus 88.9% for the placebo group (HR: 0.75; 95% CI: 0.53 to 1.07). While the aspirin group showed a slight improvement in both disease-free and overall survival, the confidence intervals for both hazard ratios crossed the threshold of 1, indicating that the results were not statistically significant.

The findings suggest that while aspirin may have some benefit in preventing recurrence, the evidence is not strong enough to recommend it as a routine adjuvant therapy for all high-risk colorectal cancer patients. The positive trends observed could be due to random variation, and the actual effect of aspirin may range from beneficial to negligible or even slightly harmful.

Subgroup Analysis and Potential Benefits

A subgroup analysis hinted that patients who were not treated with oxaliplatin during their chemotherapy might experience some benefit from aspirin, but this observation was not statistically significant after multiple comparison adjustments. This suggests that aspirin’s potential benefits may be more pronounced in certain patient populations, although these findings require further investigation.

In addition to these findings, the trial highlighted the need for further research to understand the specific patient groups who may benefit from aspirin. Ongoing biomarker studies within ASCOLT are focused on identifying genetic mutations or other factors that might predict a positive response to aspirin therapy. For example, patients with mutations in the PIK3CA gene or overexpression of COX-2 might be more likely to benefit from aspirin due to the role of these factors in cancer progression and inflammation.

Aspirin’s Role in Cancer Prevention

Despite the inconclusive results from the ASCOLT trial, the potential for aspirin as a secondary colorectal cancer prevention tool remains an area of active research. Aspirin has long been studied for its cancer-preventive properties, particularly in the context of colorectal cancer. A number of observational studies have shown that long-term aspirin use can reduce the risk of developing colorectal cancer in the general population, especially in those with a family history or genetic predisposition. For patients who have already been treated for colorectal cancer, however, the evidence for aspirin’s efficacy is less clear.

Some studies have suggested that aspirin may have a role in preventing recurrence, but the results have been inconsistent. Previous randomized trials have shown mixed results, with some reporting a small reduction in cancer recurrence, while others found no significant benefit. The ASCOLT trial adds to this body of evidence by providing the first randomized, double-blind, placebo-controlled data on aspirin’s role in preventing colorectal cancer recurrence following adjuvant therapy.

Future Directions

While the ASCOLT trial did not provide conclusive evidence supporting the use of aspirin as a routine treatment for colorectal cancer recurrence, it has opened the door for further research into the specific subsets of patients who may benefit. As mentioned earlier, ongoing biomarker studies are exploring the potential for genetic factors, such as PIK3CA mutations or COX-2 overexpression, to predict which patients might benefit most from aspirin therapy. Additionally, a planned meta-analysis that incorporates results from other similar trials may help clarify aspirin’s role in colorectal cancer prevention.

The findings from ASCOLT also underscore the importance of continued exploration into new treatments and strategies for colorectal cancer. Despite improvements in surgical techniques, chemotherapy regimens, and targeted therapies, colorectal cancer remains a major cause of morbidity and mortality worldwide. The search for additional ways to prevent recurrence and improve patient outcomes must continue, with a focus on identifying effective therapies for high-risk patients who are at the greatest risk of relapse.

The ASCOLT trial provides important insights into the potential role of aspirin in preventing colorectal cancer recurrence. While the results showed no significant benefit in the overall population, they suggest that aspirin may offer modest benefits for some patients, particularly those not treated with oxaliplatin during chemotherapy. Ongoing research, including biomarker studies and a planned meta-analysis, will help further clarify the potential role of aspirin in secondary cancer prevention.

Ultimately, the ASCOLT trial reinforces the complexity of cancer treatment and the need for personalized medicine. While aspirin is a promising, inexpensive, and widely available drug, its use in preventing colorectal cancer recurrence should be considered on a case-by-case basis, with further research needed to identify the patient populations that may benefit most. The search for effective adjuvant therapies for colorectal cancer continues, and aspirin may yet play a role in improving outcomes for certain patients.