Aspirin in colorectal cancer: does it still have a place in secondary prevention?
The negative results of the ASCOT trial should not deter researchers from investigating the drug’s potential in some molecularly distinct subgroups.
The adjuvant use of aspirin has been investigated in many trials for the secondary prevention of colorectal cancer (CRC), based on epidemiological data showing that the nonsteroidal anti-inflammatory drug (NSAID) reduces the risk of cancer mortality by 29% to 10%. 47% and reduces overall mortality and mortality risk in patients after diagnosis ( Curr Colorectal Cancer Rep . 2016;12:27–34).
Despite the lack of clarity regarding the mechanism of action of aspirin in the prevention of primary or recurrent colorectal cancer (CRC), several studies have shown that it plays a role in reducing the number and size of adenomatous polyps , which are correlate with an increased risk of malignant transition to cancer ( Cancer Biol Ther . 2022;23:446–461).
Following curative-intent treatment of localized disease, there has been speculation about a potential use of daily low-dose aspirin as an adjuvant to prevent the development of metachronous metastatic CRC, which occurs in up to 14-34% of patients ( Cancer Epidemiol .2014);38:448–454; J Clin Med . 2023;12:2072). However, studies conducted so far have reported conflicting results on the benefit of aspirin in the secondary prevention of CRC ( Gastroenterology . 2016;150:114–122.e4; Lancet . 2018;392:2583–2594; Gut . 2012 ;61:255– 261).
Eagerly awaited by oncologists eager to close the debate on whether aspirin should be considered part of the adjuvant approach in the treatment of CRC, the results of the ASCOLT trial presented at the ESMO 2023 Congress (Madrid, October 20-24) were negative ( LBA29). The study did not show any superior benefit for the anti-inflammatory agent compared to placebo in terms of 5-year disease-free survival in patients with high-risk Dukes C and Dukes B CRC (20.6% versus 22.8%, respectively; risk index). [HR] 0.91; 95% confidence interval [CI] 0.73-1.13; p=0.38).
Although negative, these results provide some useful ideas for designing additional trials to investigate a potential role for adjuvant aspirin. Although ASCOLT was a well-designed study, it did not capture the heterogeneity of colorectal cancer (CRC) and, so far, has not provided evidence of molecular characteristics showing a distinct benefit for subgroups of patients. Emerging data suggest that tumor PIK3CA mutation status, cyclooxygenase-2 (COX2) and human leukocyte antigen class I expression, along with certain germline polymorphisms, may help identify individuals who they can earn more.
In previous trials, COX2 inhibitors and NSAIDs such as aspirin have been shown to be active in reducing mortality in CRC in some subsets of patients, for example when the PIK3CA mutational pathway is involved (Clin Oncol (R Coll Radiol 2016;28:317–326; Hosp Pharm . 2020;55:168–180). Furthermore, a beneficial trend for cancer-related survival has been observed with regular aspirin use after diagnosis in patients with CRC with PIK3CA mutation ( N Engl J Med . 2012;367:1596–1606).
Will we continue to investigate aspirin in the adjuvant setting?
One lesson to be learned from this negative study is that aspirin should not be used in an unselected population to reduce the risk of all types of colorectal cancer (CRC). It is not a one-size-fits-all therapy and its harmful effects must be taken into account . In a meta-analysis of randomized trials of low-dose aspirin versus controls, the estimated incidence of major gastrointestinal bleeding was 1.1 events per 1000 person-years (odds ratio 1.55, 95% CI 1.27–1.90). ; p<0.001) ( Clin Gastroenterol Hepatol 2011;9:762–768.e6). The side effects of aspirin must be carefully monitored and their incidence counterbalanced by their effectiveness.
Consequently, the recommendation of aspirin for all patients with CRC should be approached with caution and its use limited to clinical trials. Although we do not expect a large proportional decrease in the incidence of CRC relapses with aspirin, this agent could still play a role in secondary prevention. Preventing cancer in the first place or its recurrence after treatment is usually not the result of a single action, but the contribution of each individual factor is important, and long-term adjuvant aspirin could be important in regulating a key factor in cancer in some individuals.
Many other trials are still ongoing and could provide more definitive answers, such as Add-Aspirin (NCT02804815), ASPIRIN (NCT02301286), ALASCC A (NCT02647099) and for people with colon cancer with a PIK3CA mutation only, SAKK 41/13 – Aspirin (NCT02467582).
Discussed summary:
Chia JW, et al. Aspirin after standard adjuvant therapy for colorectal cancers (ASCOLT) – An international, phase III, randomized, placebo-controlled trial. ESMO Congress 2023, LBA29. Proffered Paper Session 2 – Gastrointestinal tumors, lower digestive, 10.23.2023, h. 08:30 – 10:00, Barcelona Auditorium – Hall 9
