Aspirin in colorectal cancer – has it still a place in secondary prevention?

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 non-steroidal anti-inflammatory drug (NSAID) lowers cancer mortality risk by 29–47% and reduces overall mortality risk in patients after diagnosis (Curr Colorectal Cancer Rep. 2016;12:27–34).

Despite a lack of clarity on aspirin’s mechanism of action in preventing primary or recurrent CRC, several studies have demonstrated that it plays a role in reducing the number and size of adenomatous polyps, which are correlated with a higher risk of malignant transition to cancer (Cancer Biol Ther. 2022;23:446–461). Following curative-intent treatment of localised disease, a potential use of daily low-dose aspirin in the adjuvant setting has been speculated 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 about the benefit of aspirin in secondary CRC prevention (Gastroenterology. 2016;150:114–122.e4; Lancet. 2018;392:2583–2594; Gut. 2012;61:255–261).

Eagerly awaited by oncologists who were hoping to close the debate on whether aspirin should be considered part of the adjuvant approach to CRC treatment, findings from the ASCOLT trial presented at the ESMO Congress 2023 (Madrid, 20–24 October) were negative (LBA29). The study showed no superior benefit for the anti-inflammatory agent compared with placebo in terms of disease-free survival at 5 years in patients with Dukes’ C and high-risk Dukes’ B CRC (20.6% versus 22.8%, respectively; hazard ratio [HR] 0.91; 95% confidence interval [CI] 0.73–1.13; p=0.38).

Despite being negative, these results nevertheless provide some useful insights to design further trials to investigate a potential role for adjuvant aspirin. While ASCOLT was a well-designed study, it did not capture the heterogeneity of CRC and so far, it has not provided evidence for molecular features that show a distinct benefit for subgroups of patients. Emerging data suggest that tumour PIK3CA mutation status, expression of cyclo-oxygenase-2 (COX2) and human leukocyte antigen class I, along with certain germline polymorphisms, may all help to identify individuals who stand to gain the most. 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). Also, a beneficial trend for cancer-related survival has been observed with regular use of aspirin post-diagnosis in patients with PIK3CA-mutated CRC (N Engl J Med. 2012;367:1596–1606).

Shall we continue to investigate aspirin in the adjuvant setting? A lesson to learn from this negative study is that aspirin should not be used in an unselected population to reduce the risk of all types of CRC. It is not a one-size-fits-all therapy, and its harmful effects should be taken into consideration. In a meta-analysis of randomised trials of low-dose aspirin versus controls, the estimated incidence of a major gastrointestinal bleed was 1.1 event per 1,000 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 should be carefully monitored, and their incidence counterbalanced against efficacy. Consequently, the recommendation of aspirin for all patients with CRC should still 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. The prevention of cancer from occurring in the first place or from recurring after treatment, is not usually the result of a single action, but the contribution of each individual factor matters, and long-term adjuvant aspirin could be important in regulating a key factor in some individuals.

Many other trials are still ongoing and could provide more definitive answers, such as Add-Aspirin (NCT02804815), ASPIRIN (NCT02301286), ALASCCA (NCT02647099) and for individuals with PIK3CA-mutated colon cancer only, SAKK 41/13 – Aspirin (NCT02467582).