Colorectal cancer is one of the most common cancers in Norway, which also has one of the highest incidence rates in the world. Previous research has raised hopes that aspirin might reduce the risk of colorectal cancer returning after treatment. However, a large Scandinavian clinical trial led by Oslo University Hospital has found no such benefit for patients who had surgery for colorectal cancer that had spread to the liver.

Approximately 30 per cent of patients with colorectal cancer develop liver metastases during the course of their disease. Once the disease has spread, it is much more difficult to treat than primary colorectal cancer confined to the bowel.

Patients rarely die from the primary tumour itself. It is the metastatic disease that is usually life-threatening."

Sheraz Yaqub, Professor, University of Oslo and consultant hepatobiliary surgeon, Oslo University Hospital

For many patients, surgery offers the best chance of a cure."But even when we remove the tumours surgically, the cancer returns in more than half of patients," says Yaqub.

Previous studies have suggested a protective effect of aspirin

Previous observational studies have suggested that aspirin use after colorectal cancer treatment may be associated with a lower risk of recurrence and improved survival. More recent randomised trials have investigated whether aspirin can provide such benefits, particularly in patients with specific molecular alterations in their tumours.

Yaqub and his colleagues wanted to find out whether aspirin could have the same preventive effect in patients whose colorectal cancer had spread to the liver. "We wanted to know whether we could prevent the cancer from returning by giving aspirin to these patients as well," Yaqub says.

The study has now been published in The Lancet Gastroenterology & Hepatology.

An inexpensive and widely available medicine

Aspirin has long been used to treat pain, fever and inflammation. Its potential to prevent cancer recurrence has therefore attracted considerable interest.

"Aspirin is inexpensive, widely available and has been used for more than a century. Its effects and side effects are well known, which made it an attractive candidate for preventing cancer recurrence," says Yaqub.

Could aspirin prevent recurrence after treatment for liver metastases?

The researchers conducted ASAC, a randomised, double-blind, placebo-controlled trial investigating whether aspirin could reduce the risk of recurrence after curative-intent treatment of colorectal cancer liver metastases.

A total of 466 patients were randomized at 14 hospitals in Norway, Sweden and Denmark. All had undergone treatment (surgery or local ablation) for colorectal cancer liver metastases. The participants were randomly assigned to receive either aspirin 160 mg daily or an identical placebo for up to three years.

"For most patients, the cancer returns within the first two years after surgery. That is why we followed participants for three years," says Yaqub.

No reduction in recurrence with aspirin

The researchers found that aspirin did not reduce the risk of the cancer returning, compared with placebo. Patients who received aspirin also had a lower overall survival rate, but this finding should be interpreted with caution. Serious adverse events were more common in the aspirin group. "We found no benefit from aspirin in preventing cancer recurrence in these patients. The finding of lower overall survival, together with higher frequency of serious adverse events also raise concerns," says Yaqub. "Our results show that aspirin should not be routinely recommended to prevent recurrence after curative-intent treatment of colorectal cancer liver metastases," he adds.

Why randomized trials matter

In an earlier study, Yaqub and colleagues linked information from the Norwegian Cancer Registry and the Norwegian Prescription Database. That registry-based study suggested that patients with colorectal cancer who were taking aspirin lived longer than those who were not.

However, studies based on health registries cannot show with certainty whether a treatment was the reason for the difference. "Registry studies can identify associations, but they cannot establish whether aspirin itself is responsible for improved survival. Randomised, placebo-controlled trials provide much stronger evidence about the effects of treatment," he explains.

Why might aspirin benefit some patients but not others?

The reasons are not yet clear, but differences in disease stage and tumour biology may play a role.

The ASAC trial was conducted alongside the Scandinavian ALASCCA trial. Both studies examined molecular changes in tumour tissue. The ALASCCA study found that aspirin reduced recurrence in some patients with localised colorectal cancer whose tumours carried specific alterations in the PI3K signalling pathway. In contrast, the ASAC trial found no benefit for patients who had been treated for colorectal cancer that had spread to the liver, including those with the molecular alterations examined in the study. "What works for one group of patients does not necessarily work for another. We cannot simply transfer results from patients with primary colorectal cancer to patients who have been treated for liver metastases," says Yaqub.

Do not stop taking aspirin without medical advice

The ASAC trial investigated the effect of starting aspirin after cancer treatment. Patients who were already taking aspirin were not eligible to take part. The findings therefore do not mean that people who already take aspirin for other medical reasons should stop treatment. "Patients who are already taking aspirin for cardiovascular disease or other medical indications should not stop treatment because of these findings. Any changes should be discussed with their treating physician," Yaqub says.