Randomized clinical intervention trial of acetylsalicylic acid secondary prevention in colorectal cancer

Acetylsalicylic acid (Aspirin) is a cheap and safe drug that may have a preventive effect against development of several types of cancer, particularly colorectal cancer (primary preventive effect). Experimental and clinical data indicate that the effect may be even more pronounced after surgery (secondary preventive effect). This clinical intervention trial aims to provide an answer to the question of whether there is a secondary preventive effect. We will examine the effect of treatment with acetylsalicylic acid following surgery of liver metastases from colorectal cancer (3 years of treatment). Disease free survival will be coupled with patient benefit and health economy analyses. If an effect of treatment is convincingly demonstrated this might benefit patients with colorectal cancer in the future as it may be relevant to treat patients with acetylsalicylic acid to reduce the risk of and/or time to recurrence. The first patient was enrolled in December 2017 at Oslo University Hospital. The study is a Scandinavian collaboration with participation from five university hospitals in Norway, six in Sweden, and three in Denmark. Joining forces with all the hepatobiliary surgical sites in Scandinavia will make it possible to include the estimated patients in this trial. Trial website gives continuously updates (www.asac.no). Last patient was included January 2022.

Although a tumor with activating mutations should be recognized as foreign by the immune system and eliminated, many cancer cells evade the immune system and are therefore selected and propagated. We have, as one tumor immune evasion mechanism, described how peripherally induced regulatory T cells express COX-2, secrete prostaglandin E2 (PGE2) and elicit the immunosuppressive cAMP pathway in effector T cells. Furthermore, we have shown in two clinical observational studies that PGE2 has a third role (in a ddition to its proliferative and angiogenic effects) in tumor immune evasion particularly in colorectal cancer (CRC) by suppressing tumor immunity and how the level of immune suppression this is linked to clinical outcome post-surgery. Hindering the immun e evasion in order to boost anti-tumor immunity is particularly important once the cancer is established, e.g. after cancer surgery. Here, we shall capitalize on our findings and progress to an interventional multi-centre, randomized clinical trial on sec ondary prevention of perturbing PGE2 signaling by COX inhibition in CRC patients with liver metastasis undergoing liver resection (interventional drug: acetylsalicylic acid (ASA), 160 mg OD, 3 years; design: randomised, placebo-controlled, 400 patients in each arm) and with disease recurrence, CRC-specific mortality and cost as endpoints (WP1). This will be accompanied by studies of Health-related Quality of Life and resource use to assess patient and societal benefits in both of the above (WP3). ASA inte rvention may have significant cost-effectiveness, but publicly funded studies are required for re-purposing of such a generic drug (no industry interest). [A parallel registry study on primary CRC patients (2007-11 cohort, Cancer Registry of Norway, CRC Clin.Reg.) coupled with the Norwegian Prescription Database to stratify on ASA users and non-users and assessing effect on the risk of disease recurrence (metastases) (WP2) is funded elsewhere.]