Potential Role For Metformin In Colorectal Cancer Chemoprevention

Taking metformin after polypectomy may reduce the risk of polyp recurrence in patients without diabetes

medwireNews: Compared with placebo, treatment with low-dose metformin significantly reduces the post-polypectomy risk of developing subsequent metachronous colorectal polyps or adenomas in patients without diabetes, find Japanese researchers.

In a commentary accompanying the research in The Lancet Oncology, Andrew Chan, from Massachusetts General Hospital and Harvard Medical School in Boston, USA, describes the results as “exciting”, writing that they “represent the first randomised controlled trial evidence of an effect of metformin on an established surrogate endpoint for cancer.”

Furthermore, he writes that the double-blind trial establishes “the anti-neoplastic efficacy of metformin in non-diabetic patients, refuting the notion that the association of metformin with lower cancer risk recorded in patients with diabetes is merely due to improved disease control.”

Researcher Atsushi Nakajima, from Yokohama City University School of Medicine, and colleagues explain that recent research indicates that metformin suppresses tumourigenesis and cancer cell growth by activating the AMPK enzyme, which downregulates the mTOR pathway critical for tumour cell metabolism. And preclinical studies in a nondiabetic mouse model suggest that metformin may protect against colorectal cancer.

In this phase III trial, 71 nondiabetic patients who had undergone colorectal polypectomy were randomly assigned to receive oral metformin 250 mg once a day for a year, while their 62 counterparts were given placebo.

A follow-up colonoscopy after a year showed that the incidence of total polyps, including hyperplastic polyps and adenomas, and of adenomas alone was significantly lower in the metformin than in the placebo group, at 38.0% versus 56.5% and 30.6% versus 51.6%, respectively. The corresponding risk ratios were 0.67 and 0.60.

Six patients in the metformin arm and eight in the placebo arm experienced an adverse event, all of which were grade 1. The most common side effects among metformin-treated participants were constipation (4%) and rash (3%).

A median of 91% of patients in the metformin group and 92% in the placebo arm adhered to treatment, report the study authors.

And they conclude: “For practical chemoprevention, a drug generally needs to have the following attributes: safety, good compliance, cost-effectiveness, and a clear mechanism of action. Metformin meets these criteria.”

However, the commentator notes several limitations – such as the small cohort comprising patients at high risk of recurrence and the lack of data on other conventional doses of metformin. He also points out that patients did not undergo a clearing colonoscopy prior to randomisation, therefore, “some of the polyps found on the 1-year colonoscopy might have included prevalent lesions missed at the baseline examination rather than incident tumours.”

“These issues notwithstanding, these exciting findings should sustain optimism that metformin might have a role in cancer prevention, thereby encouraging and informing the development of more definitive randomised controlled trials”, Andrew Chan concludes.

Reference

Higurashi T, Hosono K, Takahashi H, et al. Metformin for chemoprevention of metachronous colorectal adenoma or polyps in post-polypectomy patients without diabetes: a multicentre double-blind, placebo-controlled, randomised phase 3 trial.Lancet Oncol; Advance online publication 2 March 2016. doi: http://dx.doi.org/10.1016/S1470-2045(15)00565-3

Chan AT. Metformin for cancer prevention: a reason for optimism.Lancet Oncol; Advance online publication 2 March 2016. doi: http://dx.doi.org/10.1016/S1470-2045(16)00006-1  

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