COX2 Inhibitor and Beta Blocker Combo to Reduce CRC Metastasis?

Sharon Worcester

August 18, 2020

Perioperative administration of the beta blocker propranolol and the COX2 inhibitor etodolac significantly improved biomarkers of malignancy and metastasis and was associated with a reduction in recurrence rates after colorectal tumor resection in a randomized, placebo-controlled study.

The study included 34 patients (median age, 58 years) who underwent colorectal tumor resection in Israel. It was published online June 13 in Cancer.

On intent-to-treat analysis, 3-year recurrence rates were 12.5% in the treatment group (n = 16) and 33.3% in the placebo group (n = 18). This difference was not statistically significant (P = .239). However, in protocol-compliant patients, the respective rates were 0% and 29.4% (P = .054), but the study was not powered to assess drug effects on recurrence and survival, the researchers note.

With regard to tumor molecular markers, results showed that the combination reduced epithelial-to-mesenchymal transition and tumor-infiltrating CD14-positive monocytes and CD19-positive B cells. There was an increase in tumor-infiltrating CD56-positive natural killer cells, Rita Haldar, MA, of Tel Aviv University, Israel, and her colleagues note.

Transcriptional activity analysis showed a favorable effect on 12 of 19 potential colorectal cancer–related transcription factors, with alterations that have previously been linked with improved outcomes.

In the trial, the patients in the treatment group received oral etodolac 400 mg twice daily for 20 perioperative days beginning 5 days before surgery and oral propranolol at twice-daily doses of 20 mg for the 5 days before surgery, 80 mg on the day of surgery, 40 mg on postoperative days 1 to 7, and 20 mg for the last 7 days.

The treatments were well tolerated. Minor complications occurred at similar rates in the treatment and placebo groups, note the researchers. No severe surgical complications occurred in the treatment group; one occurred in the placebo group.

The findings indicate that the treatment protocol is "empirically safe, easy to administer, and inexpensive and has overall favorable molecular impacts on tumor tissues," the researchers conclude.

Data from the study provide a strong rationale for future trials powered to assess the impact of this combination on disease-free and overall survival in patients with colorectal cancer.

"Haldar et al should be applauded for their steadfast pursuit of repurposed drugs for the treatment of cancer," Michael Low, MD, and his colleagues at Morningside Center for Innovative and Affordable Medicine at Emory University, Atlanta, Georgia, write in an accompanying editorial.

The concept of using perioperative interventions "to alter the deleterious effects of surgery" is not new, and evidence of potential benefit is abundant, the editorialists note.

The focus of the current study on beta-adrenergic blockade and COX2 inhibition is supported both by the agents' known suppressive effects on relevant pathways and by preclinical data, the editorialists write.

The study is limited by several factors, including small sample size, patient-reported compliance, and a failure to account for use of chemotherapy. The editorialists emphasize that use of these agents in the perioperative period "is of paramount importance and may have long-lasting antitumoral effects." They hope "that larger trials focusing on these and other agents will soon prove that to be true."

The study was supported by an Israel Science Foundation grant. The authors and Lowe have disclosed no relevant financial relationships.

Cancer. Published online June 13, 2020. Abstract, Editorial

Sharon Worcester is a staff journalist for MDedge News, part of the Medscape Professional Network.

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