Favorable safety outcomes of a perioperative propranolol and etodolac regimen in cancer patients in four randomized controlled trials

Background: The perioperative use of the β-adrenergic blocker, propranolol, and/or the semi-selective COX-2 inhibitor, etodolac, has improved biomarkers of cancer metastasis in several small randomized controlled trials (RCTs). In colorectal cancer (CRC) patients, the combined regimen showed potential to improve disease-free survival (DFS). Methods: We report data from our four RCTs including 148 patients with breast (n = 38), colorectal (n = 34 & n = 46), and pancreatic (n = 30) cancers. Treatment began 5 days pre-operatively, and continued for 5-30 postoperatively. Propranolol (slow-release) was initiated at 20 mg twice daily (b.i.d), increased to 80 mg b.i.d on surgery day, and gradually decreased thereafter to 20 mg b.i.d. Etodolac was provided at 400 mg b.i.d. The primary endpoints were perioperative safety outcomes, including adverse events (AEs) up to 30-day postoperatively, and 16 blood indices. Secondary outcomes were long-term oncological outcomes of 8-year DFS and overall survival (OS). Results: Bradycardia occurred in 12% of treated vs. 3% of placebo patients (p = 0.057), and was easily resolved by temporary withholding β-blockade. Weakness, nausea, pain, infection, bleeding, leakage, tissue-healing, or death were not significantly affected. Drug treatment promoted eosinophils in pancreatic cancer patients (p = 0.015), increased potassium (p = 0.013), and decreased albumin (p = 0.016) in CRC patients; however, these effects did not remain significant after false discovery rate (FDR) correction. In CRC, treatment improved 8-year DFS (2/15 vs. 9/18, p = 0.034), although this exploratory analysis was underpowered. Conclusion: These findings suggest the safety of this inexpensive and easy-to-implement perioperative propranolol and etodolac regimen in patients participating in these RCTs. Clinical Trial Registration: https://clinicaltrials.gov/study/NCT00502684, https://clinicaltrials.gov/study/NCT00888797, https://clinicaltrials.gov/study/NCT03919461, https://clinicaltrials.gov/study/NCT03838029, identifier NCT00502684, NCT00888797, NCT03919461, NCT03838029.