Improving Cancer Survival Through Perioperative Attenuation of Adrenergic-Inflammatory Signaling

Oncological surgery is a life-saving intervention, yet aspects of the perioperative period, including the surgical procedure itself, also promote progression of metastatic disease. Perioperative inflammation and stress responses, mediated through the abundant secretion of prostaglandins (PGs) and catecholamines (CAs), are prominent factors driving many of the prometastatic effects of the perioperative period. PGs and CAs exert synergistic prometastatic impacts through similar intracellular molecular pathways (e.g., cAMP-PKA-NF-κB), acting upon the malignant tissue, antimetastatic immunity, and metastases microenvironment, each through several known mechanisms. Animal studies provide robust evidence that perioperative inhibition of CA and/or PG signaling reduce metastatic progression and increase postoperative survival rate, and indicate that a combined blockade approach is markedly advantageous, as each factor independently is sufficient to exert deleterious effects. Clinical retrospective studies, assessing the use of either nonsteroidal antiinflammatory drugs (NSAIDs) or beta blockers, are heterogeneous and have provided inconclusive results that are cancer- and context-specific. Randomized controlled trials that have concluded only recently assessed the effectiveness of perioperative separate or combined use of COX inhibitors and beta blockers. These studies provided promising results, indicating effectiveness in improving prometastatic biomarkers, but were underpowered to assess long-term cancer outcomes. The nonselective beta blocker propranolol and the semiselective COX2 inhibitor etodolac were employed in most of these recent clinical trials, and trial patients exhibited minimal-to-no adverse effects. Larger studies are needed to assess whether these agents improve disease-free survival and overall survival after cancer surgery, yet off-label perioperative use of these agents could already be considered in patients to reduce perioperative cancer risk.