Perioperative biobehavioral interventions to prevent cancer recurrence through combined inhibition of β-adrenergic and cyclooxygenase 2 signaling

Abstract

Evidence suggests that excess perioperative activation of the sympathetic nervous system and the consequent release of catecholamines (ie, epinephrine and norepinephrine) in the context of cancer surgery and inflammation may significantly facilitate prometastatic processes. This review first presents biomedical processes that make the perioperative timeframe pivotal in determining long-term cancer outcomes nonproportionally to its short duration (days to weeks). Then, it analyzes the various mechanisms via which the excess release of catecholamines can facilitate the progression of cancer metastases in this context by directly affecting the malignant tissues and by regulating, via indirect pathways, immunological and other mechanisms that affect metastatic progression in the tumor microenvironment and systemically. In addition, this review addresses the need to supplement β-adrenoreceptor blockade with cyclooxygenase 2 inhibition, especially during surgery and shortly thereafter, because similar mechanisms are simultaneously activated by surgery-induced inflammatory responses. Importantly, this review presents translational and clinical evidence showing that perioperative β-adrenoreceptor blockade and cyclooxygenase 2 inhibition can reduce the prometastatic process and cancer recurrence, and the clinical feasibility and safety of this approach are demonstrated as well. Lastly, alternative psychophysiological approaches to the use of β-adrenergic blockers are presented because a substantial portion of patients have medical contraindications to this pharmacological treatment. The adaptation of existing psychophysiological interventions to the perioperative period and principles for constructing new approaches are discussed and exemplified. Overall, pharmacobehavioral interventions, separately or in combination, could transform the perioperative timeframe from being a prominent facilitator of metastatic progression to an opportunity for arresting or eliminating residual disease, potentially improving long-term survival rates in cancer patients.

Keywords: adrenergic; cancer; cyclooxygenase 2 (COX2) inhibitor; metastases; perioperative; psychophysiological; psychosocial; stress response; surgery; β-blocker.

Figure 1.

Vicious stress-inflammatory cycle. Psychological stress (eg, fear and anxiety) leads to the release of Epi and NE by SNS nerve fibers and adrenal medulla. The release of Epi and NE promotes the metabolism of arachidonic acid, which leads to PG synthesis, which in turn induces inflammation and pain and leads to further SNS activation. The cAMP-PKA pathway is activated by both PGs and CAs; this leads to diverse prometastatic transcription factor activity (eg, through CREB and NFkB) in tumor cells and their micro-environment and, in various immune cells, promotes prometastatic tumor cell characteristics while reducing the host environment capacity for arresting metastasis. Together, these processes lead to successful tumor cell survival, EMT, migration, invasion into adjacent or distant tissue, inflammation, and angiogenesis, and this results in accelerated growth of metastases (for details, see the Perioperative Costimulatory and Synergistic Effects of CAs and PGs on Prometastatic Processes, Direct Effects of SIRs on Metastasis, and Indirect Effects of SIRs on Metastasis sections). CA indicates catecholamine; cAMP, cyclic adenosine monophosphate; CCL2, C-C motif chemokine ligand 2; COX, cyclooxygenase; CREB, cyclic adenosine monophosphate response element–binding protein; CTL, cytotoxic T cell; ECM, extracellular matrix; EMT, epithelial-to-mesenchymal transition; Epi, epinephrine; IL, interleukin; MMP, matrix metallopeptidase; NE, norepinephrine; NFkB, nuclear factor κB; NK, natural killer; PG, prostaglandin; PKA, protein kinase A; SNS, sympathetic nervous system; STAT, signal transducer and activator of transcription; TF, transcription factor; VEGF, vascular endothelial growth factor.