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. Cancer 2019;125:45-56.

Chronic Stress Promotes Cancer Development

“…At the same time, we suggest that stress hormones should be used with caution, especially glucocorticoids (77) to treat patients with cancer and related complications. Finally, it is notable that β-blockers have been relatively widely used in clinical research (78,79) and are often administered as adjuvants in cancer treatment in recent years [(80-84); Table 2], especially in breast cancer treatment. Though other related drugs have shown promise for treating cancer, there remains insufficient evidence for their clinical application.…”

Surgical stress and cancer progression: the twisted tango

“…In another trial, perioperative β-blockade significantly inhibits recurrence and metastasis of triple-negative breast cancer [135]. Patients undergoing radical mastectomy surgery exhibit increased levels of circulating epinephrine, norepinephrine, PGE 2, peripheral FOXP3 mRNA, and Treg populations; daily propranolol (60 mg) decreased Treg elevation, underlining surgery-induced catecholamines promotion of Tregs [136, 137]. Propranolol also inhibits thromboxane synthesis and reduces platelet aggregation, further contributing to its anti- metastatic properties [154].…”

Gαs-coupled receptor signaling and sleep regulate integrin activation of human antigen-specific T cells

“…The findings are also important for understanding immunosuppression present in a variety of pathologies characterized by increased levels of adenosine (e.g., hypoxia, sleep apnea, and tumor growth), catecholamines (e.g., chronic stress and sleep disturbances), or PGs (e.g., tumor growth and malaria) (Kilunga Kubata et al, 1998; Hoskin et al, 2008; Sloan et al, 2010; Brudvik and Taskén, 2012). Furthermore, the results suggest that Gα s -coupled receptors of catecholamines, PGs, and adenosine might constitute immune checkpoint inhibitors, which could be manipulated for therapeutic purposes in various diseases, such as cancer (Leone et al, 2015b; Ohta, 2016; Ricon et al, 2019).…”