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.

IntroductionThe stressful pre-operative period exerts a profound impact on psychological, physiological and immunological outcomes. Oncological surgeries, in particular, elicit significantly higher stress responses than most other surgeries. Managing these responses through psychological interventions may improve long-term outcomes. The purpose of the current research was to review studies that have explored pre-operative psychological interventions in cancer patients in order to map the types of current interventions and provide an initial assessment of whether these interventions improved psychological, physiological, and/or immunological indices as well as long-term cancer outcomes.MethodsA systematic literature search for studies that included pre-operative psychological interventions in oncology patients was conducted, using the databases PubMed and Web of Science. Inclusion criteria included studies pertaining to oncological surgery in adults, study designs that included a clearly defined pre-operative psychological intervention and control group.ResultsWe found 44 studies, each using one of the following interventions: psychoeducation, cognitive interventions, relaxation techniques, integrated approaches. All the studies reported improved immediate post-operative psychological, physiological, and/or immunological outcomes. Only a few studies addressed long-term cancer outcomes, and only one reported improved survival.ConclusionsResearch on pre-operative interventions with cancer patients is missing systematic methods. Studies provide varying results, which makes it difficult to compare them and reach reliable conclusions. There is considerable heterogeneity in the literature regarding the specific intervention used, the timing of intervention, the characteristics of the patients studied and the outcome measures. In order to improve research in this field, including the measurement of long-term outcomes, we suggest some steps that should be taken in further research.

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Experimental and clinical studies have shown that the sympathetic nervous system (SNS) stimulates cancer progression and reduces the efficacy of oncological treatment. These effects may be reduced by pharmacological and psychotherapeutical approaches attenuating SNS tone. Therefore, it is necessary to identify those cancer survivors whose sympathetic modulation is excessively increased. For determination of SNS modulation, non-invasive method of heart rate variability (HRV) is widely used. In our study, HRV was determined from 5-min heartbeat recordings in healthy volunteers and in women with benign or malignant breast neoplasias, both in newly diagnosed patients and in women after initial treatment. We showed impaired cardio-vagal regulation in breast cancer patients (linear methods) and also found the increased sympathetic modulation indicated by the non-linear (the symbolic dynamics 0V%) parameter. This non-linear HRV analysis seems to be more sensitive than the linear one, indicating significant differences also in survivors after initial therapy in comparison to healthy controls. The lower sample entropy revealed reduced complexity in heart rate control in both breast cancer survivors groups. These findings suggest that HRV detection represents an inexpensive, easy, and reliable method for identification of those patients with breast cancer whose sympathetic modulation is significantly increased and in which the interventions, aimed at normalizing the balance in the autonomic nervous system (e.g. psychotherapy, biofeedback, treatment by β-blockers) may be the most effective.