Improving Cancer Survival Through Perioperative Attenuation of Adrenergic-Inflammatory Signaling

The Perioperative Period—An Underutilized “Window-of-Opportunity” to Prevent Metastatic Disease

The occurrence of metastatic disease is the leading cause of death in most patients with cancer. Accumulating evidence suggests that the perioperative period, days to weeks before and after surgery, is a critical time frame in which multiple factors profoundly affect initiation, progression, and/or elimination of metastases, providing a critical window of opportunity to prevent metastatic disease. Surgery is the primary life-saving therapeutic approach for many patients with cancer. However, even after successful surgery, minimal residual disease (MRD) in the form of scattered single tumor cells and/or micrometastases are evident in a substantial portion of patients. Additionally, several aspects of oncological surgery have been shown or suggested to promote metastasis, including: (i) increased secretion of stress hormones ^, ; (ii) local and systemic inflammation ^, ; (iii) shedding of tumor cells into the circulation ^, ; (iv) blood transfusions ^, ; (v) hypothermia ; and (vi) use of specific anesthetic/analgesic agents ^{, ,} (e.g., intravenous lidocaine and propofol-TIVA are potentially preferred approaches in colorectal and lung cancers). Specifically, these processes act directly on tumor cells and promote their capacity to survive, extravasate, migrate, seed, and release proangiogenic factors and additional progrowth/prometastatic factors while inhibiting a patient’s antimetastatic immune response. These processes are hypothesized to act synergistically on preexisting micrometastases and on isolated tumor cells scattered at the time of surgery, and thereby catalyze cancer recurrence that may not become evident for months or years following surgery when metastases reach a detectable size. For the patient receiving cancer resection surgery, the perioperative period thereby represents a vulnerability to cancer recurrence, which also provides an opportunity for effective intervention.

Clinical examples indicate that the inhibition of prometastatic perioperative processes can improve long-term cancer outcomes, indicating the nonproportional high impact of this short timeframe, specifically: (i) adherence to Enhanced Recovery After Surgery (ERAS) protocols in colorectal cancer (CRC) surgery ^, ; (ii) enhancing perioperative immunity through use of short preoperative interleukin-2 (IL-2) treatment in colorectal and pancreatic cancer ^, ; and (iii) perioperative hormone (progesterone) therapy in patients with breast cancer (BC), have all been shown to improve long-term cancer outcomes. Such clinical trials suggest that brief, targeted perioperative therapies could offset perioperative prometastatic processes, ultimately improving cancer survival. Additional therapies under investigation include inhibition of neutrophil extracellular trap (NET) formation and the use of neuroaxial anesthesia to reduce surgical stress. ^, Taken together, current evidence suggests that short-perioperative interventions (some already part of best practice guidelines ^, ) may improve patients’ long-term survival following cancer surgery.

As elaborated later, driving many of the prometastatic effects of the perioperative period is the abundant release of inflammatory and stress-related hormones that accompanies surgery. Prominent among these are prostaglandins (PGs) and catecholamines (CAs; epinephrine, EPI; norepinephrine, NE). Both PGs and CAs have been consistently shown in animal models and clinical trials to promote metastasis through their perioperative impact on tumor cells and immunity. The effects of inflammation, a hallmark of cancer, on cancer progression were noted over a hundred years ago, and the deleterious effects of CAs on cancer progression have also been thoroughly documented during the last two decades. ^, More recently, perioperative care has been dominated by ERAS programs designed to maximize short-term clinical recovery and have been utilized with great success. However, for the patient with cancer, a focus must also be placed on limiting the adrenergic-inflammatory response to reduce perioperative vulnerability to cancer metastasis, thereby improving long-term survival.

In this chapter, we (i) provide evidence for the importance of synergistically addressing inflammatory and adrenergic stress responses to surgery in order to reduce the risk for postsurgical metastatic disease and (ii) discuss how this may be achieved with simple and readily available clinical therapies.

Perioperative Stress-Inflammatory Responses: the Prometastatic Edge of the Sword

During the last three decades, translational ^{, ,} and clinical research ^{, ,} has shown that the perioperative secretion of PGs and CAs induced by anxiety, tissue damage, pain, and a variety of surgery-related procedures affects cancer cells directly and further promotes metastasis through their impact on immunity and the cancer microenvironment ^{, , ,} (reviewed in Horowitz et al., 2015 ). Importantly, PGs and CAs (i) copotentiate each other’s synthesis and secretion and (ii) their impact eventually converges on the same intracellular molecular pathways (e.g., cAMP-PKA), establishing a synergistic inflammatory-stress response (ISR) to surgery. ISRs drive cancer cells’ epithelial-to-mesenchymal transition (EMT), migration, motility, survival, invasiveness, and angiogenesis, as well as suppress anti metastatic immune activities. ^, The effects of these ISRs, mediated also through PGs and CAs, could transform a life-saving operation into a double-edged sword, excising the malignant tissue but increasing the risk of recurrence.

Inflammatory and Stress Responses Mutually Potentiate Each Other

Although stress responses and inflammatory responses are triggered separately, they also potentiate each other, creating an integrated ISR. CAs are secreted systemically (EPI) and locally released (NE) in response to sympathetic nervous system (SNS) activation due to stress and/or tissue damage. ^, Tissue damage also leads to the release of arachidonic acid, which is eventually metabolized by COX enzymes to synthesize PGs. SNS activation, through adrenergic signaling, promotes the metabolism of arachidonic acid and facilitates the synthesis of PGs. In vivo exposure to chronic stress and in vitro exposure to EPI leads to upregulation of COX2 expression in cancer cell lines and in macrophages, ^, and to increased production of PG-E2 ³⁹ (the most abundant PG) and proinflammatory cytokines such as IL-6. Importantly, adrenergic signaling can also lead to changes in lymphatic structure and flow, ^, and to recruitment of immune cells from the spleen and bone marrow into the circulation, modulating their activity in a manner that may potentiate proinflammatory responses. Peripheral inflammatory processes initiated by PG synthesis and mediated by cytokines crossing the blood–brain barrier can induce central nervous system (CNS) neuroinflammation and is known to increase and sustain adrenergic signaling. In addition, proinflammatory cytokines (e.g., IL-6) can activate nociceptors, leading to local secretion of NE, and sustained pain can induce anxiety and systemic release of EPI. Taken together, inflammatory and adrenergic signaling copotentiate each other in a manner that can lead to a self-perpetuating cycle of increasing inflammatory-adrenergic signaling (see Fig. 9.1 ).