Exploiting the critical perioperative period to improve long-term cancer outcomes

Abstract

Evidence suggests that the perioperative period and the excision of the primary tumour can promote the development of metastases—the main cause of cancer-related mortality. This Review first presents the assertion that the perioperative timeframe is pivotal in determining long-term cancer outcomes, disproportionally to its short duration (days to weeks). We then analyse the various aspects of surgery, and their consequent paracrine and neuroendocrine responses, which could facilitate the metastatic process by directly affecting malignant tissues, and/or through indirect pathways, such as immunological perturbations. We address the influences of surgery-related anxiety and stress, nutritional status, anaesthetics and analgesics, hypothermia, blood transfusion, tissue damage, and levels of sex hormones, and point at some as probable deleterious factors. Through understanding these processes and reviewing empirical evidence, we provide suggestions for potential new perioperative approaches and interventions aimed at attenuating deleterious processes and ultimately improving treatment outcomes. Specifically, we highlight excess perioperative release of catecholamines and prostaglandins as key deleterious mediators of surgery, and we recommend blockade of these responses during the perioperative period, as well as other low-risk, low-cost interventions. The measures described in this Review could transform the perioperative timeframe from a prominent facilitator of metastatic progression, to a window of opportunity for arresting and/or eliminating residual disease, potentially improving long-term survival rates in patients with cancer.

Cancer cells become less deformable and more invasive with activation of β-adrenergic signaling

“…For example, accumulation of endogenous epinephrine or norepinephrine in the tumor parenchyma might enable cancer cells to become stiffer and to generate increased traction forces so that they can survive and move through a stiffer extracellular matrix (Goldstein et al, 2003;Thaker et al, 2006). In situations of stress, such as during cancer diagnosis or surgery (Horowitz et al, 2015), elevated levels of catecholamines could possibly result in an increased occlusion of circulating cells and increased invasion of adhered cells into distant tissues, thereby contributing to increased metastasis. Stiffer cancer cells might be more likely to occlude the narrow capillaries of metastatic target organs such as the lung, which could enhance the probability of establishing a secondary metastatic site, and thus accelerate the spread of cancer.…”

Reducing the risk of post-surgical cancer recurrence: a perioperative anti-inflammatory anti-stress approach

“…However, the short perioperative period, defined as the days before to weeks post tumor excision, was suggested to facilitate the formation of new metastases and to promote the growth or outbreak of preexisting micrometastases, through numerous prometastatic, pro-angiogenic and immune-suppressive mechanisms [2]. On the other hand, surgical removal of the PT was also suggested to prevent or regress metastatic progression through various mechanisms.…”

“…The role of catecholamines & prostaglandins in post-surgical metastatic risk Catecholamines (CAs) and prostaglandins (PGs; specifically PGE2), which are abundant perioperatively, were repeatedly shown to mediate numerous pro-metastatic effects of stress and surgery, through various mechanisms [2,7]. For example, these ligands were shown to regulate the secretion of pro-and anti-inflammatory soluble factors (e.g.…”

Practical Management of Cancer Cachexia

“…Gustafsson et al have recently shown that cancer patients receiving at least 70% of the ERAS programme in the perioperative period have a significant 5-year survival advantage [31]. Therefore, the perioperative period is a window of opportunity to influence long-term survival of cancer patients, in which nutrition and particularly omega-3 fatty acids play a role [32]. Therefore, healthcare professionals should be informed that what they are doing, or not doing, today, will have an impact tomorrow.…”