Reducing the Risk of Post-Surgical Cancer Recurrence: A Perioperative Anti-Inflammatory Anti-Stress Approach

Abstract

" We believe that surgery often increases post-surgical risk of cancer recurrence through at least two dormancy-related mechanisms that are triggered by neuroendocrine and paracrine stress-inflammatory responses (SIRs) to surgery. " First draft submitted: 16 November 2017; Accepted for publication: 30 November 2017; Published online: 6 April 2018Cancer is a worldwide health problem, and is the second leading cause of death in the USA [1]. Importantly, metastatic disease remains the major cause of cancer mortality, despite advances in early detection and therapeutic interventions that have improved survival rates in many types of cancer [1]. For example, 5-year survival rates can reach up to 95% in breast cancer (BC) patients and 90% in colorectal cancer (CRC) patients when the primary tumor (PT) is detected at a localized stage, but drop to approximately 25% and 13%, respectively, if the disease has spread to distant organs [1]. Thus, understanding the mechanisms involved in pro-metastatic malignant cell transformations and in metastatic progression bears potential clinical advantages through the development of novel anti-metastatic therapeutic approaches.Here, we discuss the critical impact of the perioperative period on long-term cancer outcomes. This delicate period can act to destabilize the balance between pro-and anti-metastatic signals, potentially creating a 'snowball effect', ultimately leading to metastatic outbreak. On the other hand, the perioperative period can be favorable as it presents a window of opportunity to reverse the balance toward disease arrest, through promoting a fast-growingto-dormant transformation and/or preventing an escape from cancer dormancy in residual malignant disease. This critical period remains mostly unexploited clinically, and we suggest herein that a perioperative treatment that results in β-adrenergic blockade and COX2 inhibition will tip the scale toward disease arrest, as indeed suggested by two Phase II biomarker clinical trials we recently conducted, and by clinical observational studies. Non-proportional high impact for the short perioperative time-frame on metastatic progression & outbreakSurgery for the removal of a PT is a life-saving procedure in most cancer types. 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. These include: cessation of tumor cells shedding into the circulation and lymphatic system, elimination of pro-metastatic factors secreted by the PT (e.g., IL-6, IL-8, VEGF), and the termination of immune-suppressive effects of the excised PT. These multiple pro-and anti-metastatic processes occur simultaneously during the short perioperative period, and t...

Systemic Immune-Inflammation Index (SII) Predicts Poor Survival in Pancreatic Cancer Patients Undergoing Resection

“…Investigating 43 Recently, Haldar and Ben-Eliyahu critically discussed the impact of perioperative β-adrenergic blockade and COX2 inhibition on cancer outcomes. 45 Thus, patients with resectable PDAC who have elevated preoperative SII might benefit from anti-inflammatory and/or antiimmunotherapy prior and after surgery. Even though the results of the present study demonstrate that the SII is an independent prognostic factor in patients with PDAC undergoing resection, it has several limitations.…”

Perioperative Intervention by β-Blockade and NF-κB Suppression Reduces the Recurrence Risk of Endometriosis in Mice Due to Incomplete Excision

“…Despite such a short time period, several studies have reported that this period is critical in determining the risk of postoperative metastatic diseases in cancer in animal studies. 27,65,66 Two recently published clinical trials demonstrate that perioperative inhibition of COX-2 and b-adrenergic signaling provides a safe and effective strategy for inhibiting multiple cellular and molecular pathways related to metastasis and disease recurrence in breast cancer. 28,67 In this study, we used Andro, instead of a specific COX-2 inhibitor, simply because this drug, approved for over-thecounter medication in China for minor upper respiratory tract infection, has several desirable features.…”

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

“…Accordingly, we and others have suggested the perioperative period as a window of opportunity for arresting postsurgical metastasis. 36 Evidence from animal studies lends strong support for this claim and shows that surgery per se enhances tumor cell retention in the lungs, liver, and other target organs, 22,24,[37][38][39][40] promotes the development of preexisting micrometastases, and increases the postsurgical metastatic load. These processes and the consequent neuroendocrine SIRs that they elicit have been shown to affect tumor cells directly and indirectly through, for example, their impacts on immunity and the malignant microenvironment.…”

“…12 The fact that these relatively short-acting processes (in terms of the disease course) are capable of inflicting long-term cancer outcomes, as detailed later, indicates that the short perioperative period is a sensitive and critical timeframe in which metastatic disease may either be promoted or inhibited by a variety of physiological perturbations. 36 Evidence from animal studies lends strong support for this claim and shows that surgery per se enhances tumor cell retention in the lungs, liver, and other target organs, 22,24,[37][38][39][40] promotes the development of preexisting micrometastases, and increases the postsurgical metastatic load. 24,22 Interestingly, the elimination of the primary tumor may either suppress or enhance progression of minimal residual disease (MRD) 42 by eliminating various progrowth and/or antigrowth and angiogenic factors systemically secreted by the primary tumor.…”