Neuroimmunology Research Unit, Department of Psychology, Tel Aviv University, Tel Aviv, Israel.
Clin Cancer Res. 2012 Sep 15;18(18):4895-902. doi: 10.1158/1078-0432.CCR-12-1087. Epub 2012 Jul 2.
Surgery is a crucial intervention in most cancer patients, but the perioperative period is characterized by increased risks for future outbreak of preexisting micrometastases and the initiation of new metastases-the major cause of cancer-related death. Here we argue that the short perioperative period is disproportionately critical in determining long-term recurrence rates, discuss the various underlying risk factors that act synergistically during this period, and assert that this time frame presents an unexplored opportunity to reduce long-term cancer recurrence. We then address physiologic mechanisms that underlie these risk factors, focusing on excess perioperative release of catecholamines and prostaglandins, which were recently shown to be prominent in facilitating cancer recurrence through their direct impact on the malignant tissue and its microenvironment, and through suppressing antimetastatic immunity. The involvement of the immune system is further discussed in light of accumulating evidence in cancer patients, and given the recent identification of endogenously activated unique leukocyte populations which, if not suppressed, can destroy autologous "immune-resistant" tumor cells. We then review animal studies and human correlative findings, suggesting the efficacy of blocking catecholamines and/or prostaglandins perioperatively, limiting metastasis and increasing survival rates. Finally, we propose a specific perioperative pharmacologic intervention in cancer patients, based on simultaneous β-adrenergic blockade and COX-2 inhibition, and discuss specific considerations for its application in clinical trials, including our approved protocol. In sum, we herein present the rationale for a new approach to reduce long-term cancer recurrence by using a relatively safe, brief, and inexpensive intervention during the perioperative period.
手术是大多数癌症患者的重要治疗手段，但围手术期存在较高的风险，容易导致先前存在的微转移灶的复发，并引发新的转移灶——这是癌症相关死亡的主要原因。在这里，我们认为围手术期的短暂时间对确定长期复发率具有不成比例的重要性，讨论在此期间协同作用的各种潜在风险因素，并断言这段时间提供了一个尚未开发的机会，可以降低长期癌症复发的风险。然后，我们将探讨这些风险因素的生理机制，重点关注围手术期过量释放的儿茶酚胺和前列腺素，最近的研究表明，它们通过直接影响恶性组织及其微环境以及抑制抗转移免疫，在促进癌症复发方面发挥着重要作用。鉴于癌症患者积累的证据，我们进一步讨论了免疫系统的参与，以及最近发现的内源性激活的独特白细胞群体，如果不加以抑制，这些白细胞群体可能会破坏自身的“免疫抵抗”肿瘤细胞。然后，我们回顾了动物研究和人类相关性研究的结果，这些研究表明，围手术期阻断儿茶酚胺和/或前列腺素具有疗效，可以限制转移并提高生存率。最后，我们基于同时进行的β肾上腺素能阻断和 COX-2 抑制，提出了一种针对癌症患者的特定围手术期药物干预措施，并讨论了其在临床试验中的具体应用考虑因素，包括我们的已批准方案。总之，我们在此提出了一种新方法的基本原理，即在围手术期通过相对安全、短暂和廉价的干预来降低长期癌症复发的风险。
