Anesthesia and Cancer Recurrence: Is the Balance of Evidence Shifting?

In the last decade, much has been published in the anesthesia literature regarding the potential of anesthetic interventions (primarily epidural and regional analgesia and, to a lesser extent, perioperatively administered drugs) to attenuate recurrence after surgical removal of cancerous tumors. An initial report of the ability of thoracic paravertebral block to reduce cancer recurrence in patients who underwent breast cancer surgery was soon followed by similar results in patients with prostate and colorectal cancers. The potential importance of these findings sparked many subsequent studies (mostly retrospective reviews) of intraoperative anesthetic management of patients undergoing surgery for various types of cancer. These either showed mixed results or did not substantiate the earlier positive findings. For example, a recent meta-analysis on the use of epidurals showed a potential benefit in overall survival especially among patients undergoing colorectal surgery but failed to demonstrate any improvement in recurrence-free survival. As long as the available data are retrospective, these studies will be open to bias and confounding and hence should be interpreted with caution. Prospective trials are required to shed light on this subject, and several are under way. How could anesthetic management during the relatively brief phase of surgery affect long-term outcomes? This potential has to do with how a tumor develops, which turns out to be a very complex process. Epigenetic and genetic alterations and imbalances between promoter and suppressor genes are regarded as the progenitors of malignant cell transformation. As a result, a new cell develops, bearing a new genetic makeup and with unlimited replication capabilities: a cancer cell. It surrounds itself with a microenvironment that provides for growth and shelter and that forms a starting block for invasion and metastasis. To counteract this intrusion, highly sophisticated blood sentinels, the cells of the immune system, recognize the site of invasion and attempt to destruct the cancer cells and terminate the invasion process. This recognition and destruction of nonself cells by the immune system represent the primary defense mechanism against cancer. However, the immune system is not always able to fully protect against cancer. In some instances, cell replication intensifies, new surface antigens are exposed, the elimination capability of the immune system is overwhelmed, cancer cells escape their dormant state, and an overt tumor develops. However, even in that setting, the immune system has an important feature that becomes highly important in the surgical setting: memory. Given this natural history of cancer development, the leading hypothesis for the benefits of epidural analgesia on cancer recurrence is its ability to attenuate the immune suppression that accompanies surgical stress. On one hand, epidural local anesthetics blunt the surgical stress response; on the other, they decrease requirements for systemic opiates, which are potent immune suppressors and promote tumor cell proliferation. The net effect is that epidural analgesia maintains the immune system intact during the perioperative period. Therefore, after surgical removal of the tumor, a new balance of power is reestablished: the memory cells of the immune system are now able to reinitiate the destruction process of the “minimal residual disease” (small pockets of cancer cells in various locations of the body), thus increasing recurrence-free interval and overall survival. A significant body of basic science data supports this proposal, but in the clinical setting, it is very possible that this hypothesized sequence of events is derailed or overwhelmed by other factors. The article by Cummings et al in this issue of Regional Anesthesia and Pain Medicine suggests that the potential benefits of epidurals may indeed be counteracted by other unknown factors. The authors compared the effect of epidural analgesia with traditional pain management on outcomes in patients undergoing gastric cancer resection, using the linked Surveillance Epidemiology and End Results Medicare database to identify their study population and extract the data. No statistically significant difference was found among the groups in treated recurrence (27.5% in epidural and