Surgical resection is considered the definitive treatment for patients with solid neoplastic tumors. Recent experimental evidence, however, suggests that undergoing surgery may actually play a role—via activation of the surgical stress response—in promoting postoperative metastases. Additionally, there is a growing body of evidence to suggest that attenuation of the surgical stress response may, in fact, reduce the postoperative cancer recurrence and metastasis. One element of the surgical stress response amenable to perioperative attenuation is neuroendocrine activation by β blockade. Although initial data in animals appears promising, further research into the potential benefit of this therapeutic modality aimed at reducing postoperative cancer metastases is warranted.

Introduction

For many patients with solid tumors, surgical resection offers the best chance for a cure. Unfortunately, cancer can recur after resection and, whether locally or as a metastasis, recurrence is often devastating. The value in using all possible treatment modalities aimed at reducing cancer recurrence and metastases after surgery is obvious. Adjuvant chemotherapy and post-operative radiation are two such widely used modalities, but are there others?

There is a growing body of evidence to suggest that there may be another beneficial treatment in reducing metastases after surgery—perioperative attenuation of the surgical stress response. The stress response includes neuroendocrine activation, inflammation and activation of hypothalamic-pituitary-adrenal (HPA) axis, each of which may promote cancer cell survival and metastasis after surgery.¹ Actions taken by the anesthesiologist or surgeon during the perioperative period may decrease the surgical stress response, with the theoretical benefit of reducing postoperative cancer recurrence and metastases. One such action is the perioperative administration of β blockers. This chapter is intended as a brief review of how elements of the surgical stress response may promote cancer growth and lead to metastases after surgery and of the evidence supporting the role that perioperative β blockade may play in reducing postoperative cancer recurrence and metastases.

The Stress Response after Surgery and Cancer

The stress response is the name given to the complex series of physiological events that occur after injury or trauma, whether by accidental means or by surgery. The "surgical stress response" simply refers to the normal physiologic stress response that occurs as a result of surgery. It includes neuroendocrine activation, inflammatory changes, and activation of the HPA axis (Fig. 1). The combination of these events, in turn, leads to hemodynamic, immunological and metabolic changes. From an evolutionary standpoint, it is thought that the stress response plays a beneficial role in healing and survival after injury.²

Figure 1.

Effects of the stress response. Adapted from Brotman DJ, et. al. The cardiovascular toll of stress. Lancet 2007; 370:1089-100, © 2007 with permission of Lancet Publishing Group.

Paradoxically, with respect to cancer recurrence and metastases after surgery, the effect of the stress response may not be beneficial—specific elements of the stress response are thought to actually promote cancer growth. For example, the surgical stress induced release of norepinephrine and epinephrine² may interact with β1 and β2 receptors expressed by tumor cells increasing their invasive and proliferative potential.^1,3-5 In addition, the inflammatory component of the stress response involves the production and release of cytokines, prostaglandins and cyclooxygenase, and the chronic release of such mediators is believed to play a role in cancer progression through the inhibition of apoptosis, promotion of angiogeneisis and immunosuppression.^1,6 It also has been suggested that the acute release of such mediators during the perioperative period may also promote cancer growth.^1,7 Finally, pain activates the hypothalamic-pituitary-adrenal (HPA) axis, which has been implicated in immunosupression, reduction of NK cell activity^1,8,9 and promotion of tumor cell activity in animals.^1,10

The fact that the surgical stress response may promote cancer growth suggests that its attenuation may benefit cancer patients undergoing surgery. There is mounting evidence to support this idea. Beta blockade, COX-2 inhibition, and pain control can each minimize the surgical stress response, and, when administered in the perioperative setting, each has each been suggested to be associated with a decreased risk of cancer recurrence or metastases. This effect however-especially with respect to β blockade-has not been thoroughly investigated in humans.

Neuroendocrine Component of the Stress Response and Cancer

The neuroendocrine component of the stress response is initiated by the hypothalamus which, in response to stress, activates the sympathetic autonomic nervous system. Sympathetic activation leads to the release of catacholamines from the adrenal medulla (Fig. 2) and norepinephrine from presynaptic nerve terminals. The target of catecholamine action is adrenergic receptors, which are located throughout the body. The stress-induced release of catecholamines therefore leads to a multitude of effects. Well-known responses to sympathetic activation such as tachycardia and hypertension can change organ function within the liver, pancreas and kidney. In addition, adrenergic receptors are also present on cancer cells. What is the response of these cancer cells to sympathetic activation?

Figure 2.

Site of catecholamine production: chromaffin cells of the adrenal medulla. Reproduced with permission from ImmunoStar, Inc.

Several studies have examined the response of cancer cells to adrenergic stimulation. Epinephrine and norepinephrine have been shown to increase the in vitro invasive potential of ovarian cancer cells.³ In addition, activation of signal transducer and activator of transcription-3 (STAT-3) by the action of epinephrine and norepinephrine on β-1 and β-2 adrenergic receptors increased the matrix metalloproteinase production, invasive potential and in vivo tumor growth of ovarian cancer cells.⁴ The production of vascular endothelial growth factor also has been shown to be increased by catecholamines in ovarian cancer cells.⁵

The question that follows the above experimental evidence is whether or not attenuation of adrenergic stimulation is actually beneficial to cancer patients. With respect to breast cancer, several clinical studies have indeed found chronic β blocker usage (as opposed to β blockade during the perioperative period) to be associated with several beneficial outcomes. In one retrospective study, breast cancer patients on β blockers prior to diagnosis were found to have reduced cancer recurrence.¹¹ In another study, β blocker usage concurrent to neoadjuvant chemotherapy was associated with increased relapse free survival.¹² Finally, propranalol usage in the year prior to breast cancer diagnosis was found to be associated with lower stage and tumor grade at the time of diagnosis.¹³

Focusing on the perioperative period, several studies have demonstrated a potential benefit of attenuation of the surgical stress response by means other than β blockade. In one retrospective study, paravertebral anesthetic blocks in breast cancer patients (theoretically resulting in the lessening of the stress response via reduction of pain) were found to reduce the risk of recurrence or metastasis.¹⁴ The addition of epidural anesthesia for pain control in prostate cancer patients undergoing open radical prostatectomy was associated with a reduced risk of clinical cancer progression.¹⁵ Finally, pain control with ketolorac, a nonsteroidal anti-inflammatory which inhibits prostaglandin synthesis, was found retrospectively to decrease the risk of breast cancer recurrence and metastases.¹⁶

Perioperative β blockade and the possible association with cancer recurrence and metastases has been examined prospectively in animals. Benish, et. al., found that in rats inoculated with tumor cells, surgery alone increased tumor retention and both propranalol as well as COX-2 inhibition attenuated this negative effect.¹⁷ Additionally, they found that the initiation of drug treatment three days preoperatively yielded the same beneficial effects as a single pre-operative administration. The potential benefit of perioperative β blockade (Fig. 3) has yet to be examined in humans.

Figure 3.

Potential benefit of attenuation of the surgical stress response via perioperative β blockade. Adapted from Gottschalk A, et. al. The role of the perioperative period in recurrence of cancer after surgery. Anesth Analg 2010; 110:1636-43, © (more...)

Conclusion

There is evidence suggesting the potential benefit of perioperative attenuation of the surgical stress response with respect to cancer recurrence and metastases after surgery. One modality capable of providing such attenuation is β blockade. Retrospective data in humans shows the benefit of chronic β blockade in breast cancer progression and recurrence, and the benefit of limited perioperative β blockade has been demonstrated prospectively in animals. Further work is warranted into the investigation of this potentially beneficial treatment modality.

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