Local Anesthetics and Cancer

The Perioperative Period Is Critical for Postsurgical Cancer Outcomes

Surgery is the primary and often the most effective treatment for many solid tumors. However, even otherwise successful surgeries may disrupt and disseminate tumor cells. Disseminated tumor cells increase the risk of recurrence and metastasis. Indeed, the number of postsurgical circulating cancer cells is a negative prognostic indicator of disease-free survival.

A number of prometastatic events occur during the perioperative period as a direct consequence of surgery. For instance, direct injury to tissue causes local inflammation and a wound-healing response characterized by increased proliferation and enhanced release of angiogenic factors. These events promote the viability of residual or disseminated cancer cells. Inflammation also leads to edema, which increases the pressure of local drainage (via the lymphatic system) and enhances the propulsion of disseminated tumor cells away from the surgical site. Surgical trauma also induces a more general surgical stress response, characterized by systemic increases in catecholamines and inflammatory mediators. This can lead to immunosuppression and a reduction in the cytotoxic activity of natural killer (NK) cells. These events may tip the balance enabling micrometastases, previously suppressed by the immune system, to thrive. ^,

Anesthetics and analgesics administered during the perioperative period have the potential to exacerbate prometastatic events, and there is considerable interest in the possibility that the type of anesthetic and/or analgesic agent may influence cancer recurrence. Indeed, a number of retrospective clinical studies suggest that regional anesthesia by local anesthetics increases disease-free survival following breast and prostate cancer surgery. Here, we explore the potential benefits of using local anesthetics during the perioperative period of surgical tumor excision with regard to subsequent disease progression and/or recurrence and the mechanisms, which may underpin it.

Potential Detrimental Effects of Anesthetics and Opioid Analgesics

Opioid analgesics are effective for the management of severe pain but can cause opioid-induced respiratory depression, constipation, hyperalgesia, tolerance, and dependence. Of particular concern in the context of the perioperative period is the possibility that some opioids may cause immunosuppression. For instance, fentanyl and morphine may activate mu-opioid receptors on NK cells, attenuating their cytotoxic activity. ^, Furthermore, fentanyl and morphine may also stimulate the hypothalamic-pituitary axis to raise glucocorticoid levels, causing indirect immunosuppression. The presence of mu-opioid receptors on some tumor cells (particularly non–small cell lung cancer) suggests that opioids may directly influence cancer cell function. The impact of opioids on cancer is discussed in detail in Chapter 12 .

Volatile general anesthetics such as sevoflurane may also suppress the immune response. In mice, sevoflurane treatment reduced total leukocyte and lymphocyte cell counts in blood. There is also less infiltration of NK and T-helper cells in breast cancer tissue biopsies from patients receiving sevoflurane. Furthermore, serum from breast cancer patients receiving sevoflurane reduces the cytotoxicity of NK cells in vitro. Volatile general anesthetics may also have direct procancer effects. For instance, serum taken from breast or colon cancer patients receiving sevoflurane impairs apoptosis of breast or colon cancer cells, respectively, in vitro. ^, Sevoflurane may also enhance migration and invasion in ovarian cancers and glioblastomas. The impact of volatile anesthetics on cancer is discussed further in Chapter 11 .