Can Regional Anesthesia and Analgesia Influence the Risk of Cancer Recurrence?

What Is Regional Anesthesia?

Regional anesthesia may be defined as the administration of local anesthetic drugs around a nerve or plexus of nerves, or anatomical plane through which nerves pass, in order to render a distal site anesthetized. It can be used in conjunction with general anesthesia (GA), or it can be the sole means of anesthesia, thereby sometimes allowing the patient to be fully awake during surgery without feeling any pain.

General Benefits of Regional Anesthesia

The potential established benefits of regional anesthesia to surgical cancer patients may be summarized as:

• A reduction in intraoperative and postoperative systemic analgesia requirements

• Shorter lengths of hospital stay

• Inhibition of the surgical stress response

• Reduction in postoperative nausea and vomiting

• Fewer postoperative pulmonary complications

How Regional Anesthesia Might Influence Cancer

In 2006, a retrospective analysis of women undergoing mastectomy for breast cancer with paravertebral anesthesia and analgesia found an association between the use of this technique and improved disease-free survival time, compared with women who received volatile anesthesia and opioid analgesia. This study, although limited by its retrospective design, sparked a global interest in the question of whether regional anesthesia or analgesia during surgery of curative intent might reduce the risk of later recurrence or metastasis.

There are biologically plausible mechanisms to explain why regional anesthesia may have a role to play in reducing cancer recurrence ( Table 13.1 ) including the following.

Regional anesthesia can inhibit the stress response that is associated with surgery. The stress response to surgery has been shown to have a negative effect on natural killer cells (NK cells) and T cells, which play a key role in eliminating minimal residual cancer disease or circulating tumor cells (CTC) at the time of surgery. Simultaneously, the surgical stress response stimulates immune cells which have a protumor effect such as regulatory T cells (Tregs) and type 2 helper T cells (Th2):

• 1

  This surgical stress response also leads to activation of the hypothalamic-pituitary-adrenal (HPA) axis, which results in secretion of cortisol and catecholamines. Many cancer cells contain adrenoreceptors that when activated by catecholamines, secrete substances such as interleukin 6 (IL-6), vascular endothelial growth factor (VEG-F), and matrix metalloproteinase (MMP) enzymes, which all increase the propensity for tumor cells to invade and proliferate.

• 2

  The superior pain relief that regional anesthesia provides means that opioids can be used sparingly or not at all. While controversial, some experimental and retrospective studies suggest that perioperative use of opioids may be associated with cancer recurrence. ^, Morphine appears to have immunosuppressant effects by reducing the activity of NK cells, which play a crucial role in suppressing tumor growth. It may act directly to suppress NK cells via opioid receptors or nonopioid receptors present on immune cells, e.g., Toll-like receptor 4 (TLR-4). Morphine also acts indirectly on the periaqueductal grey area in the brain stem and sympathetic nervous system that release chemical messengers that suppress NK cytotoxicity. Cancer cells can also express opioid receptors that, when activated, can trigger a tumorigenic cascade that can result in metastasis. This has also been observed clinically with retrospective studies showing that tumors that overexpress opioid receptors are associated with poorer outcomes in prostate and squamous cell carcinoma of the esophagus. ^, Poorly controlled pain per se postoperatively has been shown to be a driving force for cancer recurrence in an animal model. Effective regional anesthesia can improve pain scores postoperatively and offer superior analgesia when compared with parenteral opioids in patients undergoing cancer operations. Pain itself is thought to have an immunosuppressive effect via stimulation of the sympathetic system and the hypothalamic pituitary adrenal axis, hence reducing the body’s defense systems against invading malignant cells. Painful stimuli can also increase circulating levels of β-endorphin which has immunosuppressant effects specifically by reducing the cytotoxic effects of NK cells. An experimental cancer model showed that effective analgesia can reduce the incidence and number of metastases.

• 3

  Similarly, volatile anesthetics have been implicated in cancer recurrence. Effective regional anesthesia can provide a dose reduction in the amount of volatile required or in some cases negate its usage entirely by allowing the operation to be performed completely under regional anesthesia with the patient awake or lightly sedated. Volatile anesthetics have been shown to upregulate the expression of hypoxia inducible factor (HIF), which can promote angiogenesis and have been implicated in facilitating cancer recurrence. However, studies have not been consistent in their findings with some suggesting that sevoflurane (a commonly used volatile anesthetic gas) may have antiproliferative effects on non–small cell lung carcinoma (NSCLC) cells. While uncertainty continues regarding the pros and cons of volatile anesthetic use during cancer surgery, regional anesthesia may, if it is the sole anesthetic technique, circumnavigate this issue entirely or perhaps reduce volatile anesthesia requirements if used in combination with general anesthesia.

• 4

  Emerging evidence suggests that amide local anesthetics may reduce the metastatic burden in both in vitro and animal models. A number of potential mechanisms exist that may explain this antitumor effect. The primary use of amide local anesthetics in anesthesia is to block sensory nerve transmission and hence provide pain relief. This is achieved by blockade of voltage-gated sodium channels (VGSCs). These channels also exist in the membrane of many cancer cells and they tend to be constitutively active. Inhibition of the alpha subunit of these channels can halt the metastatic potential of cancerous cells. While evidence to support this theory is weak, other medications that work on VGSCs such as phenytoin have been found to suppress the metastatic potential of breast cancer cells.

Non-VGSC-dependent mechanisms of tumor suppression have also been identified. Lidocaine has been shown to reduce the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) and hence suppress replication in human tongue squamous cell carcinoma cells. This was seen at concentrations that occur in clinical practice. The same study also demonstrated a direct cytotoxic effect on cancer cells with lidocaine but this was seen at concentrations much higher than could safely be achieved in vivo.

The amide local anesthetics (lidocaine and ropivacaine) have been shown to have a direct inhibitory effect on the Src oncogene. The Src pathway is involved in promoting the epithelial to mesenchymal transition which allows invasion of cancerous cells to occur. In recent years the Src tyrosine protein kinase has been viewed as an important research focus and specific “targeted therapies” (e.g., Dasatinib, Bristol-Myers Squibb, New York, NY) have been developed to inhibit its actions. Interestingly, while the amide local anesthetics were seen to have an inhibitory effect on the pathway the same was not seen for the ester class of local anesthetics (chloroprocaine).

As well as possibly enhancing the efficacy of conventional chemotherapeutic drugs, local anesthetics have also been shown to demethylate DNA in breast cancer cells in vitro ; this action can decrease tumor progression through the upregulation of tumor suppressor genes. These effects were seen at concentrations of local anesthetic typically achieved during epidural infusions. All of these antitumor effects of local anesthetic drugs may in some part explain the beneficial effects on tumor recurrence when melanoma excision is performed under local anesthetic as opposed to general anesthesia. ^, Lignocaine and bupivacaine have been shown to trigger apoptosis in human breast cancer cells. The authors of this study suggested that it might be beneficial to infiltrate tissues with these drugs during breast cancer resections. In vivo evidence suggests that lidocaine may also exert antimetastatic effects when given intravenously.

Some evidence exists that regional anesthesia may reduce intraoperative blood loss in comparison with general anesthesia (however, this was in observational trials and the quality of this evidence was rated as low). This may be an indirect benefit of regional anesthesia in terms of reducing cancer recurrence as perioperative blood transfusion may also be associated with cancer recurrence.