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:

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A reduction in intraoperative and postoperative systemic analgesia requirements
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Shorter lengths of hospital stay
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Inhibition of the surgical stress response
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Reduction in postoperative nausea and vomiting
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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.

Table 13.1

Summary of Mechanisms by Which Regional Anesthesia May Reduce Cancer Recurrence

Proposed Mechanism	Subsequent Effects
Attenuation of surgical stress response	↑ NK and CD 8 – T cells ↓ Tregs and Th2 cells ↓ Cortisol and catecholamine secretion ↓ MMPs, VEGF, IL6
Opiate-sparing effect means possible negative effects of opiates are reduced	Less suppression of NK cells Cancer cells with opiate receptors are not stimulated to replicate
Avoidance or dose reduction of volatile anesthetic gasses	↓ Expression of HIFs, which can promote angiogenesis
Improved pain relief postoperatively	↓ Stimulation of sympathetic system and HPA axis ↓ Beta endorphin ↓ Suppression of NK activity
Action of local anesthetic drugs	↑ Apoptosis of tumor cells Inhibition of metastatic pathways via VGSCs ↓ Src activation ↓ EGFR Demethylation of DNA in cancer cells
Reduction in intraoperative blood loss	Reduced requirement for blood transfusion, which in itself has been associated with cancer recurrence

EGFR , Epidermal growth factor receptor; HIF , hypoxia inducible factor; HPA , hypothalamic pituitary adrenal; IL-6 , interleukin 6; MMP , matrix metalloproteinase; NK , natural killer cells; Th2 , Type 2 helper T cells; Treg , regulatory T cells; VEGF , vascular endothelial growth factor; VGCS , voltage-gated sodium channel.

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.
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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.
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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.

Evidence for a Benefit of Regional Anesthesia in Cancer Surgery

In Vivo Data

In a rat model of mammary adenocarcinoma, rats that received spinal anesthesia as opposed to GA (with isoflurane) had lower rates of postoperative tumor burden. The potential rationale for this is that spinal anesthesia reduces the neuroendocrine stress response that occurs during surgery. This stress response has been shown to have an immunosuppressant effect, reducing the activity of NK cells in particular. These lymphocytes are an integral part of the body’s immune response to fighting tumor cells. The aforementioned study showed that regional anesthesia appeared to preserve the numbers and activity of NK cells. In the group without regional anesthesia, NK cell activity was inhibited, and this may explain the greater rate of tumor recurrence and metastasis seen in this group.

A 2007 study in mice also showed a similar benefit to spinal anesthesia, when combined with GA, in reducing the amount of liver metastasis postsurgery. Again, spinal blockade appeared to preserve the ability of NK cells to perform its defensive role against invading cancerous cells.

These animal studies provide modest evidence for the potential beneficial role of regional anesthesia in patients undergoing cancer surgery. Unfortunately, promising results from animal studies frequently do not show the same effect in human studies. In fact, only in approximately one-third of studies are results of animal trials in accordance with those of human randomized control trials and the vast majority of animal studies (approximately 90%) are not repeated using human subjects. There should be caution in extrapolating results of these experiments to our clinical practice. There remain unanswered questions as to how well the animal model replicates human physiology, particularly in the intricate arena of cancer recurrence.

Translational Studies

Translational studies may be defined as studies that bridge the gap between laboratory research and clinical research, sometimes referred to as “bedside to bench” studies. A number of recent translational studies have demonstrated a potential benefit to regional anesthesia in the cancer setting. In a pilot study, 32 women undergoing breast cancer surgery were randomized to one of either two anesthetic techniques, propofol GA combined with paravertebral regional anesthesia or GA with sevoflurane and opioid analgesia. Of the 14 cytokines associated with cancer biology that were measured in this study, 10 showed no difference between the groups; however, MMP 3 and MMP 9 were decreased postoperatively in the propofol/paravertebral group. MMPs are enzymes capable of degrading proteins of the extracellular matrix and hence play an essential role in tumor cell invasion, angiogenesis, and metastasis. MMPs are upregulated in many cancers and are associated with advanced disease and higher mortality. This study showed that regional anesthesia (with propofol) reduces MMPs and hence may have a protective role in cancer recurrence at the time of surgery.

In another translational study, 40 women undergoing breast cancer surgery were randomized to receive either paravertebral anesthesia and analgesia combined with GA or volatile anesthesia and opioid analgesia alone. The authors found that vascular endothelial growth factor C (VEGF-C) levels were elevated in the GA-alone group while they remained virtually unchanged in the patients who received paravertebral anesthesia. VEGF-C stimulates angiogenesis, which is the process by which cancerous cells generate a blood supply from the host. Angiogenesis is an essential step in tumor development and metastasis, as the tumor mass increases in size. It has been demonstrated that tumor tissue greater than 2 mm in diameter cannot survive without its own blood supply. This process of developing new blood and lymph vessels also facilitates the dissemination of cancerous cells into the systemic circulation and hence the development of metastasis. The observation that patients who received a paravertebral block had lower levels of VEGF-C postoperatively compared with those without suggests that perhaps the paravertebral block creates a microenvironment less conducive to tumor growth and metastatic spread.

Evidence from translational studies would also suggest that regional anesthesia may preserve the antitumor effect of NK cells. The effect of serum from women undergoing cancer surgery on healthy human donor NK function and cytotoxicity was evaluated. Preservation of NK function and cytotoxicity was noted in patients who had received regional anesthesia. As mentioned previously, the main function of NK cells is the recognition and destruction of virus-infected cells and tumor cells, making it one of the front-line defenses against cancerous cells. A reduction in NK cell activity is mediated via beta-adrenoreceptors located on the surface of these cells, which, when activated, trigger an increase in cAMP and protein kinase A. Regional anesthesia may ameliorate this catecholamine-driven suppression of NK cells via its ability to attenuate the stress response associated with surgery.

Cancer cells can express µ-opioid receptors (MORs). Increased expression of this receptor is associated with a higher incidence of metastasis in gastric, prostate, and non-small cell lung cancer. Another study demonstrated that anesthetic technique can influence MOR expression. In a group of 20 breast cancer patients, those who had volatile GA with opioid analgesia had higher levels of MOR expression on intraoperative biopsy specimens compared with those who had a propofol-paravertebral-based anesthetic technique. Again, this study suggests a potential benefit to regional anesthesia in cancer surgeries.

Retrospective Analysis

The initial hypothesis suggesting a benefit from regional anesthesia in cancer patients came from retrospective studies ( Table 13.2 ). Patients undergoing radical prostatectomy who received epidural analgesia combined with GA were associated with a 57% lower risk of cancer recurrence (95% confidence interval [CI], 17%–78%) compared with those who had GA and opioids. Cancer recurrence in this study was defined as increase in postoperative prostate-specific antigen (PSA) compared with its postoperative nadir that prompted adjunctive therapy. However, subsequent retrospective studies showed no significant benefit in terms of disease-free survival or biochemical recurrence in patients given neuraxial anesthesia undergoing a radical prostatectomy.

Table 13.2

Selected Studies of Regional Anesthesia and Cancer-Related Outcomes

Study Authors	Year	Trial Design	Surgery Type	Techniques Compared	Significant Results
Exadaktylos et al.	2006	RETR	Breast cancer requiring mastectomy +/– axillary clearance	GA + PVB (n = 50) vs. GA + opioid (n = 79)	Increased recurrence-free survival in PVB group at 3 years (88% vs. 77%; P = 0.012)
Bar-Yosef et al.	2001	Animal model of breast cancer metastasis	Laparotomy and inoculation with syngeneic MADB106 adenocarcinoma cells	Spinal anesthesia IV morphine	Spinal anesthesia reduced the number of pulmonary metastasis 37.2 ± 24.4 to 10.5 ± 4.7 ( P = 0.0043)
Wada et al.	2007	Mouse model of liver metastasis	Inoculation with EL4 tumor cells	Spinal + GA GA alone	Spinal group had a reduced number of liver metastasis 33.7 ± 8.9 to 19.8 ± 9.1 ( P < 0.05) and preserved NK cell activity
Deegan et al.	2010	Pilot RCT	Breast cancer surgery	Propofol/PVB (n = 15) Sevoflurane/opioid (n = 17)	Significant attenuation of elevated MMP-3 and MMP-9 in propofol/PVB group
Looney et al.	2010	RCT	Breast cancer	Propofol/PVB (n = 20) GA (n = 20)	PVB group had a decreased rise in VEGF-C postoperatively
Buckley et al.	2014	In vitro translational study	Breast cancer	Propofol/PVB (n = 5) vs. sevoflurane/opioid (n = 5)	Greater NK cell cytotoxicity seen in PVB group
Biki et al.	2008	RETR	Prostate cancer	GA + epidural vs. GA + opioid	57% lower incidence of cancer recurrence in epidural group (95% CI, 17%–78%)
Tsui et al.	2010	RCT–PHA	Prostate cancer	GA + epidural (n = 49) GA (n = 50)	No difference in disease-free survival
Tseng et al.	2014	RETR	Prostate cancer	Spinal + sedation (n = 1166) GA (n = 798)	No difference in biochemical recurrence
Cata et al.	2016	RETR	Breast cancer	PVB (n = 198); Opioid-based analgesia (n = 594)	Use of PVB not associated with a significant change in recurrence-free survival or overall survival
Merquiol et al.	2013	RETR	Laryngeal and hypopharyngeal cancer	GA + cervical epidural (n = 111) GA + opioid (n = 160)	↑ 5-year cancer-free survival in epidural group
Doiron et al.	2016	RETR	Cystectomy for bladder cancer	Thoracic epidural + GA (n = 887); GA (n = 741)	Thoracic epidural not associated with cancer-specific survival
Koumpan et al.	2018	RETR	TURBT for bladder cancer	Spinal (n = 135) GA (n = 96)	Lower incidence of cancer recurrence in spinal group
Holler et al.	2013	RETR	Colorectal cancer	Epidural + GA (n = 442) GA (n = 307)	↑ 5-year survival rate with epidural (62% vs. 54%, P < 0.02)
Day et al.	2012	RETR	Laparoscopic colorectal resection for colorectal cancer	GA + epidural (n = 107) GA + spinal (n = 144) GA + opiate (n = 173)	No difference in overall survival or 5-year disease-free survival
Oliveira et al.	2011	RETR	Ovarian cancer debulking	GA + epidural (n = 55) GA (n = 127)	Intraoperative epidural use associated with reduced recurrence risk (HR, 0.37)
Capmas et al.	2012	RETR	Ovarian cancer	GA + epidural (n = 47) GA (n = 47)	Epidural had no clear impact on cancer recurrence
Chipollini et al.	2018	RETR	Bladder cancer	GA + epidural (n = 215) GA (n = 215)	↓ Recurrence-free survival (HR, 1.67) and cancer-specific survival (HR, 1.53) in epidural group, interestingly epidural group received higher doses of morphine equivalents
Xu et al.	2014	Randomized trial	Colon cancer	Propofol + epidural (n = 20); GA (n = 20)	Epidural group had decreases in VEGF-C and IL-6 compared to GA group at 24 h post surgery
Myles et al.	2011	RCT–PHA	Abdominal cancer surgery	GA + epidural (n = 230) GA (n = 16)	No difference in overall survival or recurrence-free survival between groups
Cata et al.	2018	RETR	Craniotomies for malignant brain tumors	Scalp block + GA GA	Scalp block not associated with longer progression-free survival or longer overall survival
Lee et al.	2015	Meta-analysis	Prostate cancer surgery	Epidural/spinal GA	Improved overall survival with regional anesthesia (HR, 0.81; 95% CI, 0.68–0.96; P = 0.016)
Weng et al.	2016	Meta-analysis	21 studies including breast, prostate, colorectal, laryngeal, hepatocellular, cervical, and ovarian cancer	Neuraxial anesthesia GA	Improved overall survival in regional group (HR, 0.853; 95% CI, 0.741–0.981; P = 0.026)
Grandhi et al.	2017	Meta- analysis	Variety of cancer surgeries 67,577 patients 28 studies	RA GA	No significant benefit to RA in cancer surgery
Sessler, et al.	2019	Prospective multicenter RCT	Primary breast cancer surgery	PVB + propofol vs. sevoflurane + opioid	PVB and propofol does not improve cancer recurrence (median follow up, 36 months)