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Perioperative Anesthesia Care and Tumor Progression

Sekandarzad, Mir W. FANZCA, FFPMANZCA, DESA*; van Zundert, André A.J. MD, PhD, FRCA, EDRA, FANZCA*; Lirk, Philipp B. MD, PhD; Doornebal, Chris W. MD; Hollmann, Markus W. MD, PhD, DEAA

doi: 10.1213/ANE.0000000000001652
Pain and Analgesic Mechanisms: Narrative Review Article
Continuing Medical Education

This narrative review discusses the most recent up-to-date findings focused on the currently available “best clinical practice” regarding perioperative anesthesia care bundle factors and their effect on tumor progression. The main objective is to critically appraise the current literature on local anesthetics, regional outcome studies, opioids, and nonsteroidal anti-inflammatory drugs (NSAIDs) and their ability to decrease recurrence in patients undergoing cancer surgery. A brief discussion of additional topical perioperative factors relevant to the anesthesiologist including volatile and intravenous anesthetics, perioperative stress and anxiety, nutrition, and immune stimulation is included. The results of several recently published systematic reviews looking at the association between cancer recurrences and regional anesthesia have yielded inconclusive data and provide insufficient evidence regarding a definitive benefit of regional anesthesia. Basic science data suggests an anti tumor effect induced by local anesthetics. New refined animal models show that opioids can safely be used for perioperative pain management. Preliminary evidence suggests that NSAIDs should be an essential part of multimodal analgesia. Volatile anesthetics have been shown to increase tumor formation, whereas preclinical and emerging clinical data from propofol indicate tumor protective qualities. The perioperative period in the cancer patient represents a unique environment where surgically mediated stress response leads to immune suppression. Regional anesthesia techniques when indicated in combination with multimodal analgesia that include NSAIDs, opioids, and local anesthetics to prevent the pathophysiologic effects of pain and neuroendocrine stress response should be viewed as an essential part of balanced anesthesia.

Published ahead of print November 8, 2016.

From the *Department of Anaesthesia and Perioperative Medicine, Royal Brisbane and Women’s Hospital, The University of Queensland, Herston-Brisbane, Queensland, Australia; and Division of Anesthesiology, Intensive Care, Emergency Medicine, Pain Therapy and Palliative Care, University Medical Center Amsterdam, Amsterdam, the Netherlands.

Published ahead of print November 8, 2016.

Accepted for publication August 17, 2016.

Funding: None.

Conflicts of Interest: See Disclosures at the end of the article.

Reprints will not be available from the authors.

Address correspondence to André A.J. van Zundert, MD, PhD, FRCA, EDRA, FANZCA, Department of Anaesthesia and Perioperative Medicine, Royal Brisbane and Women’s Hospital, The University of Queensland, Butterfield St, Herston-Brisbane, Queensland, Australia. Address e-mail to vanzundertandre@gmail.com.

Cancer continues to be a major contributor to morbidity and mortality globally despite advances in prevention, diagnosis, and treatment. In the year 2015, almost 1,700,000 patients were diagnosed with cancer in the United States alone, and almost 600,000 died. Cancer remains the second most common cause of death in the United States, accounting for nearly 1 of every 4 deaths.1 Therapy for cancer is complex, and for solid tumors, surgical extirpation remains the first-line treatment, potentially combined with neoadjuvant chemotherapy and/or radiotherapy. However, as a consequence of surgery, patients develop a stress response that inhibits the action of the patients’ immune system.2 Specifically, Natural Killer (NK) cell function essential for the clearance of tumor cells is impaired.3 It is thought that, subsequently, minimal residual disease4 and circulating tumor cells5 cannot be adequately dealt with and risk of metastasis and tumor recurrence increases.2

Regional anesthesia and, to a lesser extent, the intravenous administration of local anesthetics decrease the surgical stress response.6 Therefore, it is intriguing to speculate whether the choice of anesthetic technique might translate into a clinical benefit such as prolonged survival after cancer surgery. The relevance of perioperative anesthesia techniques on the long-term outcome of cancer patients has been subjected to long-standing controversy.7–12

The aim of this narrative review is to summarize and critically review the currently available evidence regarding the potential effect of regional anesthesia on the outcome of cancer patients. In addition to that, other pertinent perioperative factors will be discussed. A brief introduction on perioperative immune pathogenesis is included.

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SOURCE OF INFORMATION

A search of PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews from inception to June 2016 was performed in collaboration with a qualified librarian to identify the relevant studies using predefined search terms. These terms were searched as subject heading, medical subject headings, and text words where appropriate (Table 1).

Table 1

Table 1

Decision for data extraction was made in accordance with the criteria as suggested by McAlister.13 Randomized controlled trials were ranked highest for the section on the effect of regional anesthesia on cancer recurrence. Human, animal, in vitro studies, as well as review articles, as deemed appropriate by the authors, were included for all sections. The search was limited to the English language.

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IMMUNE PATHOGENESIS

The principal line of defense against cancer cell invasion and metastasis is established via the host’s innate and adaptive immune response. The key players in the recognition and elimination of cancer cells during the “elimination phase” where a cancer-free state is achieved are NK cells, CD4+Th1, CD8+CTL, and cytokines including interleukin-12, interferon-α/β, interferon-γ, and tumor necrosis factor-α (TNF-α).14 NK cells, a subpopulation of large granular lymphocytes that spontaneously recognize and lyse tumor cells, play a pivotal role. Patients with reduced NK cells numbers and activities are more vulnerable to cancer and/or metastasis formation.4,9 If tumor cells survive the “elimination phase,” they may then enter an “equilibrium” state, where the host’s adaptive immune response keeps these cancer cells in a state of dormancy and prevents further tumor growth. In the final stage, the “escape phase,” tumor cells lead to clinical apparent growth as they escape the host’s immunity control and their potential to induce an immunosuppressive state by the production of various cytokines such as vascular endothelial growth factor (VEGF) and transforming growth factor-β (TGF-β).14

Inflammation at the tumor site and release of proinflammatory cytokines including interleukin-6 (IL-6), TNF-α, interleukin-1β, and prostaglandin E2 (PGE-2) may favor tumor progression.9 Furthermore, tumor cells can recruit regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages, all of which may paradoxically promote tumor growth. This is of central importance because it underlines that contrary to popular belief immune stimulation per se can in fact have detrimental consequences. Neither immune stimulation nor immune suppression individually can be attributed to positive effects on tumor progression overall.8,9

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EFFECTS OF REGIONAL ANESTHESIA AND LOCAL ANESTHETICS

The theoretical benefits of regional anesthesia on tumor inhibition can be divided into indirect and direct antiproliferative effects.

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Indirect Effects

Indirect effects include reduction of the surgically mediated neuroendocrine stress response via better preservation of NK cell activity, an increase in antitumorigenic cytokines interleukin-2 and interleukin-10 and lower percentage of circulating regulatory T cells and Th2 cells as well as reduced C-reactive protein levels on days 2+5 after surgery, thereby potentially improving the host’s immune function against tumor cells.15,16 Furthermore, opioids may lead to immunosuppression,9,17 and volatile anesthetics may promote metastasis18 such that the sparing effects of regional anesthesia on these types of drugs may theoretically further improve long-term outcome.4 Finally, pain has been described as a potent mediator of carcinogenesis in animal experiments,19 and regional anesthesia is widely considered to offer superior pain relief as compared with systemic opioid therapy for several types of surgery.20 In conclusion, the antiinflammatory, the opioid and volatile anesthetic-sparing, and the analgesic effects of regional anesthesia suggest a theoretical framework in which perioperative homeostasis is optimally preserved to ensure the best patient outcome possible.

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Direct Effects

Direct beneficial effects of regional anesthesia pertain to the effects of local anesthetic agents on the tumor cell. These include (a) inhibition of TNF-α–induced Src-activation and intercellular adhesion molecule-1 phosphorylation,21 (b) inhibition of the epidermal growth factor receptor (EGFR) pathway,22 (c) antiproliferation of mesenchymal stem cells (MSCs),23 and (d) blockade of the α-subunit of voltage-gated sodium channels.24

In addition to their cytotoxic potential, lidocaine and ropivacaine at clinically relevant doses have been shown to exert demethylating properties in vitro, thus reactivating tumor suppression and inhibiting tumor growth.25,26 When lidocaine was combined with chemotherapeutic agents, the demethylating effect was additive.25,27 Both lidocaine and bupivacaine in clinically relevant concentrations have been shown to induce apoptosis in human breast cancer cells and therefore may be ideal infiltration anesthetics in breast cancer surgery.28 This might, in part, explain the beneficial effects on tumor recurrence after melanoma resection under local anesthesia.29

Yardeni et al30 in an in vivo study have shown that intravenous lidocaine administered perioperatively reduces the surgically mediated immune perturbations including a decrease in interleukin-1 and IL-6 serum concentration. Intravenous lidocaine is currently being investigated for its potential to reduce cancer recurrence in patients undergoing breast cancer surgery (NCT01204242).31

Despite the promising preclinical data, the evidence for local anesthetics to reduce tumor progression through voltage-gated sodium channels (VGSC) inhibition is limited. A recent population-based cohort study revealed that exposure to nonlocal anesthetic VGSC blockers contrary to the above-mentioned beneficial effect of local anesthetics significantly increased mortality in breast, bowel, and prostate cancer patients.32

In conclusion, direct effects of local anesthetics can modulate survival of tumor cells and could further contribute to positive patient outcome.

However, ongoing controversy exists regarding the effect of regional anesthesia techniques and cancer outcome in clinical practice. A number of retrospective studies have been published over the past decade showing a trend toward reduced cancer recurrence rates in different cancer forms such as breast, gastrointestinal, skin, head and neck, and genitourologic cancers (Table 2).29,33–45 The majority of these studies have been either retrospective in nature or prospective cohort studies from a database or subgroup analysis from previous randomized controlled studies. This creates difficulty in interpreting and gathering clinically meaningful conclusions, because these observational studies suffer from methodological and statistical flaws and were primarily designed for hypothesis-generating purposes.9

Table 2

Table 2

After an initial wave of enthusiasm, the publication of negative trials with no benefit in cancer recurrence rates with the application of regional anesthesia techniques in prostate,46–53 breast,54,55 cervical,56 ovarian,57,58 gastric,59 esophageal,60 and colorectal61–64 cancer, or even decreased survival in the setting of radiofrequency ablation for hepatocellular carcinoma patients,65 have been adding to the confusion.

In addition, a number of recent systematic reviews and meta-analyses as well as literature reviews have attempted to shed light on the controversial debate.

A systematic review by Cata et al suggested that the evidence of the effect of regional anesthesia techniques in gastrointestinal tumor surgery on improved recurrence-free survival (RFS) or overall survival (OS) is inconclusive.66 Another review of the literature that included 7 heterogeneous studies concluded that the association between epidural anesthesia and survival of colon and rectal cancer is not clear.67

Weng et al68 suggest in their meta-analysis that there is a positive association for neuraxial anesthesia and improved overall survival (OS) hazard ratio (HR) 0.853 with 95% confidence intervals (CIs) 0.741–0.981, P = .026 (in particular, in colorectal cancer surgery HR 0.653, CI 0.430–0.991, P = .045) and improved recurrence-free survival (RFS) (HR 0.846, CI 0.718–0.998, P = .047) compared with general anesthesia.

A meta-analysis by Sun et al69 found that overall, perioperative regional anesthesia may improve survival after oncologic surgery but did not show a positive correlation between regional anesthesia and cancer recurrence.

A Cochrane review70 consisting of 4 studies (all subgroup analysis from previously conducted RCTs) with a total number of 746 participants concluded that there is currently inadequate evidence for the benefit of regional anesthesia techniques on tumor recurrence and that the quality of evidence was graded low for overall survival and very low for progression-free survival and time to tumor progression (TTP).

Pei et al71 in their meta-analysis showed no association between general-epidural anesthesia group anesthesia versus general anesthesia only and improved colorectal cancer prognosis; however, they did notice a positive trend towards the improvement in prostate cancer (follow-up ≤2 years).

Finally, another large meta-analysis72 found that epidural anesthesia/analgesia might be associated with improved overall survival in patients with operable cancer (especially in colorectal cancer) but failed to demonstrate a benefit for recurrence-free survival (RFS).

It remains doubtful as to whether prospective randomized trials on this subject can provide a conclusive answer because the lack of comparability between trial participants and nonparticipants calls into question the generalizability of cancer clinical trial results.73 Registry-based randomized trials, such as the Thrombus Aspiration in ST-Elevation Myocardial Infarction in Scandinavia (TASTEE) trial, which apply the rigor of randomization and leveraging of clinical information based on the platform of high-quality observational registries have been both cost effective and representative.74,75 The Patient Centered Outcomes Research Institute, for example, may be another stepping stone in the clinical more meaningful generation of big health care data with the aid of generating randomized studies within a network of health care systems and to use their existing infrastructure for pragmatic randomized trials.76

However, these registry-based randomized trials, which hold promise in generating meaningful outcome data, pose inherent challenges too. These include the ability for long-term follow-up and blinding, privacy issues, data quality, and information technology challenges.74

Even if large-scale outcome studies were to demonstrate a positive effect of regional anesthesia and cancer recurrence reduction, these results might not be universally applicable, and the real challenge remains to implement patient-and tumor-specific strategies including regional anesthesia techniques to specific cancer types and varying cancer stages.

In conclusion, even if a strong theoretical basis supports the notion that regional anesthesia can positively affect patient outcome after tumor surgery, the actual benefits in practice have not been definitively shown.

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EFFECTS OF ANESTHETICS AND ANALGESICS, AND PERIOPERATIVE FACTORS

Opioids

Opioids are the standard of care as potent pain-relieving agents to treat cancer-related pain and pain in the perioperative period of cancer surgery.77

It is believed that opioids promote tumor growth and metastasis. This belief is based on several lines of evidence including (a) the modulation of cellular and humoral responses leading to immunosuppression,78 (b) the direct action on tumor cells and immune or endothelial cells,79 and (c) the activation of neuroendocrine-mediated stress response leading to the progression of metastasis and angiogenesis.80 The mechanism of action is diverse and includes (a) μ-opioid receptor activation (overexpressed in cancer) leading to VEGF-dependent angiogenesis81,82 (Figure), (b) epidermal growth factor pathway activation,83 (c) NET-1 gene upregulation-induced increase in cancer cell migration,84 (d) stimulation of mitogen-activated protein kinase (MAPK) signaling pathway via G protein-coupled receptors and nitric oxide (NO) synthesis,85 leading to increased enzymatic activity of cyclooxygenase-2 (COX-2) and subsequent PGE-2 production.86

Figure

Figure

In addition, nonopioid receptors, such as the toll-like receptor 4 (TLR4) within cancer cells, have been shown to facilitate invasion and migration.87 However, downstream activation of the TLR4 with a perioperative single use of TLR4 agonist has been shown to boost both natural and adaptive immunity in experimental animal studies through the secretion of inflammatory cytokines and type-1 interferons.88

There is ongoing controversy as to the immune-modulatory effects of various opioids. Certain opioids such as fentanyl and morphine appear to be more immunosuppressive compared with oxycodone, hydromorphone, and buprenorphine or even tramadol which in fact appears to boost NK cell proliferation (Table 3).17 On that note, methadone has been shown to induce cell death and apoptosis via opioid receptor activation triggering downregulation of cAMP ex vivo and in vivo and improve the effectiveness of anticancer drugs in the treatment of glioblastoma and leukemia.89,90 These findings are corroborated even further by differential opposing immune effects within the same drug that have been reported depending on the animal model and tumor type used.79

Table 3

Table 3

The majority of studies investigating the effects of opioids on the immune system have been in vitro or animal studies.9,91 Concerns have been raised regarding the somewhat flawed design of some animal studies, that is, type of mouse model used, subtherapeutic morphine dosages (including different metabolic end-products, ie, predominance of morphine-3-glucuronide versus morphine-6-glucuronide production in mice that is not an analgesic in mice, therefore creating unequal tissue concentrations between humans and rodents), as well as mode of administration (continuous infusion versus bolus), all of which make the interpretation of the procarcinogenic effects of opioids within the murine model difficult. To circumvent these obstacles, the authors proposed to use genetically engineered mouse models of de novo tumorigenesis and expose them to surgical resection of the tumor, which not only reproduces the biology of de novo metastatic disease, but also more closely mimics the perioperative setting.79,92 Subsequent studies that followed stricter adherence to the above-proposed criteria to reflect an accurate preclinical mouse model of breast cancer metastasis concluded that morphine did not increase any tumor growth or angiogenesis.92,93 Another recent systematic review of experimental animal studies94 concluded that there was no evidence to suggest that opioids increase the risk and number of metastasis.

On the contrary, not only is morphine devoid of any immunosuppressive actions, but there is also evidence from animal studies that morphine can lead to various anticarcinogenic pathways (Figure): (a) decreased leukocyte transendothelial migration and reduced angiogenesis,95,96 (b) reduced tumor growth via decreased levels of circulating matrix metalloproteinase-9 (MMP-9) and urokinase-like plasminogen activator (uPA),97 (c) decreased interleukin-4 (IL-4) induced MMP-9 expression and “alternative” (M2) macrophage activation,98 and (d) stimulate opioid-receptor and downstream inhibitory Gi-protein–mediated activation of caspases resulting in apoptosis.89,90

Human clinical data on this controversy are equally difficult to interpret because of retrospective study designs and confounding influences as well as the effect of the endogenous opioid system per se on immunity.9 In a Danish population-based cohort study99 of more than 30,000 patients, the authors found no association between the use of opioids and breast cancer recurrence (adjusted HR 1.0, 95% CI 0.92–1.1). Cata et al100 demonstrated that the use of intraoperative opioids may be associated with decreased overall survival in the early stages of nonsmall cell lung cancer but not in more advanced cases, and concluded that, until conclusive evidence from randomized controlled trials is available, opioids should continue to be used as a key component of balanced anesthesia. Equally, remifentanil has not been shown to increase colon cancer recurrence rate in another retrospective study.101 The above said is also reflected in a consensus statement, which stated that morphine does not appear to stimulate tumor initiation and that there is currently no evidence that morphine analgesia causes cancer. Furthermore, it was concluded that it is currently unclear whether opioids augment the risk of recurrence and current available research data on this subject are insufficient to suggest a change in practice.102

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NONOPIOID ANALGESIC EFFECTS

COX-2, a key enzyme of prostaglandin synthesis, has been shown to be overexpressed in a variety of cancers.103 COX-2 mediates a wide range of pathophysiologic functions, which are associated with an increase in cancer growth and invasion, activating signaling pathways that control cell proliferation, migration, apoptosis, and angiogenesis.104 Downstream effectors of the COX signaling pathways including PGE-2, one of the key prostanoids, have been implicated in the carcinogenesis of gastrointestinal cancers.105 The prostaglandin PGE-2 receptor subtypes EP3 (in prostate cancer) and EP4 (in colorectal cancer) have been shown to be potential attractive targets in chemoprevention or treatment with nonsteroidal antiinflammatory drugs (NSAIDS) and COX-2 inhibitors (or COXIBs) in experimental settings.106,107 In vitro and animal studies have shown that treatment with celecoxib can inhibit cell proliferation, migration, and invasion103 as well as tumor volume and angiogenesis.108

A recent systematic review and meta-analysis,94 pertaining to animals only, concluded that NSAIDs are the class of medications with the highest efficacy in reducing the incidence and number of tumor metastases in experimental animal models. Large-scale epidemiologic trials, albeit in a more long-term preventive setting, have established that long-term administration of COXIBs has a protective effect on the prevention of colorectal adenoma progression.109,110

Perioperative data on this topic are scarce. A recent meta-analysis found that NSAIDs and aspirin, after but not before diagnosis, were associated with improved breast cancer survival and relapse/metastasis.111 The timing above is in contrast to a retrospective study in breast cancer patients112 undergoing mastectomy in which the authors observed that perioperative administration of ketorolac reduced relapses. Another single-center retrospective study demonstrated that the intraoperative administration of a single dose of ketorolac or diclofenac in conservative breast cancer surgery has yielded a longer disease-free survival (HR 0.57 95% CI 0.37–0.89, P = .01) and an improved overall survival (HR 0.35, 95% CI 0.17–0.70, P = .03).113,114

In conclusion, despite the positive effect of NSAIDs on long-term outcome of colorectal adenoma progression and a solid experimental evidence base, clinical data to recommend or refute perioperative NSAID administration in the cancer setting at this stage is limited.

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HYPNOTIC AGENTS

Intravenous Agents

Propofol may have antitumor effects in rodent studies and in vitro studies via (a) promotion of NK cell cytotoxicity,115 (b) reduction of cancer cell motility and invasiveness,116 (c) inhibition of cyclooxygenase (COX),117 and (d) reduction of hypoxia-inducible factor-1α (HIF-1α).118 A clinical study119 revealed that the serum of patients treated with propofol showed increased levels of activation and differentiation of peripheral T-helper cells. Furthermore, a randomized trial that assigned patients to either a propofol-epidural based group versus a sevoflurane/systemic opioids based anesthetic regime has been shown to reduce serum concentrations of serum-vascular endothelial growth factor-C (VEGF-C), TGF-β, and IL-6, all markers of angiogenesis and metastasis in colon cancer patients.120 Two other interesting studies (by the same group) revealed that serum from patients receiving propofol/paravertebral anesthesia for breast cancer surgery inhibited proliferation of breast cancer cells in vitro to a greater extent than that from patients receiving sevoflurane/opioid anesthesia-analgesia121 and increased NK cell activation and cytotoxicity to estrogen–progesterone receptor positive breast cancer cells in vitro in the propofol/paravertebral group.122 Another clinical study123 demonstrated inhibited proliferation and invasion and induced apoptosis of colon cancer cells that were exposed in vitro to serum from patients receiving a propofol epidural anesthetic compared with serum from the volatile anesthetic plus systemic opioid group. The results of the above studies have to be interpreted with caution, however, in that it remains speculative whether the effect was directly attributable to (a) propofol and/or (b) local anesthetics, and/or (c) regional anesthetic technique and/or (d) improved pain control, and/or (e) volatile-sparing effect, and/or (f) an opioid-sparing net effect, and/or (g) all of the above factors combined.

Clinically, first insights in favor of a propofol-based regime in cancer surgery are emerging. In a retrospective study of more than 7000 patients treated with elective surgery at a comprehensive cancer center over a 3-year period that evaluated long-term survival in patients receiving general anesthesia with volatile anesthetics compared with total intravenous anesthesia with propofol/remifentanil demonstrated that volatile anesthesia was associated with a hazard ratio of 1.46 (CI 1.29–1.66) for death after propensity match scoring and multivariable analysis.124 Although the retrospective design of the study does not warrant any causation, it appears to support the above basic science data.

It remains premature at this stage to advocate for a propofol total intravenous technique only based on in vitro experiments and in the absence of more clinically robust data. However, the authors feel that, in supplementation with regional analgesic techniques, propofol may potentially evolve as an attractive alternative to volatile-based anesthesia.

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Volatile Anesthetics

A renewed interest has been sparked into the carcinogenic effects of volatile anesthetics. Shi et al125 demonstrated that sevoflurane increases the proliferation of glioma stem cells (GSCs) in vitro through hypoxia-inducible factors (HIF) and thus may enhance tumor growth.

Isoflurane has been shown to increase insulin-like growth factors (IGFs) and HIF-1α in in vitro studies, which can increase the malignancy potential of cancer cells via proliferation, migration, angiogenesis, and chemoresistance.18,118 In conflict with this finding, it has been shown that sevoflurane reduces cell motility and invasion by reduction of MMP-2 and MMP-9126 and xenon inhibited migration in breast adenocarcinoma cells127 and preserved cell-mediated and humoral immune status in patients with breast cancer in a comparative study.128 Furthermore, desflurane has been implicated with improved disease-free survival in a cohort study in patients with stage 3 ovarian cancer.129

The results of the in vitro studies in the very heterogeneous nature of cancer and oncogenetics have to be interpreted cautiously. In vitro studies do not reflect the human cellular environmental a cancer cell lives in, and thus may not be ideal to extrapolate to clinical outcome.130 Clinical data surrounding N2O seem to indicate that N2O may be safe to use in cancer surgery.131,132

Summing up, ex vivo121 and experimental data116,133 suggest an antitumor effect of propofol; however, it is too premature to discount volatile anesthetics as contraindicated in cancer surgery.130

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PAIN-RELATED IMMUNE SUPPRESSION

Next to the effects of hypnotic and analgesic drugs, pain itself may influence body homeostasis and cancer progression. For example, rodent studies show that effective perioperative analgesia can prevent surgery-induced decreases in host resistance against metastasis formation,19,134 with preoperative dosing appearing to be the most effective strategy to improve host immune function.135 A recent systematic review and meta-analysis of experimental studies showed that the provision of effective analgesia reduces both the number and incidences of metastases in experimental cancer models.94

Pain-related immune suppression is thought to be due to neuroendocrine responses including triggering of the sympathetic nervous system and HPA axis136 as well as an increase in the immunosuppressive β-endorphin concentration in the peripheral immune system.137

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FUTURE AREAS OF RESEARCH DIRECTION

Randomized Controlled Trials

Several randomized controlled trials that compare regional anesthesia/analgesia techniques either alone or in combination with a general anesthetic, compared with general anesthesia and systemic opioids regarding cancer recurrence in breast cancer (NCT00418457),138 melanoma (NCT01588847),139 and colorectal surgery (NCT00684229, NCT0131861),140,141 are currently ongoing and results are eagerly awaited. However, expectations regarding obtaining conclusive proof of the superiority of one particular anesthetic technique over another from these clinical trials may have to be interpreted cautiously. As already mentioned above, the generalizability of cancer clinical trials have been called into question as to the lack of comparability between clinical trial participants and nonparticipants as well as excess complexity, expense, and time required to recruit and inadequate representativeness.73,74

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Perioperative Stress and Anxiety

Patients diagnosed with cancer experience high levels of anxiety and stress perioperatively that is translated to a pathophysiologic stress response with high levels of circulating catecholamines and cortisol levels.80 Furthermore, circulating catecholamines lead to Th2 dominance with the modulation of cellular immunity.8 Perioperative stress can lead to reduced lymphocyte numbers and HLA-DR antigen expression on lymphocytes and monocytes.142 Interestingly, the administration of β-adrenergic receptor antagonists (and COX-2 inhibitors) in mice have improved recurrence-free survival and reduced markers of postoperative immunosuppression in animal models.143,144

Perioperative treatment with β-blockers is associated with attenuating the surgical-induced reduction of NK cell cytotoxicity in animal studies.145 However, the evidence in favor of antitumor effects of β-blockers is weak at best and conflicting, with some retrospective studies showing reduced tumor recurrence and metastasis in breast cancer patients146 and longer overall survival in advanced-stage colorectal cancer patients,147 whereas others (also retrospective) show no association between β-blockade and tumor recurrence.148,149

Psychological interventions including cognitive behavioral therapy, in particular during the short perioperative timeframe when timing seems critical, might improve survival rates.80 Currently, the effectiveness to reduce immune suppression and cancer recurrence, thought to be compounded by circulating catecholamines and prostaglandins, is investigated with a combination treatment of COX-2 inhibitors and β-blockers preoperatively in breast cancer surgery.150

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Nutrition

“Immune-enhancing nutrition” consisting of specialized nutrients including glutamine, alanine, omega-3 fatty acids have been shown to reduce the incidence of infectious complications in high-risk surgical patients and reduce inflammatory and cytokine production and thus could serve as an intriguing adjunct in the prevention of tumor recurrence perioperatively in the future.151 The supplementation of omega-3 fatty acids is associated with antiinflammatory effects,152 clinical attenuation of postoperative NK cell suppression, increased resistance to metastasis formation, and enhances recurrence-free survival.153

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Immune Stimulation

Perioperative immune stimulation with agents such as TLR-9 agonist or TLR-4 agonist, both of which boost T-cell numbers and dendritic cells, might hold promise for future therapeutic options, with the caveat being that psychological and surgical stressors can render these immune stimulatory therapeutic options ineffective.80 One option to circumvent this phenomenon is to combine β-blockers and/or COX-2 inhibitors in addition to the immune stimulants to provide a synergistic effect.144,154

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CONCLUSIONS

The perioperative period is characterized by the occurrence of circulating tumor cells and minimal residual disease, which may lead to tumor recurrence. In theory, the optimal preservation of perioperative homeostasis should maximize the ability of the patient’s immune system to combat these tumor cells. It may further well be the case that anesthetic interventions are beneficial only in certain circumstances and types of cancer surgery.

The authors believe that, even though the evidence base is inconclusive, some general recommendations should be given. First, regional anesthesia has not shown to be universally beneficial in cancer surgery. However, optimal prevention of the surgical stress response coupled with effective pain treatment and potentially decreased all-cause mortality after major cancer surgery still means that regional techniques are good perioperative techniques for major open cancer surgery, such as thoracotomy, upper abdominal laparotomy for pancreatic or hepatic cancer, and individual indications. At this point, the indication for regional anesthesia should be based on the specific type of surgery and patient characteristics, rather than specifically to prevent cancer recurrence. A substantial share of the effects of regional anesthesia can be duplicated by intravenous application of local anesthetics. Therefore, they may be a viable alternative when epidural anesthesia is not indicated by evidence, such as prostate resection or laparoscopic bowel resection.

Analgesics are typically administered as multimodal regimens, and the authors believe that the preliminary evidence on NSAID warrants their use in perioperative regimens whenever feasible and opioids should continue to form a vital part in the perioperative analgesic regime.

No definitive evidence exists to recommend one type of anesthetic over another, but the experimental evidence is strongest in favor of propofol for induction and maintenance.

General interventions to preserve homeostasis such as patient blood management, temperature management, and preoperative optimization have only partly been investigated in the setting of cancer surgery, but, nevertheless, they should be a part of any comprehensive perioperative management plan for major surgery.

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ACKNOWLEDGMENT

The authors wish to thank Lars Eriksson from The University of Queensland Library, Brisbane, QLD, Australia, for his help in the preparation on this manuscript.

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DISCLOSURES

Name: Mir Wais Sekandarzad, FANZCA, FFPMANZCA, DESA.

Contribution: This author helped collect data, analyze the data, and prepare the manuscript.

Conflicts of Interest: The author has no conflicts of interest to declare.

Name: André A.J. van Zundert, MD, PhD, FRCA, EDRA, FANZCA.

Contribution: This author helped collect data, analyze the data, and prepare the manuscript.

Conflicts of Interest: The author has no conflicts of interest to declare.

Name: Philipp B. Lirk, MD, PhD.

Contribution: This author helped with the preparation of the manuscript.

Conflicts of Interest: The author has no conflicts of interest to declare.

Name: Chris W. Doornebal, MD.

Contribution: This author helped with the preparation of the manuscript.

Conflicts of Interest: The author has no conflicts of interest to declare.

Name: Markus W. Hollmann, MD, PhD, DEAA.

Contribution: This author helped collect data, analyze the data, and prepare the manuscript.

Conflicts of Interest: The author has no conflicts of interest to declare and serves as a Section Editor for the International Society for Anesthetic Pharmacology (Preclinical Pharmacology), Anesthesia & Analgesia.

This manuscript was handled by: Jianren Mao, MD, PhD.

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