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.
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).
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.
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
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.
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.
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
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.
EFFECTS OF ANESTHETICS AND ANALGESICS, AND PERIOPERATIVE FACTORS
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
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
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
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.
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.
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
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
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
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
“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
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
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.
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.
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.
2. Tai LH, de Souza CT, Bélanger S, et al. Preventing postoperative metastatic disease by inhibiting surgery-induced dysfunction in natural killer cells. Cancer Res. 2013;73:97–107.
3. Seth R, Tai LH, Falls T, et al. Surgical stress promotes the development of cancer metastases by a coagulation-dependent mechanism involving natural killer cells in a murine model. Ann Surg. 2013;258:158–168.
4. Snyder GL, Greenberg S. Effect of anaesthetic technique and other perioperative factors on cancer recurrence. Br J Anaesth. 2010;105:106–115.
5. Lim SH, Spring KJ, de Souza P, MacKenzie S, Bokey L. Circulating tumour cells and circulating nucleic acids as a measure of tumour dissemination in non-metastatic colorectal cancer surgery. Eur J Surg Oncol. 2015;41:309–314.
6. Kuo CP, Jao SW, Chen KM, et al. Comparison of the effects of thoracic epidural analgesia and i.v. infusion with lidocaine on cytokine response, postoperative pain and bowel function in patients undergoing colonic surgery. Br J Anaesth. 2006;97:640–646.
7. Sessler DI. Long-term consequences of anesthetic management. Anesthesiology. 2009;111:1–4.
8. Kurosawa S. Anesthesia in patients with cancer disorders. Curr Opin Anaesthesiol. 2012;25:376–384.
9. Ash SA, Buggy DJ. Does regional anaesthesia and analgesia or opioid analgesia influence recurrence after primary cancer surgery? An update of available evidence. Best Pract Res Clin Anaesthesiol. 2013;27:441–456.
10. Colvin LA, Fallon MT, Buggy DJ. Cancer biology, analgesics, and anaesthetics: is there a link? Br J Anaesth. 2012;109:140–143.
11. Kavanagh T, Buggy DJ. Can anaesthetic technique effect postoperative outcome? Curr Opin Anaesthesiol. 2012;25:185–198.
12. Gottschalk A, Sharma S, Ford J, Durieux ME, Tiouririne M. Review article: the role of the perioperative period in recurrence after cancer surgery. Anesth Analg. 2010;110:1636–1643.
13. McAlister FA, Clark HD, van Walraven C, et al. The medical review article revisited: has the science improved? Ann Intern Med. 1999;131:947–951.
14. Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science. 2011;331:1565–1570.
15. Kun L, Tang L, Wang J, Yang H, Ren J. Effect of combined general/epidural anesthesia on postoperative NK cell activity and cytokine response in gastric cancer patients undergoing radical resection. Hepatogastroenterology. 2014;61:1142–1147.
16. Chen WK, Ren L, Wei Y, Zhu DX, Miao CH, Xu JM. General anesthesia combined with epidural anesthesia ameliorates the effect of fast-track surgery by mitigating immunosuppression and facilitating intestinal functional recovery in colon cancer patients. Int J Colorectal Dis. 2015;30:475–481.
17. Meserve JR, Kaye AD, Prabhakar A, Urman RD. The role of analgesics in cancer propagation. Best Pract Res Clin Anaesthesiol. 2014;28:139–151.
18. Luo X, Zhao H, Hennah L, et al. Impact of isoflurane on malignant capability of ovarian cancer in vitro
. Br J Anaesth. 2015;114:831–839.
19. Page GG, Blakely WP, Ben-Eliyahu S. Evidence that postoperative pain is a mediator of the tumor-promoting effects of surgery in rats. Pain. 2001;90:191–199.
20. Liu SS, Wu CL. The effect of analgesic technique on postoperative patient-reported outcomes including analgesia: a systematic review. Anesth Analg. 2007;105:789–808.
21. Piegeler T, Votta-Velis EG, Liu G, et al. Antimetastatic potential of amide-linked local anesthetics: inhibition of lung adenocarcinoma cell migration and inflammatory Src signaling independent of sodium channel blockade. Anesthesiology. 2012;117:548–559.
22. Sakaguchi M, Kuroda Y, Hirose M. The antiproliferative effect of lidocaine on human tongue cancer cells with inhibition of the activity of epidermal growth factor receptor. Anesth Analg. 2006;102:1103–1107.
23. Lucchinetti E, Awad AE, Rahman M, et al. Antiproliferative effects of local anesthetics on mesenchymal stem cells: potential implications for tumor spreading and wound healing. Anesthesiology. 2012;116:841–856.
24. Mao L, Lin S, Lin J. The effects of anesthetics on tumor progression. Int J Physiol Pathophysiol Pharmacol. 2013;5:1–10.
25. Lirk P, Berger R, Hollmann MW, Fiegl H. Lidocaine time- and dose-dependently demethylates deoxyribonucleic acid in breast cancer cell lines in vitro
. Br J Anaesth. 2012;109:200–207.
26. Lirk P, Hollmann MW, Fleischer M, Weber NC, Fiegl H. Lidocaine and ropivacaine, but not bupivacaine, demethylate deoxyribonucleic acid in breast cancer cells in vitro
. Br J Anaesth. 2014;113(suppl 1):i32–i38.
27. Li K, Yang J, Han X. Lidocaine sensitizes the cytotoxicity of cisplatin in breast cancer cells via up-regulation of RARβ2 and RASSF1A demethylation. Int J Mol Sci. 2014;15:23519–23536.
28. Chang YC, Liu CL, Chen MJ, et al. Local anesthetics induce apoptosis in human breast tumor cells. Anesth Analg. 2014;118:116–124.
29. Schlagenhauff B, Ellwanger U, Breuninger H, Stroebel W, Rassner G, Garbe C. Prognostic impact of the type of anaesthesia used during the excision of primary cutaneous melanoma. Melanoma Res. 2000;10:165–169.
30. Yardeni IZ, Beilin B, Mayburd E, Levinson Y, Bessler H. The effect of perioperative intravenous lidocaine on postoperative pain and immune function. Anesth Analg. 2009;109:1464–1469.
32. Fairhurst C, Watt I, Martin F, Bland M, Brackenbury WJ. Sodium channel-inhibiting drugs and survival of breast, colon and prostate cancer: a population-based study. Sci Rep. 2015;5:16758.
33. Biki B, Mascha E, Moriarty DC, Fitzpatrick JM, Sessler DI, Buggy DJ. Anesthetic technique for radical prostatectomy surgery affects cancer recurrence: a retrospective analysis. Anesthesiology. 2008;109:180–187.
34. Wuethrich PY, Hsu Schmitz SF, Kessler TM, et al. Potential influence of the anesthetic technique used during open radical prostatectomy on prostate cancer-related outcome: a retrospective study. Anesthesiology. 2010;113:570–576.
35. de Oliveira GS Jr., Ahmad S, Schink JC, Singh DK, Fitzgerald PC, McCarthy RJ. Intraoperative neuraxial anesthesia but not postoperative neuraxial analgesia is associated with increased relapse-free survival in ovarian cancer patients after primary cytoreductive surgery. Reg Anesth Pain Med. 2011;36:271–277.
36. Gupta A, Björnsson A, Fredriksson M, Hallböök O, Eintrei C. Reduction in mortality after epidural anaesthesia and analgesia in patients undergoing rectal but not colonic cancer surgery: a retrospective analysis of data from 655 patients in central Sweden. Br J Anaesth. 2011;107:164–170.
37. Cummings KC III, Xu F, Cummings LC, Cooper GS. A comparison of epidural analgesia and traditional pain management effects on survival and cancer recurrence after colectomy: a population-based study. Anesthesiology. 2012;116:797–806.
38. Gottschalk A, Brodner G, Van Aken HK, Ellger B, Althaus S, Schulze HJ. Can regional anaesthesia for lymph-node dissection improve the prognosis in malignant melanoma? Br J Anaesth. 2012;109:253–259.
39. Holler JP, Ahlbrandt J, Burkhardt E, et al. Peridural analgesia may affect long-term survival in patients with colorectal cancer after surgery (PACO-RAS-Study): an analysis of a cancer registry. Ann Surg. 2013;258:989–993.
40. Hiller JG, Hacking MB, Link EK, Wessels KL, Riedel BJ. Perioperative epidural analgesia reduces cancer recurrence after gastro-oesophageal surgery. Acta Anaesthesiol Scand. 2014;58:281–290.
41. Scavonetto F, Yeoh TY, Umbreit EC, et al. Association between neuraxial analgesia, cancer progression, and mortality after radical prostatectomy: a large, retrospective matched cohort study. Br J Anaesth. 2014;113(suppl 1):i95–i102.
42. Exadaktylos AK, Buggy DJ, Moriarty DC, Mascha E, Sessler DI. Can anesthetic technique for primary breast cancer surgery affect recurrence or metastasis? Anesthesiology. 2006;105:660–664.
43. Christopherson R, James KE, Tableman M, Marshall P, Johnson FE. Long-term survival after colon cancer surgery: a variation associated with choice of anesthesia. Anesth Analg. 2008;107:325–332.
44. Merquiol F, Montelimard AS, Nourissat A, Molliex S, Zufferey PJ. Cervical epidural anesthesia is associated with increased cancer-free survival in laryngeal and hypopharyngeal cancer surgery: a retrospective propensity-matched analysis. Reg Anesth Pain Med. 2013;38:398–402.
45. Lin L, Liu C, Tan H, Ouyang H, Zhang Y, Zeng W. Anaesthetic technique may affect prognosis for ovarian serous adenocarcinoma: a retrospective analysis. Br J Anaesth. 2011;106:814–822.
46. Tseng KS, Kulkarni S, Humphreys EB, et al. Spinal anesthesia does not impact prostate cancer recurrence in a cohort of men undergoing radical prostatectomy: an observational study. Reg Anesth Pain Med. 2014;39:284–288.
47. Tsui BC, Rashiq S, Schopflocher D, et al. Epidural anesthesia and cancer recurrence rates after radical prostatectomy. Can J Anesth. 2010;57:107–112.
48. Forget P, Tombal B, Scholtès JL, et al. Do intraoperative analgesics influence oncological outcomes after radical prostatectomy for prostate cancer? Eur J Anaesthesiol. 2011;28:830–835.
49. Ehdaie B, Sjoberg DD, Dalecki PH, Scardino PT, Eastham JA, Amar D. Association of anesthesia technique for radical prostatectomy with biochemical recurrence: a retrospective cohort study. Can J Anesth. 2014;61:1068–1074.
50. Churruca I, Sabaté S, Mayoral JF, Carles Ortiz J, Sierra P, Puigvert F. Anaesthetic technique has not been associated with prostate cancer recurrence. Br J Anaesth. 2012;108:ii16.
51. Wuethrich PY, Thalmann GN, Studer UE, Burkhard FC. Epidural analgesia during open radical prostatectomy does not improve long-term cancer-related outcome: a retrospective study in patients with advanced prostate cancer. PLoS One. 2013;8:e72873.
52. Roiss M, Schiffmann J, Tennstedt P, et al. Oncological long-term outcome of 4772 patients with prostate cancer undergoing radical prostatectomy: does the anaesthetic technique matter? Eur J Surg Oncol. 2014;40:1686–1692.
53. Sprung J, Scavonetto F, Yeoh TY, et al. Outcomes after radical prostatectomy for cancer: a comparison between general anesthesia and epidural anesthesia with fentanyl analgesia: a matched cohort study. Anesth Analg. 2014;119:859–866.
54. Koonce SL, Mclaughlin SA, Eck DL, et al. Breast cancer recurrence in patients receiving epidural and paravertebral anesthesia: a retrospective, case-control study. Middle East J Anaesthesiol. 2014;22:567–571.
55. Tsigonis AM, Al-Hamadani M, Linebarger JH, et al. Are cure rates for breast cancer improved by local and regional anesthesia? Reg Anesth Pain Med. 2016;41:339–347.
56. Ismail H, Ho KM, Narayan K, Kondalsamy-Chennakesavan S. Effect of neuraxial anaesthesia on tumour progression in cervical cancer patients treated with brachytherapy: a retrospective cohort study. Br J Anaesth. 2010;105:145–149.
57. Lacassie HJ, Cartagena J, Brañes J, Assel M, Echevarría GC. The relationship between neuraxial anesthesia and advanced ovarian cancer-related outcomes in the Chilean population. Anesth Analg. 2013;117:653–660.
58. Capmas P, Billard V, Gouy S, et al. Impact of epidural analgesia on survival in patients undergoing complete cytoreductive surgery for ovarian cancer. Anticancer Res. 2012;32:1537–1542.
59. Cummings KC III, Patel M, Htoo PT, Bakaki PM, Cummings LC, Koroukian S. A comparison of the effects of epidural analgesia versus traditional pain management on outcomes after gastric cancer resection: a population-based study. Reg Anesth Pain Med. 2014;39:200–207.
60. Heinrich S, Janitz K, Merkel S, Klein P, Schmidt J. Short- and long term effects of epidural analgesia on morbidity and mortality of esophageal cancer surgery. Langenbecks Arch Surg. 2015;400:19–26.
61. Myles PS, Peyton P, Silbert B, Hunt J, Rigg JR, Sessler DI; Investigators ATG. Perioperative epidural analgesia for major abdominal surgery for cancer and recurrence-free survival: randomised trial. BMJ. 2011;342:d1491.
62. Gottschalk A, Ford JG, Regelin CC, et al. Association between epidural analgesia and cancer recurrence after colorectal cancer surgery. Anesthesiology. 2010;113:27–34.
63. Day A, Smith R, Jourdan I, Fawcett W, Scott M, Rockall T. Retrospective analysis of the effect of postoperative analgesia on survival in patients after laparoscopic resection of colorectal cancer. Br J Anaesth. 2012;109:185–190.
64. Binczak M, Tournay E, Billard V, Rey A, Jayr C. Major abdominal surgery for cancer: does epidural analgesia have a long-term effect on recurrence-free and overall survival? Ann Fr Anesth Reanim. 2013;32:e81–e88.
65. Lai R, Peng Z, Chen D, et al. The effects of anesthetic technique on cancer recurrence in percutaneous radiofrequency ablation of small hepatocellular carcinoma. Anesth Analg. 2012;114:290–296.
66. Cata JP, Hernandez M, Lewis VO, Kurz A. Can regional anesthesia and analgesia prolong cancer survival after orthopaedic oncologic surgery? Clin Orthop Relat Res. 2014;472:1434–1441.
67. Vogelaar FJ, Lips DJ, van Dorsten FR, Lemmens VE, Bosscha K. Impact of anaesthetic technique on survival in colon cancer: a review of the literature. Gastroenterol Rep (Oxf). 2016;4:30–34.
68. Weng M, Chen W, Hou W, Li L, Ding M, Miao C. The effect of neuraxial anesthesia on cancer recurrence and survival after cancer surgery: an updated meta-analysis. Oncotarget. 2016;7:15262–15273.
69. Sun Y, Li T, Gan TJ. The effects of perioperative regional anesthesia and analgesia on cancer recurrence and survival after oncology surgery: a systematic review and meta-analysis. Reg Anesth Pain Med. 2015;40:589–598.
70. Cakmakkaya OS, Kolodzie K, Apfel CC, Pace NL. Anaesthetic techniques for risk of malignant tumour recurrence. Cochrane Database Syst Rev. 2014;11:CD008877.
71. Pei L, Tan G, Wang L, et al. Comparison of combined general-epidural anesthesia with general anesthesia effects on survival and cancer recurrence: a meta-analysis of retrospective and prospective studies. PLoS One. 2014;9:e114667.
72. Chen WK, Miao CH. The effect of anesthetic technique on survival in human cancers: a meta-analysis of retrospective and prospective studies. PLoS One. 2013;8:e56540.
73. Elting LS, Cooksley C, Bekele BN, et al. Generalizability of cancer clinical trial results: prognostic differences between participants and nonparticipants. Cancer. 2006;106:2452–2458.
74. Lauer MS, D’Agostino RB Sr.. The randomized registry trial—the next disruptive technology in clinical research? N Engl J Med. 2013;369:1579–1581.
75. Fröbert O, Lagerqvist B, Olivecrona GK, et al.; TASTE Trial. Thrombus aspiration during ST-segment elevation myocardial infarction. N Engl J Med. 2013;369:1587–1597.
76. Schneeweiss S. Learning from big health care data. N Engl J Med. 2014;370:2161–2163.
77. Dalal S, Bruera E. Access to opioid analgesics and pain relief for patients with cancer. Nat Rev Clin Oncol. 2013;10:108–116.
78. Brack A, Rittner HL, Stein C. Immunosuppressive effects of opioids—clinical relevance. J Neuroimmune Pharmacol. 2011;6:490–502.
79. Afsharimani B, Doornebal CW, Cabot PJ, Hollmann MW, Parat MO. Comparison and analysis of the animal models used to study the effect of morphine on tumour growth and metastasis. Br J Pharmacol. 2015;172:251–259.
80. Horowitz M, Neeman E, Sharon E, Ben-Eliyahu S. Exploiting the critical perioperative period to improve long-term cancer outcomes. Nat Rev Clin Oncol. 2015;12:213–226.
81. Singleton PA, Lingen MW, Fekete MJ, Garcia JG, Moss J. Methylnaltrexone inhibits opiate and VEGF-induced angiogenesis: role of receptor transactivation. Microvasc Res. 2006;72:3–11.
82. Mathew B, Lennon FE, Siegler J, et al. The novel role of the mu opioid receptor in lung cancer progression: a laboratory investigation. Anesth Analg. 2011;112:558–567.
83. Fujioka N, Nguyen J, Chen C, et al. Morphine-induced epidermal growth factor pathway activation in non-small cell lung cancer. Anesth Analg. 2011;113:1353–1364.
84. Ecimovic P, Murray D, Doran P, McDonald J, Lambert DG, Buggy DJ. Direct effect of morphine on breast cancer cell function in vitro
: role of the NET1 gene. Br J Anaesth. 2011;107:916–923.
85. Gach K, Wyrębska A, Fichna J, Janecka A. The role of morphine in regulation of cancer cell growth. Naunyn Schmiedebergs Arch Pharmacol. 2011;384:221–230.
86. Farooqui M, Li Y, Rogers T, et al. COX-2 inhibitor celecoxib prevents chronic morphine-induced promotion of angiogenesis, tumour growth, metastasis and mortality, without compromising analgesia. Br J Cancer. 2007;97:1523–1531.
87. Liao SJ, Zhou YH, Yuan Y, et al. Triggering of Toll-like receptor 4 on metastatic breast cancer cells promotes αvβ3-mediated adhesion and invasive migration. Breast Cancer Res Treat. 2012;133:853–863.
88. Matzner P, Sorski L, Shaashua L, et al. Perioperative treatment with the new synthetic TLR-4 agonist GLA-SE reduces cancer metastasis without adverse effects. Int J Cancer. 2016;138:1754–1764.
89. Friesen C, Hormann I, Roscher M, et al. Opioid receptor activation triggering downregulation of cAMP improves effectiveness of anti-cancer drugs in treatment of glioblastoma. Cell Cycle. 2014;13:1560–1570.
90. Friesen C, Roscher M, Hormann I, et al. Cell death sensitization of leukemia cells by opioid receptor activation. Oncotarget. 2013;4:677–690.
91. Sacerdote P. Opioids and the immune system. Palliat Med. 2006;20(suppl 1):s9–s15.
92. Doornebal CW, Vrijland K, Hau CS, et al. Morphine does not facilitate breast cancer progression in two preclinical mouse models for human invasive lobular and HER2+
breast cancer. Pain. 2015;156:1424–1432.
93. Doornebal CW, Klarenbeek S, Braumuller TM, et al. A preclinical mouse model of invasive lobular breast cancer metastasis. Cancer Res. 2013;73:353–363.
94. Hooijmans CR, Geessink FJ, Ritskes-Hoitinga M, Scheffer GJ. A systematic review and meta-analysis of the ability of analgesic drugs to reduce metastasis in experimental cancer models. Pain. 2015;156:1835–1844.
95. Koodie L, Yuan H, Pumper JA, et al. Morphine inhibits migration of tumor-infiltrating leukocytes and suppresses angiogenesis associated with tumor growth in mice. Am J Pathol. 2014;184:1073–1084.
96. Koodie L, Ramakrishnan S, Roy S. Morphine suppresses tumor angiogenesis through a HIF-1alpha/p38MAPK pathway. Am J Pathol. 2010;177:984–997.
97. Afsharimani B, Baran J, Watanabe S, Lindner D, Cabot PJ, Parat MO. Morphine and breast tumor metastasis: the role of matrix-degrading enzymes. Clin Exp Metastasis. 2014;31:149–158.
98. Khabbazi S, Goumon Y, Parat MO. Morphine modulates interleukin-4 or breast cancer cell-induced pro-metastatic activation of macrophages. Sci Rep. 2015;5:11389.
99. Cronin-Fenton DP, Heide-Jørgensen U, Ahern TP, et al. Opioids and breast cancer recurrence: a Danish population-based cohort study. Cancer. 2015;121:3507–3514.
100. Cata JP, Keerty V, Keerty D, et al. A retrospective analysis of the effect of intraoperative opioid dose on cancer recurrence after non-small cell lung cancer resection. Cancer Med. 2014;3:900–908.
101. Kurosaki H, Fujii K, Nishikawa K. Does remifentanil affect the incidence of colon cancer recurrence? Anesth Analg. 2012;114:S459.
102. Buggy DJ, Borgeat A, Cata J, et al. Consensus statement from the BJA Workshop on Cancer and Anaesthesia. Br J Anaesth. 2015;114:2–3.
103. Yusup G, Akutsu Y, Mutallip M, et al. A COX-2 inhibitor enhances the antitumor effects of chemotherapy and radiotherapy for esophageal squamous cell carcinoma. Int J Oncol. 2014;44:1146–1152.
104. Muraki C, Ohga N, Hida Y, et al. Cyclooxygenase-2 inhibition causes antiangiogenic effects on tumor endothelial and vascular progenitor cells. Int J Cancer. 2012;130:59–70.
105. Cathcart MC, O’Byrne KJ, Reynolds JV, O’Sullivan J, Pidgeon GP. COX-derived prostanoid pathways in gastrointestinal cancer development and progression: novel targets for prevention and intervention. Biochim Biophys Acta. 2012;1825:49–63.
106. Kashiwagi E, Shiota M, Yokomizo A, et al. Prostaglandin receptor EP3 mediates growth inhibitory effect of aspirin through androgen receptor and contributes to castration resistance in prostate cancer cells. Endocr Relat Cancer. 2013;20:431–441.
107. Chang J, Vacher J, Yao B, et al. Prostaglandin E receptor 4 (EP4) promotes colonic tumorigenesis. Oncotarget. 2015;6:33500–33511.
108. Sui W, Zhang Y, Wang Z, et al. Antitumor effect of a selective COX-2 inhibitor, celecoxib, may be attributed to angiogenesis inhibition through modulating the PTEN/PI3K/Akt/HIF-1 pathway in an H22
murine hepatocarcinoma model. Oncol Rep. 2014;31:2252–2260.
109. Arber N, Spicak J, Rácz I, et al. Five-year analysis of the prevention of colorectal sporadic adenomatous polyps trial. Am J Gastroenterol. 2011;106:1135–1146.
110. Bertagnolli MM, Eagle CJ, Zauber AG, et al.; Adenoma Prevention with Celecoxib Study Investigators. Five-year efficacy and safety analysis of the Adenoma Prevention with Celecoxib Trial. Cancer Prev Res (Phila). 2009;2:310–321.
111. Huang XZ, Gao P, Sun JX, et al. Aspirin and nonsteroidal anti-inflammatory drugs after but not before diagnosis are associated with improved breast cancer survival: a meta-analysis. Cancer Causes Control. 2015;26:589–600.
112. Retsky M, Rogers R, Demicheli R, et al. NSAID analgesic ketorolac used perioperatively may suppress early breast cancer relapse: particular relevance to triple negative subgroup. Breast Cancer Res Treat. 2012;134:881–888.
113. Forget P, Bentin C, Machiels JP, Berliere M, Coulie PG, De Kock M. Intraoperative use of ketorolac or diclofenac is associated with improved disease-free survival and overall survival in conservative breast cancer surgery. Br J Anaesth. 2014;113(suppl 1):i82–i87.
114. Forget P, Vandenhende J, Berliere M, et al. Do intraoperative analgesics influence breast cancer recurrence after mastectomy? A retrospective analysis. Anesth Analg. 2010;110:1630–1635.
115. Kushida A, Inada T, Shingu K. Enhancement of antitumor immunity after propofol treatment in mice. Immunopharmacol Immunotoxicol. 2007;29:477–486.
116. Miao Y, Zhang Y, Wan H, Chen L, Wang F. GABA-receptor agonist, propofol inhibits invasion of colon carcinoma cells. Biomed Pharmacother. 2010;64:583–588.
117. Inada T, Kubo K, Kambara T, Shingu K. Propofol inhibits cyclo-oxygenase activity in human monocytic THP-1 cells. Can J Anesth. 2009;56:222–229.
118. Huang H, Benzonana LL, Zhao H, et al. Prostate cancer cell malignancy via modulation of HIF-1α pathway with isoflurane and propofol alone and in combination. Br J Cancer. 2014;111:1338–1349.
119. Ren XF, Li WZ, Meng FY, Lin CF. Differential effects of propofol and isoflurane on the activation of T-helper cells in lung cancer patients. Anaesthesia. 2010;65:478–482.
120. Xu YJ, Chen WK, Zhu Y, Wang SL, Miao CH. Effect of thoracic epidural anaesthesia on serum vascular endothelial growth factor C and cytokines in patients undergoing anaesthesia and surgery for colon cancer. Br J Anaesth. 2014;113(suppl 1):i49–i55.
121. Deegan CA, Murray D, Doran P, Ecimovic P, Moriarty DC, Buggy DJ. Effect of anaesthetic technique on oestrogen receptor-negative breast cancer cell function in vitro
. Br J Anaesth. 2009;103:685–690.
122. Buckley A, Quaid S, Johnson P, Buggy D. Serum from women undergoing breast cancer surgery, randomized to propofol-paravertebral anaesthetic technique, maintain natural killer cell anti-tumour activity compared with sevoflurane-opioid technique. Eur J Anaesthesiol. 2014;31:2.
123. Xu YJ, Li SY, Cheng Q, et al. Effects of anaesthesia on proliferation, invasion and apoptosis of LoVo colon cancer cells in vitro
. Anaesthesia. 2016;71:147–154.
124. Wigmore TJ, Mohammed K, Jhanji S. Long-term survival for patients undergoing volatile versus IV anesthesia for cancer surgery: a retrospective analysis. Anesthesiology. 2016;124:69–79.
125. Shi QY, Zhang SJ, Liu L, et al. Sevoflurane promotes the expansion of glioma stem cells through activation of hypoxia-inducible factors in vitro
. Br J Anaesth. 2015;114:825–30.
126. Liang H, Gu M, Yang C, Wang H, Wen X, Zhou Q. Sevoflurane inhibits invasion and migration of lung cancer cells by inactivating the p38 MAPK signaling pathway. J Anesth. 2012;26:381–392.
127. Ash SA, Valchev GI, Looney M, et al. Xenon decreases cell migration and secretion of a pro-angiogenesis factor in breast adenocarcinoma cells: comparison with sevoflurane. Br J Anaesth. 2014;113(Suppl 1):i14–i21.
128. Avdeev S, Stakheeva M, Odyshev V, Faltin V, Slonimskay E. Effect of xenon anaesthesia on relapse-free survival in treatment of breast cancer: relation with immune status. Eur J Anaesthesiol. 2014;31:11.
129. Elias KM, Kang S, Liu X, Horowitz NS, Berkowitz RS, Frendl G. Anesthetic selection and disease-free survival following optimal primary cytoreductive surgery for stage III epithelial ovarian cancer. Ann Surg Oncol. 2015;22:1341–1348.
130. Durieux ME. Time to dial down the vaporizer? Br J Anaesth. 2015;114:715–716.
131. Fleischmann E, Marschalek C, Schlemitz K, et al. Nitrous oxide may not increase the risk of cancer recurrence after colorectal surgery: a follow-up of a randomized controlled trial. BMC Anesthesiol. 2009;9:1.
132. Weimann J. Toxicity of nitrous oxide. Best Pract Res Clin Anaesthesiol. 2003;17:47–61.
133. Inada T, Kubo K, Shingu K. Possible link between cyclooxygenase-inhibiting and antitumor properties of propofol. J Anesth. 2011;25:569–575.
134. Page GG, Ben-Eliyahu S, Yirmiya R, Liebeskind JC. Morphine attenuates surgery-induced enhancement of metastatic colonization in rats. Pain. 1993;54:21–28.
135. Page GG, McDonald JS, Ben-Eliyahu S. Pre-operative versus postoperative administration of morphine: impact on the neuroendocrine, behavioural, and metastatic-enhancing effects of surgery. Br J Anaesth. 1998;81:216–223.
136. Page GG, Ben-Eliyahu S. The immune-suppressive nature of pain. Semin Oncol Nurs. 1997;13:10–15.
137. Sacerdote P, Manfredi B, Bianchi M, Panerai AE. Intermittent but not continuous inescapable footshock stress affects immune responses and immunocyte beta-endorphin concentrations in the rat. Brain Behav Immun. 1994;8:251–260.
142. Bartal I, Melamed R, Greenfeld K, et al. Immune perturbations in patients along the perioperative period: alterations in cell surface markers and leukocyte subtypes before and after surgery. Brain Behav Immun. 2010;24:376–386.
143. Glasner A, Avraham R, Rosenne E, et al. Improving survival rates in two models of spontaneous postoperative metastasis in mice by combined administration of a beta-adrenergic antagonist and a cyclooxygenase-2 inhibitor. J Immunol. 2010;184:2449–2457.
144. Goldfarb Y, Sorski L, Benish M, Levi B, Melamed R, Ben-Eliyahu S. Improving postoperative immune status and resistance to cancer metastasis: a combined perioperative approach of immunostimulation and prevention of excessive surgical stress responses. Ann Surg. 2011;253:798–810.
145. Benish M, Bartal I, Goldfarb Y, et al. Perioperative use of beta-blockers and COX-2 inhibitors may improve immune competence and reduce the risk of tumor metastasis. Ann Surg Oncol. 2008;15:2042–2052.
146. Powe DG, Voss MJ, Zänker KS, et al. Beta-blocker drug therapy reduces secondary cancer formation in breast cancer and improves cancer specific survival. Oncotarget. 2010;1:628–638.
147. Jansen L, Hoffmeister M, Arndt V, Chang-Claude J, Brenner H. Stage-specific associations between beta blocker use and prognosis after colorectal cancer. Cancer. 2014;120:1178–1186.
148. Cata JP, Villarreal J, Keerty D, et al. Perioperative beta-blocker use and survival in lung cancer patients. J Clin Anesth. 2014;26:106–117.
149. Sakellakis M, Kostaki A, Starakis I, Koutras A. β-blocker use and risk of recurrence in patients with early breast cancer. Chemotherapy. 2014;60:288–289.
151. Pollock GR, Van Way CW III. Immune-enhancing nutrition in surgical critical care. Mo Med. 2012;109:388–392.
152. Hao W, Wong OY, Liu X, Lee P, Chen Y, Wong KK. ω-3 fatty acids suppress inflammatory cytokine production by macrophages and hepatocytes. J Pediatr Surg. 2010;45:2412–2418.
153. Goldfarb Y, Shapiro H, Singer P, et al. Fish oil attenuates surgery-induced immunosuppression, limits post-operative metastatic dissemination and increases long-term recurrence-free survival in rodents inoculated with cancer cells. Clin Nutr. 2012;31:396–404.
154. Avraham R, Benish M, Inbar S, Bartal I, Rosenne E, Ben-Eliyahu S. Synergism between immunostimulation and prevention of surgery-induced immune suppression: an approach to reduce post-operative tumor progression. Brain Behav Immun. 2010;24:952–958.
155. Santamaria LB, Schifilliti D, La Torre D, Fodale V. Drugs of anaesthesia and cancer. Surg Oncol. 2010;19:63–81.