Next Article in Journal
Pharmacological Blockade of TGF-Beta Reduces Renal Interstitial Fibrosis in a Chronic Ischemia–Reperfusion Animal Model
Previous Article in Journal
An Investigation on the Relationships between Mass Spectrometric Collisional Data and Biological Activity/Stability of Some N-Acylethanolamine Acid Amidase (NAAA) β-Lactone Inhibitors
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
DDC
Volume 2
Issue 1
10.3390/ddc2010008
ddc-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Do Certain Anaesthetic Drugs Affect Postoperative Cancer Recurrence Rates? Implications for Drug Discovery

by
Ben A. Wilson
and
Jaideep J. Pandit
*
Nuffield Department of Anaesthetics, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 9DU, UK
*
Author to whom correspondence should be addressed.
Drugs Drug Candidates 2023, 2(1), 121-136; https://doi.org/10.3390/ddc2010008
Submission received: 18 October 2022 / Revised: 2 February 2023 / Accepted: 20 February 2023 / Published: 7 March 2023
(This article belongs to the Section Marketed Drugs)
Browse Figure
Review Reports Versions Notes

Abstract

Recurrence of cancer after primary tumour resection is a leading cause of cancer-related mortality. Preclinical research indicates that surgery induces a stress response that inhibits cell-mediated immunity as a possible basis for risk of recurrence. Other preclinical evidence suggests that, conversely, propofol and local anaesthetics diminish the effects of the surgical stress response and so could directly inhibit cancer progression, and this is supported by several retrospective cohort studies and meta-analyses. However, the first large-scale randomised clinical trial (RCT), comparing recurrence after mastectomy in patients anaesthetised with either propofol/local anaesthetic or sevoflurane/opioids, concluded that recurrence was not significantly improved in the propofol/local anaesthetic group (p = 0.84). Other cancers may prove more responsive and results from a number of ongoing RCTs, encompassing several cancer types, are currently awaited. These trials should establish whether choice of anaesthetic technique is an important determinant of cancer recurrence risk.

1. Introduction

Surgical intervention is routinely employed as a potentially curative measure for many solid tumours, but post-operative recurrence of metastatic cancer is a limitation to improvements in outcomes. Surgery can directly contribute to metastasis and promotion of tumour growth though manual handling. Moreover, the surgical stress response (SSR), and its inhibitory effect on the immune system, are associated with oncogenesis [1]. Preclinical findings about the effects of different anaesthetics on the immune system, and more directly on the prevalence of recurrence, give rise to the proposition that local anaesthetics (LAs) [2] and propofol could limit recurrence (Figure 1) [3,4].
Clinical study of this hypothesis has, so far, yielded no unanimous conclusions. However, the first large-scale clinical trial, recently published in The Lancet, determined that anaesthetic technique has no significant impact on recurrence following mastectomy [1]. It must now be established whether this study settles the issue or if further research is required.

2. Primary Tumour Resection and the Risk of Metastasis

Plasma concentration of inflammatory cytokines increases during surgery [2], remaining high up to 5 days post-operatively, depending on the degree of surgical insult [3]. Stress hormones (e.g., catecholamines and prostaglandins) are released during surgery as a result of sympathetic nervous system (SNS) and hypothalamic-pituitary-axis (HPA) signalling [4]. Dependent on the severity of the procedure, the SSR can last several days [5].
Cancer cells are released into circulation from the primary tumour handling during resection [6], establishing micro-metastases in non-affected tissues at sites remote from the primary tumour, where they can proliferate, develop their own blood supply, and ultimately form large metastatic tumours [7,8]. Thus, 59% of preoperatively asymptomatic breast cancer patients developed circulating tumour cells in the 22 years following mastectomy [9]. Cancer cell presence in plasma correlates strongly with increased risk of recurrence and poor long-term survival [10,11,12].
Surgery might also promote angiogenesis, through a hypoxia-inducible factor (HIF) pathway [13], driving metastatic tumour growth [14]. In a rabbit model of liver cancer, tumour blood flow after surgery increased alongside expression of the angiogenic proteins HIF-1α and related compounds [15]. Furthermore, study of human breast cancer patients after mastectomy has found that angiogenic gene expression increases and growth in distant metastases accelerates [16,17]. Additionally, the primary tumour can secrete both inhibitory and inductive agents, facilitating communication with disseminated cells [18]. Surgical resection disrupts the delicate balance of this control system, towards inductive signalling that could activate circulating tumour cells, promoting metastasis and recurrence [19]. Thus, endostatin and angiostatin concentrations decrease after surgery, while vascular growth and metabolic activity increase in metastases [15,20]. This implies that the primary tumour exercises inhibitory control over vascularisation of distant metastases, which is subdued following resection [21].

3. The Perioperative Period and the Immune System

The occurrence and survival of metastases is linked, intrinsically, to the immune system [20]. To understand how anaesthesia might affect recurrence, this relationship, and the impact of surgery on it, must be understood.
Cancer cells dampen the immune response by modulating the activity of immune cells [22]. Exacerbating inhibition of T, B and natural killer cells (NKCs) is commonly exhibited following surgery [2,23]. NKCs display a particularly potent level of anti-tumour activity and are thought essential in preventing spread and growth of metastases. NKCs are cytotoxic and through recognition of surface signals (e.g., lack of major histocompatibility, MHC, class-1 or the presence of a stress ligand) can selectively recognise and lyse cancer cells [24,25,26]. NKC inactivity correlates strongly with increased susceptibility to a wide range of cancers and the inhibitory effect of surgical stress on NKC activity is well documented in animals [27]. Surgery leads to reduced NKC activity and increased prevalence of metastases in mice; reversed by treatment with a prostaglandin synthesis inhibitor (indomethacin) and β-blocker (nadolol) [28]. Additionally, work in the MT/Ret mouse model showed that perioperative β-blockade (propranolol) delays primary tumour growth and metastasis development, while simultaneously increasing NKC infiltration into the tumour stroma [29]. Increased expression of programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) by immune cells activates the PD-1 and PD-L1 pathways. These pathways increase caspase-3 activity which ultimately induces cell death/apoptosis, depleting the NK and T cell population. The level of expression correlates with the severity of surgical trauma [24,30].
T-helper lymphocytes, functionally divided into TH1 and TH2 subgroups, regulate cytokine expression. Generally, an abundance of TH1 leads to stimulation of the immune system, while TH2 is immunosuppressive [31]. Surgery shifts the ratio in favour of TH2, leading to reduced levels of such immune-stimulating cytokines (termed IFN-γ, IL-2 and IL-12) and an increase in levels of immune-suppressive cytokines (e.g., IL-10 [31]). This shift towards TH2 can plausibly promote postoperative growth in micro-metastases as cell-mediated immunity is suppressed.

4. General Anaesthesia: A Janus Effect?

Surgery for cancer cannot be dissociated from anaesthesia, and a wide range of agents are used in general anaesthesia. A combination of intravenous and inhalational agents induce and maintain unconsciousness. Analgesics include local anaesthetics, NSAIDs and opioids.

4.1. Evidence of Anaesthesia Promoting Cancer Recurrence

Some pre-clinical evidence suggests that volatile anesthetics inhibit cell-mediated immunity. In mice, both isoflurane and halothane inhibit NKC cytotoxicity and metastatic spread of melanoma can increase [32]. Isoflurane upregulates expression of the angiogenic and growth-promoting proteins HIF-1α, insulin-like growth factor-1, vascular endothelial growth factor (VEGF), angiopoietin-1, and other factors, increasing the malignant activity of ovarian cancer in-vitro [33,34]. Noting that volatile agents are commonly used in combination with nitrous oxide, N2O, work in vitro found that sevoflurane increases expression of HIF-2α and key proteins in human head and neck squamous cell carcinoma; while N2O disrupts DNA, purine and thymidylate synthesis and inhibits neutrophil chemotaxis, all of which suppress the response from tumour-surveying haematopoietic cells [35,36]. N2O also significantly accelerates postoperative growth of lung and liver metastases in mice [37].
Intravenous agents were used historically to induce, rather than maintain anaesthesia (but see below). Some intravenous anaesthetics have, like the volatiles cited above, exhibited immune-suppressive properties in pre-clinical study. In human T lymphocytes in-vitro, thiopental inhibits activation of nuclear factor-kappa B (NF-κB) and neutrophil function. NF-κB suppression reduces activity of the NF-κB reporter gene which in turn limits expression of the important pro-immune factors (termed IL-2, IL-6, IL-8 and IFN-γ) [38]. Ketamine also inhibits expression of pro-immune IL-6, in addition to tumour necrosis factor-α, in-vitro [39]. Both agents have been shown to suppress NKC activity. Ketamine additionally induces apoptosis in T lymphocytes [39,40]. The action of thiopental is more protective against T lymphocyte apoptosis, suggesting complex interactions may be at play and all ‘anaesthetics’ cannot be regarded as equivalent [40].

4.2. Evidence of Anaesthesia Inhibiting Cancer Recurrence

Propofol appears to have the opposite effect, promoting aid cell-mediated immunity. Propofol increases cytotoxic T-lymphocyte activity and inhibits enzymatic production of inflammatory cytokines by cycolooxygenase-2 (COX-2) and the prostaglandin PGE2 [41,42,43]. Melamed and colleagues tracked radiolabelled cancer cells in a rat model of breast cancer following administration of thiopental, ketamine and propofol. They found that thiopental and ketamine both significantly increased metastasis and tumour retention in the lungs 24 h after treatment, probably owing to reduced NKC activity. Propofol, in contrast, caused no such effect [44]. In vitro, propofol decreases survival in hepatocarcinoma, colorectal cancer, gastric cancer, lung cancer and glioblastoma cell lines via varying mechanisms [45,46,47,48]. Propofol also inhibits production of VEGF in-vitro, leading to suppression of angiogenesis [49]. If this effect were preserved clinically, as one comparative clinical trial of propofol and volatile anesthetics suggests, this might significantly limit tumour growth [50]. These preclinical studies are potentially important as propofol, in contrast to many other intravenous agents, is now administered as part of maintenance anaesthesis throughout surgery (the technique of ‘total intravenous anaesthesia, TIVA), and not just as a single bolus dose for induction [51].

4.3. The Janus Effect: Analgesics

The Roman god Janus is depicted as having two faces looking in opposite directions. The summary of preclinical findings for general anaesthetic drugs above indicates potentially dichotomous effects, and this is also seen with opioids. On the one hand they are decidedly used to relieve pain and so obtund the stress response to surgery. Yet, some preclinical evidence suggests potential for promotion of cancer recurrence.
Morphine impedes NKC cytotoxicity with dose dependency in rats; and stimulates TH2 activity and inhibits T cell differentiation in mice [52,53,54]. A study using human breast cancer xenografts concluded that morphine induces endothelial cell proliferation and angiogenesis (emulating VEGF by activating the mitogen-activated protein kinase signalling pathway and triggering extracellular signal-regulated kinase phosphorylation); inhibits apoptosis; and promotes cell cycle progression [54]. Fentanyl, sufentanil, remifentanil and alfentanil all suppress NKC activity in animal models [55]. Additionally, sufentanil inhibits leukocyte migration and remifentanil significantly impedes leukocyte proliferation in rats [56,57].
Overexpression of the μ-opioid receptor (MOR), due to cancer, may account for several pro-oncogenic side-effects of opioid treatment [58]. Histological analysis of lung tissue from patients with non-small cell lung carcinoma (NSCLC) revealed a 5 to 10-fold increase in MOR expression. In the same comprehensive study, Mathew and colleagues found that administration of morphine and enkephalin (MOR agonists) increases in vitro lung carcinoma growth. Meanwhile, treatment with the opioid antagonist methylnaltrexone or silencing of MOR expression reduces growth by 50–80%. Additionally, if injected with lung cancer cells, MOR-knockout mice develop no significant tumours compared with wild-type controls. Furthermore, chronic methylnaltrexone administration suppresses tumour growth and limits metastasis in mice injected with lung cancer cells [59]. In human non-small cell lung cancer cells, activation of MOR regulates opioid-induced growth factor receptor signaling, stimulating proliferation and migration of cancer cells. MOR activation may also promote pro-metastatic, epithelial-mesenchymal transition [60].
In contrast, animal studies indicate that higher doses of morphine do not promote tumour growth. Surgery-induced metastasis of mammary adenocarcinoma is blocked in rats administered high doses of morphine. An equivalent high dose had no effect on metastasis in non-operated rats [61]. Additionally, peri-operative, and in particular pre-operative, administration of morphine attenuated surgery-induced tumour growth in rats undergoing laparotomy [62]. It is important to note that a significantly higher dose of morphine is necessary to inhibit release of stress hormones than to induce analgesia [2,63]. Peri-operative administration of high-dose opioids may, therefore, be effective in diminishing the oncogenic effects of the SSR, despite the incidence of direct opioid-mediated suppression of immunity.
Non-steroidal anti-inflammatory drugs (NSAIDS) inhibit COX enzymes, impeding prostaglandin synthesis. Cancer cells express high levels of COX-2 and synthesise PGE2, potentially as a mechanism of immune evasion [64]. PGE2 is associated with promotion of cancer progression [65]. In animal models of cancer, COX-2 inhibitors attenuate angiogenesis; increase NKC cytotoxicity; and inhibit metastasis [66,67,68,69]. If administered after surgery, NSAIDS may also reverse some of the deleterious effects of surgical stress and treatment with opioids. An interesting study, using a murine model of breast cancer treated chronically with morphine, found the COX-2 inhibitor celocoxib inhibits opioid-induced angiogenesis, tumour growth and metastasis, improving survival while not compromising, and potentially benefitting, analgesia [70]. Clinically, meta-analysis indicates that long-term use of NSAIDs could reduce both risk of developing cancer, and risk of metastasis in cancer patients [71,72]. A randomised clinical trial (RCT) into the effects of perioperative NSAID administration on recurrence is ongoing (NCT03172988).
In preclinical study, local anaesthetics appear to successfully suppress tumour growth and metastasis by modulating gene expression; inhibiting proliferation, migration and invasion; and are directly cytotoxic [73]. However, precise mechanisms have not yet been elucidated. Local anaesthetics work by inhibiting voltage gated sodium channels (VGSCs) thus disrupting neural nociceptive signal transmission. VGSCs are overexpressed in many cancer cells, which additionally express a range of ion channels not present in their terminally differentiated equivalents [74,75]. Importantly, continuous intravenous lidocaine infusion throughout surgery is now being promoted to aid analgesia, albeit with caution [75].
The local anaesthetic procaine demonstrates significant demethylating ability and can inhibit tumour cell proliferation by modulating cell-signalling pathways [76]. In lung cancer cell culture, procaine reactivates Wnt inhibitory factor-1 and down-regulates the Wnt canonical pathway (an important inhibitor of proliferation) [77]. Procaine also up-regulates expression of RASSF1A mRNA in nasopharyngeal carcinoma cells, inhibiting proliferation [78]. In vitro, ropivacaine, lidocaine and bupivacaine have all shown an antiproliferative effect on mesenchymal stem cells [79]. Epidermal growth factor receptor (EGFR) mutations are frequent in cancer cells [80]. EGFR, a tyrosine kinase receptor, is important in the epithelial cell proliferation pathway. Lidocaine can inhibit EGFR in tongue cancer (HT1080 fibrosarcoma). This inhibits proliferation by preventing shedding of heparin-binding epidermal growth-factor-like growth factor, which consequently cannot phosphorylate EGFR [81].
Tetracaine and lidocaine demonstrate an interesting ability to inhibit kinesin motility and protrusion of microtubules in breast cancer cells [82]. This inhibition hinders aggregation and reattachment, ultimately decreasing invasive ability and metastasis. A direct association has been shown between invasiveness of cancer and its relative VGSC activity, with greater expression of VGSCs exhibited in the most invasive ovarian cancer variants [83,84] Additionally, VGSCs appear to exercise control over VEGF signaling and other angiogenic functions in cultured umbilical vein endothelial cells [85]. A murine study found that peri-operative intravenous lidocaine reduces pulmonary metastasis after surgical resection with sevoflurane anaesthesia, likely by inhibiting expression of pro-inflammatory and angiogenic cytokines [86].
Administration of a clinically relevant dose of lidocaine or bupivacaine results in apoptosis of neuroblastoma, breast cancer, and thyroid cancer cells, [87,88,89] perhaps with sparing of healthy (mammary epithelial) cells. Apoptosis was triggered by induction of caspase-7, 8 and 9. Caspase-7 activity and evidence of apoptosis were also present in human breast cancer xenografts following local anaesthetic administration [88].

5. Evidence from Clinical Research

In summary, the pre-clinical evidence highlights propofol and local anaesthetics as the most promising agents to prevent cancer recurrence. The results from clinical research for these agents are mixed [90,91,92,93,94,95,96,97,98,99,100,101,102,103,104].

5.1. Propofol

Table 1 summarises some of the results of retrospective and prospective studies. It is not intended to be a meta-analysis (which are discussed below) but presented to reflect the inconsistency in results. In a large-scale study involving 7030 patients, encompassing several cancer types, volatile agents were associated with significantly lower survival after multivariable analysis [91]. This was corroborated in retrospective study of colorectal, gastric and liver cancer patients [97,100,102] However, the evidence does not unanimously support a beneficial effect for propofol. Several retrospective studies found no significant difference in recurrence or survival between volatile and propofol groups. Furthermore, no significant benefit was shown in, small-scale, RCTs [92,103] A recent meta-analysis of 12 retrospective cohort studies found significant benefit to overall survival in TIVA groups (hazard ratio, HR = 0.73, 95% CI = 0.60–0.89) and improved, although not significant, recurrence-free survival with TIVA (HR = 0.73, 95% CI = 0.47 − 1.14) [104].
There are several factors to consider in interpreting these results. It is indeed interesting that retrospective studies point to some potential effect (i.e., elicit some ‘signal’ from the ‘noise’). However, a true effect requires an RCT and even with randomisation it is not possible to even out potential patient factors that are more influential than the type of anaesthetic. Note also that, even with a volatile-based anaesthetic, bolus propofol is invariably used for induction [105]. Study across a wider range of cancer types is warranted, because not all are identical in, for example, how they exhibit recurrence or the types of receptor targets they express. Finally, as a pragmatic observation, TIVA is currently used in less than 10% of all surgeries, in part because of concerns about other complications and side effects including accidental awareness during surgery [106].

5.2. Local Anaesthetics

Encouraging findings from early retrospective cohort studies have indicated that use of local anaesthetics during the peri-operative period could reduce incidence of cancer recurrence [107]. Table 2 summarises some of the results [108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143]. Like Table 1, this is not a meta-analysis and there are some important caveats to interpretation. Results from retrospective studies are inconsistent. A meta-analysis of 10 retrospective studies found that local anaesthesia during prostatectomy was associated with improved overall survival (HR = 0.81, 95% CI = 0.68 − 0.96) [144]. Similarly, a meta-analysis of 21 studies indicated that administration of neuraxial blockade (epidural or intrathecal) was associated with both longer recurrence-free survival (HR = 0.85, 95% CI = 0.72 − 1.0) and overall survival (HR-0.85, 95% CI = 0.74 − 0.98) [145]. However, another meta-analysis of 28 studies, found no association between local anaesthesia and improved survival or reduced recurrence [146]. As described previously, Sessler et al. determined that the combination of local anaesthesia and propofol (putatively the most promising combination) did not improve recurrence in breast cancer patients following mastectomy [1]. While this provides strong evidence that local anaesthetics are unlikely to improve breast cancer patient outcome specifically, this does not exclude the possibility, however remote, that other cancer types may respond more positively.
Table 2 reflects the caution that in all these studies, the local anaesthesia intervention is not equivalent. Paravertebral blocks are very different from epidural or intraperitoneal injection of local anaesthetic, and so on. Moreover, the plasma levels of local anaesthetic achieved with any of these are very low, so the only putative mechanism is through obtunding the stress response to surgery with analgesia.

6. Conclusions: Drug Development

The currently negative outcomes from RCTs do not support routine use of either propofol, local anaesthetic, or any other anaesthetic regimen as something to reduce risk of cancer recurrence. Studies may have failed to take account of several other perioperative factors, including blood transfusion and hypothermia, have been associated with increased recurrence [147,148,149,150]. Several large-scale RCTs are nearing completion that in part address these limitations (Table 3). However, an argument could also be made that if even these RCTs fail to demonstrate any positive results, then a time may come when research efforts and expense should be directed elsewhere rather than seeking marginal gains in this field of enquiry.
However, the preclinical evidence of beneficial properties of propofol and local anaesthetics with regard to cancer recurrence is more persuasive. While the dichotomy may be disappointing—interpreted for example as a failure in translating from bench to bedside—in fact the preclinical data may guide drug discovery. General anaesthetics are chemically diverse, and it is increasingly appreciated that they work on a range of molecular target receptors. If their primary mechanism of action with respect to hypnosis is poorly understood, then it would seem more difficult to ascertain their mechanisms with respect to ‘secondary’ actions such as on cancer recurrence. Indeed, the notion of a ‘common’ mechanism of action for all agents is superceded by the theory that each agent produces unconsciousness in its own unique way [151]. Secondly, it is also being appreciated that, even for a given type of cancer (breast, prostate, etc), the surface cell markers and expression of relevant molecules or receptors may differ greatly across patients. Therefore, the positive results with preventing cancer recurrence may reveal, with further research, precisely which molecular targets are susceptible to the positive effects of general and/or local anaesthetics. In other words, the way forward may not be ever larger RCTs, in which the ‘average’ effect in a randomly sampled patient group is analysed; but, instead, more discrete analysis of which cancer subtypes (characterised by receptor expression) are amenable to beneficial effects of which anaesthetic agents.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Sessler, D.I.; Pei, L.; Huang, Y.; Fleischmann, E.; Marhofer, P.; Kurz, A.; Mayers, D.B.; Meyer-Treschan, T.A.; Grady, M.; Tan, E.Y.; et al. Recurrence of breast cancer after regional or general anaesthesia: A randomised controlled trial. Lancet 2019, 394, 1807–1815. [Google Scholar] [CrossRef] [PubMed]
  2. Wolf, A.R. Effects of regional analgesia on stress responses to pediatric surgery. Pediatr. Anesth. 2012, 22, 19–24. [Google Scholar] [CrossRef]
  3. Angele, M.K.; Faist, E. Clinical review: Immunodepression in the surgical patient and increased susceptibility to infection. Crit. Care 2002, 6, 298–305. [Google Scholar] [CrossRef] [PubMed]
  4. Heaney, Á.; Buggy, D.J. Can anaesthetic and analgesic techniques affect cancer recurrence or metastasis? Br. J. Anaesth. 2012, 109 (Suppl. 1), i17–i28. [Google Scholar] [CrossRef] [PubMed]
  5. Page, G.G. Surgery-induced immunosuppression and postoperative pain management. AACN Clin. Issues 2005, 16, 302–309. [Google Scholar] [CrossRef] [PubMed]
  6. Coffey, J.C.; Wang, J.H.; Smith, M.J.F.; Bouchier-Hayes, D.; Cotter, T.G.; Redmond, H.P. Excisional surgery for cancer cure: Therapy at a cost. Lancet Oncol. 2003, 4, 760–768. [Google Scholar] [CrossRef] [PubMed]
  7. Eschwège, P.; Dumas, F.; Blanchet, P.; Le Maire, V.; Benoit, G.; Jardin, A.; Lacour, B.; Loric, S. Haematogenous dissemination of prostatic epithelial cells during radical prostatectomy. Lancet 1995, 346, 1528–1530. [Google Scholar] [CrossRef]
  8. O’Riain, S.C.; Buggy, D.J.; Kerin, M.J.; Watson, R.W.G.; Moriarty, D.C. Inhibition of the stress response to breast cancer surgery by regional anesthesia and analgesia does not affect vascular endothelial growth factor and prostaglandin E2. Anesth. Analg. 2005, 100, 244–249. [Google Scholar] [CrossRef]
  9. Meng, S.; Tripathy, D.; Frenkel, E.P.; Shete, S.; Naftalis, E.Z.; Huth, J.F.; Beitsch, P.D.; Leitch, M.; Hoover, S.; Euhus, D.; et al. Circulating tumor cells in patients with breast cancer dormancy. Clin. Cancer Res. 2004, 10, 8152–8162. [Google Scholar] [CrossRef]
  10. Lloyd, J.M.; McIver, C.M.; Stephenson, S.A.; Hewett, P.J.; Rieger, N.; Hardingham, J.E. Identification of early-stage colorectal cancer patients at risk of relapse post-resection by immunobead reverse transcription-PCR analysis of peritoneal lavage fluid for malignant cells. Clin. Cancer Res. 2006, 12, 417–423. [Google Scholar] [CrossRef]
  11. Yamaguchi, K.; Takagi, Y.; Aoki, S.; Futamura, M.; Saji, S. Significant detection of circulating cancer cells in the blood by reverse transcriptase-polymerase chain reaction during colorectal cancer resection. Ann. Surg. 2000, 232, 58–65. [Google Scholar] [CrossRef] [PubMed]
  12. Tavare, A.N.; Perry, N.J.S.; Benzonana, L.L.; Takata, M.; Ma, D. Cancer recurrence after surgery: Direct and indirect effects of anesthetic agents. Int. J. Cancer 2012, 130, 1237–1250. [Google Scholar] [CrossRef] [PubMed]
  13. Slingo, M.E.; Pandit, J.J. Oxygen sensing, anaesthesia and critical care: A narrative review. Anaesthesia 2022, 77, 213–223. [Google Scholar] [CrossRef] [PubMed]
  14. Zhao, T.; Xia, W.H.; Zheng, M.Q.; Lu, C.Q.; Han, X.; Sun, Y.J. Surgical excision promotes tumor growth and metastasis by promoting expression of MMP-9 and VEGF in a breast cancer mode. Exp. Oncol. 2008, 30, 60–64. [Google Scholar]
  15. Li, H.; Zhao, B.; Liu, Y.; Deng, W.; Zhang, Y. Angiogenesis in residual cancer and roles o HIF-1α, VEGF and MMP-9 in the development of residual cancer after radiofrequency ablation and surgical resection in rabbits with liver cancer. Folia Morphol. 2020, 79, 71–78. [Google Scholar]
  16. Demicheli, R.; Miceli, R.; Moliterni, A.; Zambetti, M.; Hrushesky, W.J.; Retsky, M.W.; Valagussa, P.; Bonadonna, G. Breast cancer recurrence dynamics following adjuvant CMF is consistent with tumor dormancy and mastectomy-driven acceleration of the metastatic process. Ann. Oncol. 2005, 16, 1449–1457. [Google Scholar] [CrossRef]
  17. Wang, H.L.; Ning, T.; Li, M.; Lu, Z.J.; Yan, X.; Peng, Q.; Lei, N.; Zhang, H.; Luo, F. Effect of endostatin on preventing postoperative progression of distant metastasis in a murine lung cancer model. Tumari 2011, 97, 787–793. [Google Scholar] [CrossRef]
  18. Demicheli, R.; Retsky, M.W.; Hrushesky, W.J.M.; Baum, M.; Gukas, I.D. The effects of surgery on tumor growth: A century of investigations. Ann. Oncol. 2008, 19, 1821–1828. [Google Scholar] [CrossRef]
  19. Wu, F.P.K.; Westphal, J.R.; Hoekman, K.; Mels, A.K.; Statius Muller, M.G.; de Waal, R.W.; Beelen, R.H.; van Leeuwen, P.A.; Meijer, S.; Cuesta, M.A. The effects of surgery, with or without rhGM-CSF, on the angiogenic profile of patients treated for colorectal carcinoma. Cytokine 2004, 25, 68–72. [Google Scholar] [CrossRef]
  20. Peeters, C.F.J.M.; de Geus, L.F.; Westphal, J.R.; de Waal, R.M.; Ruiter, D.J.; Wobbes, T.; Oyen, W.J.; Ruers, T.J. Decrease in circulating anti-angiogenic factors (angiostatin and endostatin) after surgical removal of primary colorectal carcinoma coincides with increased metabolic activity of liver metastases. Surgery 2005, 137, 246–249. [Google Scholar] [CrossRef]
  21. Dunn, G.P.; Old, L.J.; Schreiber, R.D. The three Es of cancer immunoediting. Annu. Rev. Immunol. 2004, 22, 329–360. [Google Scholar] [CrossRef]
  22. Spranger, S.; Bao, R.; Gajewski, T.F. Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature 2015, 523, 231–235. [Google Scholar] [CrossRef] [PubMed]
  23. Shakhar, G.; Ben-Eliyahu, S. Potential prophylactic measures against postoperative immunosuppression: Could they reduce recurrence rates in oncological patients? Ann. Surg. Oncol. 2003, 10, 972–992. [Google Scholar] [CrossRef] [PubMed]
  24. Ben-Eliyahu, S.; Page, G.G.; Yirmiya, R.; Shakhar, G. Evidence that stress and surgical interventions promote tumor development by suppressing natural killer cell activity. Int. J. Cancer 1999, 80, 880–888. [Google Scholar] [CrossRef]
  25. Snyder, G.L.; Greenberg, S. Effect of anaesthetic technique and other perioperative factors on cancer recurrence. Br. J. Anaesth. 2010, 105, 106–115. [Google Scholar] [CrossRef] [PubMed]
  26. Conrick-Martin, I.; Kell, M.R.; Buggy, D.J. Meta-analysis of the effect of central neuraxial regional anesthesia compared with general anesthesia on postoperative natural killer T lymphocyte function. J. Clin. Anesth. 2012, 24, 3–7. [Google Scholar] [CrossRef]
  27. Brittenden, J.; Heys, S.D.; Ross, J.; Eremein, O. Natural killer cells and cancer. Cancer 1996, 77, 1226–1243. [Google Scholar] [CrossRef]
  28. Melamed, R.; Rosenne, E.; Shakhar, K.; Schwartz, Y.; Abudarham, N.; Ben-Eliyahu, S. Marginating pulmonary-NK activity and resistance to experimental tumor metastasis: Suppression by surgery and the prophylactic use of a β-adrenergic antagonist and a prostaglandin synthesis inhibitor. Brain Behav. Immun. 2005, 19, 114–126. [Google Scholar] [CrossRef]
  29. Vojvodic, A.; Vojvodic, P.; Vlaskovic-Jovicevic, T.; Sijan, G.; Dimitrijevic, S.; Peric-Hajzler, Z.; Matovic, D.; Wollina, U.; Tirant, M.; Thuong, N.V.; et al. Beta blockers and melenoma. J. Med. Sci. 2019, 7, 3110–3112. [Google Scholar]
  30. Xu, P.; Zhang, P.; Sun, Z.; Wang, Y.; Chen, J.; Miao, C. Surgical trauma induces postoperative T-cell dysfunction in lung cancer patients through the programmed death-1 pathway. Cancer Immunol. Immunother. 2015, 64, 1383–1392. [Google Scholar] [CrossRef]
  31. Lin, E.; Calvano, S.E.; Lowry, S.F. Inflammatory cytokines and cell response in surgery. Surgery 2000, 127, 117–126. [Google Scholar] [CrossRef] [PubMed]
  32. Markovic, S.N.; Knight, P.R.; Murasko, D.M. Inhibition of interferon stimulation of natural killer cell activity in mice anesthetized with halothane or isoflurane. Anesthesiology 1993, 78, 700–706. [Google Scholar] [CrossRef] [PubMed]
  33. Luo, X.; Zhao, H.; Hennah, L.; Ning, J.; Liu, J.; Tu, H.; Ma, D. Impact of isoflurane on malignant capability of ovarian cancer in vitro. Br. J. Anaesth. 2015, 114, 831–839. [Google Scholar] [CrossRef]
  34. Manicom, A.; Pandit, J.J. A narrative review of the role of anaesthesia and peri-operative medicine in improving outcomes after surgery for advanced ovarian cancer. Gynecol. Pelvic Med. 2022, 5, 21–28. [Google Scholar] [CrossRef]
  35. Ferrell, J.K.; Cattano, D.; Brown, R.E.; Patel, C.B.; Karni, R.J. The effects of anesthesia on the morphoproteomic expression of head and neck squamous cell carcinoma: A pilot study. Transl. Res. 2015, 166, 674–682. [Google Scholar] [CrossRef] [PubMed]
  36. Moudgil, G.C.; Gordon, J.; Forrest, J.B. Comparative effects of volatile anaesthetic agents and nitrous oxide on human leucocyte chemotaxis in vitro. Can. Anaesth. Soc. J. 1984, 31, 631–637. [Google Scholar] [CrossRef]
  37. Shapiro, J.; Jersky, J.; Katzav, S. Anesthetic drugs accelerate the progression of postoperative metastases of mouse tumors. J. Clin. Investig. 1981, 68, 678–685. [Google Scholar] [CrossRef]
  38. Loop, T.; Liu, Z.; Humar, M.; Benzing, A.; Pahl, H.L.; Geiger, K.K.; Pannen, B.H.J. Thiopental inhibits the activation of nuclear factor kappa B. Anesthesiology 2002, 96, 1202–1213. [Google Scholar] [CrossRef]
  39. Braun, S.; Gaza, N.; Werdehausen, R.; Hermanns, H.; Bauer, I.; Durieux, M.E.; Hollmann, M.W.; Stevens, M.F. Ketamine induces apoptosis via the mitochondrial pathway in human lymphocytes and neuronal cells. Br. J. Anaesth. 2010, 105, 347–354. [Google Scholar] [CrossRef]
  40. Roesslein, M.; Schibilsky, D.; Muller, L.; Goebel, U.; Schwer, C.; Humar, M.; Schmidt, R.; Geiger, K.K.; Pahl, H.L.; Pannen, B.H.; et al. Thiopental protects human T lymphocytes from apoptosis in vitro via the expression of heat shock protein 70. J. Pharmacol. Exp. Ther. 2008, 325, 217–225. [Google Scholar] [CrossRef]
  41. Cassinello, F.; Prieto, I.; del Olmo, M.; Rivas, S.; Strichartz, G.R. Cancer surgery: How may anesthesia influence outcome? J. Clin. Anesth. 2015, 27, 262–272. [Google Scholar] [CrossRef] [PubMed]
  42. Kushida, A.; Inada, T.; Shingu, K. Enhancement of antitumor immunity after propofol treatment in mice. Immunopharmacol. Immunotoxicol. 2007, 29, 477–486. [Google Scholar] [CrossRef] [PubMed]
  43. Ke, J.J.; Zhan, J.; Feng, X.B.; Wu, Y.; Rao, Y.; Wang, Y.L. A comparison of the effect of total intravenous anaesthesia with propofol and remifentanil and inhalational anaesthesia with isoflurane on the release of pro- and anti-inflammatory cytokines in patients undergoing open cholecystectomy. Anaesth. Intensive Care 2008, 36, 74–78. [Google Scholar] [CrossRef] [PubMed]
  44. Melamed, R.; Bar-Yosef, S.; Shakhar, G.; Shakhar, K.; Ben-Eliyahu, S. Suppression of natural killer cell activity and promotion of tumor metastasis by ketamine, thiopental, and halothane, but not by propofol: Mediating mechanisms and prophylactic measures. Anesth. Analg. 2003, 97, 1331–1339. [Google Scholar] [CrossRef]
  45. Liu, S.-Q.; Zhang, J.L.; Li, Z.W.; Hu, Z.H.; Liu, Z.; Li, Y. Propofol inhibits proliferation, migration, invasion and promotes apoptosis through down-regulating miR-374a in hepatocarcinoma cell Lines. Cell. Physiol. Biochem. 2018, 49, 2099–2110. [Google Scholar] [CrossRef]
  46. Zhang, W.; Wang, Y.; Zhu, Z.; Zheng, Y.; Song, B. Propofol inhibits proliferation, migration and invasion of gastric cancer cells by up-regulating microRNA-195. Int. J. Biol. Macromol. 2018, 120, 975–984. [Google Scholar] [CrossRef]
  47. Liu, W.Z.; Liu, N. Propofol inhibits lung cancer a549 cell growth and epithelial-mesenchymal transition process by upregulation of microrna-1284. Oncol. Res. 2018, 27, 1–8. [Google Scholar] [CrossRef]
  48. Hsu, S.-S.; Jan, C.-R.; Liang, W.-Z. Evaluation of cytotoxicity of propofol and its related mechanism in glioblastoma cells and astrocytes. Environ. Toxicol. 2017, 32, 2440–2454. [Google Scholar] [CrossRef]
  49. Xu, Y.-B.; Du, Q.H.; Zhang, M.Y.; Yun, P.; He, C.Y. Propofol suppresses proliferation, invasion and angiogenesis by down-regulating ERK-VEGF/MMP-9 signaling in Eca-109 esophageal squamous cell carcinoma cells. Eur. Rev. Med. Pharmacol. Sci. 2013, 17, 2486–2494. [Google Scholar]
  50. Looney, M.; Doran, P.; Buggy, D.J. Effect of anesthetic technique on serum vascular endothelial growth factor C and transforming growth factor β in women undergoing anesthesia and surgery for breast cancer. Anesthesiology 2010, 113, 1118–1125. [Google Scholar] [CrossRef]
  51. Martinez-Vazquez, P.; Lindner, C.; Melia, U.; Pandit, J.J.; Martinez-Vazquez, P. Be Aware, Unaware and Confusion Everywhere: TIVA and Awareness. In Taking on TIVA.; Irwin, M.G., Wong, G.T.C., Lam, S.K., Eds.; Cambridge University Press: Cambridge, UK, 2019; pp. 63–72. [Google Scholar]
  52. Beilin, B.; Martin, F.C.; Shavit, Y.; Gale, R.P.; Liebeskind, J.C. Suppression of natural killer cell activity by high-dose narcotic anesthesia in rats. Brain Behav. Immun. 1989, 3, 129–137. [Google Scholar] [CrossRef] [PubMed]
  53. Das, J.; Kumar, S.; Khanna, S.; Mehta, Y. Are we causing the recurrence-impact of perioperative period on long-term cancer prognosis: Review of current evidence and practice. J. Anaesthesiol. Clin. Pharmacol. 2014, 30, 153. [Google Scholar] [CrossRef]
  54. Gupta, K.; Kshirsagar, S.; Chang, L.; Schwartz, R.; Law, P.Y.; Yee, D.; Hebbel, R.P. Morphine stimulates angiogenesis by activating proangiogenic and survival-promoting signaling and promotes breast tumor growth. Cancer Res. 2002, 62, 4491–4498. [Google Scholar] [PubMed]
  55. Shavit, Y.; Ben-Eliyahu, S.; Zeidel, A.; Beilin, B. Effects of fentanyl on natural killer cell activity and on resistance to tumor metastasis in rats. Neuroimmunomodulation 2004, 11, 255–260. [Google Scholar] [CrossRef] [PubMed]
  56. Hofbauer, R.; Moser, D.; Salfinger, H.; Frass, M.; Kapiotis, S. Sufentanil inhibits migration of human leukocytes through human endothelial cell monolayers. Anesth. Analg. 1998, 87, 1181–1185. [Google Scholar] [CrossRef] [PubMed]
  57. Sacerdote, P.; Gaspani, L.; Rossoni, G.; Panerai, A.E.; Bianchi, M. Effect of the opioid remifentanil on cellular immune response in the rat. Int. Immunopharmacol. 2001, 1, 713–719. [Google Scholar] [CrossRef]
  58. Singleton, P.A.; Mirzapoiazova, T.; Hasina, R.; Salgia, R.; Moss, J. Increased μ-opioid receptor expression in metastatic lung cancer. Br. J. Anaesth. 2014, 113 (Suppl. S1), i103–i108. [Google Scholar] [CrossRef]
  59. Mathew, B.; Lennon, F.E.; Siegler, J.; Mirzapoiazova, T.; Mambetsariev, N.; Sammani, S.; Gerhold, L.M.; LaRiviere, P.J.; Chen, C.T.; Garcia, J.G.; et al. The novel role of the mu opioid receptor in lung cancer progression: A laboratory investigation. Anesth. Analg. 2011, 112, 558–567. [Google Scholar] [CrossRef]
  60. Lennon, F.E.; Mirzapoiazova, T.; Mambetsariev, B.; Poroyko, V.A.; Salgia, R.; Moss, J.; Singleton, P.A. The Mu opioid receptor promotes opioid and growth factor-induced proliferation, migration and Epithelial Mesenchymal Transition (EMT) in human lung cancer. PLoS ONE 2014, 9, e91577. [Google Scholar] [CrossRef]
  61. Page, G.G.; Ben-Eliyahu, S.; Yirmiya, R.; Liebeskind, J.C. Morphine attenuates surgery-induced enhancement of metastatic colonization in rats. Pain 1993, 54, 21–28. [Google Scholar] [CrossRef]
  62. Page, G.G.; Mcdonald, J.S.; 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. [Google Scholar] [CrossRef] [PubMed]
  63. Duncan, H.P.; Cloote, A.; Weir, P.M.; Jenkins, I.; Murphy, P.J.; Pawade, A.K.; Rogers, C.A.; Wolf, A.R. Reducing stress responses in the pre-bypass phase of open heart surgery in infants and young children: A comparison of different fentanyl doses. Br. J. Anaesth. 2000, 84, 556–564. [Google Scholar] [CrossRef] [PubMed]
  64. Wojtowicz-Praga, S. Reversal of tumor-induced immunosuppression by TGF-β inhibitors. Investig. New Drugs 2003, 21, 21–32. [Google Scholar] [CrossRef] [PubMed]
  65. Marnett, L.J.; DuBois, R.N. COX-2: A target for colon cancer prevention. Annu. Rev. Pharmacol. Toxicol. 2002, 42, 55–80. [Google Scholar] [CrossRef] [PubMed]
  66. Pai, R.; Soreghan, B.; Szabo, I.L.; Pavelka, M.; Baatar, D.; Tarnawski, A.S. Prostaglandin E2, transactivates EGF receptor: A novel mechanism for promoting colon cancer growth and gastrointestinal hypertrophy. Nat. Med. 2002, 8, 289–293. [Google Scholar] [CrossRef]
  67. Chang, S.H.; Liu, C.H.; Conway, R.; Han, D.K.; Nithipatikom, K.; Trifan, O.C.; Lane, T.F.; Hla, T. Role of prostaglandin E2-dependent angiogenic switch in cyclooxygenase 2-induced breast cancer progression. Proc. Natl. Acad. Sci. USA 2004, 101, 591–596. [Google Scholar] [CrossRef]
  68. Iñiguez, M.A.; Rodríguez, A.; Volpert, O.; Fresno, M.; Redondo, J.M. Cyclooxygenase-2: A therapeutic target in angiogenesis. Trends Mol. Med. 2003, 9, 73–78. [Google Scholar] [CrossRef]
  69. Glasner, A.; Avraham, R.; Rosenne, E.; Benish, M.; Zmora, O.; Shemer, S.; Meiboom, H.; Ben-Eliyahu, S. 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. [Google Scholar] [CrossRef]
  70. Farooqui, M.; Li, Y.; Rogers, T.; Griffin, R.J.; Song, C.W.; Gupta, K. 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. [Google Scholar] [CrossRef]
  71. Zhao, X.; Xu, Z.; Li, H. NSAIDs use and reduced metastasis in cancer patients: Results from a meta-analysis. Sci. Rep. 2017, 7, 1875. [Google Scholar] [CrossRef]
  72. Zhao, Y.S.; Zhu, S.; Li, X.W.; Wang, F.; Hu, F.L.; Li, D.D.; Zhang, W.C.; Li, X. Association between NSAIDs use and breast cancer risk: A systematic review and meta-analysis. Breast Cancer Res. Treat. 2009, 117, 141–150. [Google Scholar] [CrossRef] [PubMed]
  73. Xuan, W.; Hankin, J.; Zhao, H.; Yao, S.; Ma, D. The potential benefits of the use of regional anesthesia in cancer patients. Int. J. Cancer 2015, 137, 2774–2784. [Google Scholar] [CrossRef] [PubMed]
  74. Fraser, S.P.; Diss, J.K.; Chioni, A.M.; Mycielska, M.E.; Pan, H.; Yamaci, R.F.; Pani, F.; Siwy, Z.; Krasowska, M.; Grzywna, Z. Voltage-gated sodium channel expression and potentiation of human breast cancer metastasis. Clin. Cancer Res. 2005, 11, 5381–5389. [Google Scholar] [CrossRef] [PubMed]
  75. Pandit, J.J.; McGuire, N. Unlicensed intravenous lidocaine for postoperative pain: Always a safer ‘licence to stop’ than to start. Anaesthesia 2021, 76, 156–160. [Google Scholar] [CrossRef] [PubMed]
  76. Tada, M.; Mazeki, F.; Fukai, K.; Sakamoto, A.; Arai, M.; Mikata, R.; Tokuhisa, T.; Yokosuka, O. Procaine inhibits the proliferation and DNA methylation in human hepatoma cells. Hepatol. Int. 2007, 1, 355–364. [Google Scholar] [CrossRef]
  77. Gao, Z.; Xu, Z.; Hung, M.S.; Lin, Y.C.; Wang, T.; Gong, M.; Zhi, X.; Jablons, D.M.; You, L. Procaine and procainamide inhibit the Wnt canonical pathway by promoter demethylation of WIF-1 in lung cancer cells. Oncol. Rep. 2009, 22, 1479–1484. [Google Scholar] [PubMed]
  78. Zhou, H.; Xu, M.; Luo, G.; Zhang, Y. Effects of procaine on human nasopharyngeal carcinoma cell strain CNE-2Z. J. Clin. Otorhinolaryngol. Head Neck Surg. 2007, 21, 1118–1121. [Google Scholar]
  79. Lucchinetti, E.; Awad, A.E.; Rahman, M.; Feng, J.; Lou, P.H.; Zhang, L.; Ionescu, L.; Lemieux, H.; Thébaud, B.; Zaugg, M. Antiproliferative effects of local anesthetics on mesenchymal stem cells: Potential implications for tumor spreading and wound healing. Anesthesiology 2012, 116, 841–856. [Google Scholar] [CrossRef]
  80. Mammoto, T.; Higashiyama, S.; Mukai, M.; Mammoto, A.; Ayaki, M.; Mashimo, T.; Hayashi, Y.; Kishi, Y.; Nakamura, H.; Akedo, H. Infiltration anesthetic lidocaine inhibits cancer cell invasion by modulating ectodomain shedding of heparin-binding epidermal growth factor-like growth factor (HB-EGF). J. Cell. Physiol. 2002, 192, 351–358. [Google Scholar] [CrossRef]
  81. 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. [Google Scholar] [CrossRef]
  82. Yoon, J.R.; Whipple, R.A.; Balzer, E.M.; Cho, E.H.; Matrone, M.A.; Peckham, M.; Martin, S.S. Local anesthetics inhibit kinesin motility and microtentacle protrusions in human epithelial and breast tumor cells. Breast Cancer Res. Treat. 2011, 129, 691–701. [Google Scholar] [CrossRef] [PubMed]
  83. Roger, S.; Rollin, J.; Barascu, A.; Besson, P.; Raynal, P.I.; Iochmann, S.; Lei, M.; Bougnoux, P.; Gruel, Y.; Le Guennec, J.Y. Voltage-gated sodium channels potentiate the invasive capacities of human non-small-cell lung cancer cell lines. Int. J. Biochem. Cell Biol. 2007, 39, 774–786. [Google Scholar] [CrossRef] [PubMed]
  84. Gao, R.; Shen, Y.; Cai, J.; Lei, M.; Wang, Z. Expression of voltage-gated sodium channel · subunit in human ovarian cancer. Oncol. Rep. 2010, 23, 1293–1299. [Google Scholar] [PubMed]
  85. Andrikopoulos, P.; Fraser, S.P.; Patterson, L.; Ahmad, Z.; Burcu, H.; Ottaviani, D.; Diss, J.K.; Box, C.; Eccles, S.A.; Djamgoz, M.B. Angiogenic functions of voltage-gated Na+ channels in human endothelial cells: Modulation of vascular endothelial growth factor (VEGF) signaling. J. Biol. Chem. 2011, 286, 16846–16860. [Google Scholar] [CrossRef]
  86. Johnson, M.Z.; Crowley, P.D.; Foley, A.G.; Xue, C.; Connolly, C.; Gallagher, H.C.; Buggy, D.J. Effect of perioperative lidocaine on metastasis after sevoflurane or ketamine-xylazine anaesthesia for breast tumour resection in a murine model. Br. J. Anaesth. 2018, 121, 76–85. [Google Scholar] [CrossRef]
  87. Perez-Castro, R.; Patel, S.; Garavito-Aguilar, Z.V.; Rosenberg, A.; Recio-Pinto, E.; Zhang, J.; Blanck, T.J.; Xu, F. Cytotoxicity of local anesthetics in human neuronal cells. Anesth. Analg. 2009, 108, 997–1007. [Google Scholar] [CrossRef]
  88. Chang, Y.-C.; Liu, C.L.; Chen, M.J.; Hsu, Y.W.; Chen, S.N.; Lin, C.H.; Chen, C.M.; Yang, F.M.; Hu, M.C. Local anesthetics induce apoptosis in human breast tumor cells. Anesth. Analg. 2014, 118, 116–124. [Google Scholar] [CrossRef]
  89. Chang, Y.-C.; Hsu, Y.C.; Liu, C.L.; Huang, S.Y.; Hu, M.C.; Cheng, S.P. Local anesthetics induce apoptosis in human thyroid cancer cells through the mitogen-activated protein kinase pathway. PLoS ONE 2014, 9, e89563. [Google Scholar] [CrossRef]
  90. Enlund, M.; Berglund, A.; Andreasson, K.; Cicek, C.; Enlund, A.; Bergkvist, L. The choice of anaesthetic-sevoflurane or propofol-and outcome from cancer surgery: A retrospective analysis. Upsala J. Med. Sci. 2014, 119, 251–261. [Google Scholar] [CrossRef]
  91. Wigmore, T.J.; 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. [Google Scholar] [CrossRef]
  92. Sofra, M.; Fei, P.C.; Fabrizi, L.; Marcelli, M.E.; Claroni, C.; Gallucci, M.; Ensoli, F.; Forastiere, E. Immunomodulatory effects of total intravenous and balanced inhalation anesthesia in patients with bladder cancer undergoing elective radical cystectomy: Preliminary results. J. Exp. Clin. Cancer Res. 2013, 32, 6. [Google Scholar] [CrossRef] [PubMed]
  93. Lee, J.H.; Kang, S.H.; Kim, Y.; Kim, H.A.; Kim, B.S. Effects of propofol-based total intravenous anesthesia on recurrence and overall survival in patients after modified radical mastectomy: A retrospective study. Korean J. Anesthesiol. 2016, 69, 126–132. [Google Scholar] [CrossRef] [PubMed]
  94. Kim, M.H.; Kim, D.W.; Kim, J.H.; Lee, K.Y.; Park, S.; Yoo, Y.C. Does the type of anesthesia really affect the recurrence-free survival after breast cancer surgery? Oncotarget 2017, 8, 90477–90487. [Google Scholar] [CrossRef]
  95. Yoo, S.; Lee, H.B.; Han, W.; Noh, D.Y.; Park, S.K.; Kim, W.H.; Kim, J.T. Total intravenous anesthesia versus inhalation anesthesia for breast cancer surgery: A retrospective cohort study. Anesthesiology 2019, 130, 31–40. [Google Scholar] [CrossRef]
  96. Huang, Y.-H.; Lee, M.S.; Lou, Y.S.; Lai, H.C.; Yu, J.C.; Lu, C.H.; Wong, C.S.; Wu, Z.F. Propofol-based total intravenous anesthesia did not improve survival compared to desflurane anesthesia in breast cancer surgery. PLoS ONE 2019, 14, e0224728. [Google Scholar] [CrossRef]
  97. Wu, Z.F.; Lee, M.S.; Wong, C.S.; Yeh, T.T.; Lai, H.C.; Wu, K.L.; Wu, Z.F.; Tseng, W.C. Propofol-based total intravenous anesthesia is associated with better survival than desflurane anesthesia in colon cancer surgery. Anesthesiology 2018, 129, 932–941. [Google Scholar] [CrossRef] [PubMed]
  98. Oh, T.K.; Kim, K.; Jheon, S.; Lee, J.; Do, S.H.; Hwang, J.W.; Song, I.A. Long-term oncologic outcomes for patients undergoing volatile versus intravenous anesthesia for non-small cell lung cancer surgery: A retrospective propensity matching analysis. Cancer Control 2018, 25, 1073274818775360. [Google Scholar] [CrossRef]
  99. Jun, I.J.; Jo, J.Y.; Kim, J.I.; Chin, J.H.; Kim, W.J.; Kim, H.R.; Lee, E.H.; Choi, I.C. Impact of anesthetic agents on overall and recurrence-free survival in patients undergoing esophageal cancer surgery: A retrospective observational study. Sci. Rep. 2017, 7, 14020. [Google Scholar] [CrossRef] [PubMed]
  100. Zheng, X.; Wang, Y.; Dong, L.; Zhao, S.; Wang, L.; Chen, H.; Xu, Y.; Wang, G. Effects of propofol-based total intravenous anesthesia on gastric cancer: A retrospective study. OncoTargets Ther. 2018, 11, 1141–1148. [Google Scholar] [CrossRef] [PubMed]
  101. Dong, J.; Zeng, M.; Ji, N.; Hao, S.; Zhou, Y.; Gao, Z.; Gu, H.; Zhang, L.; Ma, D.; Peng, Y.; et al. Impact of anesthesia on long-term outcomes in patients with supratentorial high-grade glioma undergoing tumor resection. J. Neurosurg. Anesthesiol. 2019, 32, 227–233. [Google Scholar] [CrossRef]
  102. Meng, X.Y.; Zhang, X.P.; Sun, Z.; Wang, H.Q.; Yu, W.F. Distant survival for patients undergoing surgery using volatile versus IV anesthesia for hepatocellular carcinoma with portal vein tumor thrombus: A retrospective study. BMC Anesthesiol. 2020, 20, 233. [Google Scholar] [CrossRef] [PubMed]
  103. Kim, N.Y.; Jang, W.S.; Choi, Y.D.; Hong, J.H.; Noh, S.; Yoo, Y.C. Comparison of biochemical recurrence after robot-assisted laparoscopic radical prostatectomy with volatile and total intravenous anesthesia. Int. J. Med. Sci. 2020, 17, 449–456. [Google Scholar] [CrossRef] [PubMed]
  104. Jin, Z.; Li, R.; Liu, J.; Lin, J. Long-term prognosis after cancer surgery with inhalational anesthesia and total intravenous anesthesia: A systematic review and meta-analysis. Int. J. Physiol. Pathophysiol. Pharmacol. 2019, 11, 83–94. [Google Scholar] [PubMed]
  105. Sury, M.R.; Palmer, J.H.; Cook, T.M.; Pandit, J.J. The state of UK anaesthesia: A survey of National Health Service activity in 2013. Br. J. Anaesth. 2014, 113, 575–584. [Google Scholar] [CrossRef]
  106. Pandit, J.J.; Andrade, J.; Bogod, D.G.; Hitchman, J.M.; Jonker, W.R.; Lucas, N.; Mackay, J.H.; Nimmo, A.F.; O’Connor, K.; O’Sullivan, E.P.; et al. 5th National Audit Project (NAP5) on accidental awareness during general anaesthesia: Summary of main findings and risk factors. Br. J. Anaesth. 2014, 113, 549–559. [Google Scholar] [CrossRef]
  107. Biki, B.; Mascha, E.; Moriarty, D.C.; Fitzpatrick, J.M.; Sessler, D.I.; Buggy, D.J. Anesthetic technique for radical prostatectomy surgery affects cancer recurrence: A retrospective analysis. Anesthesiology 2008, 109, 180–187. [Google Scholar] [CrossRef]
  108. Tsui, B.C.H.; Rashiq, S.; Schopflocher, D.; Murtha, A.; Broemling, S.; Pillay, J.; Finucane, B.T. Epidural anesthesia and cancer recurrence rates after radical prostatectomy. Can. J. Anesth. 2010, 57, 107–112. [Google Scholar] [CrossRef]
  109. Wuethrich, P.Y.; Hsu Schmitz, S.F.; Kessler, T.M.; Thalmann, G.N.; Studer, U.E.; Stueber, F.; Burkhard, F.C. Potential influence of the anesthetic technique used during open radical prostatectomy on prostate cancer-related outcome: A retrospective study. Anesthesiology 2010, 113, 570–576. [Google Scholar] [CrossRef]
  110. Forget, P.; Tombal, B.; Scholtès, J.L.; Nzimbala, J.; Meulders, C.; Legrand, C.; Van Cangh, P.; Cosyns, J.P.; De Kock, M. Do intraoperative analgesics influence oncological outcomes after radical prostatectomy for prostate cancer? Eur. J. Anaesthesiol. 2011, 28, 830–835. [Google Scholar] [CrossRef]
  111. Wuethrich, P.Y.; Thalmann, G.N.; Studer, U.E.; Burkhard, F.C. 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. [Google Scholar] [CrossRef]
  112. Roiss, M.; Schiffmann, J.; Tennstedt, P.; Kessler, T.; Blanc, I.; Goetz, A.; Schlomm, T.; Graefen, M.; Reuter, D.A. 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. [Google Scholar] [CrossRef] [PubMed]
  113. Sprung, J.; Scavonetto, F.; Yeoh, T.Y.; Kramer, J.M.; Karnes, R.J.; Eisenach, J.H.; Schroeder, D.R.; Weingarten, T.N. 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. [Google Scholar] [CrossRef] [PubMed]
  114. Scavonetto, F.; Yeoh, T.Y.; Umbreit, E.C.; Weingarten, T.N.; Gettman, M.T.; Frank, I.; Boorjian, S.A.; Karnes, R.J.; Schroeder, D.R.; Rangel, L.J.; 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. S1), i95–i102. [Google Scholar] [CrossRef]
  115. Tseng, K.S.; Kulkarni, S.; Humphreys, E.B.; Carter, H.B.; Mostwin, J.L.; Partin, A.W.; Han, M.; Wu, C.L. 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. [Google Scholar] [CrossRef] [PubMed]
  116. Christopherson, R.; James, K.E.; Tableman, M.; Marshall, P.; Johnson, F.E. Long-term survival after colon cancer surgery: A variation associated with choice of anesthesia. Anesth. Analg. 2008, 107, 325–332. [Google Scholar] [CrossRef]
  117. Gottschalk, A.; Ford, J.G.; Regelin, C.C.; You, J.; Mascha, E.J.; Sessler, D.I.; Durieux, M.E.; Nemergut, E.C. Association between epidural analgesia and cancer recurrence after colorectal cancer surgery. Anesthesiology 2010, 113, 27–34. [Google Scholar] [CrossRef]
  118. 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. [Google Scholar] [CrossRef]
  119. Cummings, K.C.; Xu, F.; Cummings, L.C.; Cooper, G.S. 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. [Google Scholar] [CrossRef]
  120. 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. [Google Scholar] [CrossRef]
  121. Holler, J.P.N.; Ahlbrandt, J.; Burkhardt, E.; Gruss, M.; Röhrig, R.; Knapheide, J.; Hecker, A.; Padberg, W.; Weigand, M.A. 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. [Google Scholar] [CrossRef]
  122. Vogelaar, F.J.; Abegg, R.; van der Linden, J.C.; Cornelisse, H.G.; van Dorsten, F.R.; Lemmens, V.E.; Bosscha, K. Epidural analgesia associated with better survival in colon cancer. Int. J. Color. Dis. 2015, 30, 1103–1107. [Google Scholar] [CrossRef] [PubMed]
  123. MacFater, W.S.; Xia, W.; Barazanchi, A.W.H.; MacFater, H.S.; Lightfoot, N.; Svirskis, D.; Kahokehr, A.A.; Hill, A.G. Association between perioperative intraperitoneal local anaesthetic infusion and long-term survival and cancer recurrence after colectomy: Follow-up analysis of a previous randomized controlled trial. Aust. N. Z. J. Surg. 2020, 90, 802–806. [Google Scholar] [CrossRef] [PubMed]
  124. Hiller, J.G.; Hacking, M.B.; Link, E.K.; Wessels, K.L.; Riedel, B.J. Perioperative epidural analgesia reduces cancer recurrence after gastro-oesophageal surgery. Acta Anaesthesiol. Scand. 2014, 58, 281–290. [Google Scholar] [CrossRef]
  125. Cummings, K.C.; Patel, M.; Htoo, P.T.; Bakaki, P.M.; Cummings, L.C.; Koroukian, S.A. 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. [Google Scholar] [CrossRef] [PubMed]
  126. Shin, S.; Kim, H.I.; Kim, N.Y.; Lee, K.Y.; Kim, D.W.; Yoo, Y.C. Effect of postoperative analgesia technique on the prognosis of gastric cancer: A retrospective analysis. Oncotarget 2017, 8, 104594–104604. [Google Scholar] [CrossRef]
  127. Wang, Y.; Wang, L.; Chen, H.; Xu, Y.; Zheng, X.; Wang, G. The effects of intra- and post-operative anaesthesia and analgesia choice on outcome after gastric cancer resection: A retrospective study. Oncotarget 2017, 8, 62658–62665. [Google Scholar] [CrossRef]
  128. Li, W.; Li, Y.; Huang, Q.; Ye, S.; Ye, S.; Rong, T. Short and long-term outcomes of epidural or intravenous analgesia after esophagectomy: A propensity-matched cohort study. PLoS ONE 2016, 11, e0154380. [Google Scholar] [CrossRef]
  129. 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. [Google Scholar] [CrossRef]
  130. De Oliveira, G.S.; Ahmad, S.; Schink, J.C.; Singh, D.K.; Fitzgerald, P.C.; McCarthy, R.J. 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. [Google Scholar] [CrossRef]
  131. Capmas, P.; Billard, V.; Gouy, S.; Lhommé, C.; Pautier, P.; Morice, P.; Uzan, C. Impact of epidural analgesia on survival in patients undergoing complete cytoreductive surgery for ovarian cancer. Anticancer Res. 2012, 32, 1537–1542. [Google Scholar]
  132. Lacassie, H.J.; Cartagena, J.; Brañes, J.; Assel, M.; Echevarría, G.C. The relationship between neuraxial anesthesia and advanced ovarian cancer-related outcomes in the Chilean population. Anesth. Analg. 2013, 117, 653–660. [Google Scholar] [CrossRef]
  133. Tseng, J.H.; Cowan, R.A.; Afonso, A.M.; Zhou, Q.; Iasonos, A.; Ali, N.; Thompson, E.; Sonoda, Y.; O’Cearbhaill, R.E.; Chi, D.S.; et al. Perioperative epidural use and survival outcomes in patients undergoing primary debulking surgery for advanced ovarian cancer. Gynecol. Oncol. 2018, 151, 287–293. [Google Scholar] [CrossRef]
  134. Doiron, R.C.; Jaeger, M.; Booth, C.M.; Booth, C.M.; Wei, X.; Robert Siemens, D. Is there a measurable association of epidural use at cystectomy and postoperative outcomes? A population-based study. Can. Urol. Assoc. J. 2016, 10, 321–327. [Google Scholar] [CrossRef] [PubMed]
  135. Weingarten, T.N.; Taccolini, A.M.; Ahle, S.T.; Dietz, K.R.; Dowd, S.S.; Frank, I.; Boorjian, S.A.; Thapa, P.; Hanson, A.C.; Schroeder, D.R.; et al. Perioperative management and oncological outcomes following radical cystectomy for bladder cancer: A matched retrospective cohort study. Can. J. Anesth. 2016, 63, 584–595. [Google Scholar] [CrossRef] [PubMed]
  136. Choi, W.J.; Baek, S.; Joo, E.Y.; Yoon, S.H.; Kim, E.; Hong, B.; Hwang, J.H.; Kim, Y.K. Comparison of the effect of spinal anesthesia and general anesthesia on 5-year tumor recurrence rates after transurethral resection of bladder tumors. Oncotarget 2017, 8, 87667–87674. [Google Scholar] [CrossRef] [PubMed]
  137. Koumpan, Y.; Jaeger, M.; Mizubuti, G.B.; Tanzola, R.; Jain, K.; Hosier, G.; Hopman, W.; Siemens, D.R. Spinal anesthesia is associated with lower recurrence rates after resection of nonmuscle invasive bladder cancer. J. Urol. 2018, 199, 940–946. [Google Scholar] [CrossRef] [PubMed]
  138. Chipollini, J.; Alford, B.; Boulware, D.C.; Forget, P.; Gilbert, S.M.; Lockhart, J.L.; Pow-Sang, J.M.; Sexton, W.J.; Spiess, P.E.; Poch, M.A.; et al. Epidural anesthesia and cancer outcomes in bladder cancer patients: Is it the technique or the medication? A matched-cohort analysis from a tertiary referral center. BMC Anesthesiol. 2018, 18, 157. [Google Scholar] [CrossRef]
  139. Zimmitti, G.; Soliz, J.; Aloia, T.A.; Gottumukkala, V.; Cata, J.P.; Tzeng, C.W.; Vauthey, J.N. Positive impact of epidural analgesia on oncologic outcomes in patients undergoing resection of colorectal liver metastases. Ann. Surg. Oncol. 2016, 23, 1003–1011. [Google Scholar] [CrossRef]
  140. Gottschalk, A.; Brodner, G.; Van Aken, H.K.; Ellger, B.; Althaus, S.; Schulze, H.J. Can regional anaesthesia for lymph-node dissection improve the prognosis in malignant melanoma. Br. J. Anaesth. 2012, 109, 253–259. [Google Scholar] [CrossRef][Green Version]
  141. Merquiol, F.; Montelimard, A.S.; Nourissat, A.; Molliex, S.; Zufferey, P.J. 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. [Google Scholar] [CrossRef]
  142. Myles, P.S.; Peyton, P.; Silbert, B.; Hunt, J.; Rigg, J.R.; Sessler, D.I.; ANZCA Trials Group Investigators. Perioperative epidural analgesia for major abdominal surgery for cancer and recurrence-free survival: Randomised trial. Br. Med. J. 2011, 342, d1491. [Google Scholar] [CrossRef] [PubMed]
  143. Wu, H.L.; Tai, Y.H.; Chan, M.Y.; Tsou, M.Y.; Chen, H.H.; Chang, K.Y. Effects of epidural analgesia on cancer recurrence and long-term mortality in patients after non-small-cell lung cancer resection: A propensity score-matched study. BMJ Open 2019, 9, e027618. [Google Scholar] [CrossRef] [PubMed]
  144. Lee, B.M.; Singh Ghotra, V.; Karam, J.A.; Karam, J.A.; Hernandez, M.; Pratt, G.; Cata, J.P. Regional anesthesia/analgesia and the risk of cancer recurrence and mortality after prostatectomy: A meta-analysis. Pain Manag. 2015, 5, 387–395. [Google Scholar] [CrossRef]
  145. 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. [Google Scholar] [CrossRef] [PubMed]
  146. Grandhi, R.K.; Lee, S.; Abd-Elsayed, A. The relationship between regional anesthesia and cancer: A meta-analysis. Ochsner 2017, 17, 345–361. [Google Scholar]
  147. Cata, J.P.; Lasala, J.; Pratt, G.; Feng, L.; Shah, J.B. Association between perioperative blood transfusions and clinical outcomes in patients undergoing bladder cancer surgery: A systematic review and meta-analysis study. J. Blood Transfus. 2016, 2016, 9876394. [Google Scholar] [CrossRef]
  148. Agnes, A.; Lirosi, M.C.; Panunzi, S.; Santocchi, P.; Persiani, R.; D’Ugo, D. The prognostic role of perioperative allogeneic blood transfusions in gastric cancer patients undergoing curative resection: A systematic review and meta-analysis of non-randomized, adjusted studies. Eur. J. Surg. Oncol. 2018, 44, 404–419. [Google Scholar] [CrossRef]
  149. Li, S.-L.; Ye, Y.; Yuan, X.-H. Association between allogeneic or autologous blood transfusion and survival in patients after radical prostatectomy: A systematic review and meta-analysis. PLoS ONE 2017, 12, e0171081. [Google Scholar] [CrossRef]
  150. Ben-Eliyahu, S.; Shakhar, G.; Rosenne, E.; Levinson, Y.; Beilin, B. Hypothermia in barbiturate-anesthetized rats suppresses natural killer cell activity and compromises resistance to tumor metastasis: A role for adrenergic mechanisms. Anesthesiology 1999, 91, 732–740. [Google Scholar] [CrossRef]
  151. Pandit, J.J. Monitoring (un)consciousness: The implications of a new definition of ‘anaesthesia’. Anaesthesia 2014, 69, 801–807. [Google Scholar] [CrossRef]
Ddc 02 00008 g001
Figure 1. Outline of the effect of surgery (green lines) in promoting inflammation and a generalized surgical stress response that could in turn promote cancer recurrence; either directly or via inhibition (red line) of cell-mediated immunity. Theoretically, drugs used in anaesthesia could inhibit this cancer recurrence pathway at several points: non-steroidal anti-inflammatory drugs (NSAIDs) at the inflammatory stage; or general anaesthetics (GA), local anaesthetics (LA) or opioids in obtunding the stress response.
Figure 1. Outline of the effect of surgery (green lines) in promoting inflammation and a generalized surgical stress response that could in turn promote cancer recurrence; either directly or via inhibition (red line) of cell-mediated immunity. Theoretically, drugs used in anaesthesia could inhibit this cancer recurrence pathway at several points: non-steroidal anti-inflammatory drugs (NSAIDs) at the inflammatory stage; or general anaesthetics (GA), local anaesthetics (LA) or opioids in obtunding the stress response.
Ddc 02 00008 g001
Table 1. Summary of some clinical studies comparing propofol (TIVA) vs. volatile-based anaesthesia in cancer recurrence. The second column of study type indicates whether the study is retrospective cohort (RC) or randomized control (RCT). The third column shows the numbers of patients in the propofol vs. volatile (VA) arms. The next columns indicate the agent used, the cancer type. The sixth column is the end point, being overall survival (OS); recurrence-free survival (RFS); tumour-node-metastasis stage (TNM); presence of metastasis (PM); biochemical recurrence (BCR), or not reported (nr). The last three columns indicate the hazard ratio, confidence intervals and rank (marked + for a ‘positive’ result or − for a ‘negative’ outcome indicating no effect on cancer recurrence).
Table 1. Summary of some clinical studies comparing propofol (TIVA) vs. volatile-based anaesthesia in cancer recurrence. The second column of study type indicates whether the study is retrospective cohort (RC) or randomized control (RCT). The third column shows the numbers of patients in the propofol vs. volatile (VA) arms. The next columns indicate the agent used, the cancer type. The sixth column is the end point, being overall survival (OS); recurrence-free survival (RFS); tumour-node-metastasis stage (TNM); presence of metastasis (PM); biochemical recurrence (BCR), or not reported (nr). The last three columns indicate the hazard ratio, confidence intervals and rank (marked + for a ‘positive’ result or − for a ‘negative’ outcome indicating no effect on cancer recurrence).
StudyStudy TypePropofol/VAVolatile AgentCancer TypeEnd PointHazard Ratio95% CIResult
Enlund
et al. (2014) [90]		RC1935/903SevofluraneVariousOS0.860.60–1.24−
Wigmore
et al. (2016) [91]		RC3316/3714Sevoflurane or isofluraneVariousOS0.680.60–0.78+
Sofra
et al. (2013) [92]		RCT14/14SevofluraneBladderOSnrnr, p = 0.14−
Lee
et al. (2016) [93]		RC152/173SevofluraneBreastOSnrnr, p = 0.38−
RFS0.480.27–0.86+
Kim
et al. (2017) [94]		RC56/2589Sevoflurane, isoflurane, enflurane or desfluraneBreastOS1.140.49–2.60−
Yoo
et al. (2019) [95]		RC3085/2246Sevoflurane, isoflurane, enflurane or desfluraneBreastOS0.960.69–1.33−
RFS0.960.69–1.32−
Huang
et al. (2019) [96]		RC344/632DesfluraneBreastOS1.130.67–1.92−
Wu
et al. (2018) [97]		RC657/706DesfluraneColorectalOS0.270.22–0.35+
Oh
Et al. (2016) [98]		RC194/749SevofluraneNon-small cell lungOS0.900.64–1.26−
RFS1.310.84–2.04−
Jun
et al. (2017) [99]		RC731/191Sevoflurane, isoflurane or desfluraneOesophagealOS0.630.50–0.81+
RFS0.700.56–0.89+
Zheng
et al. (2018) [100]		RC1506/1350SevofluraneGastricOS0.650.56–0.75+
Dong
et al. (2019) [101]		RC154/140SevofluraneGliomaOSnrnr, p = 0.76−
OS (Low Karnofsky)0.600.39–0.93+
Table 2. Studies investigating recurrence following surgery with LA analgesia/anaesthesia or any opioid analgesia and general anaesthetic (GA). RC = retrospective cohort study; RCT = randomised clinical trial; OS = overall survival; RFS = recurrence free survival; TTR = time to recurrence; P/O = postoperative; I/O = intraoperative; SP = systemic progression; CSS = cancer specific survival; BCR = biochemical recurrence; PVB = paravertebral block; PCA = patient-controlled analgesia; IP = intraperitoneal; nr = not reported.
Table 2. Studies investigating recurrence following surgery with LA analgesia/anaesthesia or any opioid analgesia and general anaesthetic (GA). RC = retrospective cohort study; RCT = randomised clinical trial; OS = overall survival; RFS = recurrence free survival; TTR = time to recurrence; P/O = postoperative; I/O = intraoperative; SP = systemic progression; CSS = cancer specific survival; BCR = biochemical recurrence; PVB = paravertebral block; PCA = patient-controlled analgesia; IP = intraperitoneal; nr = not reported.
StudyStudy TypeLA/ControlLA TechniqueControl TechniqueCancer TypeEnd PointHazard Ratio95% CIResult
Sessler et al. (2019) [1]RCT1043/1065LA PVB + propofolOpioid + sevofluraneBreastRFS0.970.74–1.28−
Biki et al. (2008) [107]RC102/123Epidural LA + GAOpioid + GAProstateBCR0.430.22–0.83+
Tsui et al. (2010) [108]RCT49/50Epidural LA + GAGAProstateBCR1.330.64–2.77−
Wuethrich et al. (2010) [109]RC103/158Epidural LA + GAOpioid + NSAID + GAProstateOS0.610.29–1.28−
PFS0.450.27–0.75+
Forget et al. (2011) [110]RC578/533Epidural LA + GAGAProstateBCR0.840.52–1.17−
Wuethrich et al. (2013) [111]RC67/81Epidural LA + GAOpioid + NSAID + GAProstateOS1.170.63–2.17−
Local RFS1.160.41–3.29−
Distant RFS0.560.26–1.25−
Roiss et al. (2014) [112]RC3047/1725Spinal LA + GAGAProstateOS0.900.51–1.60−
RFS1.110.54–2.27−
BCR1.090.85–1.41−
Sprung et al. (2014) [113]RC486/486Epidural LA + GAOpioid + GAProstateOS0.810.61–1.08−
RFS1.270.96–1.67−
Scavonetto et al. (2014) [114]RC1642/1642Neuraxial LA + GAGAProstateOS0.760.57–1.00+
SP0.360.17–0.76+
Tseng et al. (2014) [115]RC1166/798Spinal LA + SedativeGAProstateBCR0.910.70–1.18−
Christopherson et al. (2008) [116]RCT85/92Epidural LA + GAGAColorectalOS1.430.75–2.70−
Gottschalk et al. (2010) [117]RC256/253Epidural LA + GAGAColorectalRFS0.820.49–1.35−
Gupta et al. (2011) [118]RC562/93Epidural LA + GAPCA + GAColorectalOS (colon)0.820.30–2.19−
OS (rectal)0.450.22–0.90+
Cummings et al. (2012) [119]RC9278/40377Epidural LA + GAGAColorectalOS0.910.87–0.94+
RFS1.050.95–1.15−
Day et al. (2012) [120]RC251/173Epidural or Spinal LA + GAPCA + GAColorectalOSNrnr, p = 0.622−
Holler et al. (2013) [121]RC442/307Epidural LA + GAGAColorectalOS0.73nr, p < 0.002+
Vogelaar et al. (2015) [122]RC399/189Epidural LA + GAGAColorectalOS0.770.63–0.95+
MacFater et al. (2020) [123]RCT37/19IP LA + GAIP Saline +GAColorectalOS0.65nr, p = 0.620−
Hiller etc. (2014) [124]RC97/43Epidural LA + GAGAGastricOS0.420.0.21–0.83+
TTR0.330.17–0.63+
Cummings et al. (2014) [125]RC766/1979Epidural LA + GAGAGastricOS0.930.84–1.03−
Shin et al. (2017) [126]RC4325/374Epidural PCAi.v. PCAGastricOS0.670.43–1.13−
RFS1.100.86–1.40−
Wang et al. (2017) [127]RC1390/2856Epidural LA + GAGAGastricOS0.650.58–0.73+
Li et al. (2016) [128]RC178/178Epidural LA + GAGAOesophagealOSNrnr, p = 0.470−
RFSNrnr, p = 0.460−
Lin et al. (2011) [129]RC106/37Epidural LA + GAOpioid + GAOvarianOS0.820.70–0.96+
de Oliviera et al. (2011) [130]RC55/127Epidural LA + GAGAOvarianP/O TTR0.860.52–1.41−
I/O TTR0.370.19–0.73+
Capmas et al. (2012) [131]RC47/47Epidural PCA + GAGAOvarianOS1.250.39–4.04−
RFS1.180.61–2.31−
Lacassie et al. (2013) [132]RC37/43Epidural LA + GAGAOvarianTTR0.720.40–1.33−
Tseng et al. (2018) [133]RC435/213Epidural LA + GAGAOvarianOS0.640.49–0.82+
RFS0.750.60–0.94+
Doiron et al. (2016) [134]RC887/741Epidural LA + GAGABladderOS0.910.80–1.03−
Weingarten et al. (2016) [135]RC195/195Spinal LA + GAGABladderOS1.090.77–1.53−
Choi et al. (2017) [136]RC718/158Spinal LAGABladderRFS0.620.48–0.79+
Koumpan et al. (2018) [137]RC135/96Spinal LAGABladderRFS0.490.27–0.88+
TTR0.640.46–0.88+
Chipollini et al. (2018) [138]RC215/215Epidural LA. + GAGABladderRFS1.671.14–2.45−
CSS1.531.04–2.25−
Zimmitti et al. (2016) [139]RC390/120Epidural LA +GAGALiverOS0.720.49–1.07−
RFS0.740.56–0.95+
Gottschalk et al. (2012) [140]RC52/221Spinal LAGAMelanomaOSNrnr, P = 0.087+
Merquiol et al. (2013) [141]RC111/160Epidural LA + GAOpioid + GAHead and neckOS0.820.70–0.96+
Myles et al. (2011) [142]RCT230/216Epidural LA + GAGAAbdominal surgery (e.g., colorectal)RFS0.950.76–1.17−
Wu et al. (2018) [143]RC1799/392Epidural LA + GAOpioid + GANSCLCOS0.810.58–1.31−
RFS0.930.76–1.14−
Table 3. Some ongoing registered clinical trials examining questions related to anaesthesia technique and cancer outcomes. The first column is the trial registration number; the second the study design; the third the target sample size; the fourth column is the comparison (TIVA, total intravenous anaesthesia; VA, volatile anaesthesia; LA, local anaesthesia; GA, general anaesthesia; PCA, patient-controlled analgesia). The fifth column shows the cancer type; the sixth column the end-points (OS, overall survival; RFS, recurrence-free survival). The last column indicates the planned/expected study completion date.
Table 3. Some ongoing registered clinical trials examining questions related to anaesthesia technique and cancer outcomes. The first column is the trial registration number; the second the study design; the third the target sample size; the fourth column is the comparison (TIVA, total intravenous anaesthesia; VA, volatile anaesthesia; LA, local anaesthesia; GA, general anaesthesia; PCA, patient-controlled analgesia). The fifth column shows the cancer type; the sixth column the end-points (OS, overall survival; RFS, recurrence-free survival). The last column indicates the planned/expected study completion date.
StudyStudy DesignParticipationAgentsCancer TypeEnd PointExpected Completion Date
NCT03034096Multicentre prospective2000Propofol TIVA vs. VAVariousOS +RFSDecember 2020
NCT01975064Multicentre prospective8000Propofol TIVA vs. sevofluraneBreast + ColorectalOSDecember 2023
NCT02786329Single-centre prospective, 2 × 2 factorial450Propofol TIVA vs. VA and lidocaine vs. placeboColorectalOS + RFSDecember 2021
NCT02840227Multicentre prospective2000Epidural LA + GA vs. opioid + GANon-small cell lung carcinomaRFSDecember 2021
NCT01318161Single-centre prospective300Ropivacaine vs. morphine PCAColorectalOS + RFSDecember 2021
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Wilson, B.A.; Pandit, J.J. Do Certain Anaesthetic Drugs Affect Postoperative Cancer Recurrence Rates? Implications for Drug Discovery. Drugs Drug Candidates 2023, 2, 121-136. https://doi.org/10.3390/ddc2010008

AMA Style

Wilson BA, Pandit JJ. Do Certain Anaesthetic Drugs Affect Postoperative Cancer Recurrence Rates? Implications for Drug Discovery. Drugs and Drug Candidates. 2023; 2(1):121-136. https://doi.org/10.3390/ddc2010008

Chicago/Turabian Style

Wilson, Ben A., and Jaideep J. Pandit. 2023. "Do Certain Anaesthetic Drugs Affect Postoperative Cancer Recurrence Rates? Implications for Drug Discovery" Drugs and Drug Candidates 2, no. 1: 121-136. https://doi.org/10.3390/ddc2010008

APA Style

Wilson, B. A., & Pandit, J. J. (2023). Do Certain Anaesthetic Drugs Affect Postoperative Cancer Recurrence Rates? Implications for Drug Discovery. Drugs and Drug Candidates, 2(1), 121-136. https://doi.org/10.3390/ddc2010008

Article Metrics

Back to TopTop