© Springer International Publishing Switzerland 2016
Karen Stuart-Smith (ed.)Perioperative Medicine – Current Controversies10.1007/978-3-319-28821-5_1414. Can Perioperative Interventions During Cancer Surgery Affect Recurrence or Metastasis?
(1)
Department of Anaesthesia, Mater University Hospital, School of Medicine & Medical Science, University College Dublin, Dublin, Ireland
(2)
Outcomes Research, Cleveland Clinic, Ohio, USA
Abstract
Cancer continues to be a key cause of morbidity and mortality worldwide and its overall incidence continues to increase. Anaesthetists are increasingly faced with the challenge of managing cancer patients, either for surgical resection to debulk or excise the primary tumour, surgical emergencies in patients on chemotherapy, or for the analgesic management of acute or chronic pain. Metastatic recurrence is usually the cause of death in cancer patients. There is some experimental data suggesting that surgery, some general anaesthetics, acute postoperative pain and opioid analgesics may accelerate tumour growth and potentially increase the risk of metastatic recurrence. It has been hypothesized that awareness of perioperative factors promoting metastasis could enable designing anaesthetic and analgesic techniques that might attenuate these factors and reduce recurrence or metastasis. Evaluation of emerging literature indicates a signal from cell culture models of cancer cell growth supporting aspects of this hypothesis. Retrospective clinical studies of the association between various anaesthetic techniques, including regional anaesthesia, have yielded conflicting results. Currently, the most compelling evidence is for a direct effect of amide local anaesthetics on cancer cell metastatic potential, inhibiting migration by both a sodium channel and intracellular signaling mechanisms. Only prospective, randomized, clinical trials can prove a cause-and-effect link between anaesthetic technique and cancer. Although a number are ongoing, they are necessitate prolonged patient follow-up and large patient numbers, but their results will inform best practice in the perioperative care of cancer patients.
Keywords
Anaesthesia, generalAnaesthesia regionalLocal anaestheticsCancer, metastasisCancer, recurrence14.1 Introduction
Cancer is among the leading causes of morbidity and mortality worldwide, with approximately 14 million new cases and 8.2 million cancer related deaths in 2012 [1]. Most mortality from cancer is attributable to recurrence or metastatic spread to other organs, rather than direct effects of the primary tumour itself. The mechanism of metastasis remains the subject of ongoing research, and is beyond the scope of the present review, but the “seed and soil” hypothesis outlines a plausible mechanism by which tumour cells may be dispersed and thrive to become the focus of subsequent metastatic disease [2].
In 2006 it was postulated that anaesthetic and perioperative interventions during primary cancer surgery might attenuate the risk of recurrence or metastasis [15] This chapter will summarise the rationale by which different anaesthetic and analgesic techniques and other perioperative interventions might influence the risk of metastasis either in a detrimental or beneficial manner, and the evidence base underpinning it.
14.2 Understanding Cancer Metastasis
Carcinogenesis is caused by mutation, whereby normal cells are reprogrammed to undergo uncontrolled cell division, upsetting the balance between cell proliferation and programmed death (apoptosis). Due to high metabolic activity, cancer cells must establish their own vascular supply, a process termed angiogenesis. This requires the release of pro-angiogenic factors such as prostaglandin (PGE2) and vascular endothelial growth factor (VEGF) from the tumour. Some cells separate from the primary tumour and invade the basement membrane of lymphatics and blood vessels. From here they are passively transported to distal organs and seed in a capillary bed, where the tumour cells can establish their own blood supply and continue to grow forming distant metastasis.
In order for the tumour cells to form an established metastatic site, the host immune elimination mechanisms must be overcome and the cells must adapt to an adverse growth environment [3].
14.3 The Immune System, Cancer and Anaesthesia
Natural Killer cells (NK) and T-cell lymphocytes represent the primary immune response against neoplasm development. NK cells are large lymphocytes that are able to recognise and lyse tumour cells with prior sensitization. A reduction in NK activity is found to be associated with increased numbers of circulating tumour cells and metastasis in animal models and in breast, colon and prostate cancer patients [4, 5].
In a translational study, serum from women randomized to receive either a propofol-paravertebral or standard volatile agent-opioid analgesic anaesthetic technique in women undergoing surgery for breast cancer was incubated with NK cells and breast cancer cells, the former anaesthetic technique was associated with preserved NK cytotoxicity and increased cancer cell apoptosis. As this observed difference could only be attributed to anaesthetic technique, the implication is that the propofol-paravertebral anaesthetic technique creates a serum milieu that facilitates immune activity against cancer cells [6]. In a separate prospective study of non-small cell lung cancer patients, NK cell dysfunction was evident whether regional anaesthesia was used or not, highlighting the independent depressive effect of cancer and surgery on innate immunity.
T-cell lymphocytes are part of the adaptive immune system, which requires sensitization by means of tumour-specific antigen. Infiltration of tumour by T cell lymphocytes is associated with favourable prognosis in colorectal cancer, as reported in the analysis of tumour specimens of a large cohort of patients with colorectal cancer, who were followed up for 15 years [7].
In contrast, some immune cells facilitate tumour progression. Tumour associated macrophages (TAM), were found to aid tumour extravasation and growth in animal models of breast cancer [8]. Myeloid-derived suppressor cells (MDSC), which accumulate in lymph nodes and bone marrow as well as tumour sites and inhibits both innate and adaptive immunity as shown in human and experimental animal models [9].
Sevoflurane and isoflurane (but not isoflurane) are implicated in T lymphocyte apoptosis in vitro. These volatile anaesthetic agents increase mitochondrial membrane permeability, which indirectly favours tumour dissemination by weakening cellular Immunity [10].
14.4 Influence of Surgery on Tumour Progression
Surgery remains the primary treatment of many localised solid neoplasms. However, manipulation of the tumour during surgery may accelerate tumour dissemination as a result of dispersal of malignant cells via the vascular and lymphatic systems to distant organs [11]. Although the vast majority are handled by the body’s cellular immunity, some may develop the conditions necessary to facilitate cellular development locally to the point of becoming self-sustaining metastatic lesion [3]. Secondly, the surgical stress response, involving both neuroendocrine and cytokine elements [12], depresses cellular immunity transiently during this critical period. Studies have demonstrated NK cell dysfunction following surgery [13], furthermore, the inflammatory state triggered by the surgical stress leads to activation of several pro inflammatory cytokines, importantly, pro-angiogenic factors such as vascular endothelial growth factor (VEGF) stimulated by prostaglandins PGE2 [14].
14.5 Anaesthetic Agents and Their Impact on Cancer Recurrence
14.5.1 Intravenous Agents
Propofol was found to inhibit the migration of breast cancer cells in vitro, via an inhibitory action on neuroepithelial cell transforming geneNET1 [16]. In another cell culture model, Propofol down-regulates hypoxia-inducible factor 1-alpha (HIFα), which promotes neoangeogensis essential for tumour growth [17].
In a rat inoculation model of cancer, rats were inoculated with a cancer cell known to metastasize to the lung. The animals were subjected to surgery (e.g. a laparotomy) under different forms of anaesthesia using propofol, ketamine, thiopental or halothane. Animals were followed up for NK cells activity and they were scarified weeks later to assess for lung metastasis. Propofol has been shown to preserve NK cell activity, in contrast to the other agents who were associated with decreased NK cells, with ketamine being the most deleterious; decreased NK cytotoxic activity was associated with increased metastasis and progression of cancer in this model [5].
A translational study which took serum from women randomised to receive either a Propofol- paravertebral anaesthetic technique for breast cancer surgery found that this serum caused more cancer cell apoptosis and contained less of the angiogenesis factor VEGF compared with the serum from patients who had received standard balanced anaesthesia for their breast cancer surgery, consisting of sevoflurane vapour and opioid analgesia [18, 19].
Besides the immunomodulatory effects on NK cells [5], ketamine is also found to inhibit maturation of dendritic cells which influence T-cell lymphocytes activation [20].
Taken together, the evidence from largely in vitro studies suggests that propofol has at least a neutral or perhaps a potentially beneficial effect on molecular factors effecting cancer cell development, whereas the opposite signal is emerging from similar studies on ketamine. There are insufficient data on other, less frequently used IV induction agents to comment.
14.5.2 Inhalation Agents
Inhalation agents been shown to aid tumour progression in cell culture models. Many have a direct effect on promoting growth and progression of breast cancer cells in vitro. This has been demonstrated with sevoflurane [21]. Similarly, exposure of colon cancer cells to isoflurane has been shown to protect them against apoptosis, the underlying mechanism involves over expression of cancer cells to caveolin-1, a structural molecule of the cellular wall, suggesting potential resistance to chemotherapeutic agents [22]. Isoflurane was also found to enhance renal cell migration by a Hypoxia Inducible Factor alpha (HIF alpha) mechanism [23]. Sevoflurane also activates (HIFα) [17, 24]. Recently published studies demonstrated expansion of glioma cells when exposed to sevoflurane and isoflurane, associated with increased proliferation and angiogenesis of ovarian cancer cell cultures [24, 25].
The noble gas xenon, which has clinically significant anaesthetic properties, has been shown to inhibit migration of breast adenocarcinoma cells in vitro to a greater extent than sevoflurane [26].
By contrast, nitrous oxide does not enhance cancer cell migration or proliferation, despite the fact that it interferes with DNA synthesis. Secondary analysis of two randomised controlled trials that were designed originally to examine the cardiovascular effect of N2O, demonstrate no difference in mortality in the cancer subgroup who received N2O, compared to patients who did not receive it [27, 28].
Taken together, the balance of evidence seems to indicate the potential of volatile agents to adversely affect metastasis, the safety of nitrous oxide, and the potential of xenon to deliver a beneficial effect, subject to future clinical evaluation. While these long-term clinical trials are in progress, clinicians should continue to choose anaesthetic drugs and techniques based on their assessment of individual patients’ co-morbidities.
14.5.3 Opioids
Opioids are commonly used to provide intraoperative analgesia and as an adjunct of anaesthesia, in addition to post-operative pain management following surgery, and palliation of chronic cancer pain. Although known to alter the immune system at both cellular and humeral level, the evidence for their influence on the cancer process is somewhat inconsistent, but the balance of current evidence suggests that opioids may have an adverse effect. In terms of the immune system, NK cell dysfunction is demonstrated in an animal inoculation model of cancer injected with fentanyl [29], with the extent of metastasis being proportional to the dose given and inversely proportional to the degree of NK cell activity. In another animal study, morphine reduced macrophage toll-like receptors activity [30], an effect that is believed to be mediated by μ-opioid receptors MOR. Similarly, opioid-sparing techniques for postoperative analgesia of breast cancer patients resulted in preservation of cytotoxic effect of NK cells [6]. A retrospective analysis of patients with non-small cell lung cancer, suggests an association between increased doses of opioids during the initial postoperative period and a higher recurrence rate within 5 years [31]. These findings could be linked to another study where analysis of tissue samples obtained from lung cancer patients, showed significantly increased expression of μ-opioid receptors (MOR) in cancer tissues compared with adjacent control (P = 0.0242); furthermore, a twofold increase in MOR expression in patients with metastatic disease was observed compared with non-metastatic ones (P = 0.0013) [32].
On the other hand, chronic high dose morphine promotes apoptosis in some cancer cell lines in vitro [33].
The endogenous opiate (B-endorphin) in contrast appears to have anti-cancer properties; β-endorphin neuron transplantation reduces the incidence of cancer in rat models of breast cancer [34]. Although not fully understood, attenuation of the surgical stress response by this opioid and increased peripheral NK cell activity are plausible mechanisms of this effect [35].
On balance therefore, there appears to be a signal suggesting that opioids may adversely affect the processes of resisting cancer. However, there is insufficient evidence to date to justify a change of practice. Patients for whom opioids are indicated should continue to receive them, at the discretion of their anaesthetist and the multidisciplinary team.
14.6 Non-steroidal Anti-inflammatory Drugs (NSAIDs)
Non-steroidal anti-inflammatory drugs interrupt the synthesis of prostaglandins from arachidonic acid by inhibition of the cyclooxygenase enzyme COX-2. Prostaglandins are pro-inflammatory cytokines that facilitate malignant cell migration and invasion as evident from several studies of different epithelial tumours [36–38]. A laboratory study of human breast cancer cells linked over-expression of COX-2 to increased level of pro-urokinase plasminogen activator, resulting in an increased potential for motility and invasiveness [39].
Alternative studies suggest that use of NSAIDs reduces risk of certain cancers, A meta-analysis of eight randomised controlled trials (RCTs) of the use of aspirin for prevention of vascular events, found benefit of daily use of aspirin in prevention of some common cancers, especially adenocarcinomas [40]. Similarly, a review of 91 epidemiological studies concluded that regular use of NSAIDs, principally ibuprofen and aspirin, is associated with reduction of common malignancies including GI tract, breast, lung, prostate and ovaries [41]. The use of intraoperative ketorolac and diclofenac for conservative breast cancer surgery was associated with improved disease-free survival (DFS) in a retrospective analysis of a cohort of 720 patients [42].
The sum of currently available evidence therefore is suggestive of a beneficial role of NSAIDs in cancer protection; further specifically designed, prospective, randomized studies are warranted before any recommendations can be made about changes in practice.
14.7 Steroids
Dexamethasone is used routinely as an antiemetic during anaesthesia. However, its potential long term effect on cancer progression was highlighted by a recent retrospective study with 4 years median follow up, where patients undergoing elective surgery received dexamethasone or placebo. While there was no difference in disease–free survival, a significant increase in metastatic recurrence was observed in patients receiving dexamethasone [43]. Again, this association requires cause-and-effect evaluation in a randomized controlled trial.
14.8 Local Anaesthetics
Several studies attribute anti-proliferative properties among cancer cells to amide local anaesthetics. A number of mechanisms underpinning this effect have been elucidated. Voltage gated sodium channels (VGSC), which are the site of action of local anaesthetics, are also expressed by a number of tumour cells, VGSC are thought to create a hyper-excitable state that is implicated in the process of metastasis. Therefore, it is plausible to suggest that inhibition of VGSC should lead to tumour suppression [44]. The amide local anaesthetic ropivacaine has been shown in vitro to inhibit metastatic colon cancer cells by deactivating VGSC [45].
Local anaesthetics also exhibit anti-inflammatory activity, and inhibition of various pro-inflammatory molecules was tested in cell culture models. Lidocaine inhibits epidermal growth factor activity at receptor level, thereby; suppressing the growth of cancer cells in vitro [46].
Inhibition of lung cancer cell migration by lidocaine and ropivacaine was associated with the inhibition of tumour necrosis factor-α and intercellular adhesion molecule-1 phosphorylation in a cell culture model of colon cancer cells [47].
An alternative and interesting mode of action of local anaesthetics is modulation of gene expression via demethylation of deoxyribonucleic acid (DNA). Two cell culture studies examined this effect and found that most amide, but not ester local anaesthetics, interfered with cancer cell DNA in this way [46, 48], in these experiments, breast cancer cell lines were incubated with different local anaesthetics, and lidocaine and ropivacaine but not bupivacaine demonstrated the inhibitory effect on breast cancer cells [49]. Moreover, this property was shown to improve the cytotoxic effect of different chemotherapeutic agents like 5-aza-2′-deoxycytidine (DAC) [49] and cisplatin on breast cancer cells in vitro [48].
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