Implicating anaesthesia and the perioperative period in cancer recurrence and metastasis
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Cancer, currently the leading cause of death in the population aged less than 85 years, poses a significant global disease burden and is anticipated to continue to increase in incidence in both developed and developing nations. A substantial proportion of cancers are amenable to surgery, with more than 60% of patients undergoing tumour resection. Up to 80% of patients will receive anaesthesia for diagnostic, therapeutic or palliative intervention. Alarmingly, retrospective studies have implicated surgical stress in disease progression that is predominantly characterised by metastatic disease—the primary cause of cancer-associated mortality. Our understanding of the mechanisms of surgical stress and impact of perioperative interventions is, however, far from complete. Accumulating evidence from preclinical studies suggests that adrenergic-inflammatory pathways may contribute to cancer progression. Importantly, these pathways are amenable to modulation by adapting surgical (e.g. minimally invasive surgery) and anaesthetic technique (e.g. general vs. neuraxial anaesthesia). Disturbingly, drugs used for general anaesthesia (e.g. inhalational vs. intravenous anaesthesia and potentially opioid analgesia) may also affect behaviour of tumour cells and immune cells, suggesting that choice of anaesthetic agent may also be linked to adverse long-term cancer outcomes. Critically, current clinical practice guidelines on the use of anaesthetic techniques, anaesthetic agents and perioperative adjuvants (e.g. anti-inflammatory drugs) during cancer surgery do not take into account their potential effect on cancer outcomes due to a lack of robust prospective data. To help address this gap, we provide an up-to-date review of current clinical evidence supporting or refuting the role of perioperative stress, anaesthetic techniques and anaesthetic agents in cancer progression and review pre-clinical studies that provide insights into biological mechanisms.
KeywordsVolatile anaesthesia Intravenous anaesthesia Perioperative period Cancer recurrence Metastasis Cancer outcome
Cancer is a leading cause of disease worldwide  and with an ageing population, who present with more comorbid disease, the burden of cancer is expected to continue to increase . In fact, cancer is now the leading cause of death in the population aged less than 85 years, having surpassed death from cardiovascular disease. As a consequence of the growing incidence of cancer an increasing number of patients will present for surgical resection of primary or metastatic solid tumours. Up to 80% of cancer patients require anaesthesia during their cancer care for diagnostic, therapeutic, or palliative procedures ; with over 60% of cancer patients requiring anaesthesia for primary surgical resection of their cancer . As such, it is clear that surgery, and thus anaesthesia, remains a critical component of cancer treatment.
However, despite significant advances over the last few decades in surgical techniques (laparoscopic and minimally invasive surgery) and accompanying neoadjuvant and adjuvant cancer therapies (chemotherapy, radiotherapy, immunotherapy), the burden of oncologic disease and subsequent death from metastatic disease continues to be prevalent. Importantly, the ongoing failure to successfully prevent and/or treat metastatic disease accounts for up to 90% of cancer related deaths . Recognition of the lethality of metastatic disease has broadened research efforts: to not only search for curative treatments, but also to develop techniques to minimise occurrence and to control metastatic disease progression . As the evolving genetic and phenotypic signatures of a single tumour over the course of the disease provides an explanation for the clinical observation that metastatic disease may escape therapies aimed at the primary counterpart , the ability to prevent the progression of metastatic disease becomes increasingly important. Specifically, interest in the role of the perioperative period and anaesthetic technique in promoting or modulating metastatic disease to potentially impact long-term cancer outcomes is increasingly seen as a research priority .
The complexity of the perioperative period is evident; with multiple components that may affect cancer outcomes. Surgery itself activates neural and inflammatory signaling pathways, which have been implicated in immune dysfunction and cancer progression [7, 8, 9, 10, 11, 12]. Additionally, there is evidence that cancer outcomes may also be influenced by choice of anaesthetic technique (e.g. general vs. neuraxial anaesthesia) [7, 13], choice of anaesthetic agent (e.g. inhalational vs. intravenous anaesthesia) , accompanying use of pharmacological adjuncts (e.g. non-steroidal anti-inflammatory drugs, opioids, beta-blockers), non-pharmacological interventions such as fluid management, blood transfusion , temperature management and perioperative nutrition and the occurrence of postoperative complications with delayed return to intended postoperative adjuvant therapies [7, 13, 16]. In particular, the last decade has seen conflicting evidence regarding the role of opioids in cancer progression and remains a topic of contention within published anaesthesia research [17, 18, 19]. However, the role of anaesthetic/analgesic adjuncts, including beta-blockers, NSAIDs and opioid analgesia, is beyond the scope of this review. The multifactorial complexity of the perioperative setting  highlights the need to systematically investigate the role of perioperative interventions in cancer progression and to identify strategies that modulate cancer outcomes. As such, this review provides a focused overview of the current evidence for the role of anaesthetic agents in modulating cancer progression and a discussion of the proposed underlying mechanisms.
Anaesthetics and cancer outcomes
General anaesthetic agents: propofol-based intravenous versus inhalational anaesthesia
The possibility that anaesthetic agents impact long-term cancer outcomes has increasingly become the focus of pre-clinical and clinical research  and underpins the emerging field of onco-anaesthesia . Current anaesthetic agents are used for induction and maintenance of general anaesthesia and include propofol, an intravenously administered phenol derivative, and inhalational volatile anaesthetic agents such as sevoflurane. It is increasingly suggested that the use of volatile anaesthesia for cancer surgery may be associated with worse cancer outcomes compared to intravenous anaesthesia with propofol; this phenomenon has been reported in a number of retrospective cohort studies. For example, general anaesthesia was associated with a lower overall survival compared with local anaesthesia for excision of cutaneous melanoma . In breast cancer patients, modified radical mastectomy under volatile-based anaesthesia had no effect on survival but was associated with higher cancer recurrence than when mastectomy was performed under propofol-based intravenous anaesthesia . Two large recently published retrospective studies investigated the relationship between anaesthetic type and cancer outcome. A Swedish group analysed 2838 breast and colorectal cancer patients and reported an improvement in 1-year overall survival with propofol compared to sevoflurane anaesthesia. This finding, however, lost statistical significance after adjustment for confounding factors by multivariate analysis . In contrast, a retrospective study from a UK group reported a 5% improved overall survival at 5 years in 2607 patients (after propensity score matching) who were exposed to propofol-based intravenous anaesthesia compared to volatile anaesthesia. Multivariate analysis by cancer type revealed that the improved survival was predominantly observed in gastrointestinal and urological cancer subtypes . In contrast, a retrospective study of patients undergoing surgery for glioblastoma found no improvement in survival or disease progression with propofol-based intravenous anaesthesia, over volatile anaesthesia . Given the retrospective nature of these studies, confounding factors—including differences in histological type, stage of cancer and adjuvant chemo-radiotherapy regimens, surgical technique and underlying neuraxial anaesthetic interventions—limit the power of the results and precludes these small cohort studies from a high quality meta-analysis to allow more meaningful interpretation. These studies have, however, identified a phenomenon that warrants further investigation. To address this, a number of large, prospective clinical trials are underway (NCT01975064 , NCT02660411 , NCT03034096 , ACTRN12617001065381 ) to directly investigate the impact of choice of anaesthetic agent on cancer recurrence and survival. It will be a number of years before follow-up is complete.
In an attempt to identify plausible mechanisms that underlie the impact of anaesthetic agents on cancer recurrence, researchers are looking concurrently to pre-clinical studies for answers. These studies may also identify potential targets for clinical intervention. As early as 1981, increased metastasis was observed in mice undergoing lower limb amputation for hind foot Lewis Lung carcinoma or B16 melanoma under general anaesthesia (pentothal sodium, ketamine, halothane or nitrous oxide) compared to controls that had their hind limb amputated without anaesthesia . The effect of volatile anaesthetic agents on development of lung metastasis was studied in mice with B16 melanoma cells injected intravenously after exposure to volatile anaesthesia (halothane, isoflurane). Such exposure was accompanied by a significant increase in lung metastasis formation, compared to when tumour cells were injected without anaesthesia . Similarly, the impact of anaesthetic exposure before intravenous inoculation with MADB106 breast cancer cells was studied in Fischer 344 rats, with increased lung tumour retention reported after exposure to a volatile anaesthetic (halothane) or intravenous agents such as ketamine and thiopental, but not after intravenous propofol exposure . The in vivo behaviour of tumours over a 4-week period was also observed in mice injected with subcutaneous osteosarcoma cells and exposed to continuous propofol infusion. Pulmonary metastasis was reduced in mice exposed to propofol infusion compared to vehicle control . It is important to note the limitations of preclinical studies, including in vitro and in vivo study designs with limited clinical relevance. For example, these studies employed models that only replicate the latter processes in metastasis (i.e. extravasation and colonisation), but not the effects of surgical stress and perioperative factors on the pre-existing and often undiagnosed micrometastatic niche, during surgery on the primary tumour. These studies also investigated anaesthetic agents that are no longer used in clinical practice. To our knowledge, there are no reports of studies that have investigated the effect of anaesthetic agents on local recurrence after resection of an orthotopic primary tumour in in vivo models. As such, these data limit the ability to draw meaningful conclusions that may be translated into clinical outcomes. However, these studies do begin to identify potential underlying mechanisms that activate cancer-promoting pathways and highlight the need for further research on cancer progression and metastasis after surgical resection in orthotopic models of spontaneously metastasising cancer under clinically applicable anaesthetic agents and anaesthetic techniques.
In vitro studies provide insight into the potential underlying mechanisms whereby anaesthetic agents may promote cancer. The successful growth of a cancer requires a number of fundamental adaptations by cancer cells . As tumours grow, they secrete cytokines which promote further tumour cell proliferation through paracrine signaling . In addition, tumour cells develop selective responsiveness to external signals that normally govern cell growth . Altered responsiveness to growth factors within the extracellular matrix that surrounds the tumour can induce cell proliferation in what would otherwise be quiescent cells. Furthermore, tumour cells can recruit and modulate the activity of stromal cells within the tumour microenvironment to support their growth. They do this through multiple mechanisms including downregulating apoptosis , initiating angiogenesis , inducing epithelial–mesenchymal transition  to allow extravasation [38, 39] and avoidance of anoikis to promote survival and growth at the metastatic site . To investigate the role of anaesthetic agents in modulating this behaviour of cancer cells in vitro studies have explored the effect of anaesthetic drugs on cancer cell lines. Exposure of cell lines to volatile anaesthetics has been shown to inhibit apoptosis via downregulation of Bcl-2 expression  or caveolin-dependent mechanisms , and increase migration and invasion through the actions of hypoxia inducible factor 1α (HIF1 α) and phosphoinositide 3 Kinase (PI3K)-AKT signaling [42, 43]. In contrast, exposure of cancer cell lines to propofol induced apoptosis via inhibition of mechanistic target of rapamycin (mTOR) activity  and down-regulation of anti-apoptotic gene, p53 , reduced cell proliferation by increasing mIR-143 expression and limited invasion by decreased matrix metalloproteinase (MMP) expression [46, 47].
While the effects described above may be due to direct actions on cancer cells, there is also evidence that the actions of anaesthetic agents may be indirect. When MDA-MB-231 breast cancer cells were exposed to serum collected from patients 24 h after surgery under volatile-opioid-based anaesthesia, the cells displayed decreased apoptosis and increased proliferation compared to cells treated with serum from patients exposed to propofol anaesthesia accompanied by a regional (paravertebral) anaesthetic block with local anaesthetic agent [48, 49]. These findings raise the possibility that soluble factors that are released into circulation during surgery affect cancer cell behaviour. While these findings are consistent with the in vitro studies described above, they also raise the possibility of anaesthetic modulation of cancer cell behaviour via indirect mechanisms, possibly through neural-inflammatory pathways. However, it is important to recognize the significant shortfall of in vitro data, often with limited translation in to clinically meaningful trial results [50, 51]. It is for this reason that additional studies are needed to elucidate exact mechanisms of how anaesthetic agents may affect the behaviour of cancer cells, and, more importantly, how we may be able to intervene clinically to modulate their effects.
Anaesthetic technique: regional anaesthesia
Regional anaesthesia describes the targeted administration of local anaesthetic drugs to block sensory innervation in defined areas of the body and thereby facilitate surgery. Neuraxial regional anaesthesia, including epidural or spinal anaesthesia, allows prolonged postoperative analgesia and has the potential to attenuate the surgical stress response through sympatholytic effects . The impact of neuraxial techniques on modulation of cancer outcomes is limited to retrospective cohort studies and post hoc analysis of studies intended for other purposes . The true impact of regional anaesthesia on post-surgical cancer progression therefore remains debated; with those studies reporting a link between the use of perioperative regional anaesthetic techniques and improved cancer outcomes [13, 23, 54, 55, 56, 57, 58, 59, 60, 61, 62] being met with an equal number of studies refuting any correlation [63, 64, 65, 66, 67, 68, 69, 70]. Unsurprisingly, a systematic review of studies that included 446 patients reported no benefit in overall survival with the use of perioperative regional anaesthesia  during cancer surgery. However, there are a number of limitations to the design of these studies that need consideration when drawing conclusions from the systematic review. Firstly, only four randomised control trials were included in the review, and analysis for cancer outcomes was conducted post-hoc in each of the studies. There was significant heterogeneity in these studies, with mixed cancer types (abdominal, prostate and colon cancers) and a variety of tumour stages within each cohort [53, 72, 73, 74]. Additionally, accurate tumour staging, details on the efficacy of the regional anaesthesia block and the total dose-exposure to regional anaesthesia were not consistently reported . In light of this, the absence of an effect must be carefully considered given the limited ability of these retrospective studies to account for such potential confounders including type of cancer, stage of cancer, efficacy of regional anaesthesia, timing and duration of anaesthesia and surgical severity, amongst others. Other studies do adjust for confounders, and in one study, longer administration and effective regional anaesthesia (that is, not requiring additional breakthrough analgesia) was associated with improved 2-year survival in gastro-oesophageal cancer patients . This effect was maintained regardless of the presence of more advanced disease (indicated by increased lymphovascular space invasion determined by histology) suggesting that effective regional anaesthesia may play a significant role in the perioperative care of cancer patients with varying disease severity . The effect of neuraxial techniques may be attributable to the opioid-sparing effects of regional anaesthesia, sympatholytic effects, or due to direct systemic absorption of local anaesthetic agents. Carefully designed, adequately powered prospective studies, with endpoints of effective regional anaesthesia and total opioid consumption are needed to further elucidate the impact on cancer outcomes.
In contrast to the multitude of counter opposing clinical data that have explored the use of regional anaesthesia and cancer outcomes, the in vivo evidence for regional anaesthesia affecting cancer outcomes is limited, with only two in vivo animal studies reporting the impact of regional anaesthesia on cancer outcomes. Each of these studies examined lung retention and growth of tumour cells that were intravenously injected in mice that were anaesthetised with general anaesthesia alone, or with regional anaesthesia by spinal block [76, 77]. While these findings raise the possibility that regional anaesthesia may be beneficial to long term outcomes, additional studies are needed to investigate primary tumour resection in spontaneously metastasising orthotopic tumours and further exploring the underlying molecular and cellular mechanisms. Without the use of such clinically relevant in vivo models, support for or against the role of regional anaesthesia in improving cancer outcomes is still lacking.
Anaesthetic technique: intravenous administered local anaesthetic agents
In addition to their use in neuraxial techniques and in local infiltration local anaesthetic (specifically lidocaine) can also be delivered systemically by intravenous administration to provide analgesia, in addition to its indicated intravenous use for treatment of cardiac dysrhythmias. Local anaesthetics block transmission of nerve signals by inhibition of ligand binding at voltage-gated sodium channels. Voltage-gated sodium channels are present on multiple cancer cell types, including breast, cervical, colon cancer, melanoma, prostate and non-small cell lung cancer  and in vitro studies have shown that activation of these channels promotes cancer cell invasion to drive cancer progression [79, 80]. A number of in vitro studies examining the effect of local anaesthetic agents on tumour cell biology have reported that lignocaine and ropivacaine, but not bupivacaine, increases demethylation of tumour cells to promote apoptosis. This effect was increased when co-treatment with chemotherapy occurred [81, 82, 83, 84, 85, 86]. A number of studies found treatment of tumour cells with lidocaine also potentiated hyperthermia-induced tumour cell apoptosis [85, 87, 88]. No clear mechanism has been implicated in these studies, although a number of non-voltage-gated sodium channel-mediated pathways have been suggested, including inhibition of Src signaling (a pathway implicated in transactivation of VEGF by opioids, which may underlie the potential increase in angiogenesis and cancer spread by opioids) [89, 90], DNA demethylation [81, 82, 83] and impaired glycolysis . Only one in vivo study has investigated the impact of systemic lidocaine administration on tumour progression and found that clinically relevant doses delayed the growth of primary mammary adenocarcinomas and fibrosarcomas at the orthotopic site . Further mechanistic interrogation is needed to understand the mechanisms involved and the potential clinical relevance of these initial findings.
Perioperative immune function
The critical function of immune cells within the tumour microenvironment to either impede or promote tumour growth has been characterized over the past decade. There is also growing recognition that exposure to anaesthetic agents and the adrenergic-inflammatory stress response to surgery exerts a detrimental effect on the immune system. This identifies the perioperative period as a time of immense vulnerability and suggests that it is crucial to understand both the impact of the perioperative period on long term cancer outcomes and the impact of immunomodulatory strategies during this period of vulnerability.
Anaesthetic agents and immune function
Early in the process of tumour growth, circulating tumour cells are already present throughout the body  and although associated with a poorer clinical prognosis , less than 0.01% of circulating tumour cells actually succeed in establishing metastatic tumours . This suggests that the hostility of a non-native environment must be overcome for the successful proliferation of cancers cells at a metastatic site and that the same immune profile and environment that enables the growth of the primary tumour must also be established at the metastatic site. The findings that multiple receptor targets on immune cells are amenable to modulation by anaesthetic drugs  renders plausibility to anaesthetic agents playing a role in modulating immune function, especially within the tumour or metastatic microenvironment, with either detrimental or favorable effects.
Clinical studies have investigated the effect of anaesthetic agents on postoperative alteration of immune cell number and function including neutrophils, natural killer cells [95, 96], macrophages  and T cell function [95, 98]. Whilst these correlative data give us an idea of the cell types that are modulated by anaesthetic agents, the effect on cancer progression is unclear. To date, no clinical studies have investigated the impact of anaesthetic agents used during cancer surgery on postoperative immune function and long term cancer outcomes. Given the number of variables involved in the perioperative period that potentially modulate immune cell function, it would indeed be a challenge to design a clinical study with enough power to investigate this as a primary endpoint. Nonetheless, epidemiological data from studies in non-cancer surgery suggest that an increased inflammatory response associates with worse postoperative outcomes. Propensity score-matched patients having major orthopaedic surgery with total hip replacement had significantly greater cancer-related and cardiac-related deaths in a 10-year follow-up period than those having minor orthopaedic surgery with metal-on-metal resurfacing, suggesting that the increased inflammatory response and/or greater exposure duration to anaesthetic agents may have a detrimental impact on immune function with predisposition to cancer in susceptible individuals .
In vivo animal studies have investigated the impact of anaesthetic agents on immune cell function and demonstrated impaired immune cell function after exposure to volatile anaesthesia in mice [100, 101], rats [32, 102], pigs [103, 104] and dogs . These studies found that use of volatile anaesthesia was accompanied by suppression of natural killer cell activity [97, 105], reduced recruitment of macrophages [97, 101] and dendritic cells  and a shift from an anti-tumour T helper cell (Th1) population to a cancer promoting T-helper (Th2) cell population [76, 97, 101]. Volatile anaesthetic agents have also been shown to increase inflammatory cytokines , while propofol has anti-inflammatory and anti-oxidative effects [107, 108]. It should be recognised that gross analysis of immune cell number or assessment of immune cell function in ex vivo environments may not accurately represent the role of these cells in the clinical tumour microenvironment. Whilst an increasing body of evidence is providing insights into the potential mechanisms of action of anaesthetic agents on immune cell function, as summarised in a recent review , the studies alone are unable to comprehensively explain the impact of anaesthetic exposure during cancer surgery on long term cancer outcomes in patients.
Surgical stress and immune function
Within minutes of surgical incision, a physiological stress response is activated within the body to maintain homeostasis and to repair tissue damage . Local and systemic responses essential for wound repair are activated, with release of inflammatory mediators such as cytokines, prostaglandins and acute phase reactants such as C-reactive protein, fibrinogen and macroglobulins . These molecules flood to the site of tissue damage, and are accompanied by the activation of platelets, release of coagulation factors to establish haemostasis  and release of bone marrow-derived progenitors to assist in tissue repair . The local response to tissue injury activates the sympathetic nervous system leading to release of catecholaminergic neurotransmitters including noradrenaline from peripheral autonomic nerve terminals where it acts by binding to alpha- and beta-adrenergic receptors. This is also linked to activation of the hypothalamic–pituitary–adrenal (HPA) axis and a consequent release of adrenaline and cortisol from the adrenal glands [112, 113, 114, 115]. Cortisol secretion from the adrenal cortex occurs within hours of tissue injury and varies with the magnitude of surgical trauma . Physiologically, cortisol plays a role in modulating the immune response to tissue damage [116, 117] as cortisol inhibits the further release of prostaglandins such as PGE2 and other acute phase reactants . This in turn signals to the immune system to self-regulate by the release of regulatory T cells that limit the immune response once wound healing is complete . Whilst this negative feedback response may have developed as an evolutionary response to regulate the immune response, in the context of major surgery the immunosuppressive effect of high levels of cortisol  can have unintended consequences in the context of cancer; the promotion of an anti-inflammatory immune response may be harnessed by the tumour cells to promote their survival and proliferation . In the presence of persistent stimulation such as ongoing infection or an overactive auto-immune response the continued immune and hypercoagulant response becomes detrimental to the clinical state of the patient, rather than therapeutic .
Clinical studies have examined the impact of surgery on postoperative inflammatory markers and immune cell populations  and have shown that the magnitude of surgical insult predicts the levels of post-operative circulating inflammatory mediators [121, 122]. Levels of circulating immune cells have also been shown to be negatively affected by surgical stress, with reports of post-operative reductions in natural killer cells, T-helper cells and cytotoxic T cells, and an increase in T-regulatory cells [123, 124, 125, 126]. In breast and cervical cancer patients, perioperative administration of propranolol  and parecoxib  preserved the pre-operative immune profile of patients compared to untreated counterparts. This is confirmed by a recent randomized placebo-controlled biomarker trial of 38 early-stage breast cancer patients having surgery . This study reported that perioperative treatment with a beta-adrenergic antagonist (propranolol) and a cyclooxygenase-2 (COX-2) inhibitor (etodolac) prevented surgery-induced increase in serum interleukin-6 and C-reactive protein and reduction in stimulated interleukin-12 and interferon-gamma production. Furthermore, combined etodolac and propranolol treatment reduced the mobilization of CD16- “classical” monocytes and enhanced the expression of CD11a on circulating natural killer cells. Tumour analysis also showed that in patients who received treatment with propranolol and etodolac that multiple cellular and molecular pathways related to metastasis and disease recurrence were inhibited, with significantly (i) decreased epithelial-to-mesenchymal transition, (ii) reduced activity of pro-metastatic/pro-inflammatory transcription factors (GATA-1, GATA-2, early-growth-response-3/EGR3, signal transducer and activator of transcription-3/STAT-3), and (iii) decreased tumor-infiltrating monocytes while increasing tumor-infiltrating B cells. Despite this evidence, few clinical studies have been able to support a causal link between magnitude of surgical stress, postoperative immunosuppression and long-term cancer outcomes. In 2002, a randomized control trial in which patients with colorectal cancer underwent open or laparoscopic resection a significant improvement in overall survival was seen with laparoscopic compared to open surgery in patients with stage III colorectal cancer, but not for other cancer stages . Despite a number of attempts to replicate these results, no other studies have published supporting results. However, a number of studies have shown that chronic postoperative inflammation, seen in patients who suffer anastomotic and wound complications after surgery, are at greater risk of cancer recurrence .
In vivo studies have linked surgery and activation of neural-immune signaling pathways with changes in immune cells. However, the link to metastasis is less clear, with major surgery linked to metastasis formation in animals (compared with minor surgery) in some [132, 133] but not all studies . Adrenergic activation increases release of myeloid progenitor cells (leading to the formation of neutrophils, macrophages and dendritic cells) with an increase in myeloid derived suppressor cells (MDSCs) and increased T-regulatory cells that suppress cell-mediated immunity with inhibition of T cell function, increased T cell apoptosis and decreased natural killer cell activity . Additionally, the adrenergic-inflammatory response to surgery has been shown to increase formation of neutrophil extracellular traps (NETs) in metastatic target organs that may trap circulating tumour cells and promote tumour cell colonization within liver and lung sinusoids . In other studies, animals treated with perioperative immune preserving strategies such as use of perioperative beta-adrenergic receptor blockers and non-steroidal anti-inflammatory agents , Toll Like Receptor-4 (TLR4) agonists  and perioperative anticoagulants  showed a reduction in metastasis formation from intravenously injected tumour cells compared with untreated controls. Similarly, in vivo studies have reported a favourable shift in anti-tumour immunity by beta-blockers in mouse models of melanoma and breast cancer, with decreased MDSC recruitment, increased lymphocytic cytotoxicity, and decreased tumour proliferation and angiogenesis [8, 140]. However, the design of these studies does not take into consideration spontaneous dissemination of cancer cells after resection of a primary tumour and so may fail to model the effect of perioperative events on the complex interactions of cancer cells with their microenvironment. This highlights the need for well-designed in vivo models that take into account our increasing knowledge of the complexity and heterogeneity in patient biology, and events in the perioperative period.
A body of evidence is emerging in an attempt to address the question of the impact of choice of anaesthetic agents, anaesthetic technique and surgical stress on long-term cancer outcomes. However, to answer the question definitively and to provide supporting evidence for optimal perioperative onco-anaesthetic practice further studies, which comprehensively interrogate the relationship between anaesthesia exposure and cancer progression, are needed. In particular, a number of considerations need to be taken into account in order to improve the quality of published evidence and provide clinically relevant evidence-based onco-anaesthetic guidelines. Prospective clinical studies are needed to interrogate the clinical impact of anaesthetic technique on cancer outcomes whilst minimising the confounders inherent in the current retrospective data. Clinical studies would also benefit from drawing on mechanisms identified in pre-clinical and translational studies regarding the effects of anaesthetic agents on immune function, modulation of surgical stress and cancer progression. To guide these translational studies, the quality of evidence derived from in vivo studies needs to be clinically relevant. Given the limitations of intravenously injected cancer cells and non-clinically relevant treatment regimens used in many in vivo studies, it is imperative that future in vivo studies are developed using clinical relevant models of spontaneously metastasising cancer from orthotopic sites. By doing this, the effect of anaesthetic agents and that of surgical stress on primary tumour growth, metastasis and the role of the tumour microenvironment in modulating these effects can be studied.
It is also important to consider the multitude of complex clinical factors which may all play a part in the perioperative modulation of cancer. In addition to simply defining the ability of anaesthetic agents to affect cancer progression, a number of questions remain to be answered. Do anaesthetic agents act directly on tumour cells and their microenvironment to impact cancer progression? Do anaesthetic agents interact with other clinical variables within the perioperative period? Do anaesthetic agents and anaesthetic techniques modulate the stress response induced by surgery? What pharmacological (e.g. beta-adrenergic antagonists and cyclooxygenase-2 inhibitors) and non-pharmacological adjuncts should be adopted to optimise the anti-tumour promoting effect of anaesthetic drugs during cancer surgery? How long do the modulating effects of anaesthetic agents last, and what can be done to control these effects over the entire perioperative period? In answering these questions, the benefits are likely to be multiple: the ability to provide high quality evidence-based guidelines for onco-anaesthetic practice, guidance in identifying key biomarkers as potential real-time clinical markers to identify at-risk patients and tailoring of interventions and monitoring of response to therapy in order to achieve the optimal perioperative practice for best oncologic outcome.
Findings of these studies may also have implications for many preclinical cancer studies, not just those that explore surgical outcomes after cancer resection surgery. In vivo studies rely heavily on the use of anaesthesia for establishing tumours, handling of mice during imaging protocols, and other interventions. Currently the main anaesthetic techniques used in in vivo research include the volatile anaesthetic, isoflurane, and intravenous anaesthetics, ketamine, thiopentone and phentobarbitol . As evidence emerges that anaesthetic drugs may have significant impact on biological pathways of interest in cancer research, it cannot be ignored that the use of certain anaesthetics may modulate the phenotype of these models. Whether or not this impacts the results seen in in vivo studies (or accounts for discrepancies in in vivo and clinical data) remains unknown, but should be of increasing consideration to research scientists undertaking pre-clinical research in cancer biology and onco-immunology as a significant confounding variable.
Surgery remains the primary mode of cure for cancer, and is likely to remain so for the foreseeable future. Hence, hundreds of thousands of patients undergo oncological surgery every year. Therefore, it is critical to determine the role of anaesthetic agents on cancer outcomes. The complexity of the observed phenomenon, which includes the interplay between multiple factors including anaesthetic agents, surgical stress and perioperative adrenergic-inflammatory and immune modulation, means that the true impact of anaesthesia on cancer progression remains unclear. Both clinical and pre-clinical studies will play complementary and important roles in improving our understanding. It will continue to be important to test hypotheses in prospective clinical studies that remain the gold standard of evidence for changing clinical practice. A number of studies are now underway to confirm or refute the findings of preclinical and retrospective clinical studies. The implications will be significant for patient care, and a sustained focus on high quality onco-anaesthesia research should be encouraged.
Bridging the gap from research to evidence-based intervention remains a slow and complicated process , but the potential to improve clinical practice and positively impact on patient outcome is enormous . This underpins the need for a continued focus on research and translation into clinical practice in the field of onco-anaesthesia. The outcomes will benefit cancer patients through personalised anaesthetic regimes that are adapted to specific diagnoses, and seek to minimise short and medium-term complications and prevent long-term cancer recurrence.
This work was supported by the David and Lorelle Skewes Foundation, the Peter Mac Foundation, the Australian and New Zealand College of Anaesthetists and the National Cancer Institute (Grant No. CA160890).
- 1.Ferlay JSI, Ervik M (2013) Cancer incidence and mortality worldwide. GLOBOCAN. IARC CancerBase No. 11 International Agency for Research on Cancer, LyonGoogle Scholar
- 2.Sullivan R, Peppercorn J, Sikora K, Zalcberg J, Meropol NJ, Amir E, Khayat D, Boyle P, Autier P, Tannock I, Fojo T, Siderov J, Williamson S, Camporesi S, McVie J, Purushotham A, Naredi P, Eggermont A, Brennan M, Steinberg M, De Ridder M, McCloskey S, Verellen D, Roberts T, Storme G, Hicks R, Ell P, Hirsch B, Carbone D, Schulman K, Catchpole P, Taylor D, Geissler J, Brinker NG, Meltzer D, Kerr D, Aapro M (2011) Delivering affordable cancer care in high-income countries. Lancet Oncol 12(10):933–980. doi: 10.1016/s1470-2045(11)70141-3 PubMedCrossRefGoogle Scholar
- 3.Alkire B, Raykar N, Shrime M, Weiser T, Bickler S, Rose J, Nutt C, Greenberg S, Kotagal M, Riesel J, Esquivel M, Uribe-Leitz T, Molina G, Roy N, Meara J, Farmer P (2015) Global access to surgical care: a modelling study. Lancet Glob Health 3(6):e316–e323. doi: 10.1016/S2214-109X(15)70115-4 CrossRefGoogle Scholar
- 5.Newton P, Mason J, Venkatappa N, Jochelson M, Hurt B, Nieva J, Comen E, Norton L, Kuhn P (2015) Spatiotemporal progression of metastatic breast cancer: a Markov chain model highlighting the role of early metastatic sites. NPJ Breast Cancer 1:15018. doi: 10.1038/npjbcancer.2015.18 PubMedPubMedCentralCrossRefGoogle Scholar
- 8.Sloan EK, Priceman SJ, Cox BF, Yu S, Pimentel MA, Tangkanangnukul V, Arevalo JM, Morizono K, Karanikolas BD, Wu L, Sood AK, Cole SW (2010) The sympathetic nervous system induces a metastatic switch in primary breast cancer. Cancer Res 70(18):7042–7052. doi: 10.1158/0008-5472.can-10-0522 PubMedPubMedCentralCrossRefGoogle Scholar
- 10.Le C, Nowell C, Kim-Fuchs C, Botteri E, Hiller J, Ismail H, Pimentel M, Chai M, Karnezis T, Rotmensz N, Renne G, Gandini S, Pouton C, Ferrari D, Möller A, Stacker S, Sloan E (2016) Chronic stress in mice remodels lymph vasculature to promote tumour cell dissemination. Nat Commun 7:10634. doi: 10.1038/ncomms10634 PubMedPubMedCentralCrossRefGoogle Scholar
- 11.Chang A, Le C, Walker A, Creed S, Pon C, Albold S, Carroll D, Halls M, Lane J, Riedel B, Ferrari D, Sloan E (2016) Beta2-Adrenoceptors on tumor cells play a critical role in stress-enhanced metastasis in a mouse model of breast cancer. Brain Behav Immun 57:106–115. doi: 10.1016/j.bbi.2016.06.011 PubMedPubMedCentralCrossRefGoogle Scholar
- 12.Creed S, Le C, Hassan M, Pon C, Albold S, Chan K, Berginski M, Huang Z, Bear J, Lane J, Halls M, Ferrari D, Nowell C, Sloan E (2015) Beta2-adrenoceptor signaling regulates invadopodia formation to enhance tumor cell invasion. Breast Cancer Res 17(1):145. doi: 10.1186/s13058-015-0655-3 PubMedPubMedCentralCrossRefGoogle Scholar
- 23.Lee J, Kang S, Kim Y, Kim H, Kim B (2016) Effects of propofol-based total intravenous anaesthesia on recurrence and overall survival in patients after modified radical mastectomy: a retrospective study. Korean J Anesthesiol 69(2):126–132. doi: 10.4097/kjae.2016.69.2.126 PubMedPubMedCentralCrossRefGoogle Scholar
- 25.Cata J, Hagan K, Bhavsar S, Arunkumar R, Grasu R, Dang A, Carlson R, Arnold B, Potylchansky Y, Lipski I, McHugh T, Jimenez F, Nguyen A, Feng L, Rahlfs T (2017) The use of isoflurane and desflurane as inhalational agents for glioblastoma surgery. A survival analysis. J Clin Neurosci 35:82–87. doi: 10.1016/j.jocn.2016.10.006 PubMedCrossRefGoogle Scholar
- 26.Enlund M, Bergkvist L (2016) Cancer and anaesthesia: survival after radical surgery—a comparison between propofol or sevoflurane anaesthesia (CAN). Avaliable via ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01975064?term=NCT01975064&rank=1. Accessed 28 Aug 2017
- 27.Wang D, Zhang Y (2016) Impact of anaesthesia maintenance methods on long-term survival rate. Available via ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02660411?term=NCT02660411&rank=1. Accessed 28 Aug 2017
- 28.Demaria S, Afonso A, Bennett-Guerrero E (2017) General anesthetics in cancer resection surgery (GA-CARES) Trial (GA-CARES). Available via ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03034096?term=NCT03034096&rank=1. Accessed 28 Aug 2017
- 29.Riedel B (2017) Volatile anaesthesia and perioperative outcomes related to cancer (VAPOR-C): a feasibility study. Available via Australian New Zealand Cliical Trials Registry. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=373249&isReview=true. Accessed 28 Aug 2017
- 32.Melamed R, Bar-Yosef S, Shakhar G, Shakhar K, Ben-Eliyahu S (2003) 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 97(5):1331–1339PubMedCrossRefGoogle Scholar
- 40.Wu G, Chen W, Sung C, Jean Y, Hung C, Chen F, Hsieh M, Wen Z (2009) Isoflurane attenuates dynorphin-induced cytotoxicity and downregulation of Bcl-2 expression in differentiated neuroblastoma SH-SY5Y cells. Acta Anaesthesiol Scand 53(1):55–60. doi: 10.1111/j.1399-6576.2008.01828.x PubMedCrossRefGoogle Scholar
- 41.Kawaraguchi Y, Horikawa Y, Murphy A, Murray F, Miyanohara A, Ali S, Head B, Patel P, Roth D, Patel H (2011) Volatile anesthetics protect cancer cells against tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis via caveolins. J Am Soc Anesthesiol 115(3):499–508. doi: 10.1097/ALN.0b013e3182276d42 CrossRefGoogle Scholar
- 47.Wu K, Yang S, Hsia T, Yang J, Chiou S, Lu C, Wu R, Chung J (2012) Suppression of cell invasion and migration by propofol are involved in down-regulating matrix metalloproteinase-2 and p38 MAPK signaling in A549 human lung adenocarcinoma epithelial cells. Anticancer Res 32(11):4833–4842PubMedGoogle Scholar
- 54.Jang D, Lim C, Shin Y, Ko Y, Park S, Song S, Kim B (2016) A comparison of regional and general anesthesia effects on 5 year survival and cancer recurrence after transurethral resection of the bladder tumor: a retrospective analysis. BMC Anesthesiol 16(1):1. doi: 10.1186/s12871-016-0181-6 CrossRefGoogle Scholar
- 58.Merquiol F, Montelimard A, Nourissat A, Molliex S, Zufferey P (2013) 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 38(5):398–402. doi: 10.1097/AAP.0b013e31829cc3fb PubMedCrossRefGoogle Scholar
- 59.Gupta A, Björnsson A, Fredriksson M, Hallböök O, Eintrei C (2011) 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 107(2):164–170PubMedCrossRefGoogle Scholar
- 62.de Oliveira Jr G, Ahmad S, Schink J, Singh D, Fitzgerald P, McCarthy R (2011) 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 36(3):271–277. doi: 10.1097/AAP.0b013e318217aada PubMedCrossRefGoogle Scholar
- 65.Sprung J, Scavonetto F, Yeoh T, Kramer J, Karnes R, Eisenach J, Schroeder D, Weingarten T (2014) Outcomes after radical prostatectomy for cancer: a comparison between general anesthesia and epidural anesthesia with fentanyl analgesia: a matched cohort study. Anesth Analg 119(4):859–866. doi: 10.1213/ANE.0000000000000320 PubMedCrossRefGoogle Scholar
- 66.Roiss M, Schiffmann J, Tennstedt P, Kessler T, Blanc I, Goetz A, Schlomm T, Graefen M, Reuter D (2014) Oncological long-term outcome of 4772 patients with prostate cancer undergoing radical prostatectomy: does the anaesthetic technique matter? Eur J Surg Oncol 40(12):1686–1692. doi: 10.1016/j.ejso.2014.02.223 PubMedCrossRefGoogle Scholar
- 69.Wuethrich P, Thalmann G, Studer U, Burkhard F (2013) 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 8(8):e72873. doi: 10.1371/journal.pone.0072873 PubMedPubMedCentralCrossRefGoogle Scholar
- 73.Binczak M, Tournay E, Billard V, Rey A, Jayr C (2013) Major abdominal surgery for cancer: does epidural analgesia have a long-term effect on recurrence-free and overall survival? Annales francaises d’anesthesie et de reanimation 32(5):e81–e88. doi: 10.1016/j.annfar.2013.02.027 CrossRefGoogle Scholar
- 79.Roger S, Guennec J, Besson P (2004) Particular sensitivity to calcium channel blockers of the fast inward voltage-dependent sodium current involved in the invasive properties of a metastastic breast cancer cell line. Br J Pharmacol 141(4):610–615. doi: 10.1038/sj.bjp.0705649 PubMedPubMedCentralCrossRefGoogle Scholar
- 80.Roger S, Rollin J, Barascu A, Besson P, Raynal P, Iochmann S, Lei M, Bougnoux P, Gruel Y, Le Guennec J (2007) Voltage-gated sodium channels potentiate the invasive capacities of human non-small-cell lung cancer cell lines. Int J Biochem Cell Biol 39(4):774–786. doi: 10.1016/j.biocel.2006.12.007 PubMedCrossRefGoogle Scholar
- 89.Piegeler T, Votta-Velis E, Liu G, Place A, Schwartz D, Beck-Schimmer B, Minshall R, Borgeat A (2012) Antimetastatic potential of amide-linked local anesthetics inhibition of lung adenocarcinoma cell migration and inflammatory src signaling independent of sodium channel blockade. J Am Soc Anesthesiol 117(3):548–559. doi: 10.1097/ALN.0b013e3182661977 CrossRefGoogle Scholar
- 90.Lennon F, Mirzapoiazova T, Mambetsariev B, Poroyko V, Salgia R, Moss J, Singleton P (2014) The mu opioid receptor promotes opioid and growth factor-induced proliferation, migration and epithelial mesenchymal transition (EMT) in human lung cancer. PLoS ONE 9(3):e91577. doi: 10.1371/journal.pone.0091577 PubMedPubMedCentralCrossRefGoogle Scholar
- 103.Kalimeris K, Christodoulaki K, Karakitsos P, Batistatou A, Lekka M, Bai M, Kitsiouli E, Nakos G, Kostopanagiotou G (2011) Influence of propofol and volatile anaesthetics on the inflammatory response in the ventilated lung. Acta Anaesthesiol Scand 55(6):740–748. doi: 10.1111/j.1399-6576.2011.02461.x PubMedCrossRefGoogle Scholar
- 114.Kruimel J, Pesman GJ, Sweep C, van der Vliet J, Liem T, Jansen J, van der Meer J, Naber A (1999) Depression of plasma levels of cytokines and ex-vivo cytokine production in relation to the activity of the pituitary-adrenal axis, in patients undergoing major vascular surgery. Cytokine 11(5):382–388. doi: 10.1006/cyto.1999.0440 PubMedCrossRefGoogle Scholar
- 120.Gaudilliere B, Fragiadakis G, Bruggner R, Nicolau M, Finck R, Tingle M, Silva J, Ganio E, Yeh C, Maloney W, Huddleston J, Goodman S, Davis M, Bendall S, Fantl W, Angst M, Nolan G (2014) Clinical recovery from surgery correlates with single-cell immune signatures. Sci Transl Med 6(255):255ra131. doi: 10.1126/scitranslmed.3009701 PubMedPubMedCentralCrossRefGoogle Scholar
- 122.Veenhof A, Sietses C, Von Blomberg B, Van Hoogstraten I, Vd Pas M, Meijerink W, vd Peet D, Vd Tol M, Bonjer H, Cuesta M (2011) The surgical stress response and postoperative immune function after laparoscopic or conventional total mesorectal excision in rectal cancer: a randomized trial. Int J Colorectal Dis 26(1):53–59PubMedCrossRefGoogle Scholar
- 128.Ma W, Wang K, Du J, Luan J, Lou G (2015) Multi-dose parecoxib provides an immunoprotective effect by balancing T helper 1. Th2, Th17 and regulatory T cytokines following laparoscopy in patients with cervical cancer. Mol Med Rep 11(4)(Th1):2999–3008. doi: 10.3892/mmr.2014.3003 PubMedCrossRefGoogle Scholar
- 129.Shaashua L, Shabat-Simon M, Haldar R, Matzner P, Zmora O, Shabtai M, Sharon E, Allweis T, Barshack I, Hayman L, Arevalo J, Ma J, Horowitz M, Cole S, Ben-Eliyahu S (2017) Perioperative COX-2 and β-adrenergic blockade improves metastatic biomarkers in breast cancer patients in a phase-II randomized trial. Clin Cancer Res. doi: 10.1158/1078-0432.ccr-17-0152 PubMedCrossRefPubMedCentralGoogle Scholar
- 131.Mirnezami A, Mirnezami R, Chandrakumaran K, Sasapu K, Sagar P, Finan P (2011) Increased local recurrence and reduced survival from colorectal cancer following anastomotic leak: systematic review and meta-analysis. Ann Surg 253(5):890–899. doi: 10.1097/SLA.0b013e3182128929 PubMedCrossRefGoogle Scholar
- 136.Tohme S, Yazdani H, Al-Khafaji A, Chidi A, Loughran P, Mowen K, Wang Y, Simmons R, Huang H, Tsung A (2016) Neutrophil extracellular traps promote the development and progression of liver metastases after surgical stress. Cancer Res 76(6):1367–1380. doi: 10.1158/0008-5472.can-15-1591 PubMedPubMedCentralCrossRefGoogle Scholar
- 137.Glasner A, Avraham R, Rosenne E, Benish M, Zmora O, Shemer S, Meiboom H, Ben-Eliyahu S (2010) 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 184(5):2449–2457. doi: 10.4049/jimmunol.0903301 PubMedCrossRefGoogle Scholar
- 138.Matzner P, Sorski L, Shaashua L, Elbaz E, Lavon H, Melamed R, Rosenne E, Gotlieb N, Benbenishty A, Reed S, Ben-Eliyahu S (2016) Perioperative treatment with the new synthetic TLR-4 agonist GLA-SE reduces cancer metastasis without adverse effects. Int J Cancer 138(7):1754–1764. doi: 10.1002/ijc.29885 PubMedCrossRefGoogle Scholar
- 139.Seth R, Tai L, Falls T, de Souza C, Bell J, Carrier M, Atkins H, Boushey R, Auer R (2013) Surgical stress promotes the development of cancer metastases by a coagulation-dependent mechanism involving natural killer cells in a murine model. Ann Surg 258(1):158–168. doi: 10.1097/SLA.0b013e31826fcbdb PubMedCrossRefGoogle Scholar
- 141.Gargiulo S, Greco A, Gramanzini M, Esposito S, Affuso A, Brunetti A, Vesce G (2012) Mice anesthesia, analgesia, and care, part I: anesthetic considerations in preclinical research. ILAR J 53(1). doi: 10.1093/ilar.53.1.55
- 142.Lipsky M, Sharp L (2001) From idea to market: the drug approval process. Journal Am Board Fam Pract 14(5):362–367Google Scholar
- 143.Fleming E, Perkins J, Easa D, Conde J, Baker R, Southerland W, Dottin R, Benabe J, Ofili E, Bond V, McClure S, Sayre M, Beanan M, Norris K (2008) The role of translational research in addressing health disparities: a conceptual framework. Ethn Dis 18(2 Suppl 2):S2-155–S2-160Google Scholar