|Year : 2015 | Volume
| Issue : 3 | Page : 528-534
Anesthesia and cancer recurrences: The current knowledge and evidence
Sukhminder Jit Singh Bajwa1, Smriti Anand2, Gurpreet Kaur1
1 Department of Anaesthesiology and Intensive Care, Gian Sagar Medical College and Hospital, Ramnagar, Rajpura, Punjab, India
2 Department of Anaesthesiology and Intensive Care, Maharishi Markendeshwar Medical College and Hospital Solan, Himachal Pradesh, India
|Date of Web Publication||9-Oct-2015|
Sukhminder Jit Singh Bajwa
Department of Anaesthesiology and Intensive Care Medicine, House No. 27-A, Ratan Nagar, Tripuri, Patiala - 147 001, Punjab
Source of Support: None, Conflict of Interest: None
Surgical removal of solid tumors is of utmost importance as total resection can be curative. The surgical insult however itself may result in tumor micrometastasis coupled with depression of cell-mediated immunity culminating in tumor recurrence. Recent research suggests that few anesthetic agents or procedures can influence pathophysiology of metastasis in the postoperative period. Whereas opioids and volatile anesthetics have been implicated in angiogenesis and immunosuppression, evidences accumulated over the recent years have undoubtedly highlighted the attenuation of immunosuppression by regional anesthetic agents thereby making it superior over general anesthesia in preventing cancer recurrence. As anesthetic drugs are given at that time when patient is at the maximum risk of spread of metastasis, thus an understanding of the effect of anesthesia drugs and their impact on tumor metastasis is important so that appropriate anesthetic strategy can be made to improve long term survival in these patients. The purpose of the present review is therefore to emphasize the pivotal role of various anesthetic agents and anesthesia techniques in preventing tumor recurrence after surgery.
Keywords: Cancer, cancer recurrence, general anesthesia, immunosuppression, regional anesthesia
|How to cite this article:|
Bajwa SS, Anand S, Kaur G. Anesthesia and cancer recurrences: The current knowledge and evidence. J Can Res Ther 2015;11:528-34
| > Introduction|| |
In spite of breakthrough in oncology, cancer still remains one of the important silent killers. Recurrence is the major cause of mortality. It has been estimated that about 9 million newer cases of cancer are diagnosed annually, worldwide, with overall mortality of 4.5 million. In India itself, 7 lakh newer cases of cancer are diagnosed per year, with 3.5 lakh annual deaths. Although cancer spares no age, increasing age is undoubtedly an important risk factor; 75% cancers developing above 55 years of age.  The increasing incidence of cancer puts an enormous responsibility on the anesthesiologist, not only during perioperative period but also during chronic cancer pain management. Surgical stress coupled with subsequent neuroendocrine and inflammatory responses culminating in attenuation of cell-mediated immunity makes the perioperative period most vulnerable for tumor metastasis. , In fact, the type of anesthesia technique employed also influences cancer recurrence, thereby laying an equal onus on the anesthesiologist in long term tumor outcome.
| > Search strategies|| |
The present review is compiled to highlight the understanding of the effect of anesthesia drugs and their impact on tumor metastasis. The measures adopted included extensive scrutiny of literary evidence from internet resources, journals and textbooks of medicine, oncology, anesthesiology and intensive care. The strategies included exploration of full text articles and abstracts from various search engines such as PubMed, Medscape, Scopus, Science Direct, Medline, Yahoo, Google Scholar and many others which included key words like Cancer, Immunosuppression, General anesthesia, Regional anesthesia, Cancer recurrence.
| > Biology of cancer metastasis|| |
Cancer results from the abnormal, unregulated proliferation of cells that can invade other tissues through blood and lymphatics. As per the 'seed and soil' theory of tumor metastasis, there is initial progressive cellular growth and proliferation, during which the nutrient supply of the cells is catered by diffusion.  However as the cellular proliferation becomes extensive, angiogenesis commences in response to the release of vascular endothelial growth factor and prostaglandin E 2 , released from the tumor cells.  These cells can encroach the surrounding host stroma and enter circulation via lymphatics and blood stream, from where they can embolize to faraway sites, become entrapped in capillary beds or extravasate into the organ parenchyma, where they again proliferate and thereby repeat the cycle. 
| > Immune response and cancer|| |
Immune response particularly the cell mediated immunity comprising of cytotoxic T lymphocytes, natural killer (NK) cells, NK-T-cells, dendritic cells and macrophages has a pivotal role in keeping a check on cancerous cells.  NK cells are particularly critical defense against tumor cells and a decrease in their numbers has been associated with significant increase in the tumor recurrence, as has been substantiated by various animal studies. , Interleukin (IL)-2, IL-4, IL-10, interferon (INF) γ as well as T helper 1 (Th1) cytokines enhance the cytotoxic potential of T- and NK cells.  Cytotoxic T-cells have also been implicated as a protective defense against tumor metastasis, as also the mononuclear cells and the dendritic cells.  This has been further corroborated by the fact that the incidence of tumor metastasis escalates in patients receiving immunosuppressive therapy e.g., organ transplant recipients, patients of multiplemyeloma, melanoma, breast carcinomas, Wilm's tumor and colorectal cancers.  Interleukin 17 (IL-17), another cytokine produced by Th 17 cells, on the contrary, not only stimulates tumor cell proliferation, angiogenesis, lymphangiogenesis, tumor spread but has also been implicated in immune resistance and chemoresistance. 
| > Effect of surgery on tumor cell metastasis|| |
Though surgery has been considered as a vital treatment modality against primary tumor, paradoxically it has deleterious effects in tumor metastasis. Various mechanisms of how surgery affects tumor metastasis have been postulated based on literary evidence [Table 1].
It has been found that mechanical manipulation of the primary tumor results in shedding of the tumor cells into the circulation, leading to tumor spread.  Also surgery is associated with increased proliferation and depressed apoptosis of tumor cells,  increased motility and invasion by free malignant cells by evoking the release of matrix metalloproteinases (MMP's)  and by augmenting angiogenesis.  Additional perioperative factors implicated in tumor metastasis include blood transfusion, pain, severe hypothermia and depression of cell mediated immunity during surgery. ,, Allogenic leukocytes in transfused blood suppress T lymphocytes and NK cells. Stored red blood cells alter membrane determinants, preoccupying effector cells and thus tumor cells are left unattended. Also it has been concluded from the previous studies that transfusion is less harmful than stored blood in view of progressing malignancies. Pain suppresses NK cell activity. Hypothermia increases glucocorticoid release and depresses both cell mediated and humoral immunity. Psychological stress with added surgical stress causes enhanced secretion of stress hormones, which in turn induces tumor progression and increased cancer mortality.  Studies also show that NK cells mediate effects of stress on tumor development.  Surgical stress promotes angiogenesis in vivo and these effects can be blocked with propranolol.  Beta antagonism along with COX (cyclooxygenase) inhibition and immunostimulation have shown synergistic effects.  Also lesser invasive procedure like laparoscopy is associated with lesser suppression of immunity and subsequent lesser recurrence rate than laparotomy. 
| > Effect of anesthesia on tumor cell metastasis|| |
Evidences accumulated over the years have thrown insight into the importance of regional anesthesia over general anesthesia in attenuating tumor metastasis, thereby having favorable long term outcome.
| > Effects of general anesthetic agents|| |
Intravenous anesthetic agents
It has been found that ketamine by inhibiting the NK cell activity induced by its sympathomimetic activity results in adverse oncological outcome.  Infact experimental studies have shown that risk of tumor metastasis with ketamine is more than 2.5 fold.  Thiopental also accentuates cancer recrudesce by significantly decreasing number of circulating natural killer cells per milliliter of blood.  Both these agents reduce number and activity of NK cells. Propofol on the contrary by inhibiting matrix MMP attenuates the tumor cells ability to invade and spread.  MMP is the key enzyme involved in breakdown of basement membrane and thus promoting metastasis. Isoflurane upregulates HIF-1 alpha in prostate cancer cells due to increase in markers and mediators of angiogenesis, proliferation and chemoresistance. Addition of propofol on isoflurane treatment suppresses all of those effects.  The effect of benzodiazepines on tumor recrudesce is controversial [Table 2]. Whereas some studies show a positive correlation, others have refuted the same. ,
Volatile anesthetic agents have been found to induce apoptosis of immune competent cells like NK cells and human T-lymphocytes and have a deleterious effect on tumor metastasis. Halogenated inhalational anesthetic agents by inducing hypoxia-inducible-factor 1α (HIF-1α) in neoplastic cells, augments angiogenesis with subsequently poor outcome.  HIFs are the transcription factors which regulate various genes that control proliferation, angiogenesis and metabolism. This factor is essential for survival of healthy cells and is also co-opted by cancer cells to promote their survival. Upregulation of HIF has a direct corelation with severity of tumor and subsequent metastasis as well as chemoresistance and consequent poor outcome as has been evidenced by increased mortality in carcinomas of bladder, breast, brain, cervix, ovaries and malignant melanomas.  Levels of reactive oxygen species increase during use of inhalational agents, thus revealing another pathway by which these agents upregulate HIFs.  In fact isoflurane exposure in ovarian cancer cells has been associated with enhanced tumor cell multiplication and production of metastatic markers resulting in enhanced metastatic potential.  In vitro studies have elucidated the diminution of interferon induced NK cytotoxicity by halothane as well as isoflurane.  Sevoflurane by altering the release of cytokines (IL-1β and TNF-α) by NK-cells is equally putative.  In humans, however isoflurane has been reported to have a beneficial effect in colon cancers. 
Nitrous oxide has been incriminated in interference of DNA, purine, and thymidylate synthesis and abrogation of neutrophil funcion.  Experimental studies have shown nitrous oxide to be an important culprit in liver metastasis.  However, no significant correlation has been demonstrated between nitrous oxide exposure and tumor relapse in a randomized controlled trial. 
Muscle relaxants have no effect on tumor progression.
Opioids are being increasingly used by the anesthesiologists not only in the perioperative period but also to allay chronic cancer pain. Studies conducted over the recent years have however given intimidating results with opioids implicating them as possible culprits in cancer progression. There are myriad ways in which opioids exert their pro-tumor effect [Table 3] Opioids by stimulating the μ opioid receptors (MOR) expressed in vascular endothelium, trigger the VEGF-mediated angiogenesis.  They also accentuate immunosuppression.  Morphine, which at one time was considered to be the cancer patients' best and final friend, is in fact the most putative agent of this class. Apart from inducing angiogenesis, it also increases vascular permeability and provides a nexus for tumor spread. Studies done over the years have shown that morphine via different mechanisms can trigger as well as suppress tumor growth in vivo and in vitro. Whereas at concentrations of >10 μM, morphine attenuates tumor multiplication and its intermittent injections in vitro decreased tumor proliferation; , Gupta et al., have elucidated tumor neovascularization in human breast xenograft model in mice in therapeutic doses of morphine.  This variability is due to tumor attenuation by prolonged high doses of morphine and accentuation with single or low daily dosing with morphine.  Morphine also exhibits anti-apoptotic effect.  Also it is known to inhibit adhesion and migration of 26-L5 colon tumor cells to extracellular matrix and thereby dramatically reduce lung metastasis in vitro.  Tramadol, which has a serotonergic as well as nor-adrenergic activity, has been shown to suppress the surgery induced lung metastasis in vitro.  Fentanyl inhibits the NK cell cytotoxicity postoperatively.  Sufentanyl and alfentanil on the other hand affect leukocyte function, inhibit NK cells and suppress mitogen triggered lymphocyte multiplication. 
Non-steriodal Anti-inflammatory drugs (NSAIDS) and COX-inhibitors
COX-2 inhibitors have anti-angiogenesis affect and also exhibit a dramatic reduction in tumor recurrence. In fact a lower recrudesce rate of breast neoplasms has been reported in women on chronic COX-2 inhibitor therapy.  NSAIDS even if given as a single dose peri-operatively significantly reduces the rate of cancer recurrence post surgery. 
| > Effects of local anesthetic agents|| |
Local anesthetic agents block afferent sensory impulses and provide adequate pain relief, reducing plasma concentration of various mediators, preserving cell mediated immunity.  Local anesthetics mainly act by curbing the voltage-gated sodium channels (VGSC) in the excitable state. These VGSC are expressed both in vivo as well as in vitro in various malignancies including breast cancer, cervical cancer, colon and prostrate cancers.  It has been found that downregulation of VGSC gene aborts the ability of the tumor cells to metastasize while the upregulation of VGSC Nav1.5 gene enhances the susceptibility of prostrate neoplastic cells to invade and spread.  Local anesthetic agents also have antiproliferative effect on tumor cells. This has been elucidated with lidocaine and ropivacaine on mesenchymal cells as well as human fibroblasts in vitro studies. , Lidocaine and tetracaine are also known to impair kinesin motor machinery of neoplastic cells, which quashes microtubular protrusions and prevent metastasis [Table 4].  Amides are also known to affect the Src signaling and subsequent metastasis of lung cancer cells.  Ropivacaine has been shown to have its anti-inflammatory role due to impairment of Src tyrosine protein kinase activity and intercellular adhesion molecule-1-phosphorylation. Lidocaine and Ropivacaine provide endothelial barrier protection in endothelial cells in lungs by decreasing adhesion of neutrophils and endothelial hypermeability, reflecting their anti-inflammatory properties.  Some of the antitumor effects of local anesthetic agents are also mediated via its ability act through potassium or calcium channels. These agents also inhibit transcription pathways. Cytotoxic effects also correlate with their potency and lipophilicity. 
| > Regional anesthesia techniques and cancer recurrences|| |
Regional anesthesia has been found to be associated with favorable prognosis in patients undergoing oncosurgery. By aborting surgery mediated neuroendocrine stress response and preserving the immune function, regional anesthesia alone or when combined with general anesthesia has protective effect in curbing post-surgical tumor recrudesce. In a study done by Koltun et al., it has been seen that epidural anesthesia recieving patients during colectomy had lower plasma levels of epinephrine and cortisol, compared to patients receiving general anesthesia and also the NK cell activity was better preserved in patients receiving regional anesthesia.  Also locoregional anesthesia by providing better pain relief, significantly decreases the requirement of intra- and perioperative opioids as well as release of endogenous opioids, thereby preventing their adverse effects. Additionally, by reducing the doses of other general anesthetic agents, it attenuates immunosuppression. Another mechanism by which tumor relapse is obtunded, is by crippling of lymphatic drainage by regional anesthetics [Table 5]. 
Peripheral nerve blocks
Peripheral nerve blocks, when performed by safe hands, can be beneficial in patients undergoing oncosurgeries, especially with perineural catheters left in situ with consequent reduction or complete avoidance of perioperative opioids for analgesia.  In a retrospective study done in patients with breast cancer significantly favorable survival rates were seen when paravertebral block was given (94%) as compared to those who received general anesthesia (77%). 
General anesthesia when combined with thoracic epidural anesthesia not only curtails surgical stress response but also preserves immunity. Experimental studies on rats have shown beneficial effects of spinal anesthesia when combined with general anesthesia during laparotomy in curtailing lung metastasis.  In other study done on patients with prostrate cancer when surgery was done under general anesthesia combined with epidural technique, a lower incidence of tumor relapse was observed than when general anesthesia with intravenous opioids was employed. 
However, certain compelling results have also been obtained with regional anesthesia techniques. In a retrospective study done on patients undergoing radical prostatectomy, no added advantage of regional anesthesia over general anesthesia was elucidated.  Similarly, no beneficial effects of attenuating post surgery tumor progression was seen with epidural anesthesia in patients undergoing laparotomy for colorectal cancers.  Most of these studies being retrospective are subject to selection bias and influenced by various confounding factors. Only prospective clinical trials can really unfold the appropriate effects of regional anesthetic techniques on tumor relapses. One such published study is the MASTER trial, done on patients undergoing major abdominal surgery who were randomized to receive general anesthesia with either opioid or epidural technique. This study had several limitations as different types of surgeries were analyzed together, so correlation with particular cancer would have been masked, was an underpowered study and details of the postoperative events like chemotherapy and radiotherapy were not available. This study demonstrated no major difference in tumor free period between the two groups; the exact dose of volatile anesthetic used, being the confounding factor in this trial.  Other clinical trials are underway, the results of which will unveil this enigma. These trials on patients with breast, lung and colon cancers are being conducted at Cleveland Clinic, Mater University Hospital, and University of Dusseldorf. Outcomes are expected to be in 2015, 2018, and 2022 respectively. 
| > Conclusion|| |
Though surgery remains the mainstay of treatment for various malignancies, its associated neuroendocrine stress response coupled with immunosuppression has an adverse effect in long term tumor outcome. Its challenging to estimate cancer recurrence because follow-up of patients is irregular along with dropouts, patient only visits the oncosurgeon and he may not be aware of the implications of anesthetic agents, poor collaboration with surgical team and the anesthesiologist may concentrate only on short term outcome in terms of safe intraoperative period and may not pay attention to anesthetic agents and technique. Type of anesthetic agent used as well as the technique employed also allays or delays tumor recrudesce, thereby emphasizing the equally pivotal role of anesthesiologist. While most of the intravenous (except propofol) and volatile anesthetic agents induce post surgical tumor metastasis via different mechanisms, regional anesthetics per se by preserving immunity and attenuating neurosurgical stress response are largely protective. However, more supportive evidences are needed before extrapolating the results of these researches, for which various clinical trials are underway. Meanwhile, need of the hour is to stick to those regimens, which offer significant benefits against tumor relapses as per the available clinical data. According to the consensus statement from British Journal of Anesthesia workshop on cancer and anesthesia, anesthetic or analgesic technique might affect cancer outcomes is intriguing, there is currently insufficient evidence to support any change in clinical practice. Role of opioids is controversial, as long term opioid use in sub analgesic doses in mice without surgery suggests that it enhances cancer growth. At the same time, opioid use in analgesic doses in mouse models resembling perioperative settings, has shown either protective effect or no effect. Whether use of morphine augments risk of metastasis or recurrence after cancer surgery, is not clear. Thus, there is paucity of data to indicate any change of clinical practice. Also, Randomized clinical trials are needed to evaluate the effects of adjunct medications like regional anesthesia, intravenous lidocaine and NSAIDs, on cancer recurrence during anesthesia for primary cancer surgery. Also, collaboration is needed with other specialists like medical and surgical Oncologists, to study link between anesthetic techniques and cancer outcomes in cancer patients posted for surgery. 
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]