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Surgical excision is the cornerstone of treatment for solid tumors. Metastatic disease is the most important cause of cancer-related death patients affected with cancer. The likelihood of tumor metastases depends on the balance between the metastatic potential of the primary tumor and the antimetastatic host defenses. Among them, cell-mediated immunity and natural killer (NK) cell function are critical components.
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A wealth of basic science data supports the hypothesis that the surgical stress response increases the likelihood of cancer dissemination during and after cancer surgery. Therefore, anesthetic management can potentially influence mid- and long-term outcome. Au contraire, surgery can inhibit major host defenses and promote the occurrence of metastases. Anesthetic techniques and drug choice also can affect the immune system. Together, these two interventions can have profound interactions with a patient’s immune defenses. The aims of this chapter are to review how the immune system can be influenced by surgery and anesthesia and discuss the possible mechanisms behind a potential benefit of one intervention over the other in this setting.
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THE IMMUNE SYSTEM: THE IMPORTANCE OF Th1/Th2 RATIO
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Intact immune responses to cancer cells are crucial in preventing and inhibiting tumor occurrence. The modern concept of immunoediting includes these processes: elimination, equilibrium, and escape.1,2 This implies that impairment in immune surveillance during the elimination process allows the escape of cancer cells from the protective immune attack. The appearance of clinically apparent tumors through the equilibrium process may occur, rendering the tumor cells more resistant to the immune system.
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The NhK, CD4+ Th1 (T helper 1), and CD8+ CTL (cytotoxic lymphocyte) cells are the major antitumor immune effector cells, whereas Th2 (T helper 2), tumor-associated macrophages (TAM), and regulatory T (Treg) cells are the among the most important cells in the promotion of tumor settlement, growth, and progress by inhibiting the immune responses against cancer.3,4 Other mediators like proinflammatory cytokines,5 catecholamines,6 prostaglandins,6 and high levels of signal transducer and activator of transcription 3 (STAT3) factor activity7 are also involved in the process of postoperative metastases. NK cells have a crucial role particularly in eliminating metastases without prior sensitization and major histocompatibility complex (MHC) restriction.8 Therefore, preservation or activation of the function of NK cells is important. In this context, Th1 cells, characterized by interleukin (IL) 2, IL-12, and interferon gamma (IFN-γ) secretions are mandatory to induce antitumor CTL9 and to activate NK cells.8 On the other hand, Th2 cells differentiated by IL-4 and IL-10 can induce Th17 cells, Treg cells, TAMs, and myeloid derived suppressor cells (MDSCs),10 which have a major role in promoting tumor growth and metastasis by inhibiting antitumor immune responses like Th1 induction, CTL function, and NK activity.11
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The role of proinflammatory cytokines (IL-6, tumor necrosis factor alpha [TNF-α], IL-13) should be outlined because release from infiltrating leukocytes close to the primary tumor site can activate nuclear factor κB (NF-κB) and STAT3 in cancer cells and can contribute to cancer proliferation and survival.12 NK cell function can also be downregulated by prostaglandins, especially prostaglandin E2 (PGE2) by shifting cytokine balance toward Th2 dominance13 and promoting tumor angiogenesis.10
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Th1-type responses are necessary for antitumor immunity. It has been shown that, in general, cancer patients have a Th2-dominant status.14 Surgery per se induces the Th1/Th2 balance toward Th2 immune response.15 This is explained by the surgical activation of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis.16
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ANESTHETIC INTERVENTIONS AND POTENTIAL EFFECTS ON IMMUNOMODULATION
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Anesthetic techniques or drugs may have a direct impact on the immune balance of cancer patients. This section reviews the established and hypothetical effects of various anesthetic interventions, pharmacological agents and perioperative occurrences that may affect immunomodulation.
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Hypotension, Hypovolemia, and Hypoxia
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The occurrence of hypotension/hypovolemia during surgery is are some of the factors responsible for the activation of the sympathetic system. The resulting tissue hypoxia may increase the expression of the intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) as well as P-selectin and E-selectin in vascular endothelium.17 This initiates the systemic inflammatory response syndrome (SIRS), responsible for a depressed Th1 response18 and therefore a shift toward the Th2 response phenotype.
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Hypothermia is a common occurrence during surgery. In vitro human investigation has demonstrated that monocytes incubated at temperature lower than 36°C reduced human leukocyte antigen (HLA)-DR expression, delayed TNF-α clearance, and increased IL-10 release.19 In vivo animal studies have shown a suppression of NK cell activity.19
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Hyperglycemia during surgery is the result of the activation of the stress response. Acute hyperglycemia inhibits glucose-6-phosphatase dehydrogenase, the enzyme necessary for the formation of nicotinamide adenine dinucleotide phosphate,20 which will block the functions of monocytes and neutrophils. The risk of infection is increased, and the occurrence of microvascular inflammation engenders an increased release of proinflammatory cytokines (IL-6, TNF-α) from immune cells.20
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However, no data showing that perioperative hyperglycemia is associated with tumor spread or metastasis are available.
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Allogenic blood transfusion is recognized to have diverse negative immunomodulatory effects. However, blood transfusion is also a marker for sicker patients. In this context, it has been shown that anemia per se also has negative immune effects. Therefore, it is important to find the right balance, and avoiding unnecessary transfusions.
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Volatile anesthetics have been shown to have suppressive effects on immune cells. Halothane,21 isoflurane,22 and sevoflurane23 suppress NK cell activity. The precise mechanism by which these agents interact with the immune system is not clear. However, a recent study showed that pretreatment with isoflurane can enhance resistance to apoptosis of colon cancer cells after exposure to anticancer drugs in vitro via a caveolin-dependent mechanism.24
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Propofol at a clinical concentration does not appear to have significant effects on NK cells and lymphocytes. Propofol, but not thiopental or ketamine, does not suppress NK cell activity in whole blood and does not increase susceptibility to tumor metastases.21 A comparison between propofol and isoflurane25 showed that propofol, but not isoflurane, increased the Th1/Th2 ratio, which is beneficial for patients with cancer. On the other hand, sevoflurane anesthesia26 increased proinflammatory cytokine IL-17 and decreased the Th1/Th2 ratio. Propofol also has inhibiting activity against cyclooxygenase (COX) 2.27 This is beneficial because in most human cancer cells COX-2 is overexpressed. COX-2 expression is critical for the production of PGE2, which promotes tumor progression, VEGF (vascular endothelial growth factor) production in cancer cells, NK cell inhibition, and Th2 polarization.27
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Midazolam28 and ketamine29 impair dendritic cell induction of Th1-type immune response in vitro and in vivo. Dendritic cells and Th1-type cells are important players in host defense against tumor. Ketamine also upregulates PGE230 and increases lung metastases through NK cell inhibition in rat models.
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Morphine-induced immunosuppression is mediated by its binding to a member of the seven-transmembrane G-protein-coupled μ-opioid receptors (MORs) on immune cells.31 The μ-receptor, which is morphine sensitive, is responsible for its immunomodulation.32 Interestingly, fentanyl, despite sharing analgesic properties with morphine, does not bind to μ3-receptor.33 However, morphine administration reduces CTL and NK cell functions31,34 and IL-2 and IFN-γ expression in T cells.35,36 It also enhances IL-4 expression in T cells37 favoring Th2 differentiation. Fentanyl was shown to have a suppressive effect on NK activity in nonsurgical individuals but to have a positive effect in operative subjects.38 In contrast, remifentanil did not impair NK activity.39
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Epidemiologic studies suggested that patients who receive general anesthesia with opioids rather than local anesthetics (LAs) or regional anesthetics may have a greater rate of cancer recurrence.40 Beilin et al41 investigated NK cell cytotoxic activity in 40 patients undergoing major surgery, who were randomized to receive either a high-dose fentanyl anesthesia regimen, including midazolam as a single dose and isoflurane if necessary, or low-dose fentanyl, with isoflurane and nitrous oxide used for anesthetic maintenance. In vitro NKA was suppressed in all patients, but high-dose fentanyl resulted in a slower rate of recovery of NK cell activity compared to low-dose fentanyl.
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Sacerdote et al42 studied the effects of morphine and tramadol in patients undergoing abdominal surgery for uterine carcinoma. Phytohemaglutinin-induced T-lymphocyte proliferation and NKA were evaluated. In the morphine group, lymphoproliferative values were attenuated by surgical stress and stayed depressed after the administration of morphine, whereas in the tramadol group these values came back to baseline after the administration of tramadol. NKA was increased by tramadol.
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Gupta et al43 demonstrated that morphine stimulates angiogenesis by activating proangiogenic signaling via Gi/Go-coupled G-protein receptors and nitric oxide. In clinically relevant plasma concentrations, morphine stimulated human microvascular endothelial cell proliferation and promoted tumor neovascularization in a human breast tumor xenograft model in mice, which led to the progression of the tumor.
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Singleton et al44 showed that μ-opioid agonists in clinical concentrations transactivate the VEGF receptors, and that the opioid-induced angiogenesis was blocked by both naloxone and the peripheral MOR antagonist methylnaltrexone. This group suggested that because μ-opioid agonists can alter the endothelial barrier integrity and affect vascular permeability, during tumor surgery, they could potentially facilitate transmigration of cells through the endothelium. This process was shown to be attenuated by methylnaltrexone.45
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Mathew et al46 reported that the expression of MORs was increased in lung cancer cells (Lewis lung carcinoma) and that the silencing of MOR in those cells reduced tumor growth and metastasis in mouse models.
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Subsequently, Lennon et al47 published the results of their more recent study where the effect of overexpression of the MOR on lung cancer progression was examined. The authors tested their hypothesis in vitro (H358 human non-small cell lung cancer [NSCLC] cells) and in vivo (human lung cancer xenograft models/nude mouse model). They demonstrated that MOR1 overexpression in H358 human NSCLC cells increased proliferation, migration, invasion, transendothelial migration, and activation of two serine/threonine kinases implicated in cancer progression (Akt [protein kinase B] and mammalian target of rapamycin [mTOR]). In addition, the same effect of increased tumor growth and lung metastasis was observed in human NSCLC xenografts. The authors suggested that these results may provide a plausible explanation for the differences in recurrence rates observed in different contexts.40,48,49,50
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In conclusion, there are currently epidemiologic, animal, and cellular studies that suggest a possible role of MOR on tumor growth and metastasis that warrants further investigation.
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REGIONAL ANESTHESIA AND CANCER METASTASES
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Local Anesthetics and Cancer In Vitro
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In vitro studies have demonstrated the antiproliferative or cytotoxic effect of LAs on cancer cells. Martinsson et al51 evaluated the effect of ropivacaine on the proliferation of human colon adenocarcinoma cells in vitro. Ropivacaine inhibited the growth of these cells in a dose-dependent manner. The effective concentrations were within the therapeutic range, similar to the ones found in the colon of the patients treated rectally with ropivacaine. In the same study, lidocaine was found to be less potent than ropivacaine in inhibiting cell proliferation.
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Sakaguchi et al52 investigated the effects of lidocaine on proliferation of a human tongue cancer cell line that has a high level of epidermal growth factor receptor (EGFR) expression. Lidocaine in clinical concentrations suppressed EGF-induced proliferation of the malignant cells and inhibited EGF-stimulated tyrosine kinase activity of EGFR without cytotoxicity.
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Lucchinetti et al53 reported the results of the antiproliferative effects of LAs on mesenchymal stem cells (MSCs) and the potential implications for tumor spreading and wound healing. MSCs play a key role in tumor growth and metastasis by releasing growth factors, enhancing angiogenesis, immunomodulation, and epithelial-to-mesenchymal transformation. MSCs also contribute to tissue repair. The authors tested the effect of increasing concentrations of the amide LAs lidocaine, ropivacaine, and bupivacaine on proliferation, colony formation, in vitro wound healing, and bone differentiation assays of culture-expanded bone-marrow–derived murine MSCs. They demonstrated that MSCs are sensitive to the antiproliferative effects of LAs at concentrations of 10–100 μM. Their results suggested that mechanisms involved in this antiproliferative action may include the inhibition of NF-κB-ICAM-1 signaling pathway as well as the inhibition of mitochondrial respiration with adenosine triphosphate (ATP) depletion.
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Effects of Anesthetic Techniques on Cellular Immunity
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In the absence of surgery, general or epidural anesthesia has only minor effects on immune cell functions.54 However, several preliminary studies in humans have indicated the beneficial effects of epidural anesthesia on immune cell functions in the setting of surgery-induced tissue trauma/stress.
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Koltum et al55 compared, in 20 patients who underwent colectomy under laparotomy for various diagnosis, the effect of awake epidural anesthesia (AEA) versus general endotracheal anesthesia (GETA) on natural killer cell cytotoxicity (NKCC). They found that AEA significantly preserved perioperative NKCC compared to GETA.
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Hole et al56 evaluated the phagocytic capabilities as well as the ability of monocytes to induce lysis of malignant cells in 18 patients undergoing total hip arthroplasty performed under either general or epidural anesthesia. While the phagocytic function of the monocytes derived from patients in the epidural group was found to be increased, the ability to induce lysis in malignant cells of the monocytes derived from patients who underwent general anesthesia was significantly reduced.
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Wada et al23 demonstrated in a rat model that sevoflurane anesthesia and laparotomy diminished tumoricidal activity in liver mononuclear cells (Th cells). On the contrary, a spinal block attenuated this effect. Bar-Yosef et al57 showed the beneficial effects of spinal anesthesia on lung tumor retention in rats. The group with laparotomy plus general anesthesia had a 17-fold increase in lung metastasis. Spinal block reduced this effect by 70%. The authors concluded that surgical stress in rats promoted the development of metastasis, which was significantly attenuated by regional anesthesia.
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Data from Retrospective Studies
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In recent years, a number of retrospective studies suggested that regional anesthesia may have a beneficial effect on reducing cancer recurrence and metastasis.
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Such studies are often limited by the accuracy of the available medical records, the lack of control in selection and measurement bias, and multiple uncontrolled confounding factors that could have an impact on cancer recurrence.
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In one of the first published retrospective studies indicating the beneficial effects of regional anesthesia, Schlagenhauff et al58 evaluated the prognostic impact of general and regional anesthesia for the excision of primary cutaneous melanoma. The authors examined follow-up data of 4329 patients. The study concluded that there was a significantly increased risk of death for patients treated with general anesthesia for the primary excision of melanoma, thus favoring regional anesthesia for this procedure.
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Exadaktylos et al59 conducted a small retrospective study based on the review of the medical records from patients that underwent mastectomy and axillary dissection for breast cancer. The patients had received either general anesthesia combined with paravertebral anesthesia/analgesia or general anesthesia combined with patient-controlled morphine analgesia. The authors examined the records of 129 patients who had a follow-up time of 32 ± 5 months. Their results suggested that the use of paravertebral anesthesia and analgesia for breast cancer surgery versus opioid use was associated with a metastasis/recurrence-free survival benefit of 94% versus 77% at 37 months.
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Christopherson et al,48 in a retrospective study, evaluated the long-term survival after resection of colon cancer under general anesthesia with or without epidural anesthesia in 177 patients. Analysis was performed separately for patients with and without metastasis because the presence of distant metastasis had the greatest effect on survival. Their results suggested that the patients with epidural analgesia had an improved survival (p = .012), up to 1.5 years; thereafter, the type of anesthesia did not appear to affect survival (p = .27).
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Biki et al49 evaluated retrospective date for prostate cancer recurrence in patients who received either general anesthesia with epidural anesthesia/analgesia (n = 102) or general anesthesia with postoperative opioid analgesia (n = 123). The primary outcome measure was the incidence of “biochemical recurrence,” that is, an increase in prostate-specific antigen (PSA) after radical prostatectomy compared with its immediate postoperative peak value, which was the cause for initiation of adjuvant treatment. Adjustment for confounding factors was performed, and the results showed that patients who received general anesthesia combined with epidural analgesia had a 57% (95% CI, 17%–78%) lower risk of cancer recurrence than patients who had general anesthesia and postoperative opioids.
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Tsui et al50 evaluated the effect of adjunctive epidural LA and opioid infusion on disease recurrence following radical prostatectomy for adenocarcinoma under general anesthesia. This study was a retrospective analysis of a small randomized trial conducted for other purposes, such as pain control, blood loss, and the need for perioperative blood transfusion. The authors conducted a prolonged follow-up chart review to determine clinically evident or biochemical recurrence of prostate cancer. The median follow-up time was 4.5 years, and no difference in disease-free survival between the epidural and the control group was observed. Because the study had a different endpoint, it was significantly underpowered for evaluating cancer recurrence.
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Ismail et al60 examined retrospective data to determine the effect of neuraxial anesthesia in the progression of cervical cancer in 132 patients who were treated with brachytherapy. The use of neuraxial anesthesia during the first brachytherapy (most invasive one) was not associated with a reduced risk of local or systemic recurrence, long-term mortality from tumor recurrence, or all-cause mortality after adjusting for other prognostic factors. The study have failed to demonstrate a difference between the general and the regional anesthesia groups due to the underpowered sample size. Other factors that might have contributed to this result are the minimally invasive nature of the therapeutic procedure used for this treatment and the short duration of the neuraxial anesthesia.
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Gottschalk et al61 reviewed the records of 669 patients undergoing colorectal surgery to determine the association between perioperative epidural analgesia and cancer recurrence. The primary outcome of the study was time to cancer recurrence. In this study, the epidural and nonepidural groups were compared in all available potential confounders, and their relationship with cancer recurrence was analyzed by using a multivariable Cox proportional hazards regression model. Overall, no association between epidural use and recurrence was found (p = .43), with an adjusted estimated hazard ratio (HR) of 0.82 (95% CI 0.49–1.35). However, the authors found that the epidural-by-age interaction was statistically significant (p = .03). Epidural analgesia was associated with reduced cancer occurrence in patients older than 64 years, suggesting that age and tumor type may play an important role.
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Wuethrich et al62 evaluated the effect of anesthetic technique on disease progression and long-term survival in patients receiving general anesthesia plus intraoperative and postoperative thoracic epidural analgesia (n = 103) in comparison to patients receiving general anesthesia alone (n = 158). The patients underwent open retropubic radical prostatectomy with extended lymph node dissection. The authors’ assessment was more detailed in that they evaluated biochemical recurrence-free survival, clinical progression-free survival, cancer-specific survival, and overall survival. It was demonstrated that general anesthesia combined with epidural analgesia resulted in improved clinical progression-free survival (HR 0.45, 95% CI 0.27–0.75, p = .002). No significant difference was found between general anesthesia plus postoperative ketorolac-morphine analgesia and general anesthesia plus intraoperative and postoperative thoracic epidural analgesia in biochemical recurrence-free survival, cancer-specific survival, or overall survival. The authors used a historical control group, which represented a limitation.
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Myles et al63 conducted a large (n = 503) retrospective study as a follow-up to the Multicenter Australian Study of Epidural Anaesthesia and Analgesia in Major Surgery (MASTER). This multicenter randomized clinical trial tested the hypothesis that combined epidural and general anesthesia reduced the frequency of major postoperative complications compared with general anesthesia and opioid analgesia. The goal was to compare long-term recurrence of cancer and survival in patients who underwent major abdominal surgery under general anesthesia with the supplement consisting of intraoperative and postoperative epidural analgesia (epidural group n = 263) or under general anesthesia and postoperative opioids for analgesia (control group n = 240). The median time to recurrence of cancer or death was 2.8 (95% CI 0.7 to 8.7) years in the control group and 2.6 (0.7 to 8.7) years in the epidural group (p = .61). Recurrence-free survival was similar in both epidural and control groups. However, the fact that 50% of the epidurals did not work is a major weakness of this study and raised serious doubts concerning the validity of the results.
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De Oliveira et al,64 in a recent retrospective study, studied any association between intraoperative neuraxial regional anesthesia and decreased ovarian cancer recurrence. The study reviewed data from 182 patients who underwent primary cytoreductive surgery for ovarian cancer. All the patients received general anesthesia. Of those, 127 received intravenous opioids for postoperative pain control, and 55 received epidural catheters. Of these patients, 26 received epidural anesthesia intra- as well as postoperatively for analgesia. The rest of the patients had the epidural only for postoperative pain control. The authors found that in the intraoperative/postoperative epidural group the mean time to cancer recurrence was 73 (56–91) months, which was longer than for either the epidural postoperative group at 33 (21–45) months (p = .002) or the nonepidural group at 38 (30–47) months (p = .001).
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In a recently published retrospective study, Cummings et al65 compared the effects of epidural analgesia and traditional pain management on survival and cancer recurrence after colectomy. A cohort of 42,151 patients over 66 years old who underwent colectomy was identified from the Medicare-Surveillance, Epidemiology and End Results database. Of these patients, 22.9% (n = 9670) had an epidural at the time of resection. The results of this study demonstrated that the epidural use was associated with improved survival in patients with nonmetastatic colon cancer. Five-year survival was 61% in the epidural group and 55% in the nonepidural one.
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Day et al66 undertook a retrospective analysis of the effect of postoperative analgesia on survival in patients after laparoscopic resection of colorectal cancer. The data of 424 patients were analyzed. The three groups (epidural = 107, spinal block = 144, and patient-controlled analgesia = 173) were similar regarding patient and surgical characteristics. In the epidural group, patients received a mixture of bupivacaine and fentanyl for 48 hours. The authors did not find any difference between the groups in overall survival.
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Some of the discussed retrospective studies provided results suggesting that regional anesthesia might have a beneficial affect in reducing cancer recurrence and some did not. The interpretation of the results of these investigations is complex because neither the LAs nor the concentration and the time and duration of application are known. Moreover, some analgesic regimens were a mixture of LA and opioid. Consequently, no clear-cut conclusions or recommendations for clinical care can be made (Table 17–1).
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Clinical recommendations are also precluded because the clinical assessment of these results is even more difficult as no information regarding surgical technique is available. Although the possibility that regional anesthesia may reduce the incidence of metastasis is exciting, currently it is a hypothesis as adequately powered prospective randomized clinical trials are needed to validate the current observational results. What is known however, is that LAs have anti-inflammatory properties and do affect the mediators of inflammation at the molecular level. There is also evidence that inflammatory mechanisms may play a role in cancer metastasis.
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INFLAMMATION AND CANCER
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Epidemiological studies and molecular investigations of genetically modified mice and led to the conclusion that the mechanisms leading to inflammation and cancer may be linked.67,68,69,70 The presence of inflammatory cells and inflammatory mediators in tumors, tissue remodeling, and angiogenesis is similar to that seen in chronic inflammatory responses that precede and constitute the hallmark of cancer-related inflammation.
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Cancer and inflammation are connected by two pathways: an intrinsic one and an extrinsic one.71 The intrinsic pathway is activated by genetic events such as mutations, chromosomal rearrangements, and so on that affect oncogenes. Cells that are transformed by these events produce inflammatory mediators, thereby generating an inflammatory microenviroment in the tumor area. By contrast, in the extrinsic pathway it is the inflammatory or infectious condition that is responsible for the risk of developing cancer at certain sites, such as colon, prostate, and pancreas. The two pathways lead to a common one and follow the activation of the nuclear transcription factor NF-κB and other transcription factors.
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These factors regulate the production of inflammatory mediators such as cytokines and chemokines, which in turn recruit and activate various leukocytes. The cytokines activate the same key transcription factors in inflammatory cells, stromal cells, and tumor cells. This results in the subsequent release of more inflammatory mediators and the formation of a cancer-related inflammatory milieu (Figure 17–1).71
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Role of the ICAM-1 and Src Protein Tyrosine Kinase on Inflammation and Metastasis
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The role of cell adhesion molecules (CAMs) such as ICAM-1, VCAM-1, E-selectin, and P-selectin has been studied extensively in the process of inflammation.72 Similarly, CAMs have been implicated in tumor progression.73 Some circulating cancer cells have been shown to extravasate to a secondary site using a process similar to inflammatory cells.74 This process shared by inflammatory and cancer cells may partially explain the link between inflammation and the occurrence of metastasis. Furthermore, it may help to understand the therapeutic benefit of anti-inflammatory drugs in cancer treatment.
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Scientific evidence has implicated a role of ICAM-1 in tumor invasion in vitro and in metastasis in vivo and hence in the malignant potential of various types of cancer. Kageshita et al75 have demonstrated that ICAM-1 expression in primary lesions and the serum of patients with malignant melanoma was associated with a reduction in the disease-free interval and survival. Also, a significantly higher level of serum ICAM-1 (sICAM-1) was detected in the patients with liver metastasis, and its levels were increased in serial blood samples obtained from patients with progressing disease. Similar results were reported in a study that examined the role of ICAM-1 in the invasion of human breast cancer cells.74
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Maurer et al76 determined that overexpression of ICAM-1, V-CAM-1, and endothelial leukocyte adhesion molecule 1 (ELAM-1) influenced the tumor progression in colorectal cancer. High expression of ICAM-1 in tumors was an indicator of metastatic potential and poor prognosis.77 Because ICAM-1 is associated with a variety of cancer types and has a role in cancer metastasis, it can be also used as a biomarker for tumor prognosis as well as a target for therapeutic interventions.78,79,80
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Current evidence has shown that the binding of apical cell surface associated mucin (MUC-1) on circulating tumor cells to the ICAM-1 on the endothelial cells could represent one of the first crucial steps in metastasis. This molecule is a mucin-glycosylated phosphoprotein that lines the apical surface of epithelial cells in the lung and several other organs. Roland et al81 proposed that this binding results in a release of cytokines and chemokines that attract macrophages and upregulate tumor production of ICAM-1. Macrophages produce more cytokines that attract neutrophils (polymorphonuclear neutrophils, PMNs), which adhere to the ICAM-1 of the tumor cell surface. This interaction causes degranulation of the PMNs, releasing proteases, with subsequent deterioration of the endothelial barrier promoting extravasation of the tumor cells and formation of metastatic sites.82,83,84,85
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Another potent regulator of endothelial permeability and the inflammatory responses in tissue cells is Src kinase.86 Src protein tyrosine kinase (PTK) family members have been identified as essential for the recruitment and activation of monocytes, macrophages, neutrophils, and other immune cells.87 The Src family of nonreceptor protein tyrosine kinases plays a critical role in a variety of cellular signal transduction pathways, regulating such diverse processes as cell division, motility adhesion, angiogenesis, and survival. Activation of Src family kinases is common in a variety of human cancers, may occur through different mechanisms, and is frequently a critical event in tumor progression. Src kinases appear to be important in the proliferation of the tumor, disruption of cell/cell contacts, migration, invasiveness, and resistance to apoptosis. Src family kinases are thus attractive targets for use as anticancer theurapeutics.88
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It has been demonstrated that once tumor cells leave their primary site, they enter the blood vessels and again they extravasate to form satellite lesions. It was shown in mice that endothelial barrier disruption by VEGF-mediated Src activation potentiated tumor cell extravasation and metastasis. Some of the metastatic tumor cells secrete VEGF, which subsequently activates Src and compromises the endothelial barrier by disrupting a VE-/-β-catenin complex in lung endothelial cell-cell junctions. This is supported by the findings that mice genetically deficient in the c-Src are resistant to tumor cell metastasis.89 Src is also an upstream regulator of Rho family GTPases (guanosine triphosphatases) such as Rac and Rho, which together regulate dynamic changes in the cytoskeleton and control the disassembly of actin-based cytoskeletal structures and cell-matrix adhesions.90
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Finally, another protein that plays a role in inflammation by attracting monocytes and macrophages to the site is the monocyte chemoattractant protein 1 (MCP-1). This is a chemokine that exerts strong chemoattractant activities on monocytes, T cells, and NK cells.91 In addition to promoting the transmigration of circulating monocytes into tissues, MCP-1 exerts various other effects on these cells, including superoxide anion induction chemotaxis and calcium flux.92 Its production is also associated with angiogenesis and tumor invasion. Goede et al93 analyzed the angiogenesis-inducing capability of MCP-1 and found it was a potent angiogenic factor when implanted into the rabbit cornea, with an effect similar to the specific angiogenic VEGF. Moreover, serum levels of MCP-1 have been found to be elevated in lung cancer patients with bone metastases.94
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Evidence of Antimetastatic Effect of Local Anesthetics
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Anti-inflammatory properties of ropivacaine have been demonstrated in different experimental models of lung injury.95 Lidocaine also has well-documented anti-inflammatory properties and a safer profile for systemic toxicity. As mentioned, inflammatory processes involving Src tyrosine protein kinase and ICAM-1 play a role in cancer metastasis. It could be hypothesized that the amide LAs might attenuate the metastatic process of cancer cells in a similar manner to the inflammatory one.
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In a recent study, we showed that lidocaine and ropivacaine may inhibit inflammatory cytokine signaling, proliferation, and migration of lung adenocarcinoma cells.96 The following in vitro study was performed: NCI-H838 lung cancer cells were incubated with TNF-α in the absence/presence of ropivacaine or lidocaine (1 nM, 1 μM, 10 μM, 100 μM). Cell lysates were analyzed for Src activation (phosphor-Y419 Src) and ICAM-1 phosphorylation (phosphor-Y512 ICAM-1) via Western blot. MCP-1 production, cell proliferation, and migration were also evaluated. The results of this work showed that both lidocaine and ropivacaine inhibited Src activation induced by inflammatory mediators TNF-α (Figures 17–2 and 17–3). We also showed that both lidocaine and ropivacaine attenuated TNF-α-induced MCP-1 production in H838 cancer cells, and that they inhibited their proliferation and migration as well (Figure 17–4). Interestingly, the ester LA chloroprocaine did not demonstrate these properties, suggesting these effects were specific to the amide type of LAs.
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To support the direct inhibition of Src tyrosine protein kinase by the amide LAs, the cells were treated with veratridine, a sodium channel activator and tetrodotoxin (TTX), a non-LA sodium channel inhibitor. We did not observe any alteration in the phosphorylation status of Src and ICAM-1 after treatment with veratridine compared to untreated cells, indicating that the phosphorylation of these two proteins was independent from sodium channel activation. The application of TTX had no effect on the phosphorylation status of these proteins, neither after treatment with TTX alone compared to untreated cells nor after coincubation with TNF-α compared to TNF-α alone. Taken together with the results obtained in the experiments with veratridine, we postulated that the observed effects of the inhibition of Src and ICAM-1 phosphorylation were independent of sodium channel inhibition.
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Metastatic disease after cancer surgery remains a crucial issue. Cancer dissemination is a multistep process in which many cellular and molecular regulatory mechanisms may be involved and are targets for therapeutic interventions.
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Traditional systemic therapy is delayed for weeks after major surgery to allow wound healing and thus avoiding the risks of immunosuppression and postoperative infections. However, recent studies demonstrated that cellular and molecular events that are critical to the metastatic process may be significantly influenced during and immediately after surgery.97 The perioperative period may be a window of therapeutic opportunity because metastasis may be initiated during this period. Preliminary studies using LAs have shown encouraging results for cancer outcomes. So far, the potential beneficial effect of regional anesthesia to improve long-term outcome after cancer surgery has contributed mainly to the inhibition of the neuroendocrine stress response to surgery and to the reduction in the requirements of the volatile anesthetics and opioids.
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The amide LAs block TNF-α-induced Src activation and ICAM-1 phosphorylation in vitro. Both of these processes may favor the extravasation of tumor cancer cells and metastasis. Cytokines such as TNF-α increase the expression of ICAM-1 in the H838 NSCLC. Src protein tyrosine kinase, which lies both upstream and downstream of activated ICAM-1, functions as a regulator of endothelial permeability and is also involved in signaling epithelial-to-mesenchymal transformation and extravasation of cancer cells, a process necessary for tumor metastasis. The activity of these two systems is significantly inhibited in vitro by the application of amide-type LAs. The immediate postoperative period is a crucial time in surgical oncology because no treatment will be started for a few weeks. The application of amide-type LAs in the perioperative period may be beneficial in preventing metastasis. However, the current preliminary data require further studies before any clinical recommendations can be made.
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