Journal of Clinical Anesthesia (2015) xx, xxx–xxx

Cancer surgery: how may anesthesia influence outcome? Fernando Cassinello MD, PhD (Anesthesiology)a,1 , Isabel Prieto MD (Radiation Oncology)a,⁎, Mercedes del Olmo MD (Anesthesiology) a , Sonia Rivas MD (Surgery)a , Gary R. Strichartz PhD (Professor of Anesthesia and Pharmacology)b a

IDC-Salud Fundacion Jimenez Diaz University Hospital, 28040 Madrid, Spain 1 Pain Research Center, Department of Anesthesia. Harvard Medical School, Brigham and Women's Hospital, Boston, 02115 MA, USA

b

Received 31 July 2014; revised 12 December 2014; accepted 17 February 2015

Keywords: Local anesthetics; Opioids; P-substance; Propofol; Regional anesthesia; Cancer surgery

Abstract Objective: To review the published literature regarding the effects of anesthesia on cancer surgery to prevent tumor cell proliferation/migration or induce apoptosis. Background: Surgery is the main treatment for potentially curable solid tumors, but most cancer-related deaths in patients who have received previous surgical treatment are caused by metastatic disease. There is increasing evidence that anesthetic technique has the potential to affect long-term outcome after cancer surgery. Methods: This work reviews the English published literature that was obtained by performing a search of the PubMed database up to January 2014. We selected articles that provided evidence or reviewed the possible actions of anesthetics on cancer cells or the influence of anesthesia in recurrence/outcome. Results: Inhaled anesthetics induce immunosuppression and activate inflammatory cascade activation, whereas propofol has a protective action. Opioids might promote cancer recurrence and metastasis. In vitro and in vivo studies have demonstrated that local anesthetics inhibit proliferation and migration of cancer cells and induce apoptosis. Conclusions: Anesthesiologists should follow current best clinical practice and include all strategies that effectively decrease pain and attenuate stress. Regional anesthesia and multimodal analgesia, adding antiinflammatory drugs, play an unquestionable role in the control of perioperative pain and may improve recurrence-free survival. © 2015 Elsevier Inc. All rights reserved.

1. Background ⁎ Correspondence: Isabel Prieto, MD, IDC-Salud Fundacion Jimenez Diaz University Hospital, Avda. Reyes Católicos no. 2, 28040 Madrid, Spain. Tel.: + 34 656956571; fax: + 34 915504931. E-mail addresses: [email protected] (F. Cassinello), [email protected] (I. Prieto). 1 Tel.: +34 629688623.

http://dx.doi.org/10.1016/j.jclinane.2015.02.007 0952-8180/© 2015 Elsevier Inc. All rights reserved.

Cancer treatment is evolving as we learn more about the molecular basis of cancer and new therapeutic targets are discovered. However, despite the use of radical surgery, chemotherapy and radiotherapy, and new hormonal and

2 Anesthesia, cancer progression, cancer outcome, substance P immunological treatments, recurrences and metastases continue to appear. Surgery is the main treatment for potentially curable solid tumors, but most cancer-related deaths in patients who have received previous surgical treatment are caused by metastatic disease. It was first hypothesized, a century ago, that surgery promotes local recurrence and distant spread of cancer. Several theories have been advanced to explain this fact, most notably residual minimal disease, dissemination of tumor cells at the time of surgery, and, possibly, a switch from tumor dormancy to proliferation. Recent discoveries have examined the possible influence of metabolic, neuroendocrine, inflammatory, and immunological changes that occur perioperatively and are related to or induced by anesthesia. Indeed, there is increasing evidence that anesthetic technique and other perioperative factors have the potential to affect long-term outcome after cancer surgery. The findings of these studies suggest that strategies to reduce perioperative opioid requirements by adding local or regional anesthesia may increase long-term survival, as opioids have shown a proliferative effect on cancer cells, while local anesthetics (LAs) may directly prevent proliferation and migration or induce apoptosis. Different possible targets are proposed for opioids and anesthetics. Inhaled anesthetics and opioids can stimulate hypoxia-inducible factor secretion, which activates proliferation of cancer cells, although the inflammatory cascade and cell immunity can also cause these effects. Therefore, use of anti-inflammatory drugs or preservation of immunity may be a reasonable goal. Opioids stimulate angiogenesis and tumor progression through μ-opioid receptors (MORs). β-Adrenergic block can reduce stress and improve outcome. LAs also have antiproliferative actions, and different mechanisms are proposed. We have suggested inhibition of substance P action, but other authors have associated LA with other targets such as up-regulation of Ras association domain family 1 isoform A (RASSF1A) messenger RNA (mRNA) that hampers cells proliferation, induction of apoptosis by activation of caspases, inhibition of kinesin motility and microtentacle protrusion, DNA demethylation, and inhibition of the epidermal growth factor receptor or cell cycle modifications secondary to blockage of voltage-gated sodium channels. This work reviews the published literature about the effects of anesthesia on cancer in vitro and in vivo and the influence of anesthesia on postsurgical survival and recurrence. The PubMed database was searched up to January 2014. The results were restricted to articles written in English. The search terms included “anesthesia and cancer,” “anesthesia and cancer recurrence,” “anesthetics and cancer,” “anesthetics and apoptosis,” “anesthetics and proliferation,” and “anesthetics and migration.” We selected articles that provided evidence on, suggested, or reviewed the possible actions of anesthetics on cancer cells or the influence of anesthesia in recurrence.

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2. Surgery, surgical stress, and cancer progression Some authors, such as Demicheli et al [1], demonstrated that surgery itself plays a fundamental role in cancer progression and metastatic recurrence. Nearly a century ago, Tizzer [2] reported that surgery induced tumor growth in animals inoculated with cancer cells. Van der Bij et al [3] following their survey postulated that blood vessel integrity in the liver is compromised after abdominal trauma, resulting in enhanced extracellular matrix exposure, which enables tumor cell adhesion and metastatic outgrowth after resection of the primary tumor. Disseminated tumor cells detected in blood or in peritoneal lavage represent an independent prognostic factor in patients undergoing surgery for colorectal cancer and may identify patients at high risk for recurrence [4]. One explanation for the role of surgery in cancer progression is the immunosuppressive effects of surgery, which are well known. Postoperative immune suppression lasts for several days and is proportional to tissue damage [5]. Surgery and the resultant stress response result in depression of natural killer (NK) cell function, which is associated with increased tumor growth and metastasis. A severe defect of T lymphocyte proliferation and cytokine secretion after major surgery has been detected [6]. It is relevant that interferon γ–inducing factor, interleukin-12 (IL-12) and T-helper 1 (Th1) cytokines increase the cytotoxic activities of T and NK cells, whereas IL-4 and IL-10 and T helper 2 (Th2) cytokines increase humoral immunity and suppress the Th1 response. In 2007, Wada et al [7] reported that combined spinal and general anesthesia may attenuate the surgery-induced suppression of innate tumor immunity, including NK cell activity, and preserve the Th1/Th2 cytokine balance, thus reducing metastatic activity after surgery. There are other causes of perioperative immunosuppression, such as hypothermia, transfusion, or the hypothalamic-pituitary-adrenal axis stimulation that is activated by postoperative pain [8]. In 2002, Coussens and Werb [9] published an extensive and detailed review on inflammation and cancer. This work characterizes the biochemical, cellular, and immunologic changes that occur during the inflammatory process secondary to tissue injury. In response to this damage, proinflammatory cytokine levels are elevated, systemically and locally; these cytokines include tumor necrosis factor α (TNF-α), IL-1β, IL-2, transforming growth factor α, insulin-like growth factor I and II, platelet-derived growth factor, and basic fibroblast growth factor, all of which could modify tissue repair. Surgery can thus generate a microenvironment that is rich in inflammatory cells and growth/survival factors, including tumor-associated macrophages, which, far from controlling the neoplastic cells, produce a number of potent angiogenic and lymphangiogenic growth factors, cytokines, and proteases, which promote neoplastic progression.

3 Prostaglandin E2 (PGE-2), one product of the cyclooxygenase (COX) pathway, modulates the immune system by selectively suppressing macrophage, neutrophil, Th1, and NK cell function while promoting a Th2 response [10]. Increased expression of COX-2 and increased PGE-2 levels have been associated with many cancers. The development of COX-2 selective inhibitors raised expectations of better targeting of the tissues that sustain inflammation and neoplasm, but an increased risk of cardiovascular (CV) complications was detected. Inhibition of COX-2–dependent prostacyclin, an important antithrombotic, in the absence of a complete suppression of COX-1–dependent platelet function, might play a role in CV toxicity. Nonsteroidal anti-inflammatory drugs (NSAIDs), which mainly act by inhibiting platelet COX-1–dependent thromboxane A2, may help to improve immune function and bolster host defenses against cancer progression, without these CV hazards. In support of this overall goal, the report of Goldfarb et al [11] demonstrated a reduction in the postoperative immunosuppression and metastatic progression in rat models using a pharmacological blockade of catecholamines and prostaglandins with propranolol and etodolac, respectively. In addition, a retrospective analysis of breast cancer patients showed an association between preoperative administration of NSAIDs and a lower recurrence of cancer [12]. Another factor that seems to promote cancer cell proliferation and recurrence is neovascularization. The mediators of this process of angiogenesis include vascular epidermal growth factor (VEGF) and transforming growth factor (TGF) β. Some authors have shown that VEGF increases during the postoperative period, with greater concentration seen in the surgical site and in proportion to the tissue damage [13,14]. Release of matrix metalloproteinases (MMPs) during surgery also increases the motility and invasive capacity of free cancer cells [10]. Tumor cells start to penetrate the surrounding normal tissue, reaching the vessels and entering the host circulation. Decreased levels of endogenous antiangiogenic mediators accompany this increased level of VEGF.

3. General anesthetics and cancer progression Anesthetic and analgesic agents administered during surgery might influence cancer cell activity. Some specific techniques have been linked with tumor recurrence and long-term outcome [8]. Melamed et al [15] demonstrated in rat models that some anesthetics (eg, ketamine, thiopental, halothane, but not propofol) increase the probability of tumor metastasis, apparently by suppressing NK cell activity. Ketamine was the most deleterious, and its effects were prevented by peripheral blockade of β-adrenoreceptors combined with low levels of immunostimulation.

Nitrous oxide reduces purine and thus DNA synthesis and also suppresses neutrophil chemotaxis, potentially facilitating the spread of cancer [16]. Shapiro et al [17] demonstrated that both nitrous oxide and halothane accelerated postoperative progression of spontaneous lung metastases in rats. In their comprehensive review, Tavare et al [18] described the direct effect of anesthetics on hypoxia-inducible factor-1 (HIF-1) which is up-regulated by inhaled anesthetics and inhibited by propofol. This phenomenon is thought to occur via receptor-mediated signals modifying HIF gene expression. It has been hypothesized that an up-regulation of HIFs may contribute to cancer recurrence. Propofol seems to exhibit a different profile, as it exerts protective effects through various mechanisms, including an anti-inflammatory effect, inhibition of COX-2 and reduction of PGE-2, weak β-adrenoreceptor binding, enhancement of antitumor immunity, and NK function preservation [19-21]. Propofol conjugates (propofol-docosahexaenoate and propofol-eicosapentaenoate) have been shown to inhibit cellular adhesion and migration and to induce apoptosis in breast cancer cells [22]. The studies, conducted by González-Correa et al [23], showed that propofol reduces the concentration of cytokines (IL-1, TNF-α, and IL-6) and stimulates neutrophils to increase nitric oxide synthesis. Other investigators demonstrated the differences between inhaled agents and intravenous propofol. Surgery-induced inflammatory response and inhibition of cell-mediated immunity seem to be more pronounced after balanced anesthesia (general anesthesia using opiate analgesics, muscle relaxants and inhalational agents), compared with maintained intravenous anesthesia (propofol infusion plus opioids). The absolute number of CD3 +, CD4 +, and CD8 + and the expression of HLA-DR and activation marker CD25 +, CD26 +, and CD69 + all decreased more after surgery with balanced anesthesia. Plasma concentrations of IL-6 significantly increased during and after surgery with balanced anesthesia, without relation to the reported postoperative pain [24]. In contrast, propofol promotes activation and differentiation of peripheral T-helper cells preserving cellular immunity and antitumor activity [25,26]. Deegan et al [27] demonstrated that serum from patients receiving propofol/paravertebral local anesthesia for breast cancer surgery inhibited proliferation of negative estrogen receptor breast adenocarcinoma cells in vitro, compared to serum from patients receiving sevoflurane/ opioid anesthesia-analgesia. Overall, the literature suggests that propofol acting on inflammatory mediators and cancer cells has an antimetastatic role. More studies of in vivo responses and in vitro mechanisms will be necessary to confirm this suggestion. The influence of surgery, anesthesia technique, administered drugs, and other perioperative factors on cancer local recurrence, proliferation, and metastasis is summarized in Fig. 1.

4 Anesthesia, cancer progression, cancer outcome, substance P

4. Perioperative opioids and cancer progression Opioids are the primary drugs used in perioperative pain management, and their analgesic effect is beneficial in reducing pain and its consequent surgical stress. There is a growing interest in investigating the relationship between opioids and tumor progression, although the results obtained thus far are controversial. Perioperative opioids may produce cellular and humoral immunosuppression. Research data have demonstrated that opioids have a suppressive effect on phagocytic, NK, B, and T cells [28-30]. Activation of the MOR expressed on T lymphocytes by the endogenous opioid β-endorphin or by morphine results in intracellular cAMP elevation, activating the cAMP-dependent PKA and ultimately preventing the interaction of Lck (leukocyte-specific protein tyrosine kinase)—which is essential for the initiation of T-cell receptor signaling—with the T-cell receptor complex and IL-2 induction [31]. This effect is greater with morphine, but it also occurs with other opioids. Tramadol also stimulates adrenergic, serotonergic, and opioid receptors but does not suppress immune functions [32]. Other synthetic opioids as such as hydromorphone, oxycodone, and buprenorphine have lower immunosuppressive activity [33]. Gupta [34] demonstrated a proangiogenic effect of opioids in breast cancer xenografts. Experimental findings of Singleton and Moss [35] support the hypothesis that opioids affect tumor progression, and these authors suggested that the MOR is linked to angiogenesis and oncogenic signaling. The observed effect involved Src-mediated VEGF receptor transactivation and was opiate concentration

• • • • • • • • •

Cancer Surgery

Stress, HPA stimulation Inhaled anesthetics Ketamina, Tiophental Opioids /Pain Hypothermia Blood transfusion Inflammation Catecholamines

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dependent. Lennon et al [36] provided evidence in human lung cancer that MOR overexpression increased serine-threonine kinase Akt and mammalian target of rapamycin activation, with the consequent endothelial cell proliferation, migration, and actin cytoskeletal reorganization required for angiogenesis. Surveys with fentanyl and remifentanil, however, are not conclusive about cell proliferation and metastases [37,38], raising questions about the molecular specificity of these effects. Zilla et al [39] studied MOR expression and opioid requirements in a retrospective study in advanced prostate cancer and concluded that higher MOR expression and the use of higher opioid dose to treat cancer-related pain were associated with shorter survival. Opioid antagonists might inhibit peripheral effects on angiogenesis and immune response. Continuous infusion of the peripheral opioid antagonist methylnaltrexone, a drug designed to reverse opiate-induced constipation, in mice inoculated with cancer cells has been shown to attenuate tumor growth and to reduce lung metastasis [40]. Singleton et al demonstrated the synergistic effects of methylnaltrexone with 5-fluorouracil and bevacizumab on inhibition of VEGF-induced angiogenesis [41]. However, the interaction between opiates and the immune system is complex. Morphine has been shown to have direct antiproliferative and proapoptotic effects on different cancer cells. Tumor growth and lung metastasis were inhibited by repeated administration of morphine in a mouse model, suggesting that morphine given to relieve cancer pain also inhibits tumor growth and metastasis [42]. Page [5] published relevant articles, providing strong evidence in animals that pain-relieving interventions significantly reduce

Inhibition

• Regional anesthesia • Local anesthetics • Naltrexone • β-bloquers • Cox-inhibitors

Angiogenesis; VEGF •Opioids •Catecholamines •PG Inhibition • Naltrexone • β-bloquers • Cox-inhibitors

• MMP • Kinesin motility

Proliferation Recurrence Metastasis

Invasivity Inhibition

• Local anesthetics

Fig. 1 Influence on cancer recurrence and metastasis of cancer surgery, anesthesia technique, perioperative factors, and drugs administered. Abbreviations: HPA, hypothalamus pituitary axis; PG, prostaglandin; Cox-inhibitors, cyclooxygenase inhibitors.

5 the tumor-enhancing effects of surgery and postsurgical recovery. They further analyzed the impact of morphine administration on the neuroendocrine, behavioral, and metastatic-enhancing effects of surgery, concluding that presurgical administration of morphine is key to optimizing its beneficial effects on surgery-induced metastasis [43]. In conclusion, effective analgesia is needed in the perioperative period to ablate the stress response to pain and, additionally, the effects of surgery on the immune system. Considering the possibility that morphine might have direct effects on tumor growth, via cell proliferation and a proangiogenic action, the coadministration of a μ-opioid peripheral antagonist that is capable of reversing the unwanted effects of the drug deserves serious attention. Although there are no prospective clinical trials directed to demonstrating the angiogenic, proliferative, and prometastatic actions of morphine, relative to other analgesic drugs, we believe that there is sufficient in vitro and in vivo evidence to support implementing effective alternative strategies to control postoperative pain.

5. Local-regional anesthesia and cancer surgery Combining regional and general anesthesia in major surgery has become common practice in many institutions and is expected to reduce the requirement for inhaled general anesthetics and opioids. Combined or given separately, regional anesthesia attenuates the neuroendocrine stress response to surgery and avoids perioperative immunosuppression. An animal study demonstrated that regional anesthesia and analgesia reduced the metastatic burden in animals inoculated with adenocarcinoma cells after surgery [44]. Exadaktylos et al [45], following a retrospective analysis with 129 breast cancer patients, concluded that paravertebral anesthesia and analgesia for breast cancer surgery reduce the risk of recurrence or metastasis during the initial 3 years of follow-up. Deegan et al [46] published an interesting trial with 32 patients randomized to propofol/paravertebral or sevoflurane/opioid anesthesia, analyzing cytokine and matrix metalloproteinase responses to primary breast cancer surgery. The results showed that paravertebral anesthesiaanalgesia for breast cancer surgery alters a minority of cytokines involved in regulating perioperative cancer immunity. Other authors who carried out similar surveys found that paravertebral blockade reduces VEGF and transforming growth factor β expression [47]. Le Cras et al [48] showed that the ratio of Th1/Th2 cells was higher in patients who had prostate surgery with spinal rather than general anesthesia. Some retrospective works link regional anesthesia with longer survival and lower incidence of cancer recurrence, but the results are controversial. In 2010, Schnabel et al [49] published a meta-analysis of randomized controlled trials analyzing efficacy and safety of paravertebral blocks for

breast cancer surgery. They concluded that a reduced need for postoperative morphine among the group of patients undergoing surgery with paravertebral block correlated with a lower recurrence of breast cancer. In 2013, Chen and Miao [50] published a meta-analysis of retrospective and prospective studies and concluded that epidural anesthesia and/or analgesia were associated with improved overall survival in patients undergoing surgery for operable cancer types (especially in colorectal cancer), although the analysis does not support an association between epidural anesthesia and cancer recurrence. In related work, Myles et al [51] conducted a randomized trial comprising 446 patients undergoing major abdominal surgery for cancer. The researchers found that the use of epidural block in these patients was not associated with improved cancer-free survival. However, following a prospective study that included 669 patients with colorectal cancer, Gottschalk et al [52] found that the benefit with epidural block was only observed in older patients. The authors added that the benefit of regional anesthesia on cancer recurrence might depend on the specific tumor type. Similar controversial results have been found in prostate cancer [53,54]. Further evaluation is required to determine the significance of these results regarding regional anesthesia. Ongoing prospective clinical trials are seeking to investigate the influence of regional anesthesia on survival after breast, lung, and colorectal tumor surgery [55-57]. Perioperative phenomena that may influence recurrence and survival in cancer surgery are listed in Table 1.

6. Cellular effects of LAs: apoptosis activation, migration inhibition, and cancer cell proliferation LAs have been shown to affect certain tumor cells' vital cycle and processes critical for metastasis, such as apoptosis, migration, and proliferation (Table 2). Hollman and Durieux [81] have suggested that the antimetastatic effects of LAs are due to their systemic actions. LAs show pleiotropic effects that are unrelated to sodium channel blockade but include neuroprotective, anti-inflammatory, bronchodilator, antithrombotic, and anti-infectious activity. Yardeni et al [58], in a survey performed with 65 female patients, found that preoperative and intraoperative intravenous lidocaine improves immediate postoperative pain management and reduces surgery-induced immune alterations. There was significantly less ex vivo production of IL-1ra and IL-6 by peripheral blood mononuclear cells, whereas the lymphocyte proliferation response to phytohemagglutinin-M was better maintained than in the control group. Marret et al [82], using meta-analysis, concluded that continuous intravenous administration of lidocaine during and after abdominal surgery decreases the need for opioids, although the authors did not analyze the immunologic effects.

6 Anesthesia, cancer progression, cancer outcome, substance P Table 1

F. Cassinello et al.

Perioperative phenomena that may influence recurrence and survival in cancer surgery References

Surgery

Inflammation

Opioids

Anesthesia

Surgery produces immunosuppression, enables tumor cell adhesion, and increases the release of metalloproteinases and VEGF. All these factors promote cancer progression, metastatic recurrence, increase motility/invasiveness of cancer cells, and increase neovascularization Relief of cancer and perioperative pain inhibits tumor growth and metastasis Inflammation produces angiogenic and lymphangiogenic factors, cytokines, and proteases that potentiate neoplastic progression NSAIDs reduce immunosuppression and reduce tumour progression. Perioperative morphine induces immunosuppression. Hydromorphone, oxycodone, and buprenorphine have lower immunosuppressive activity, and tramadol does not suppress immune functions Opioids have proangiogenic effect Methylnaltrexone inhibits angiogenesis and immune response, attenuates tumor growth, and reduces lung metastasis in mice inoculated with cancer cells The higher MOR expression and opioid dose requirement is associated with shorter survival Some general anesthetics (ketamine, thiopental, and halothane) suppress NK cell activity and increase metastases Inhaled anesthetics up-regulate HIF, which can facilitate cancer spread and contribute to cancer recurrence Propofol is better than inhaled anesthesia in terms of immunity and induces apoptosis in breast cancer cells General anesthesia combined with regional anesthesia/analgesia improves immune outcome and reduces metastatic burden in animals, risk of metastasis in breast cancer, VEGF and TGF-β expression Some studies have shown controversial results in terms of survival with epidural anesthesia/analgesia Prospective ongoing clinical trials are investigating influence of regional anesthesia in some tumor outcomes

LAs in clinically relevant concentrations are known to induce apoptosis in vitro. In 1997, Kim et al [59] showed the apoptotic promotion by dibucaine in neuroblastoma cell lines, leading to membrane damage and changes in the intracellular calcium levels that induced membrane-damaging free radical production. Arita et al [60] confirmed this apoptotic capability in promyelocytic leukemia cells 3 years later. Dibucaine activated various caspase activities and induced mitochondrial membrane depolarization and the release of cytochrome C. The recently published article by Chang et al [61] using breast cancer cells confirmed this proapoptotic hypothesis. The apoptotic action of LAs was more pronounced in malignant breast cancer cells than in mammary epithelial cells. Arai et al [83] demonstrated in lymphoma cell lines that LAs at optimal concentrations enhance hyperthermia-induced apoptosis, increasing intracellular calcium and activating mitochondria-dependent pathways (caspase 3). Procaine could inhibit cell growth in human nasopharyngeal carcinoma cells and up-regulate the expression of RASSF1A mRNA, which may play an important role in inhibiting cell proliferation [63]. This apoptotic potency of LAs correlates with lipid solubility, but it seems to be independent of the chemical class (ester/amide) [84]. α-Lipoic acid prevents bupivacaine-induced neuron injury in vitro through a phosphatidylinositol 3-kinase (PI3K)/Akt-dependent mechanism. α-Lipoic acid has been shown to activate the PI3K/Akt signaling pathway in mouse

[1,3,5,6,8,10,13,14]

[5,41,42] [9] [10-12] [28-33]

[34-36] [39,40] [43] [15] [16-18] [19-26] [7,44-49]

[51-54] [55-57]

neuroblastoma cells, a pathway critical for cell growth and survival [64]. Kim et al [85] recently reported that LAs inhibit tissue factor induction in activated monocytes by inhibiting tissue factor mRNA synthesis. Whether this result derives from a direct or an indirect action of LAs on DNA transcription is not known. Yoon et al [65] showed that tetracaine inhibits kinesin motility and microtentacle protrusion in human epithelial and breast tumor cells. This inhibitory effect consequently hampered tumor cell aggregation and reattachment, thus decreasing metastatic progression. Lirk et al [66] studied lidocaine in breast cancer cell lines in vitro. They found that lidocaine exposure results in the demethylation of DNA at clinically relevant concentrations, particularly in positive estrogen receptor breast cancer cells. Epigenetic mechanisms are responsible for the expression of DNA, as they regulate the methylation of specific DNA regions. Increases in methylation levels can deactivate tumor suppressor genes and lead to the progression of cancer. So, decreasing methylation levels may have a therapeutic benefit. LAs are frequently administered to tumors and surrounding tissues during surgery of the head and neck area. These drugs are slightly more toxic on oral squamous cell carcinoma cells in vitro than on normal oral cells [62]. Apoptosis induction was monitored by internucleosomal DNA fragmentation and caspase 3, 8, and 9 activation.

7 Table 2

Local anesthetics effects on cancer cells

LA effects on cancer cell

References

Improve immediate postoperative pain and reduce surgery-induced immune alterations Produce changes in intracellular calcium levels inducing free radicals production and activating apoptosis pathways (dibucaine) Up-regulate the expression of RASSF1A inhibiting cell proliferation (procaine) Activate the PI3K/Akt pathway (bupivacaine) Inhibit kinesin motility and microtentacle protrusion, decreasing metastatic progression (tetracaine) Demethylate DNA with tumor-suppressive effect (lidocaine and procaine) Inhibit EGFR activity (lidocaine) Inhibit VGSC decreasing cell proliferation/ invasiveness and angiogenesis Inhibit TNF-α Reactivate wingless-type inhibitor factor 1 and down regulate the wingless-type canonical pathway suggesting antiproliferative effects (procaine and procainamide) Promote antiproliferative effect on mesenchymal stem cells (ropivacaine, lidocaine, and bupivacaine) Interact on cellular membrane, including receptors, and second messengers

[58] [59-62]

[63] [64] [65]

[66,67] [68,69] [70-75] [76] [77]

[78]

[79,80]

Abbreviation: EGFR, epidermal growth factor receptor.

Dibucaine was the most cytotoxic, followed by tetracaine, bupivacaine, or ethylaminobenzoate, whereas lidocaine, procaine, and mepivacaine were much less cytotoxic. Lidocaine has shown an antiproliferative effect on human tongue cancer cells with inhibition of the activity of epidermal growth factor receptor [68]. LAs block peripheral nerve conduction through the inhibition of voltage-gated sodium channels (VGSCs). Some surveys have demonstrated a relation between the sodium-channel activity (increase of sodium levels inside the cell) and cancer cell proliferation/invasiveness. The inactivation of the “neonatal” splice variant of Nav1.5 (subtype of VGSC) decreases cell migration and increases the sensitivity to tetrodotoxin, a VGSC blocker that has very low potency for normal Nav1.5 channels [70]. Roger et al [71] found a relation between invasiveness in lung cancer cells and VGSC activity. A significant portion of the epidermal growth factor–induced enhancement of migration occurred via VGSC activity, considering that tetrodotoxin partially inhibited this effect [72]. Gillet et al [73] proposed that the VGSC effects on invasiveness could be linked to cathepsin activity. Matrigel invasion is significantly decreased in the presence of specific inhibitors of cathepsins B and S (CA-074 and Z-FL-COCHO, respectively), and coapplication of tetrodotoxin does not further reduce cell invasion. Protein kinase A increases both mRNA levels and protein of Nav1.5, activating migration of breast cancer cell [74].

Gao et al [86] studied different VGSC expressions in ovarian cancer cells and found a higher expression in some subtypes, particularly Nav1.5 in the most invasive line cells. The authors suggested this finding as a possible novel therapeutic target in ovarian cancer treatment. Piegeler et al [76] recently published a retrospective analysis of the antimetastatic potential of amide-linked LAs. The described inhibition of adenocarcinoma cell migration by lidocaine and ropivacaine was associated with the inhibition of both TNF-α–induced Src-activation and phosphorylation of intercellular adhesion molecule-1. The role of VGSC in these effects was also evaluated, but the authors concluded that this TNF-α inhibition constitutes an independent molecular mechanism. Andrikopoulos et al [75] concluded that VGSCs regulate multiple angiogenic functions and VEGF signaling in human umbilical vein endothelial cells. These results imply that targeting VGSC expression/activity could be a novel strategy for controlling angiogenesis. Some publications describe the relationship between LAs and cancer cell proliferation. Tada et al [67] demonstrated that procaine had growth-inhibitory and demethylating actions on human hepatoma cells in vitro and in vivo. The authors proposed procaine as a candidate agent for future therapies to treat hepatocellular carcinoma. In 2009, Gao et al [77] reported that procaine and procainamide reactivate wingless-type inhibitory factor-1 in lung cancer cells and down-regulate the wingless-type canonical pathway, suggesting a protective activity against cancer cell proliferation. Antiproliferative effects of ropivacaine, lidocaine, and bupivacaine have also been shown on mesenchymal stem cells. Multiple transcriptional programs related to cell differentiation, tumorigenesis, and metastasis were negatively affected by ropivacaine [78]. Mammoto et al [69] found that infiltration anesthesia with lidocaine inhibits cancer cell invasion by modulating ectodomain shedding of heparin-binding epidermal growth factor– like growth factor (HB-EGF). LAs not only block the impulses by inhibiting VGSC but also exert different actions on calcium channels and on a wide variety of second messengers including adenylate cyclase, guanylate cyclase, calmodulin-sensitive protein, ion pumping enzymes Na + /K + -ATPase and Ca 2 + / Mg2 + -ATPase, phospholipase C, and protein kinase C [79]. LAs also interact directly with membrane phospholipids and proteins, including various receptors. Furutani and Kohno [80] showed evidence indicating that LAs could inhibit N-methyl- D -aspartate–induced glutamatergic transmission in the spinal cord, preventing chronic pain development and cancer cell proliferation, as N-methyl-D-aspartate receptor antagonists do. An inhibitory effect on other ion channel-coupled receptors has also been shown, including 5-HT3, GABA, glycine, and nicotinic acetylcholine receptor [87]. Fig. 2 shows a scheme of possible molecular effects of LAs on cancer cells that may explain published inhibition of proliferation, migration, invasiveness, and apoptotic stimulus.

8 Anesthesia, cancer progression, cancer outcome, substance P Further investigations will be required to fully understand the actions of LAs and their influence on cancer progression or recurrence.

7. Substance P and cancer Substance P (SP) is a neuropeptide that belongs to the tachykinin family, facilitating pain through activation of the neurokinin 1 (NK-1) receptor. The NK-1 G protein-coupled receptor has widespread distribution in the central nervous system and in peripheral tissues. There are numerous studies suggesting that this receptor system could play an important role in the development of cancer. It is known that SP has a mitogenic action on several human cancer cell lines (eg, neuroblastoma, glioma, melanoma, retinoblastoma, pancreas carcinoma) and that NK-1 receptor antagonists exert an antitumor action against human cancer cells [88,89]. There is a growing interest in these findings on different types of cancer cells. In several interesting surveys, Muñoz et al [90] have demonstrated an inhibitory action of NK-1 receptor antagonists on retinoblastoma, lung and breast cancer, and other cancer cell lines. NK-1 antagonists induce apoptosis, inhibit migration, and show antitumor activity. Other authors have observed similar results with brain, breast, and pancreatic tumors [91–93]. Garcia-Recio et al [94] described an important antioncogenic cooperation between NK-1R and human epidermal growth factor receptor 2 after finding a link between inflammation and cancer progression that may be

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targetable by SP antagonists. For this reason, NK-1 antagonists have been proposed as a new generation of anticancer drugs [95]. Other surveys have measured SP levels in different tissues from patients who received LA agents for intense pain. According to the studies, SP levels decreased after administration of epidural or neuronal blockade [96,97]. Li et al [98] published in 1995 that LAs inhibit both SP binding and the related increase in intracellular calcium. The authors concluded that a direct action of LAs on tachykinin-mediated neurotransmission exists during regional anesthesia. As we have suggested [99], these links between local anesthesia, SP, and cancer progression should be explored further.

8. Conclusion We have reviewed how anesthesia may influence the outcome of cancer surgery. Inhaled anesthetics induce immunosuppression and activate the inflammatory cascade, whereas propofol has a protective action. Opioids might promote cancer recurrence and metastasis, as demonstrated in vitro and in animal studies. Some clinical retrospective publications also suggest an improvement in survival by procedures that reduce perioperative morphine dosing. Although beyond the scope of this review, it is possible that treating chronic pain in cancer patients with morphine may promote cancer progression. If this is confirmed, this

Fig. 2 Possible molecular effects of local anesthetics on cancer cells that may explain published inhibition of proliferation, migration, invasiveness, and apoptotic stimulus. Abbreviations: EGF, epidermal growth factor; WNT, wingless-type; G, G-protein; FADD, Fas-associated protein with death domain.

9 major analgesic strategy should be revised, and we should consider using other opioids, combining treatment with peripherally restricted MOR antagonists, or prescribing other therapeutic alternatives. In vitro and in vivo studies have demonstrated that LAs inhibit proliferation and migration of cancer cells and induce apoptosis. Avoiding use of opioids or minimizing the dose by administering regional or local anesthesia preserves immunity, reduces the stress response, and improves analgesia. While we await the results of ongoing prospective clinical trials, we should follow current best practice in anesthesia and include all strategies that effectively decrease pain and attenuate stress. Regional anesthesia and multimodal analgesia, adding anti-inflammatory drugs, plays a highly probable beneficial role in the control of perioperative pain and may improve recurrence-free survival.

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