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Anesthesia, cytokines and cancer recurrence

Yuji Kitamura

Department of Anesthesia, McGill University Health Centre, Montreal Children’s Hospital, Montreal, QC, Canada

Iolanda Di Biaso

Instituto comprensivo “KOINÈ”, Monza, Italy

Pablo Mauricio Ingelmo

Department of Anesthesia, McGill University Health Centre, Montreal Children’s Hospital, Montreal, QC, Canada

Gianluca Bertolizio

Department of Anesthesia, McGill University Health Centre, Montreal Children’s Hospital, Montreal, QC, Canada

E-mail :

DOI: 10.15761/GAPM.1000122

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Cytokines are essential mediators for the regulation of both innate and acquired immunity and hematopoiesis. They modulate immune cell signaling, activation, adhesion and functioning. They regulate the individual response to several insults such as infection, inflammation, trauma, and pain. Moreover, the balance between pro-inflammatory and anti-inflammatory cytokines is critical for the evolution of surgical complications and tumor progression.

Several drugs, including anesthetic agents, influence cytokines secretion. Opioids, inhalational agents, intravenous and local anesthetics have shown different effects on immune system and cytokine expression. Therefore, anesthesia may play an important role in postoperative recovery and outcome of cancer patients.

The aim of the present article is to review the main role of some important cytokines and the effect of anesthesia techniques and drugs on their secretion. Furthermore, current clinical evidence regarding the effects of anesthesia on cancer recurrence will be discussed.

Key words

cytokines, general anesthesia, regional anesthesia, surgical stress and cancer

Cytokines and immune system

Cytokines are proteins expressed in both innate and acquired immune system and are often named according to the secreting cells (i.e., lymphocytes, interleukins, etc.). They are essential mediators of the natural (non-specific, innate) immunity, which is the initial step of the inflammatory response. They also play a pivotal role during the specific immunity, which occurs after exposure to antigens, as they regulate lymphocyte and leukocytes activation, growth and differentiation, and the immune-mediated inflammation [1].

The cytokines have different structures, but also common aspects, which are summarized in Table 1.

Common aspects of Cytokine

Their secretion is brief and limited in time

They have pleiotropic properties, because they have the same effect on multiple cells

They may affect other cytokines

They may have autocrine, paracrine or endocrine function

They bind specific receptor on the membrane

The expression their receptor on target cells is regulated by signals that are outside the cell

The targeted cell responds with phenotype modifications and acquisition of new functions

Their secretion is brief and limited in time

Table1. Common aspect of cytokines

The aim of the present article is to review the main role of some important cytokines and the effect of anesthesia techniques and drugs on their secretion.

Cytokines receptors

The cytokines receptors are formed by one or more transmembrane proteins: the extracellular portion binds the cytokine, whereas the cytoplasmic part starts the signal cascade. Based on the extracellular portion, they are divided in five categories.

1)    Type I receptors, which have fourα -helical stands and contain four cysteine residues and the amino acid motif tryptophan-serine-X-tryptophan-serine (WSXWS).

  • Type II receptors, structurally similar to Type I receptors, but without the sequence WSXWS.
  • Interferon receptors, which have domains rich of cysteine and can induce apoptosis or stimulate gene expression;
  • Immunoglobulin receptors, which have extracellular domain for immunoglobulins (Ig) and different mechanisms for single transduction;
  • Seven-transmembrane spanning family receptors, which pass the membrane seven times and transduce the signal through G-protein pathway.

Cytokines function

Provided that the same cytokine may be produced during both innate and acquired immunity response, cytokines can be classified according to their functions:

  • Cytokines regulating the innate immunity and secreted by stimulated macrophages;
  • Cytokines regulating the acquired immunity and secreted by lymphocytes;
  • Cytokines stimulating the hematopoiesiss and secreted by bone marrow, leucocytes and other cells.

Cytokine expressed during the innate immunity response

Tumor necrosis factor (TNF-α, TNF-β)

The TNF is responsible for the initial phase of acute inflammatory response, especially against Gram-negative bacteria. It exists in two forms, α and β, which have similar effects and equally bind both forms of the TNF receptor (TNFR-I and TNFR-II).

It is mainly produced by mononuclear phagocytes after bacterial infection (i.e., after contact to LPS), but it can also be secreted by T-lymphocytes, NK cells and mast cells [2].

T-Lymphocytes and NK cells, trough INF-y secretion, augment TNF synthesis. In general, TNF-α promotes the recruitment of neutro phils and monocytes thought the expression on the endothelial surface of specific receptors. It also increases the body temperature (stimulating the hypothalamus along with IL-1) and the amyloid A protein concentration in the hepatocytes (similarly to IL-6 and IL-1), and promotes the secretions of prostaglandins, platelet-activating factor (PAF), glucocorticoids and eicosanoids [3].

At high concentrations, it is responsible for cachexia (loss of muscular and adipose tissue) [4], certain autoimmune disorders [5], and the decrease of myocardium contractility and vascular tone, which cause cardiovascular collapse in sepsis [6].

Interleukin-1 (IL-1)

The IL-1 is synthesized mononuclear phagocytes in response to bacterial infection and other cytokines, such as TNF. It is also secreted by neutrophils, macrophages, epithelial and endothelial cells [7]. Like TNF, IL-1 is an important mediator of the inflammatory response [8]. Both IL-1α and IL -1β bind the same receptor and have the same function, but only IL-1 β is secreted active. Two receptors associated to IL-1 exits: IL-1RI, expressed by almost all cells, and IL-1RII, present on the B-lymphocytes surface. The IL-1R does also exist in soluble form. At low concentrations, IL-1 promotes leukocytes adhesion, stimulates T-lymphocytes, B cells, macrophages, and causes the release of prostaglandins, IL-6, IL-8 and tissue factor III. At high concentrations, IL-1 induces fever, muscular and adipose catabolism and anorexia [9]. The IL-1ra represents the receptor antagonist and has the function of endogenous autoregulation of IL-1 activity [10].

Interleukin -6 (IL-6)

It is pro-inflammatory molecule and it is produced by mononuclear phagocytes, endothelial cells, and fibroblasts in response to several stimuli, such as LPS, IL-1, IL-2, TNF, INF, platelet-derived growth factor and viruses. During the innate response, it stimulates the acute-phase proteins, whereas it promotes the B-lymphocytes growth when specific immunity is initiated. It also plays a role in hematopoiesis and it has been shown to have anti-inflammatory properties [11]. Furthermore, it is involved in diseases such as lupus erythematous and rheumatoid arthritis [12]. The IL-6 binds the receptor IL-6R, which has a soluble form.

Interleukin-8 (IL-8)

It is a potent chemoattractant and activator of neutrophils [13], and it has been implicated in cardiopulmonary bypass injury [14] and multiple organ failure [15].

Interleukin-10 (IL-10)

It is a potent anti-inflammatory cytokine and it is mainly produced by activated macrophages and T-lymphocytes. It has an inhibitory effect on macrophages activation and TNF production [16]. Therefore it has a pivotal role in regulating the immunity response [17-18].

Interleukin-12 (IL-12)

It is mainly produced by mononuclear phagocytes and dendritic cells, and it is involved in both innate and acquired immunity response [19]. Intracellular bacteria, viruses, activated T-helper lymphocytes and INF-y promote IL-12 production. IL-12 stimulates NK cells, lymphocytes CD8+ and the differentiation of lymphocytes CD4+ in T helper type1 (Th1). In particular, Th1 produce INF-y, which activates macrophages.

Interleukin-15 (IL-15)

It is produced by mononuclear phagocytes in response to viral infections and LPS. It promotes the early NK cells expansion [20], and induces IL-8 production, NF-κB and fungal phagocytosis [21].

Interleukin-18 (IL-18)

It is produced by macrophages after contact to LPS and promotes the production of INF-y from NK cells and T-lymphocytes and it is involved in gram-positive sepsis [22]. Its pro-inflammatory effect is synergic to IL-12 [22].

Interferons (INF-α and INF -β)

The INF-α is mainly produced by mononuclear phagocytes, whereas INF-β is secreted by several cells, including fibroblasts. They have an important role during the early innate response to viral infections. In particular, they promote the cytotoxic action of lymphocytes CD8+ and the production of Th1.


They are a family of cytokines produced by several cells, such as endothelial and epithelial cells, and fibroblasts [23]. They mainly promote lymphocytemigration.

4 Cytokine expressed during the specific immunity response

Interleukin-2 (IL-2)

It is produced by lymphocytes CD4+ and lymphocytes CD8+ [24], and it is considered the main autocrine and paracrine growth factor for T-lymphocytes. It is responsible for clonal expansion and T-lymphocytes differentiation, as it promotes the development of cytotoxic Th1, and stimulates the production of

IL-4, TNF-α and INF-y [25]. Moreover, it promotes the proliferation and the activation of other immune cells, such as NK cells, neutrophils, macrophages and B-lymphocytes. On activated T-lymphocytes, however, it also has a pro-apoptotic function [26] to stop their inflammatory action. It binds the receptor IL-2R, which is formed by subparts α, β, and γ. The IL-R2α exists in soluble form.

Interferon y (INF-y)

It is produced by macrophages, NK cells, T-lymphocytes CD4+ Th1 and CD8+. It stimulates T-lymphocytes and NK cells, which activate both macrophages and antigen-presenting cells, and promotes the T-lymphocytes differentiation in Th1, counteracting the effects of IL-4 [27].

Interleukin-4 (IL-4)

Lymphocytes CD4+ T helper type2 (Th2) represent the main source of this cytokine, which is responsible for IgE production and Th2 differentiation [28]. It also counteracts INF-y on macrophages by downregulating IL-1, TNF-α, IL -6, and IL-8 and therefore limiting the cell-mediated response.

Interleukin-5 (IL-5)

It is produced by lymphocytes CD4+ Th2 and activated macrophages. Its main function is the promotion of eosinophil proliferation and differentiation, the proliferation of B-lymphocytes and the IgA production.

Interleukin-13 (IL-13)

It is produced by lymphocytes CD4+ Th2 and some epithelial cells. Like IL-4, it expresses anti-inflammatory effects on macrophages, monocytes and B-cells, where it counteracts INF-y, but not on T-lymphocytes [29]. It also stimulates IL-1ra [30].

Transforming growth factor-β (TGF -β)

It is produced by several immune cells and has an immunosuppressive action, like IL-10 and IL-4. In fact, it inhibits the proliferation and the differentiation of T-lymphocytes and macrophages.

Cytokine that promote the hematopoiesis

The principal cytokines involved in the hematopoiesis are IL-3, involved in immune cells differentiation, the stem cell factor (SCF), involved in stem cells differentiation and proliferation, IL-7, involved in bone marrow production of lymphocytes, and the granulocyte-macrophage colony-stimulating factors (GM-CSF, M-CSF, and G-CSF), involved in bone marrow production of leukocytes and delayed apoptosis of macrophages and neutrophils [31]. It is beyond the scope of this review to describe their function.

Anesthesia and cytokines

Immunity can be affected by anesthesia [32-34], surgical stress [34-38], surgical techniques [39], and postoperative pain [34,40]. Each anesthetic agent has different effects on the immune system [36,41,42] and therefore the type anesthesia may play a role in postoperative recovery [42] and even in cancer recurrence [43,44].

Inhalational anesthetics

Since inhalational anesthetics were brought into clinical use in the 1840s, research has been focused in finding the ideal agent, which offers smooth induction and stable maintenance of general anesthesia with minimal adverse effects [45,46]. Halogenated agents such as isoflurane, sevoflurane and desflurane are currently used to provide inhalational general anesthesia. Several studies have shown dose-dependent inhibitory effects of halogenated anesthetics on both innate and humoral immune system [42].

Halothane, enflurane, isoflurane and sevoflurane inhibit neutrophil production of reactive oxygen species (ROS), suggesting that volatiles impair a critical step of the inflammatory response [47-49]. Additionally, they have shown to increase the expression of inducible NO synthase (iNOS), which plays a role in the induction of NO release from macrophages and may have protective effects during the inflammatory reaction [50-51].

Isoflurane, sevoflurane and desflurane are associated with a significant increase of pro-inflammatory cytokines IL-1, IL-8 and TNF-α in alveolar cells [35,52-54]. They also inhibit lymphocyte proliferation and the release of IL-1β and TNF-α in peripheral blood mononuclear cells (PBMC) [55-56]. Similar results have been confirmed in children [57-58]. Halothane suppresses the activity, but not the number, of natural killer (NK) cells and promotes the retention of breast cancer metastasis in rats [59]. Isoflurane significantly decreases the Th1/Th2 ratio in humans[35] when compared to intravenous anesthetics; it also decreases circulating NK cells and increases B-lymphocytes, IFN-y, IFN-α, TNF-α and IL-2 [60].

Furthermore, inhalational balance anesthesia with sevoflurane is associated with higher IL-6 concentrations and more depressed T-lymphocyte cells (CD3+, CD4+, CD8+), activation markers (CD25+, CD26+, and CD69+) and HLA-DR molecules, in comparison to total intravenous anesthesia (TIVA) [38]. Nitrous oxide has shown to impair neutrophil chemotaxis and function and mononuclear cell production [61], and DNA synthesis [43]. In animals, it promotes lung and liver metastasis [62], but this effect has not been proven in humans [62]. Recently, the immunomodulation of new anesthetic agent xenon has been investigated [63]. Xenon is an odorless noble gas, normally present in traces in Earth's atmosphere, and it has been used as volatile anesthetic [64]. It has shown hemodynamic stability, fast recovery and neuroprotective proprieties but high costs [65].

In vitro investigations suggest that xenon has pro-inflammatory effects, increasing TNF-α and IL-6 [66], and IL-1β [67] in LPS-mediated cultures. However, a recent study on adults did not show any differences in leucocyte function in peripheral blood with xenon compared to sevoflurane [63].

Intravenous anesthetics

The modern intravenous anesthesia began in the 1930s with the introduction of barbiturates into the clinical practice, such as thiopental [68]. Benzodiazepines, like diazepam and midazolam, are GABA agonists with sedative, hypnotic, anxiolytic, anticonvulsant, and muscle relaxant properties; they are commonly used in premedication or for sedation in minor procedures [69,70]. Ketamine acts on NMDA receptors, and differs from other anesthetics because of its strong analgesic effect with minimal respiratory depression [71,72]. Etomidate is a GABA agonist used for induction of general anesthesia and sedation, and presents peculiar characteristics, such as adrenocortical suppression [73-75].

Propofol is a hypnotic and amnestic agent, used for both induction and maintenance of general anesthesia (total intravenous anesthesia, TIVA), and short procedures [76,77]. Dexmedetomidine is a α2 -adrenoceptor agonist, which induces sedative state similar to physiological sleep [78,79]. Several studies have shown that propofol impairs neutrophil, monocyte and macrophage functions. Propofol inhibits iNOS expression from macrophages and suppresses NO generation [80-82]. Other anti-inflammatory effects of propofol have been observed in LPS-stimulated macrophages [83].

On the other hand, some investigations on healthy subjects suggest that propofol has no inhibitory effect on lymphocytes [84-86], neutrophils [87] and phagocytes [88] function. Similarly, propofol does not show significant inhibition of neutrophil function in severe brain injury patients [89]. Propofol and midazolam decrease the level of extracellular IL-8 from lipopolysaccharide (LPS)-stimulated neutrophils, although intracellular IL-8 and mRNA levels increases [90]. This suggests that these agents affect the cytokine release at the post-translational level.

Propofol also inhibits the production of IL-10, TNF-α, IL-1β and IL-6 in LPS-stimulated peripheral blood mononuclear cells (PBMCs) [91], probably acting at the pre-translational level [81]. In endotoxin-exposed rats, propofol, but not ketamine, blunts the TNF-α response; on the other hand, both drugs have inhibitory effect on the increase of IL-6 and IL-10 [92]. Other studies have shown that propofol inhibits IL-8 and increases the level of the anti-inflammatory cytokine IL-10, which blocks the pro-inflammatory cytokines and induces the release of IL-1 receptor antagonist [85,90].

Propofol, like halothane, inhibits NK activity, but does not promote tumor retention in the lung [59]. A study showed the different effects of propofol and thiopental on the Th1/Th2 ratio by measuring the level of IFN-γ and IL-4 in PBM C [93]. High doses of propofol increased the Th1/Th2 ratio (INF-y/IL-4), whereas low dose did not change INF-y, IL-4 and IL-2 [93]. However, another study showed no change in Th1/Th2 ratio after propofol anesthesia [35]. Thiopentone, diazepam and ketamine have shown to negatively affect NK activity and lung tumor retention [59]. Thiopental and ketamine [94] also inhibit the LPS-induced release of IL-1, IL-6, TNF-α [95] and IL-8, and increase IL-10 [96-97]. In healthy volunteers, thiopentone and etomidate impair lymphocytes function [84]. Thiopentone may have no effect on IL-2 [93], but it decreases INF-y [93,98], IL-4 [93] and INF-y/IL-4 ratio [93], and impairs chemotaxis [99] and phagocytosis [88,99,100]. Similarly, midazolam inhibits chemotaxis [99] and IL-8 secretion [90].

Preoperative use of small doses (0.15 mg/kg) of ketamine has been shown to suppress the inflammatory response and release of IL-6 and TNF-α, without altering IL-2 secretion [95]. Etomidate causes inhibition of T-lymphocyte function in vitro [101], but other studies have shown that etomidate does not affect NF-kappa B activation in human T-lymphocytes [102]. Etomidate increases IL-10 concentration and inhibits the release of IL-1 receptor antagonist after LPS-stimulation in cultured human whole blood [85].

Dexmedetomidine, α 2-adrenoceptor agonist, has no effect on neutrophil functions in vitro [103]. On the other hand, dexmedetomidine has been shown to increase Th1/Th2 cytokine ratio in patients undergoing laparoscopic surgery [104]. Preemptive administration of dexmedetomidine also suppresses the cytokine response after LPS-induced endotoxemia in murine model [105].


Opioid are a family of drugs that binds opioid δ, and κ receptors such as µ [106,107]. They are commonly distinguished in natural (opiates), such as morphine, and synthetics, like fentanyl, remifentanil, alfentanil and sufentanil. The activation of opioid receptors produces multiple effects, such as sedation, analgesia and respiratory depression [107]. It is known that opioid receptors are also expressed on immune cells [108]. The suppressive effects of opioids on immune system have been well established [109]. In the late 19th century, it was reported that phagocytosis function of leukocytes were inhibited by opioids [110] Opioids are considered to exert the immunosuppressive effects through specific receptors expressed in the nervous system and immune cells [111,112].

The activation of these receptors in the nervous system leads to the release of glucocorticoids and catecholamines, which suppress the peripheral immune response [113,114]. Furthermore, the stimulation of opioid receptors immune cells causes the suppress of their functions, including cytokine production [115]. Morphine inhibits neutrophil, monocyte, macrophage and lymphocyte functions. The suppressive effects of morphine may be mediated mainly by their µ3 opioid receptor, which influences NO release and inhibits NF-κ B pathway and the production of pro-inflammatory molecules [116]. Studies have shown that morphine inhibits IL-10 and IL-2 production from monocytes and macrophages [117]. Morphine supresses IFN-γ and IL-2 production of T-lymphocyte [117]. In addition, chronic administration of morphine causes a decrease in Th1/Th2 ratio, as the cytokine balance shifts from Th1 cytokines (IFN-γ, IL-2) to Th2 cytokines (IL-4) [118]. Compared to morphine, synthetic opioids such as fentanyl, remifentanil, sufentanil and alfentanil seem to have minimal or no immunosuppressive effects [32]. This difference may be secondary to the µ3 receptor, which is not bind by synthetic opioids such as fentanyl [119]. Although suppressive effects of fentanyl on NK cell have been reported in animals [120], in humans it has shown that fentanyl increases activity and number of NK cells, and CD8+ cytotoxic T-lymphocytes [121], neither However, neither polymorphonuclear cells (PMNC) activity [122] nor cellular adhesion is affected [123]. Moreover, fentanyl has no effect of on the release of cytokine [85]. Clinical dosage of fentanyl and remifentanil do not change the concentration of IL-6, TNF, IL-10 and IL-2 [124], but remifentanil has been shown to attenuate the postoperative increase of IFN-γ/IL -10 ration of greater extent than fentanyl [124].

Local anesthetics

Local anesthetics, such as lidocaine, bupivacaine and ropivacaine, are drugs that block the nerve conduction, causing temporary motor and/or sensory loss. They act through the inhibition of Na+ channel on the nerve membrane [125]. They can be administered peripherally (local infiltration, topical application, plexus block), or at level of the spine (epidural and spinal anesthesia) [126,127]. Lidocaine can be also given intravenously exerting analgesic effects [128]. Several studies have investigated the effect of local anesthetics on immune system.

In vitro, lidocaine inhibits the IL-8 and IL-1β release [129,130] from epithelial cells, the IL-1β secretion from mononuclear cells and neutrophil function [130], the phagocytosis [130,131], and the migration of leukocytes [130,132]. It attenuates the formation of reactive oxygen metabolites [133], and the release of leukotrienes, IL-1-α [134], and histamine [135]. Similar effects have been demonstrated with bupivacaine and ropivacaine [130,131,136,137].

Lidocaine also inhibits interferon-inducible IL-10 secretion in intestinal epithelial cells [138], attenuates IL-1β, IL -6, IL-8 and ICAM-1 on activated human umbilical vein endothelial cells [139], and impairs the secretions of IL-2, TNF-α, INF–γ [140]. Furthermore, in animals with LPS-induced lung injury, lidocaine attenuates the release of TNF-α and IL -6 [141], whereas ropivacaine reduces the expression of ICAM-1 and the leukocyte adhesion [142]. Local anesthetics are used to perform peripheral and central blocks, which can be an adjuvant of general anesthesia or used as sole type of anesthesia. Therefore, beside the direct effect on the immune system, local anesthetics affect the immunity by blocking the sympathetic nervous system and by attenuating the surgical stress [32,36].

The combination spinal/epidural anesthesia has been shown a significant reduction of postoperative cortisol peak with respect to general anesthesia [143]. This effect has been confirmed after several major surgeries [144]. Similarly, epidural anesthesia preserves NK cell cytotoxicity after abdominal surgery with respect to general anesthesia alone [145]. Finally, epidural anesthesia, but not general anesthesia, has shown no impairment of cytokine production [146].

Does the type of anesthesia influence the risk of cancer recurrence? Clinical evidence

Intraoperative tumor disruption, decrease antiangiogenic factors, augmentation of growth factors and surgery-related immunosuppression have been proposed as surgical factors promoting cancer recurrence [34].

Most of the studies that investigated the influence of anesthesia on cancer recurrence have been done in animals.

Clinical studies regarding the effect on anesthesia and analgesia techniques on the immune function are lacking [34,44]. Interest has been focused to local anesthesia (peripheral and central blocks), which has shown beneficial effects on immunity after surgery [147] and may affect surgical outcome of oncologic patients [43,148-150]. Regional anesthesia is believed to be beneficial against cancer recurrence due to reduced exposure to immunosuppressive agents (i.e., nitrous oxide), reduced surgical stress and adrenergic stimulation, but the mechanism is still unclear [147]. In fact, in absence of surgical stress, both general and local anesthesia have minor and transient effects on immune function [151].

On the other hand, cancer proliferation involves several stimuli and mediators, which can be all affected by the anesthetics [147,152].

The benefits of epidural anesthesia over general anesthesia on cancer recurrence have yet to be established.

NK cells activity was investigated in patients undergoing laparotomy colectomy under either general anesthesia or epidural anesthesia alone [145]. Patients receiving general anesthesia had a significant reduction of NK cells activity (36% vs. 22%, p=0.02) respect to preoperative values, whereas the epidural group did not shown significant changes. Moreover, postoperative stress biomarkers (plasma and epinephrine and cortisol levels, and urinary cortisol) were reduced in the epidural group only. However, in this study the surgical indications included both cancer and not cancer lesions, patients were randomized, and NK cells activity was not compared between groups, making the results questionable.

Patients undergoing surgical resection of non-small cell lung cancer, in fact, showed a postoperative decrease of percentage (13.07 ± 9.81% vs. 9.6 ± 6.57% compared to preoperative values, P<0.001) and function (31.61 ± 21.96%,13.61 ± 9.36% compared to preoperative values, P=0.001) despite the use of epidural analgesia [153].

On the other hand, the association of general and epidural anesthesia demonstrated to attenuate the increase of IL-2 and to promote the return to baseline levels of CD3+, CD4+ and CD4+/CD8+ cells after osteosarcoma resection [154]. This data may suggest that the combination of general/epidural anesthesia contributes to restoration of IL-2 and lymphocytes T helper after surgery. However, it must be noted that the study included children, who were unlikely randomized in the epidural group (no general anesthesia/sedation).

Furthermore both the sample size and the statistical tests are questionable. It is also possible that the type of general anesthetic agent (intravenous vs. inhalational) may blunt the beneficial effects of epidural. In fact, propofol has shown to increase Th1/Th2 ratio and T-helper cells percentage respect to isoflurane in patients undergoing pulmonary lobectomy for non-small-cell lung cancer [155].

Nevertheless, several studies have shown that paravertebral analgesia enhances antitumorigenic cytokines, such as IL-10 [156] and decreases breast cancer function [157].

In particular, a retrospective analysis [158] investigated the recurrence-free survival time in patients undergoing breast cancer resection under general anesthesia with or without paravertebral analgesia. The paravertebral anesthesia group showed better tumor-free and metastasis-free survival compared to general anesthesia at 24 and 36 months (94% vs. 82% and 87% vs. 77%, respectively). Recently, women undergoing surgery for biopsy-proven primary breast were randomized to receive either TIVA with regional technique (paravertebral block) or general anesthesia with opioid (morphine) analgesia. Patients’ serum was collected and exposed to estrogen receptor-negative breast cancer cells and cells apoptosis was measured. Women in the regional group showed higher breast cancer cells apoptosis ratios compared to patients who received balanced anesthesia with sevoflurane and morphine (0.40 vs. 0.22, P=0.001) [159]. This data were confirmed in a another study [160] from the same institution, where

TIVA with paravertebral block was associated to greater human donor NK cell cytotoxicity. Regional anesthesia has shown similar results after ovarian, colon and prostate surgery, but no in patients affected by melanoma [147].

Cata et al. [44] have recently reviewed over 140 studies to investigate the outcome of orthopedic oncologic surgical patients. Authors did not find any study suitable for metanalysis, but they confirmed the benefit of regional anesthesia in breast cancer recurrence. Moreover, they mentioned that little data exist in favor to regional anesthesia after gastrointestinal and genitourinary surgery.

In children data are lacking. Only few studies investigated the effect of anesthesia on children’s immunity [58], and none regarding cancer recurrence.

However, data have shown that the surgical stress has an important impact in the child’s immunosuppression [161-163].

In children, regional anesthesia is almost always used in association to sedation or general anesthesia and has shown little or no benefits respect to opioids when associate to general anesthesia [40,164,165].

On the contrary, spinal anesthesia is effective in reducing stress response after surgery (IL-6, IL-8, cortisol, catecholamines) [166].

In pediatric oncology, the only study in the literature suggests that a single dose of the combination of propofol/ketamine do not alter the immune system in children affected by acute lymphoblastic leukemia [167].


The balance between pro-inflammatory and anti-inflammatory cytokine has been shown to be critical in the tumor progression. By affecting this balance, anesthesia may play an important role on outcome of cancer patients.

Compared to general anesthesia alone, epidural and peripheral anesthesia may be beneficial in reducing cancer recurrence and should be considered whenever is possible. However, further investigations are needed to clarify the relation between anesthesia and cancer, particularly in children.


The present review has been funded by the Department of Anesthesia, McGill University Health Centre, Montreal Children’s Hospital, Montreal, QC, Canada.


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Editorial Information


Andrew Herlich
University of Pittsburgh School of Medicine

Article Type

Review Article

Publication history

Received date: May 24, 2015
Accepted date: June 28, 2015
Published date: July 03, 2015


©2015 Kitamura Y. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Kitamura Y, Di Biaso I, Ingelmo PM, Bertolizio G (2015). Anesthesia, cytokines and cancer recurrence. Glob Anaesth Perioper Med 1: doi: 10.15761/GAPM.1000122

Corresponding author

Gianluca Bertolizio

Department of Anesthesia, McGill University Health Centre, Montreal Children’s Hospital, Montreal, QC, Canada.

E-mail :

Common aspects of Cytokine

Their secretion is brief and limited in time

They have pleiotropic properties, because they have the same effect on multiple cells

They may affect other cytokines

They may have autocrine, paracrine or endocrine function

They bind specific receptor on the membrane

The expression their receptor on target cells is regulated by signals that are outside the cell

The targeted cell responds with phenotype modifications and acquisition of new functions

Their secretion is brief and limited in time

Table1. Common aspect of cytokines