EDITORIAL For reprint orders, please contact: [email protected]
Minimizing immunosuppression: an alternative approach for anesthesiologists?
Maria Fernanda Ramirez1
Peter Tran1
Despite the development of effective radiotherapy and chemotherapy treatment, surgery remains one of the first-line treatments for solid cancers. Advances made in understanding the response of surgical injury in cancer patients indicate that during surgery there is an increase of angiogenesis factors, release of inflammatory mediators and activation of the neuroendocrine system that is directly proportional to the magnitude of surgical trauma and overall results in immunosuppression [1]. Moreover, growing evidence from in vitro and animal studies indicates that immune surveillance plays an important role in achieving control of tumor growth and cancer recurrence. Cancer patients characteristically present with depression of both cellular and humoral immune functions that, added to the negative consequences of surgical-induced immuno suppression, may intensify the vulnerability for proliferation of dormant tumor cells, long-distance seeding of tumor cells and, in the long-term, cancer recurrence and metastasis. To understand the contribution of the immune function on cancer patients it is
Juan Pablo Cata*1 necessary to address some basic concepts of immunology. The immune system protects the host from tumor development by the modulation of a complex system of cells and soluble mediators. Among these mediators, we can include prostaglandins, growth factors and interleukins (ILs). PGE2 plays a role in growth and invasiveness, and therefore COX-2 inhibitors have been proposed as a new therapeutic tool in neutralizing the tumorigenicity of cancer cells [2]. In addition, ILs can induce cancer cell death directly, but most importantly they can amplify cell-mediated immunity by modulating the function of natural killer (NK) cells, cytotoxic lymphocytes (CD8), NK T-cell lymphocytes, antigen-presenting cells and helper lymphocytes. The action of CD4 T-helper cells is classified according to the role and pattern of the cytokines that they secrete. For instance, a typical Th1 cell response is characterized by the production of IFN-a, IL-2 and TNF-a, and it is highly effective in enhancing the cellular immunity necessary for tumor cell destruction. By contrast, a Th2 cell response is seen
“…surgery remains one of the first-line treatments for solid cancers.”
Department of Anesthesiology & Perioperative Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard 77030, Houston, TX, USA *Author for correspondence: [email protected] 1
10.2217/PMT.13.67 © 2014 Future Medicine Ltd
Pain Manage. (2014) 4(1), 9–11
part of
ISSN 1758-1869
9
Editorial Fernanda Ramirez, Tran & Cata as an increase in IL-4, IL-5, IL-10 and IL-13, which mediate humoral response and promote tumoral growth. To complicate the matter, the Th1/Th2 balance is predominantly Th2 after cancer surgery as a result of a decrease of Th1 and/or increase of Th2 response [3]. Moreover, our group and others have shown that NK cell function is impaired postoperatively after cancer surgery [4]. Opioids, volatile anesthetics and mediators of surgical stress are known to impair the function of NK cells [1]. All of these findings indicate that the perioperative period may be a key moment for intervention and perhaps modifications of prognosis of cancer patients.
“PGE2 plays a role in growth and invasiveness, and therefore COX-2 inhibitors have been proposed as a new therapeutic tool in neutralizing the tumorigenicity of cancer cells.”
Potential benefits of regional anesthesia Surgical procedures can be performed under general anesthesia, regional anesthesia or both. A recent different perspective of regional anesthesia as a possible tool for improving cancer patients’ outcomes has opened up a new approach for anesthesiologists in the influence of long-term outcomes in cancer. The theoretical approach for the potential benefit of regional anesthesia to improve longterm outcome after cancer surgery is complex and involves several possible mechanisms. First, regional anesthesia decreases the consumption or avoids the use of general anesthetics, which have been reported to promote tumor growth. For instance, volatile anesthetics in in vitro and in vivo models have been shown to decrease the function and proliferation of lymphocytes and the secretion of proinflammatory cytokines [5]. The human data is controversial; however, Woods and colleagues suggest that the inhibition is minimal, transitory and dose dependent [6]. Propofol, one of the most common intravenous anesthetics, seems to have an anti-tumor effect due to the preservation of immune function. Mammoto et al. proposed this anesthetic agent to be a possible agent for cancer surgery because it is associated with apoptosis and inhibition of proliferation and adhesion of cancer cells when used as clinically relevant doses. In addition, propofol preserves the number and function of NK cells and the Th1/Th2 balance [7]. Second, regional anesthesia decreases or eliminates the need for opioids, which have been linked with the progression of certain types of tumor, such as breast cancer and glioblastoma multiforme in animal models [8,9]. Several authors have demonstrated that opioids are potent modulators of the immune response. The protumorigenic
10
Pain Manage. (2014) 4(1)
effect of opioids, in particular, may result from the direct modulation of the immune cells by the µ-receptor and by the indirect modulation of the hypothalamo–pituitary axis [10]. For instance, the evidence indicates that morphine at clinically relevant doses suppresses the activity of NK cells and promotes angiogenesis by the stimulation of µ-receptors on endothelial cells, which ultimately leads to tumor growth and metastasis [11]. Third, local anesthetics also have an effect on cancer cells. As an example, lidocaine decreases the ability of fibrosarcoma and osteosarcoma cells to invade and form metastases [12]. Finally, and most importantly, regional anesthesia might attenuate the neuroendocrine response and the immunosuppression associated with surgery [13], with subsequent decreases in the secretion of proinflammatory cytokines and steroids that have been described as modulators of the immune function [14]. This protective effect of regional anesthesia has been well documented in some clinical scenarios, such as lower abdominal surgery, but it seems to be insufficient to blunt neuroendocrine response in upper abdominal surgery, which could be explained by the incomplete neural blockage of afferent somatic pathways [15]. Despite accumulated basic science data suggesting the benefits of regional anesthesia in cancer, the clinical evidence is conflicting. The studies that have shown a clinical benefit in terms of cancer recurrence are retrospective and suffer from all of the possible bias of observational studies. A retrospective study by Exadaktylos et al. suggested an association between the use of regional anesthesia and lower cancer recurrence after breast cancer surgery [16]. Similar results were found by Biki and collegues in patients with prostate cancer and regional analgesia [17]. The results of Cumming et al. and Gottschalk et al. add important evidence to the debate because they did not find any association between epidural analgesia and cancer recurrence in patients with colon cancer [18,19]. For this reason, a recent meta-analysis was carried out in order to address the controversy of this topic and to clarify the benefit of regional anesthesia in cancer patients. Chen et al. concluded that epidural analgesia/anesthesia is associated with improved overall survival in patients with solid cancer, particularly in colon cancer patients; however, he did not found an asociation between epidural anesthesia and cancer recurrence [20]. These findings are disappointing, but not surprising, due to the fact that the benefit
future science group
Minimizing immunosuppression: an alternative approach for anesthesiologists? probably depends on multiple variables, including the type of cancer and the stage of the disease, among others. At this point there are questions that need to be addressed by the investigators of this fascinating topic. Could anesthesiologists find a way to effectively change cancer outcomes? Do all cancer patients benefit from this intervention? Does the benefit depend on the type of cancer, stage or site of the primary tumor? Does the timing of anesthetic/analgesic exposure matter? It is difficult to speculate that regional anesthesia might in fact have an impact on cancer recurrence; if such a phenomenon actually occurs it is perhaps in the early stages of cancer in which the tumor burden is minimal and when the surveillance References 1
Cata JP, Gottumukkala V, Sessler DI. How regional analgesia might reduce postoperative cancer recurrence. Eur. J. Pain Suppl. 5, 345–355 (2011).
2
Naruse T, Nishida Y, Hosono K, Ishiguro N. Meloxicam inhibits osteosarcoma growth, invasiveness and metastasis by COX-2-dependent and independent routes. Carcinogenesis 27, 584–592 (2006).
3
Ishikawa M, Nishioka M, Hanaki N et al. Perioperative immune responses in cancer patients undergoing digestive surgeries. World J. Surg. Oncol. 7, 7 (2009).
4
5
6
7
8
Cata JP, Bauer M, Sokari T et al. Effects of surgery, general anesthesia, and perioperative epidural analgesia on the immune function of patients with non-small cell lung cancer. J. Clin. Anesth. 25(4), 255–262 (2013). Mitsuhata H, Shimizu R, Yokoyama MM. Suppressive effects of volatile anesthetics on cytokine release in human peripheral blood mononuclear cells. Int. J. Immunopharmacol. 17, 529–534 (1995). Woods GM, Griffiths DM. Reversible inhibition of natural killer cell activity by volatile anaesthetic agents in vitro. Br. J. Anaesth. 58, 535–539 (1986). Mammoto T, Mukai M, Mammoto A et al. Intravenous anesthetic, propofol inhibits invasion of cancer cells. Cancer Lett. 184, 165–170 (2002).
future science group
9
Editorial
function of the immune system is minimally impaired. Further studies are needed to answer these questions and clarify the impact of the regional anesthesia on the surgical outcomes for cancer patients. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript. Gupta K, Kshirsagar S, Chang L et al. Morphine stimulates angiogenesis by activating proangiogenic and survival-promoting signaling and promotes breast tumor growth. Cancer Res. 62, 4491–4498 (2002). Lazarczyk M, Matyja E, Lipkowski AW. A comparative study of morphine stimulation and biphalin inhibition of human glioblastoma T98G cell proliferation in vitro. Peptides 31, 1606–1612 (2010).
10 Hernandez MC, Flores LR, Bayer BM.
Immunosuppression by morphine is mediated by central pathways. J. Pharmacol. Exp. Ther. 267, 1336–1341 (1993). 11 Franchi S, Panerai AE, Sacerdote P.
Buprenorphine ameliorates the effect of surgery on hypothalamus-pituitary-adrenal axis, natural killer cell activity and metastatic colonization in rats in comparison with morphine or fentanyl treatment. Brain Behav. Immun. 21, 767–774 (2007). 12 Mammoto T, Higashiyama S, Mukai M et al.
Infiltration anesthetic lidocaine inhibits cancer cell invasion by modulating ectodomain shedding of heparin-binding epidermal growth factor-like growth factor (HB-EGF). J. Cell Physiol. 192, 351–358 (2002). 13 Koltun WA, Bloomer MM, Tilberg AF et al.
Awake epidural anesthesia is associated with improved natural killer cell cytotoxicity and a reduced stress response. Am. J. Surg. 171, 68–72, discussion 72–63 (1996).
14 Cardinale F, Chinellato I, Caimmi S et al.
Perioperative period: immunological modifications. Int. J. Immunopathol. Pharmacol. 24, S3–S12 (2011). 15 Yokoyama M, Itano Y, Katayama H et al.
The effects of continuous epidural anesthesia and analgesia on stress response and immune function in patients undergoing radical esophagectomy. Anesth. Analg. 101, 1521–1527 (2005). 16 Exadaktylos AK, Buggy DJ, Moriarty DC,
Mascha E, Sessler DI. Can anesthetic technique for primary breast cancer surgery affect recurrence or metastasis? Anesthesiology 105, 660–664 (2006). 17 Biki B, Mascha E, Moriarty DC, Fitzpatrick
JM, Sessler DI, Buggy DJ. Anesthetic technique for radical prostatectomy surgery affects cancer recurrence: a retrospective analysis. Anesthesiology 109, 180–187 (2008). 18 Cummings KC, Xu F, Cummings LC,
Cooper GS. A comparison of epidural analgesia and traditional pain management effects on survival and cancer recurrence after colectomy: a population-based study. Anesthesiology 116, 797–806 (2012). 19 Gottschalk A, Ford JG, Regelin CC et al.
Association between epidural analgesia and cancer recurrence after colorectal cancer surgery. Anesthesiology 113, 27–34 (2010). 20 Chen WK, Miao CH. The effect of anesthetic
technique on survival in human cancers: a meta-analysis of retrospective and prospective studies. PLoS ONE 8, e56540 (2013).
www.futuremedicine.com
11
Minimizing immunosuppression: an alternative approach for anesthesiologists?
Maria Fernanda Ramirez1
Peter Tran1
Despite the development of effective radiotherapy and chemotherapy treatment, surgery remains one of the first-line treatments for solid cancers. Advances made in understanding the response of surgical injury in cancer patients indicate that during surgery there is an increase of angiogenesis factors, release of inflammatory mediators and activation of the neuroendocrine system that is directly proportional to the magnitude of surgical trauma and overall results in immunosuppression [1]. Moreover, growing evidence from in vitro and animal studies indicates that immune surveillance plays an important role in achieving control of tumor growth and cancer recurrence. Cancer patients characteristically present with depression of both cellular and humoral immune functions that, added to the negative consequences of surgical-induced immuno suppression, may intensify the vulnerability for proliferation of dormant tumor cells, long-distance seeding of tumor cells and, in the long-term, cancer recurrence and metastasis. To understand the contribution of the immune function on cancer patients it is
Juan Pablo Cata*1 necessary to address some basic concepts of immunology. The immune system protects the host from tumor development by the modulation of a complex system of cells and soluble mediators. Among these mediators, we can include prostaglandins, growth factors and interleukins (ILs). PGE2 plays a role in growth and invasiveness, and therefore COX-2 inhibitors have been proposed as a new therapeutic tool in neutralizing the tumorigenicity of cancer cells [2]. In addition, ILs can induce cancer cell death directly, but most importantly they can amplify cell-mediated immunity by modulating the function of natural killer (NK) cells, cytotoxic lymphocytes (CD8), NK T-cell lymphocytes, antigen-presenting cells and helper lymphocytes. The action of CD4 T-helper cells is classified according to the role and pattern of the cytokines that they secrete. For instance, a typical Th1 cell response is characterized by the production of IFN-a, IL-2 and TNF-a, and it is highly effective in enhancing the cellular immunity necessary for tumor cell destruction. By contrast, a Th2 cell response is seen
“…surgery remains one of the first-line treatments for solid cancers.”
Department of Anesthesiology & Perioperative Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard 77030, Houston, TX, USA *Author for correspondence: [email protected] 1
10.2217/PMT.13.67 © 2014 Future Medicine Ltd
Pain Manage. (2014) 4(1), 9–11
part of
ISSN 1758-1869
9
Editorial Fernanda Ramirez, Tran & Cata as an increase in IL-4, IL-5, IL-10 and IL-13, which mediate humoral response and promote tumoral growth. To complicate the matter, the Th1/Th2 balance is predominantly Th2 after cancer surgery as a result of a decrease of Th1 and/or increase of Th2 response [3]. Moreover, our group and others have shown that NK cell function is impaired postoperatively after cancer surgery [4]. Opioids, volatile anesthetics and mediators of surgical stress are known to impair the function of NK cells [1]. All of these findings indicate that the perioperative period may be a key moment for intervention and perhaps modifications of prognosis of cancer patients.
“PGE2 plays a role in growth and invasiveness, and therefore COX-2 inhibitors have been proposed as a new therapeutic tool in neutralizing the tumorigenicity of cancer cells.”
Potential benefits of regional anesthesia Surgical procedures can be performed under general anesthesia, regional anesthesia or both. A recent different perspective of regional anesthesia as a possible tool for improving cancer patients’ outcomes has opened up a new approach for anesthesiologists in the influence of long-term outcomes in cancer. The theoretical approach for the potential benefit of regional anesthesia to improve longterm outcome after cancer surgery is complex and involves several possible mechanisms. First, regional anesthesia decreases the consumption or avoids the use of general anesthetics, which have been reported to promote tumor growth. For instance, volatile anesthetics in in vitro and in vivo models have been shown to decrease the function and proliferation of lymphocytes and the secretion of proinflammatory cytokines [5]. The human data is controversial; however, Woods and colleagues suggest that the inhibition is minimal, transitory and dose dependent [6]. Propofol, one of the most common intravenous anesthetics, seems to have an anti-tumor effect due to the preservation of immune function. Mammoto et al. proposed this anesthetic agent to be a possible agent for cancer surgery because it is associated with apoptosis and inhibition of proliferation and adhesion of cancer cells when used as clinically relevant doses. In addition, propofol preserves the number and function of NK cells and the Th1/Th2 balance [7]. Second, regional anesthesia decreases or eliminates the need for opioids, which have been linked with the progression of certain types of tumor, such as breast cancer and glioblastoma multiforme in animal models [8,9]. Several authors have demonstrated that opioids are potent modulators of the immune response. The protumorigenic
10
Pain Manage. (2014) 4(1)
effect of opioids, in particular, may result from the direct modulation of the immune cells by the µ-receptor and by the indirect modulation of the hypothalamo–pituitary axis [10]. For instance, the evidence indicates that morphine at clinically relevant doses suppresses the activity of NK cells and promotes angiogenesis by the stimulation of µ-receptors on endothelial cells, which ultimately leads to tumor growth and metastasis [11]. Third, local anesthetics also have an effect on cancer cells. As an example, lidocaine decreases the ability of fibrosarcoma and osteosarcoma cells to invade and form metastases [12]. Finally, and most importantly, regional anesthesia might attenuate the neuroendocrine response and the immunosuppression associated with surgery [13], with subsequent decreases in the secretion of proinflammatory cytokines and steroids that have been described as modulators of the immune function [14]. This protective effect of regional anesthesia has been well documented in some clinical scenarios, such as lower abdominal surgery, but it seems to be insufficient to blunt neuroendocrine response in upper abdominal surgery, which could be explained by the incomplete neural blockage of afferent somatic pathways [15]. Despite accumulated basic science data suggesting the benefits of regional anesthesia in cancer, the clinical evidence is conflicting. The studies that have shown a clinical benefit in terms of cancer recurrence are retrospective and suffer from all of the possible bias of observational studies. A retrospective study by Exadaktylos et al. suggested an association between the use of regional anesthesia and lower cancer recurrence after breast cancer surgery [16]. Similar results were found by Biki and collegues in patients with prostate cancer and regional analgesia [17]. The results of Cumming et al. and Gottschalk et al. add important evidence to the debate because they did not find any association between epidural analgesia and cancer recurrence in patients with colon cancer [18,19]. For this reason, a recent meta-analysis was carried out in order to address the controversy of this topic and to clarify the benefit of regional anesthesia in cancer patients. Chen et al. concluded that epidural analgesia/anesthesia is associated with improved overall survival in patients with solid cancer, particularly in colon cancer patients; however, he did not found an asociation between epidural anesthesia and cancer recurrence [20]. These findings are disappointing, but not surprising, due to the fact that the benefit
future science group
Minimizing immunosuppression: an alternative approach for anesthesiologists? probably depends on multiple variables, including the type of cancer and the stage of the disease, among others. At this point there are questions that need to be addressed by the investigators of this fascinating topic. Could anesthesiologists find a way to effectively change cancer outcomes? Do all cancer patients benefit from this intervention? Does the benefit depend on the type of cancer, stage or site of the primary tumor? Does the timing of anesthetic/analgesic exposure matter? It is difficult to speculate that regional anesthesia might in fact have an impact on cancer recurrence; if such a phenomenon actually occurs it is perhaps in the early stages of cancer in which the tumor burden is minimal and when the surveillance References 1
Cata JP, Gottumukkala V, Sessler DI. How regional analgesia might reduce postoperative cancer recurrence. Eur. J. Pain Suppl. 5, 345–355 (2011).
2
Naruse T, Nishida Y, Hosono K, Ishiguro N. Meloxicam inhibits osteosarcoma growth, invasiveness and metastasis by COX-2-dependent and independent routes. Carcinogenesis 27, 584–592 (2006).
3
Ishikawa M, Nishioka M, Hanaki N et al. Perioperative immune responses in cancer patients undergoing digestive surgeries. World J. Surg. Oncol. 7, 7 (2009).
4
5
6
7
8
Cata JP, Bauer M, Sokari T et al. Effects of surgery, general anesthesia, and perioperative epidural analgesia on the immune function of patients with non-small cell lung cancer. J. Clin. Anesth. 25(4), 255–262 (2013). Mitsuhata H, Shimizu R, Yokoyama MM. Suppressive effects of volatile anesthetics on cytokine release in human peripheral blood mononuclear cells. Int. J. Immunopharmacol. 17, 529–534 (1995). Woods GM, Griffiths DM. Reversible inhibition of natural killer cell activity by volatile anaesthetic agents in vitro. Br. J. Anaesth. 58, 535–539 (1986). Mammoto T, Mukai M, Mammoto A et al. Intravenous anesthetic, propofol inhibits invasion of cancer cells. Cancer Lett. 184, 165–170 (2002).
future science group
9
Editorial
function of the immune system is minimally impaired. Further studies are needed to answer these questions and clarify the impact of the regional anesthesia on the surgical outcomes for cancer patients. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript. Gupta K, Kshirsagar S, Chang L et al. Morphine stimulates angiogenesis by activating proangiogenic and survival-promoting signaling and promotes breast tumor growth. Cancer Res. 62, 4491–4498 (2002). Lazarczyk M, Matyja E, Lipkowski AW. A comparative study of morphine stimulation and biphalin inhibition of human glioblastoma T98G cell proliferation in vitro. Peptides 31, 1606–1612 (2010).
10 Hernandez MC, Flores LR, Bayer BM.
Immunosuppression by morphine is mediated by central pathways. J. Pharmacol. Exp. Ther. 267, 1336–1341 (1993). 11 Franchi S, Panerai AE, Sacerdote P.
Buprenorphine ameliorates the effect of surgery on hypothalamus-pituitary-adrenal axis, natural killer cell activity and metastatic colonization in rats in comparison with morphine or fentanyl treatment. Brain Behav. Immun. 21, 767–774 (2007). 12 Mammoto T, Higashiyama S, Mukai M et al.
Infiltration anesthetic lidocaine inhibits cancer cell invasion by modulating ectodomain shedding of heparin-binding epidermal growth factor-like growth factor (HB-EGF). J. Cell Physiol. 192, 351–358 (2002). 13 Koltun WA, Bloomer MM, Tilberg AF et al.
Awake epidural anesthesia is associated with improved natural killer cell cytotoxicity and a reduced stress response. Am. J. Surg. 171, 68–72, discussion 72–63 (1996).
14 Cardinale F, Chinellato I, Caimmi S et al.
Perioperative period: immunological modifications. Int. J. Immunopathol. Pharmacol. 24, S3–S12 (2011). 15 Yokoyama M, Itano Y, Katayama H et al.
The effects of continuous epidural anesthesia and analgesia on stress response and immune function in patients undergoing radical esophagectomy. Anesth. Analg. 101, 1521–1527 (2005). 16 Exadaktylos AK, Buggy DJ, Moriarty DC,
Mascha E, Sessler DI. Can anesthetic technique for primary breast cancer surgery affect recurrence or metastasis? Anesthesiology 105, 660–664 (2006). 17 Biki B, Mascha E, Moriarty DC, Fitzpatrick
JM, Sessler DI, Buggy DJ. Anesthetic technique for radical prostatectomy surgery affects cancer recurrence: a retrospective analysis. Anesthesiology 109, 180–187 (2008). 18 Cummings KC, Xu F, Cummings LC,
Cooper GS. A comparison of epidural analgesia and traditional pain management effects on survival and cancer recurrence after colectomy: a population-based study. Anesthesiology 116, 797–806 (2012). 19 Gottschalk A, Ford JG, Regelin CC et al.
Association between epidural analgesia and cancer recurrence after colorectal cancer surgery. Anesthesiology 113, 27–34 (2010). 20 Chen WK, Miao CH. The effect of anesthetic
technique on survival in human cancers: a meta-analysis of retrospective and prospective studies. PLoS ONE 8, e56540 (2013).
www.futuremedicine.com
11
