- Email: [email protected]
Does anesthetic technique influence cancer?
Journal of Clinical Anesthesia (2012) 24, 1–2
Editorial
Does anesthetic technique influence cancer? The spread of cancer involves a plethora of factors, all of which may be influenced by anesthesia. In most cases, significant exposure to anesthesia is of brief duration. However, the timing of anesthesia for oncologic surgery coincides with the stirring of the hornet's nest. It is thus intriguing to wonder if anesthesia technique has an impact on disease recurrence. Definitive clinical trials of this question will be technically formidable, but in this issue of the Journal of Clinical Anesthesia Drs. Conrick-Martin, Kell, and Buggy offer an interesting meta-analysis of a carefully chosen aspect of the overall question [1]. They ask whether lymphocytes active against neoplastic cells are more detectable in cases in which epidural or intrathecal anesthesia/analgesia was performed in order to spare opioids. Comparing patients with and without opioid-sparing regional anesthesia/analgesia, difference was sought in the function of natural killer cells. First described in 1975, these cells are called “natural” because they are naturally abundant without the need for prior sensitization with a stimulating antigen [2]. That is, they are part of the innate (rather than the acquired) immune system. They are dubbed “killers” for their ability to selectively lyse neoplastic cells. The meta-analysis dealt with five studies and failed to demonstrate an obvious preservation of natural killer (NK) activity by a technique that includes regional anesthesia. In only two studies was general anesthesia actually obviated by regional anesthesia. The negative result notwithstanding, there is more work to be done. There is a big gap between acute NK activity assessments and long-term oncology observations. Indeed, NK cytotoxicity and NK cell count change significantly in humans undergoing, for instance, low-intensity exercise [3]. The changes in that example are not of the same proportion, respectively increasing by 600% and 100%. Despite the negative result of the meta-analysis of perioperative killer cell parameters, Dr. Buggy, Dr. Sessler and other colleagues have clinical evidence that regional adjuncts to anesthesia have a benefit against recurrent breast and prostate disease [4,5]. Large studies are underway [6]. In addition to the present meta-analysis, there are clinical observations which do not support a marked effect of anesthesia technique on NK cell activity or cancer recurrence 0952-8180/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.jclinane.2011.10.001
[7,8]. However, powerful effects of regional blockade have been seen in some laboratory experiments [9]. A leading hypothesis as to why regional anesthesia might inhibit cancer recurrence is that opioids are detectably immunosuppressant [10,11]. However, there is a paradox. If surgical stress is not relieved by an analgesic technique (such as administration of exogenous opioids or use of nerve blocks), endogenous opioid peptides are released and may inhibit immunity [12,13] or else enhance it [14,15]. In an interesting rodent surgery experiment, morphine actually reduced metastasis of a mammary adenocarcinoma [16]. It seems that, in some circumstances, the stress-relieving properties of an opioid may have a net positive influence on NK activity. Along with opioids, another anesthetic with immunological effects is nitrous oxide (N2O) [17]. The gas covalently inactivates the vitamin B12-dependent enzyme that converts homocysteine to the amino acid methionine. The co-substrate is methyl-tetrahydrofolate, which transfers its methyl group [18]. Accordingly, N2O reduces the supply of tetrahydrofolate needed for DNA synthesis (Fig. 1). There is thus a methotrexate-like action of N2O [19]. Inactivation of methionine synthase by N2O is irreversible, so the effect persists until fresh enzyme can be synthesized from amino acids, a process which might take days. It is unclear whether nitrous inhibition of DNA synthesis is beneficial or harmful in surgical oncology, since the phenomenon probably impacts the propagation of both neoplastic and immunologic cells [20]. Other anesthesia-related drugs also perturb the immune system. For instance, etomidate inhibits the synthesis of immunosuppressive glucocorticoids [21]. In addition, prolactin, a stimulant of immunity, is lowered by dopamine and enhanced by metoclopramide [22]. In another example, lidocaine evinces weak carcinogenicity in some experiments [23] and inhibits NK cells in vitro [24]. We must be reasonable in extrapolating such studies into clinical guidelines, or we shall become paralyzed by fear itself. Questions about anesthesia influence on cancer recurrence are fascinating. Hospitals have started to mention antirecurrence anesthesia on their websites, and overt advertisements will follow. As interesting possibilities about anesthesia and cancer are scientifically considered, media
2
Editorial
Fig. 1 Inhibition of DNA synthesis by nitrous oxide (N2O). Both N2O and methotrexate (MTX) inhibit enzymes producing tetrahydrofolate. That factor functions in a cycle in which deoxyuridine monophosphate (dUMP) is methylated to the thymidylate (dTMP) component of DNA. The cycle is also inhibited by 5-fluorouracil (5FU). The nitrous-sensitive enzyme converts the amino acid homocysteine (hcys) to methionine. In B12-dysfunction such as that provoked by N2O, tetrahydrofolate becomes trapped in the methyl state [18].
coverage will prompt patients (and surgeons) increasingly to question their anesthesiologists about an optimum plan [25]. However, in a world in which some people question the carcinogenicity of tobacco smoke, it will be tough to prove whether general anesthesia lacking regional adjuncts facilitates oncologic disease. Mark J. Young MD (Fellow) Theodore A. Alston MD, PhD (Assistant Professor) Department of Anesthesia Critical Care and Pain Medicine Massachusetts General Hospital and Harvard Medical School Boston, MA 02114, USA E-mail address: [email protected]
References [1] Conrick-Martin I, Kell MR, Buggy DJ. Meta-analysis of the effect of central neuraxial regional anesthesia compared with general anesthesia on postoperative natural killer T lymphocyte function. J Clin Anesth 2012;24(1):3-7. [2] Kiessling R, Klein E, Wigzell H. “Natural” killer cells in the mouse. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Specificity and distribution according to genotype. Eur J Immunol 1975;5:112-7. [3] Moyna NM, Acker GR, Weber KM, et al. Exercise-induced alterations in natural killer cell number and function. Eur J Appl Physiol Occup Physiol 1996;74:227-33. [4] Exadaktylos AK, Buggy DJ, Moriarty DC, Mascha E, Sessler DI. Can anesthetic technique for primary breast cancer surgery affect recurrence or metastasis? Anesthesiology 2006;105:660-4. [5] 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 2008;109:180-7.
[6] Sessler DI, Ben-Eliyahu S, Mascha EJ, Parat MO, Buggy DJ. Can regional analgesia reduce the risk of recurrence after breast cancer? Methodology of a multicenter randomized trial. Contemp Clin Trials 2008;29:517-26. [7] Hori Y, Ibuki T, Hosokawa T, Tanaka Y. The effects of neurosurgical stress on peripheral lymphocyte subpopulations. J Clin Anesth 2003;15:1-8. [8] Myles PS, Peyton P, Silbert B, Hunt J, Rigg JR, Sessler DI; ANZCA Trials Group Investigators. Perioperative epidural analgesia for major abdominal surgery for cancer and recurrence-free survival: randomised trial. BMJ 2011;342:d1491. [9] Wada H, Seki S, Takahashi T, et al. Combined spinal and general anesthesia attenuates liver metastasis by preserving TH1/TH2 cytokine balance. Anesthesiology 2007;106:499-506. [10] Hashiguchi S, Morisaki H, Kotake Y, Takeda J. Effects of morphine and its metabolites on immune function in advanced cancer patients. J Clin Anesth 2005;17:575-80. [11] Bayer BM, Daussin S, Hernandez M, Irvin L. Morphine inhibition of lymphocyte activity is mediated by an opioid dependent mechanism. Neuropharmacology 1990;29:369-74. [12] Shavit Y, Lewis JW, Terman GW, Gale RP, Liebeskind JC. Opioid peptides mediate the suppressive effect of stress on natural killer cell cytotoxicity. Science 1984;223(4632):188-90. [13] Lewis JW, Shavit Y, Terman GW, Gale RP, Liebeskind JC. Stress and morphine affect survival of rats challenged with a mammary ascites tumor (MAT 13762B). Nat Immun Cell Growth Regul 1983-1984;3: 43-50. [14] Mathews PM, Froelich CJ, Sibbitt Jr WL, Bankhurst AD. Enhancement of natural cytotoxicity by beta-endorphin. J Immunol 1983;130: 1658-62. [15] Faith RE, Murgo AJ. Inhibition of pulmonary metastases and enhancement of natural killer cell activity by methionine-enkephalin. Brain Behav Immun 1988;2:114-22. [16] Page GG, Ben-Eliyahu S, Yirmiya R, Liebeskind JC. Morphine attenuates surgery-induced enhancement of metastatic colonization in rats. Pain 1993;54:21-8. [17] Hogue CW Jr, Perese D, Vacanti CA, Alston TA. Potential toxicity from prolonged anesthesia: a case report of a thirty-hour anesthetic. J Clin Anesth 1990;2:183-7. [18] Nixon PF, Bertino JR. Impaired utilization of serum folate in pernicious anemia. A study with radiolabeled 5-methyltetrahydrofolate. J Clin Invest 1972;51:1431-9. [19] Ermens AA, Schoester M, Spijkers LJ, Lindemans J, Abels J. Toxicity of methotrexate in rats preexposed to nitrous oxide. Cancer Res 1989;49:6337-41. [20] Koblin DD. Nitrous oxide: a cause of cancer or chemotherapeutic adjuvant? Semin Surg Oncol 1990;6:141-7. [21] Tønnesen E, Brinkløv MM, Christensen NJ, Olesen AS, Madsen T. Natural killer cell activity and lymphocyte function during and after coronary artery bypass grafting in relation to the endocrine stress response. Anesthesiology 1987;67:526-33. [22] Zellweger R, Wichmann MW, Ayala A, Chaudry IH. Metoclopramide: a novel and safe immunomodulating agent for restoring the depressed macrophage immune function after hemorrhage. J Trauma 1998;44:70-7. [23] Beardsley T. Take the pain? Lidocaine comes under suspicion as a carcinogen. Sci Am 1994;270:28-9. [24] Krog J, Hokland M, Ahlburg P, Parner E, Tønnesen E. Lipid solubility- and concentration-dependent attenuation of in vitro natural killer cell cytotoxicity by local anesthetics. Acta Anaesthesiol Scand 2002;46:875-81. [25] Marcus A. Morphine and other pain relief drugs used in cancer surgery may spur return of malignancy. Available at www. ScientificAmerican.com. Accessed Jun 25, 2010.
Editorial
Does anesthetic technique influence cancer? The spread of cancer involves a plethora of factors, all of which may be influenced by anesthesia. In most cases, significant exposure to anesthesia is of brief duration. However, the timing of anesthesia for oncologic surgery coincides with the stirring of the hornet's nest. It is thus intriguing to wonder if anesthesia technique has an impact on disease recurrence. Definitive clinical trials of this question will be technically formidable, but in this issue of the Journal of Clinical Anesthesia Drs. Conrick-Martin, Kell, and Buggy offer an interesting meta-analysis of a carefully chosen aspect of the overall question [1]. They ask whether lymphocytes active against neoplastic cells are more detectable in cases in which epidural or intrathecal anesthesia/analgesia was performed in order to spare opioids. Comparing patients with and without opioid-sparing regional anesthesia/analgesia, difference was sought in the function of natural killer cells. First described in 1975, these cells are called “natural” because they are naturally abundant without the need for prior sensitization with a stimulating antigen [2]. That is, they are part of the innate (rather than the acquired) immune system. They are dubbed “killers” for their ability to selectively lyse neoplastic cells. The meta-analysis dealt with five studies and failed to demonstrate an obvious preservation of natural killer (NK) activity by a technique that includes regional anesthesia. In only two studies was general anesthesia actually obviated by regional anesthesia. The negative result notwithstanding, there is more work to be done. There is a big gap between acute NK activity assessments and long-term oncology observations. Indeed, NK cytotoxicity and NK cell count change significantly in humans undergoing, for instance, low-intensity exercise [3]. The changes in that example are not of the same proportion, respectively increasing by 600% and 100%. Despite the negative result of the meta-analysis of perioperative killer cell parameters, Dr. Buggy, Dr. Sessler and other colleagues have clinical evidence that regional adjuncts to anesthesia have a benefit against recurrent breast and prostate disease [4,5]. Large studies are underway [6]. In addition to the present meta-analysis, there are clinical observations which do not support a marked effect of anesthesia technique on NK cell activity or cancer recurrence 0952-8180/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.jclinane.2011.10.001
[7,8]. However, powerful effects of regional blockade have been seen in some laboratory experiments [9]. A leading hypothesis as to why regional anesthesia might inhibit cancer recurrence is that opioids are detectably immunosuppressant [10,11]. However, there is a paradox. If surgical stress is not relieved by an analgesic technique (such as administration of exogenous opioids or use of nerve blocks), endogenous opioid peptides are released and may inhibit immunity [12,13] or else enhance it [14,15]. In an interesting rodent surgery experiment, morphine actually reduced metastasis of a mammary adenocarcinoma [16]. It seems that, in some circumstances, the stress-relieving properties of an opioid may have a net positive influence on NK activity. Along with opioids, another anesthetic with immunological effects is nitrous oxide (N2O) [17]. The gas covalently inactivates the vitamin B12-dependent enzyme that converts homocysteine to the amino acid methionine. The co-substrate is methyl-tetrahydrofolate, which transfers its methyl group [18]. Accordingly, N2O reduces the supply of tetrahydrofolate needed for DNA synthesis (Fig. 1). There is thus a methotrexate-like action of N2O [19]. Inactivation of methionine synthase by N2O is irreversible, so the effect persists until fresh enzyme can be synthesized from amino acids, a process which might take days. It is unclear whether nitrous inhibition of DNA synthesis is beneficial or harmful in surgical oncology, since the phenomenon probably impacts the propagation of both neoplastic and immunologic cells [20]. Other anesthesia-related drugs also perturb the immune system. For instance, etomidate inhibits the synthesis of immunosuppressive glucocorticoids [21]. In addition, prolactin, a stimulant of immunity, is lowered by dopamine and enhanced by metoclopramide [22]. In another example, lidocaine evinces weak carcinogenicity in some experiments [23] and inhibits NK cells in vitro [24]. We must be reasonable in extrapolating such studies into clinical guidelines, or we shall become paralyzed by fear itself. Questions about anesthesia influence on cancer recurrence are fascinating. Hospitals have started to mention antirecurrence anesthesia on their websites, and overt advertisements will follow. As interesting possibilities about anesthesia and cancer are scientifically considered, media
2
Editorial
Fig. 1 Inhibition of DNA synthesis by nitrous oxide (N2O). Both N2O and methotrexate (MTX) inhibit enzymes producing tetrahydrofolate. That factor functions in a cycle in which deoxyuridine monophosphate (dUMP) is methylated to the thymidylate (dTMP) component of DNA. The cycle is also inhibited by 5-fluorouracil (5FU). The nitrous-sensitive enzyme converts the amino acid homocysteine (hcys) to methionine. In B12-dysfunction such as that provoked by N2O, tetrahydrofolate becomes trapped in the methyl state [18].
coverage will prompt patients (and surgeons) increasingly to question their anesthesiologists about an optimum plan [25]. However, in a world in which some people question the carcinogenicity of tobacco smoke, it will be tough to prove whether general anesthesia lacking regional adjuncts facilitates oncologic disease. Mark J. Young MD (Fellow) Theodore A. Alston MD, PhD (Assistant Professor) Department of Anesthesia Critical Care and Pain Medicine Massachusetts General Hospital and Harvard Medical School Boston, MA 02114, USA E-mail address: [email protected]
References [1] Conrick-Martin I, Kell MR, Buggy DJ. Meta-analysis of the effect of central neuraxial regional anesthesia compared with general anesthesia on postoperative natural killer T lymphocyte function. J Clin Anesth 2012;24(1):3-7. [2] Kiessling R, Klein E, Wigzell H. “Natural” killer cells in the mouse. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Specificity and distribution according to genotype. Eur J Immunol 1975;5:112-7. [3] Moyna NM, Acker GR, Weber KM, et al. Exercise-induced alterations in natural killer cell number and function. Eur J Appl Physiol Occup Physiol 1996;74:227-33. [4] Exadaktylos AK, Buggy DJ, Moriarty DC, Mascha E, Sessler DI. Can anesthetic technique for primary breast cancer surgery affect recurrence or metastasis? Anesthesiology 2006;105:660-4. [5] 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 2008;109:180-7.
[6] Sessler DI, Ben-Eliyahu S, Mascha EJ, Parat MO, Buggy DJ. Can regional analgesia reduce the risk of recurrence after breast cancer? Methodology of a multicenter randomized trial. Contemp Clin Trials 2008;29:517-26. [7] Hori Y, Ibuki T, Hosokawa T, Tanaka Y. The effects of neurosurgical stress on peripheral lymphocyte subpopulations. J Clin Anesth 2003;15:1-8. [8] Myles PS, Peyton P, Silbert B, Hunt J, Rigg JR, Sessler DI; ANZCA Trials Group Investigators. Perioperative epidural analgesia for major abdominal surgery for cancer and recurrence-free survival: randomised trial. BMJ 2011;342:d1491. [9] Wada H, Seki S, Takahashi T, et al. Combined spinal and general anesthesia attenuates liver metastasis by preserving TH1/TH2 cytokine balance. Anesthesiology 2007;106:499-506. [10] Hashiguchi S, Morisaki H, Kotake Y, Takeda J. Effects of morphine and its metabolites on immune function in advanced cancer patients. J Clin Anesth 2005;17:575-80. [11] Bayer BM, Daussin S, Hernandez M, Irvin L. Morphine inhibition of lymphocyte activity is mediated by an opioid dependent mechanism. Neuropharmacology 1990;29:369-74. [12] Shavit Y, Lewis JW, Terman GW, Gale RP, Liebeskind JC. Opioid peptides mediate the suppressive effect of stress on natural killer cell cytotoxicity. Science 1984;223(4632):188-90. [13] Lewis JW, Shavit Y, Terman GW, Gale RP, Liebeskind JC. Stress and morphine affect survival of rats challenged with a mammary ascites tumor (MAT 13762B). Nat Immun Cell Growth Regul 1983-1984;3: 43-50. [14] Mathews PM, Froelich CJ, Sibbitt Jr WL, Bankhurst AD. Enhancement of natural cytotoxicity by beta-endorphin. J Immunol 1983;130: 1658-62. [15] Faith RE, Murgo AJ. Inhibition of pulmonary metastases and enhancement of natural killer cell activity by methionine-enkephalin. Brain Behav Immun 1988;2:114-22. [16] Page GG, Ben-Eliyahu S, Yirmiya R, Liebeskind JC. Morphine attenuates surgery-induced enhancement of metastatic colonization in rats. Pain 1993;54:21-8. [17] Hogue CW Jr, Perese D, Vacanti CA, Alston TA. Potential toxicity from prolonged anesthesia: a case report of a thirty-hour anesthetic. J Clin Anesth 1990;2:183-7. [18] Nixon PF, Bertino JR. Impaired utilization of serum folate in pernicious anemia. A study with radiolabeled 5-methyltetrahydrofolate. J Clin Invest 1972;51:1431-9. [19] Ermens AA, Schoester M, Spijkers LJ, Lindemans J, Abels J. Toxicity of methotrexate in rats preexposed to nitrous oxide. Cancer Res 1989;49:6337-41. [20] Koblin DD. Nitrous oxide: a cause of cancer or chemotherapeutic adjuvant? Semin Surg Oncol 1990;6:141-7. [21] Tønnesen E, Brinkløv MM, Christensen NJ, Olesen AS, Madsen T. Natural killer cell activity and lymphocyte function during and after coronary artery bypass grafting in relation to the endocrine stress response. Anesthesiology 1987;67:526-33. [22] Zellweger R, Wichmann MW, Ayala A, Chaudry IH. Metoclopramide: a novel and safe immunomodulating agent for restoring the depressed macrophage immune function after hemorrhage. J Trauma 1998;44:70-7. [23] Beardsley T. Take the pain? Lidocaine comes under suspicion as a carcinogen. Sci Am 1994;270:28-9. [24] Krog J, Hokland M, Ahlburg P, Parner E, Tønnesen E. Lipid solubility- and concentration-dependent attenuation of in vitro natural killer cell cytotoxicity by local anesthetics. Acta Anaesthesiol Scand 2002;46:875-81. [25] Marcus A. Morphine and other pain relief drugs used in cancer surgery may spur return of malignancy. Available at www. ScientificAmerican.com. Accessed Jun 25, 2010.