Does anesthetic technique influence cancer?

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Journal of Clinical Anesthesia (2012) 24, 1–2


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



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]

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