Surgery for Cancer: Does Anesthesia Matter?

Surgery for Cancer: Does Anesthesia Matter? Skip to main page content

HOME CURRENT ISSUE PAST ISSUES CME SUBSCRIBE ONLINE HELP SUBMIT TO A&A ACTIVATE MY ACCOUNT Search GO Advanced Search ? User Name Password Sign In Surgery for Cancer: Does Anesthesia Matter? James G. Bovill, MD, PhD, FCARCSI, FRCA

From the Department of Anaesthesiology, Leiden University Medical Centre, Leiden, The Netherlands. Address correspondence to James G. Bovill, MD, PhD, FCARCSI, FRCA, Hugo de Grootlaan 31, 1422 BR Uithoorn, The Netherlands. Address e-mail to jgbovill{at}gmail.com. As anesthesiologists, we often assume that once the immediate effects of our drugs dissipate, the body returns to the preanesthetic state without long-term sequelae. However, in addition to profound immediate effects, anesthesia can also have long-term consequences. In this issue of Anesthesia & Analgesia, 2 articles deal with 1 potentially devastating consequence: an increased risk of metastatic spread of malignant cells after cancer surgery. Gottschalk et al.1 review the pathophysiology of cancer recurrence after surgery, the potential role of anesthesia on the risk of recurrence, and discuss how this might affect clinical practice. Their review is an opportune reminder that not all consequences of anesthesia disappear after the immediate postoperative period. The authors of the second article report findings from an analysis of tumor recurrence after surgery for breast cancer.2 The results suggest that intraoperative administration of the nonsteroidal antiinflammatory drug (NSAID) ketorolac significantly decreases the incidence of cancer recurrence compared with non-NSAID analgesics.

Cancer is second only to cardiovascular disease as the most frequent cause of death among adults in the developed nations. Although cancer does occur in children and young adults, nearly 75% of cases occur in individuals aged 60 years and older, and more than one-third in those aged 75 years and older.* Populations in the developed countries are aging, with a concomitant increase in age-related diseases, including cancer. As a consequence, anesthesiologists will be confronted with increasing numbers of patients presenting for cancer surgery.

Surgical removal of a malignant tumor is the primary treatment for most cancers. However, surgical manipulation can release isolated cancer cells into the bloodstream and lymphatic system. Whether these develop into metastases depends on the balance between the patient's immune defenses and the ability of the tumor cells to seed, proliferate, and attract formation of new blood vessels. Several factors can upset this balance. The immune system, by specifically identifying and destroying malignant cells (tumor immune surveillance), is a primary defense against cancer.3 Major surgery is associated with immunosuppression which, together with the release of cytokines, chemokines, and prostaglandins, can facilitate angiogenesis, tumor metastasis, and tumor invasion.4 In particular, surgery inhibits the natural killer (NK) cells that are critical in limiting the spread of malignant cells.5 They are the only cell type able to recognize and lyse cells lacking self human leukocyte antigen class I molecules. Because many tumor cells inhibit the expression of these molecules, NK cells are the major first-line defense against the development of primary tumors and the metastatic spread of established tumors.

James Cottrell defined anesthesiologists as “… doctors who keep patients alive while surgeons do things that would otherwise kill them.”6 But could our choice of anesthesia increase the risk of cancer recurrence that could kill the patient, or could a more appropriate choice of drug decrease the risk of recurrence after cancer surgery? There is increasing evidence from experimental studies and a limited number of clinical studies that some anesthetics and opioids may be contributing factors to the development of metastases after cancer surgery.1 Inhaled anesthesia, independent of other factors, may increase the risk of malignant cells escaping from immune control. Volatile anesthetics induce apoptosis in lymphocytes, reduce NK cytotoxicity, and alter the release of cytokines by NK cells in response to tumor cells.7 On the positive side, some anesthetics are cytotoxic to poorly differentiated human carcinoma cell lines and might help counteract the spread of cancer cells.8 On balance, however, it would seem prudent to limit the use of inhaled anesthesia in patients undergoing cancer surgery. Gottschalk et al.1 propose 2 alternatives: regional anesthesia and total IV anesthesia (TIVA) with propofol. Although several studies have suggested that regional anesthesia preserves immune defenses against tumor progression by attenuating the surgical stress response, most have been retrospective and have investigated regional combined with general anesthesia.9 Propofol, the most popular hypnotic used in TIVA, attenuates the surgical stress-induced adverse immune response to surgery and has antitumor activity, possibly related to inhibition of cyclooxygenase.10,11 Unfortunately, propofol is not a complete anesthetic and needs to be combined with an opioid when used in TIVA.

Opioids have several actions that can promote the dissemination of malignant cells. They stimulate angiogenesis, a key factor in the growth and dissemination of cancers, in part by activating cyclooxygenase-2 (COX-2), increasing production of prostaglandin E2, which promotes angiogenesis and tumor progression.12 Opioids also significantly influence the functioning of the immune system indirectly via the hypothalamic-pituitary axis and directly through opioid receptors, especially ?3 receptors expressed on immunocytes. These receptors are involved in signaling pathways that modulate antibody production and the activity of NK cells.13 Now, there is compelling evidence that animals, including humans, synthesize morphine and related morphinan alkaloids, and that these endogenous opioids are involved in morphinergic signaling in immune cells.14 The ?3 receptors are also expressed on human cancer cell lines, where they are coupled to constitutive nitric oxide release.15 Opioid alkaloids such as morphine bind strongly to the ?3 receptor, whereas binding of synthetic opioids such as fentanyl and the endogenous opioid peptides is considerably weaker. This explains why alkaloids such as morphine are predominantly immunosuppressive, whereas the endogenous opioid peptides are predominantly immunostimulatory.

An accepted method of reducing the dose of an opioid while maintaining satisfactory analgesia is to combine the opioid with an NSAID. The combination can decrease postoperative pain and opioid requirements by 20% to 50%. NSAIDs, especially those with COX-2 inhibitory activity, have been shown in a number of major epidemiological studies to reduce significantly the risk of several types of cancer, including colon, breast, and prostate cancers. However, those studies were related to the chronic use of NSAIDs. The article by Forget et al.2 is of particular interest because their results suggest that an NSAID, given as a single dose during surgery, may also significantly reduce cancer recurrence after surgery. They reviewed 319 consecutive patients who had mastectomy for breast cancer during a 4.5-year period. Just more than half (55%) of the patients were given ketorolac IV immediately before skin incision. Cancer recurrence after surgery was lower (P < 0.001) in patients given ketorolac (6%) compared with the 17% recurrence in patients who did not receive ketorolac. The authors acknowledge several important limitations of their study. It was retrospective, nonrandom, and patients also received a number of other drugs that could have influenced recurrence, including diclofenac administered postoperatively for pain relief to more than half of the patients. Rather surprisingly, the authors found no association between cancer recurrence and the use of diclofenac, which, similar to ketorolac, is an NSAID with approximately equal activity at COX-1 and COX-2, so it would be expected to have a similar influence on cancer recurrence. Despite these reservations, the analysis of their data is sufficiently robust that the implications of their findings cannot be ignored.

Increased expression of COX-2 occurs in many types of cancers and is a crucial element not only in the pathogenesis and dissemination of tumors but also in increasing their resistance to apoptosis, and with the generation of prostaglandins and related compounds that support carcinogenesis.16 Blocking overexpression by COX-2–selective NSAIDs can induce apoptosis and tumor regression and inhibits the angiogenesis important for tumor growth and metastasis.17 In addition to the inhibition of COX-2 and prostaglandin synthesis by NSAIDs, recent studies have suggested that COX-independent pathways may also contribute to the anticancer actions of COX-2–selective NSAIDs.18,19 This may be an action specific to celecoxib because it inhibited the growth of human prostate cancer cell lines at concentrations comparable with those achieved clinically, whereas rofecoxib had no effect over the same concentration range.19 Therefore, there are good arguments for using COX-2–specific inhibitors in anesthesia; in addition to providing analgesia thereby reducing the amount of opioids needed for optimal pain relief, they can contribute to minimizing the risk of tumor spread and growth.

Although some cancers progress very rapidly, the majority progress slowly, at least in the early stages. For some patients, malignant cells may have been present in the body for years without any clinical sign of cancer. Indeed, some individuals may never develop overt signs of cancer despite cancer cells being present. This is tumor dormancy, a phenomenon whereby cancer cells persist below the threshold of diagnostic detection for months to decades. Patients who are free of clinically detectable disease for >20 years after treatment may still have circulating tumor cells.20 Some dormant cancer cells may remain in an asymptomatic, nondetectable, and occult state for the life of the individual.21 Autopsies of victims of trauma have revealed that most apparently healthy individuals harbor microscopic primary cancers.22

Dormant tumors are kept in check by the immune system, but any disruption of this equilibrium can allow them to escape from immune control and proliferate.23,24 In addition, for a tumor to progress beyond a diameter of 1 to 2 mm requires an “angiogenic switch” characterized by an imbalance between pro- and antiangiogenic factors, allowing the development of angiogenesis. This interrupts the dormant state, triggering invasive tumor growth.25 The implication is that many, indeed perhaps the majority, of our patients may be harboring a dormant cancer. Any factor that upsets this imbalance, such as surgery and anesthesia, could trigger activation of these cells leading to the development of overt cancer. Unfortunately, at this time, there is no reliable method for detecting the presence of dormant cancer cells.

In conclusion, even though the evidence is inconclusive and at times conflicting, we cannot ignore the possibility that anesthesia may contribute to the recurrence of cancer, months or even years after cancer surgery. Less clear, but equally worrying, is the possibility that anesthesia could activate dormant cancer cells in an individual undergoing noncancer surgery, with the development of an overt cancer that otherwise might never have materialized in the lifetime of that individual. So what should we do? An obvious choice is to use regional anesthesia when feasible, alone or in combination with general anesthesia, to minimize the amount of opioid administered, and to consider using NSAIDs, especially specific COX-2 inhibitors. Of course, what we really need are good prospective, randomized, and controlled clinical trials. These studies will be difficult, requiring large numbers of patients and considerable effort. However, without the results from such studies, we cannot make the informed judgments that will allow us to offer safe anesthesia to our patients while avoiding the devastating consequences of cancer long after the anesthetic has worn off.

 Next Section Footnotes Reprints will not be available from the author.

?* Office for National Statistics. MB1 No 37—Cancer Registration Statistics 2006 England. Available at: http://www.statistics.gov.uk/. Accessed January 19, 2010.

Accepted February 7, 2010. Copyright ? 2010 International Anesthesia Research Society Previous Section  REFERENCES 1.? Gottschalk A, Sharma S, Ford J, Durieux M, Tiouririne M . The role of the perioperative period in recurrence after cancer surgery. Anesth Analg 2010;110:1636–43 Abstract/FREE Full Text 2.? Forget P, Vandenhende J, Berliere M, Machiels J-P, Nussbaum B, Legrand C, De Kock M . Do intraoperative analgesics influence breast cancer recurrence after mastectomy? A retrospective analysis. Anesth Analg 2010;110:1630–5 Abstract/FREE Full Text 3.? Swann JB, Smyth MJ . Immune surveillance of tumors. J Clin Invest 2007;117:1137–46 CrossRefMedline 4.? Demicheli R, Retsky MW, Hrushesky WJ, Baum M, Gukas ID . The effects of surgery on tumor growth: a century of investigations. Ann Oncol 2008;19:1821–8 Abstract/FREE Full Text 5.? Ben-Eliyahu S, page GG, Yirmiya R, Shakhar G . Evidence that stress and surgical interventions promote tumor development by suppressing natural killer cell activity. Int J Cancer 1999;80:880–8 CrossRefMedline 6.? Cottrell JE . View from the head of the table: against putting people to sleep. Surg Rounds 1989;12:81–8 7.? Kurosawa S, Kato M . Anesthetics, immune cells, and immune responses. J Anesth 2008;22:263–77 CrossRefMedline 8.? Kvolik S, Glavas-Obrovac L, Bares V, Karner I . Effects of inhalation anesthetics halothane, sevoflurane, and isoflurane on human cell lines. Life Sci 2005;77:2369–83 CrossRefMedline 9.? Sessler DI . Regional analgesia and cancer recurrence. Anesthesiology 2009;111:1–4 CrossRefMedline 10.? Kushida A, Inada T, Shingu K . Enhancement of antitumor immunity after propofol treatment in mice. Immunopharmacol Immunotoxicol 2007;29:477–86 Medline 11.? Inada T, Kubo K, Kambara T, Shingu K . Propofol inhibits cyclooxygenase activity in human monocytic THP-1 cells. Can J Anaesth 2009;56:222–9 Medline 12.? Amano H, Ito Y, Suzuki T, Kato S, Matsui Y, Ogawa F, Murata T, Sugimoto Y, Senior R, Kitasato H, Hayashi I, Satoh Y, Narumiya S, Majima M . Roles of a prostaglandin E-type receptor, EP3, in upregulation of matrix metalloproteinase-9 and vascular endothelial growth factor during enhancement of tumor metastasis. Cancer Sci 2009;100:2318–24 CrossRefMedline 13.? Martin-Kleiner I, Balog T, Gabrilovac J . Signal transduction induced by opioids in immune cells: a review. Neuroimmunomodulation 2006;13:1–7 Medline 14.? Zhu W, Stefano GB . Comparative aspects of endogenous morphine synthesis and signaling in animals. Ann N Y Acad Sci 2009;1163:330–9 Medline 15.? Cadet P, Rasmussen M, Zhu W, Tonnesen E, Mantione KJ, Stefano GB . Endogenous morphinergic signaling and tumor growth. Front Biosci 2004;9:3176–86 Medline 16.? Eisinger AL, Prescott SM, Jones DA, Stafforini DM . The role of cyclooxygenase-2 and prostaglandins in colon cancer. Prostaglandins Other Lipid Mediat 2007;82:147–54 CrossRefMedline 17.? Farooqui M, Li Y, Rogers T, Poonawala T, Griffin RJ, Song CW, Gupta K . COX-2 inhibitor celecoxib prevents chronic morphine-induced promotion of angiogenesis, tumour growth, metastasis and mortality, without compromising analgesia. Br J Cancer 2007;97:1523–31 CrossRefMedline 18.? Gr?sch S, Tegeder I, Niederberger E, Br?utigam L, Geisslinger G . COX-2 independent induction of cell cycle arrest and apoptosis in colon cancer cells by the selective COX-2 inhibitor celecoxib. FASEB J 2001;15:2742–4 FREE Full Text 19.? Patel MI, Subbaramaiah K, Du B, Chang M, Yang P, Newman RA, Cordon-Cardo C, Thaler HT, Dannenberg AJ . Celecoxib inhibits prostate cancer growth: evidence of a cyclooxygenase-2-independent mechanism. Clin Cancer Res 2005;11:1999–2007 Abstract/FREE Full Text 20.? Meng S, Tripathy D, Frenkel EP, Shete S, Naftalis EZ, Huth JF, Beitsch PD, Leitch M, Hoover S, Euhus D, Haley B, Morrison L, Fleming TP, Herlyn D, Terstappen LW, Fehm T, Tucker TF, Lane N, Wang J, Uhr JW . Circulating tumor cells in patients with breast cancer dormancy. Clin Cancer Res 2004;10:8152–62 Abstract/FREE Full Text 21.? Hedley BD, Chambers AF . Tumor dormancy and metastasis. Adv Cancer Res 2009;102:67–101 CrossRefMedline 22.? Udagawa T . Tumor dormancy of primary and secondary cancers. APMIS 2008;116:615–28 CrossRefMedline 23.? Koebel CM, Vermi W, Swann JB, Zerafa N, Rodig SJ, Old LJ, Smyth MJ, Schreiber RD . Adaptive immunity maintains occult cancer in an equilibrium state. Nature 2007;450:903–7 CrossRefMedline 24.? Quesnel B . Tumor dormancy and immunoescape. APMIS 2008;116:685–94 CrossRefMedline 25.? Indraccolo S, Favaro E, Amadori A . Dormant tumors awaken by a short-term angiogenic burst: the spike hypothesis. Cell Cycle 2006;5:1751–5 Medline ? 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