Editor’s Note: This thought-provoking article by Dr. Durieux raises questions that have yet to be answered and perhaps expands our conventional view of patient safety.
The immune system has developed to protect us not only from infection but also from cancer. The perioperative stress response affects our immune system. Therefore, it might be expected that in patients undergoing cancer surgery (often associated with release of cancerous cells through the body) their defenses against metastasis are suppressed just at a time when they need them the most. This raises the question whether certain anesthetic techniques might improve the ability of the body to eliminate cancer cells and improve survival. Recent evidence suggests that this is indeed the case.
In this article, we will review the effects of surgical stress and anesthetic techniques and drugs on cancer and discuss the recent data suggesting that specific anesthetic management can improve patient outcomes by reducing cancer recurrence.
The Stress Response and Cancer
Animal studies indicate that immune response control over the circulation of tumor cells and micrometastasis is carried out mainly through cell-mediated immunity (CMI), which includes cytotoxic T lymphocytes, NK (natural killer) cells, NK-T-cells, dendritic cells, and macrophages.1 NK cells are important because they can naturally recognize and kill malignant cells. A number of inflammatory mediators, such as interferon (INF) and interleukin (IL), specifically, (INF)γ, IL12, and T helper 1 (Th1) cytokines, increase the cytotoxic activity of T- and NK cells, as do IL-4 and IL-10. Th2 cytokines are involved in increasing humoral immunity and suppressing the Th1 response, and the Th2 status is thought to play a negative role in oncological immune response.2 β-adrenergic stimulation, which increases during stress states, suppresses NK activity and therefore promotes metastasis.3 Human studies show that low perioperative levels of NK activity are associated with an increased cancer related morbidity and mortality.4,5
Angiogenesis, the growth of new capillaries from existing blood vessels, is essential for the growth of a cancer cell into a macroscopic metastasis. It is a complex multi-step process involving extracellular matrix components,6 and is regulated by multiple angiogenetic factors, including interleukin 6, 8, and 1β, cyclooxygenase 2, nitric oxide, tumor necrosis factor, and insulin growth factor.
Surgery, Anesthesia, and Cancer Metastasis
Surgery, although essential for tumor cancer treatment, suppresses immunity and therefore promotes metastasis. Growth of preexisting micro metastases and dissemination of malignant cells during the perioperative period is facilitated.7,8 In addition, surgical stress activates angiogenesis, which contributes to neoplastic growth. It is conceivable that minimally invasive approaches, with less effect on the immune system, might reduce these negative effects, but this is not known.
The specific anesthesia approach used is more likely to be of relevance as many animal studies have shown that the choice of anesthetic drugs and techniques profoundly influences the immune response and, as a result, cancer metastasis.
Melamed and colleagues demonstrated in rats that ketamine, thiopental, and halothane reduced NK cell activity and increased lung tumor retention or lung metastasis. The number of circulating NK cells per milliliter of blood was reduced by ketamine and thiopental significantly; halothane showed a similar but not significant result.9 The effect of ketamine, in particular, may result from its adrenergic stimulating properties, which will suppresses NK cell activity and promotes metastasis.3 In contrast, propofol does not affect metastasis, which may be related to its (weak) β-adrenergic antagonist properties.10
Postoperative pain therapy may play a very important role in metastasis after cancer surgery. Page and colleagues demonstrated in rats that the provision of pain relief attenuates the surgery-induced increase in metastatic susceptibility, likely because of the reduction in the stress response. They demonstrated that preoperative intrathecal administration of bupivacaine plus morphine and the perioperative systemic administration of fentanyl significantly enhanced the host resistance to surgery-induced increases in lung metastasis.11 They suggested that the pain-alleviating effect of these drugs attenuated the surgery-induced promotion of metastasis rather than having direct effects on immunity, tumor cells, or other mechanisms.
On the other hand, opioids likely play a profoundly negative role. Morphine has been repeatedly shown to promote angiogenesis, and it promotes breast tumor growth in rodents.12 It is well established that opioids inhibit cellular and humoral immune function in humans.
Neuraxial Anesthesia: Animal Data
The use of epidural anesthesia alone improves postoperative outcome, attenuates the surgical stress response, and prevents inhibition of the system. In addition, regional anesthesia decreases the requirement for inhaled anesthetics and intravenous opioids, both of which have been shown to decrease the activity of natural killer cells. When administered intrathecally in small quantities, opioids do not exert the same immunosuppressive effects seen after systemic administration. This finding has significant clinical relevance, as epidural and spinal blockade is usually supplemented with small doses of opioids, and this practice is likely safe.13 Furthermore epidural analgesia blunts effectively the neuroendocrine response and thereby decreases the production of epinephrine and norepinephrine, which reduce NK cell activity.
In a mouse model it was shown that laparotomy during sevoflurane anesthesia significantly increased the number of liver metastases as compared with sevoflurane anesthesia plus spinal anesthesia. The addition of intrathecal local anesthetics attenuated the suppression of tumoricidal function of liver mononuclear cells, presumably by preserving the Th1/Th2 balance. Thereby it reduced the promotion of tumor metastasis.14
Neuraxial Anesthesia: Human Data
Two retrospective studies demonstrate that the long-term outcome for patients undergoing cancer surgery is better if they receive neuraxial anesthesia.
Exadaktylos et al. suggested in a retrospective analysis that paravertebral anesthesia and analgesia for breast cancer surgery reduces the risk of recurrence or metastasis during the initial years of follow up. This study reviewed data from 129 patients undergoing mastectomy and axillary dissection for breast cancer.15 The follow-up time was 32 ± 5 months (mean ± SD). Recurrence- and metastasis-free survival was 94% (95% confidence interval, 87–100%) and 82% (74–91%) at 24 months and 94% (87–100%) and 77% (68–87%) at 36 months in the paravertebral and general anesthesia patients, respectively (P = 0.012). These data suggest that neuraxial anesthesia might be more effective than postoperative chemotherapy to reduce metastasis.
A retrospective study from the same group studied men undergoing radical prostatectomy under general anesthesia with morphine analgesia as compared with general anesthesia combined with epidural analgesia. The authors found that the epidural technique was associated with a 65% reduction in biochemical recurrence of prostate cancer defined by increased prostate specific antigen postoperatively [Biki B.
Anesthesiology In Press]. A potential mechanism was reported in a prospective study with patients undergoing transurethral resection of the prostate. It was found that spinal anesthesia may result in less immunosuppression after surgery and that the ratio of Th1/Th2 cells was higher compared to general anesthesia.2
It is too early to recommend specific kinds of medications for the anesthesia regime or to recommend a regional technique. At this time, the mechanisms underlying these benefits are unclear. Is it the reduction in stress response provided by regional anesthesia the important factor, the reduction in opiate use, or the reduction in inhaled anesthetic requirement? The latter is suggested by a study that followed 4,329 melanoma patients and reported that substituting the use of local anesthesia for the procedure (as compared with general anesthesia) was an independent, favorable prognostic factor for less recurrence of tumor. In fact, choice of general anaesthesia for primary excision of melanoma was associated with a decrease in the survival rate, with a relative risk of 1.46 (P<0.0001).16 If reducing volatile anesthetic requirements or opiates is the main factor, it might be possible to obtain similar benefits using drugs like dexmedetomidine or intravenous lidocaine.17
It should be realized that all these studies were retrospective. Long-term prospective studies will be required (and several have been initiated) before we will know if the choice of anesthesia technique for cancer surgery has a significant impact on patient safety in the long run. Since 90% of cancer- related death is due to metastatic development, rather than directly related to the primary cancer, the potential for improving patient outcome is very significant.18
For many years, laboratory studies have suggested that our anesthetic drugs and approaches may impact tumor metastasis after cancer surgery. Techniques that prevent stress responses and increases in catecholamines, and that limit requirements for volatile anesthetics and opiates, seem effective in reducing the incidence of metastasis. Two retrospective clinical trials have demonstrated significant reductions in recurrence rates in breast and prostate cancer if neuraxial anesthesia was employed. We will have to await the results of prospective trials before definitive conclusions can be drawn, but there is at least a strong suggestion that anesthetic practice can affect patient safety for years after the surgical procedure.
Dr. Durieux is Professor of Anesthesiology and Neurological Surgery at the University of Virginia Health System in Charlottesville, VA.
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- Le Cras AE, Galley HF, Webster NR. Spinal but not general anesthesia increases the ratio of T helper 1 to T helper 2 cell subsets in patients undergoing transurethral resection of the prostate. Anesth Analg 1998;87:1421-5.
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- Sooriakumaran P, Kaba R. Angiogenesis and the tumour hypoxia response in prostate cancer: a review. Int J Surg 2005;3:61-7.
- Melamed R, Rosenne E, Shakhar K, et al. Marginating pulmonary-NK activity and resistance to experimental tumor metastasis: suppression by surgery and the prophylactic use of a beta-adrenergic antagonist and a prostaglandin synthesis inhibitor. Brain Behav Immun 2005;19:114-26.
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- 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.
- Exadaktylos AK, Buggy DJ, Moriarty DC, et al. Can anesthetic technique for primary breast cancer surgery affect recurrence or metastasis? Anesthesiology 2006;105:660-4.
- Schlagenhauff B, Ellwanger U, Breuninger H, et al. Prognostic impact of the type of anaesthesia used during the excision of primary cutaneous melanoma. Melanoma Res 2000;10:165-9.
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