Lindholm, Maj-Lis PhD; Granath, Fredrik PhD; Eriksson, Lars I. MD, PhD; Sandin, Rolf MD, PhD
There is an increased awareness that the potential harmful effects from depression of immunocompetent cells and signaling cascades in the perioperative period may impact long-term outcome. Several recent articles have reviewed the possibility that anesthesia, surgery, and related events in the perioperative period may have an effect on recurrence of malignant disease after cancer surgery.1–5 The idea that tumor cells are recognized and destroyed by the immune system has been discussed for a long time, and evolved into the concept of immunoediting.2,6 This concept theorizes that a spontaneously developed population of tumor cells, not completely destroyed by the immune system, may still be kept in equilibrium for a variable, possibly lifelong period that delays or precludes progression to a clinical disease. We investigated the hypothesis that exposure to sevoflurane anesthesia would promote progression from subclinical malignancy to a clinically identified disease in patients with no previously identified cancer. We analyzed the impact of duration of sevoflurane anesthesia (TANESTH) and, as a surrogate measure of sevoflurane effect, also of the cumulative time with a bispectral index (BIS) value under 45 (TBIS<45) as a measure of more profound anesthesia exposure, on identification of malignant disease within 5 years of surgery. As a secondary aim, we compared the incidence of new malignant diagnoses with that expected in an age- and sex-matched nonexposed (nonsurgical) population.
After receiving IRB and The Swedish National Cancer Registry approval, a prospective cohort of surgical patients without any known malignant disease at the time of surgery was studied. This cohort included 2792 cancer-free patients anesthetized with sevoflurane; the cohort was derived from a population receiving various anesthetics, in which we have previously reported the effects of BIS monitoring on the incidence of awareness and postoperative mortality.7,8 The patients consented to the initial study7 at the time of the first postoperative interview. The consent from The Swedish National Cancer Registry to use this material for the present study specifically requested that the patients were not to be contacted for additional approval and that the data handling be done without reference to patient identity, which was strictly adhered to. The inclusion criteria were age >16 years, exposure to sevoflurane anesthesia including muscle relaxation and/or endotracheal intubation, application of BIS monitoring, and absence of malignant diagnosis before or within 30 days after the index surgery. If placement of the BIS monitor electrode interfered with the surgical site, BIS monitoring was not used and the patients were excluded from the study. Patients received general anesthesia supplemented with opioids. Nitrous oxide and a concomitant epidural block were allowed according to institutional clinical guidelines. BIS monitoring was recorded in all cases and 1-minute average values were downloaded from the nonvolatile memory (BIS A-2000, BIS index version 3.4; Aspect Medical Systems, Newton, MA) using monitor settings as previously described.7
Malignant diagnoses were based on histopathological diagnosis from The National Cancer Registry of Sweden as registered before the index operation, at the index operation, or within the first 5 postoperative years. Notably, malignancy registered within 30 days after surgery was not included in the data, because malignancy was considered clinically relevant at the time of the index operation. All cancer data were manually checked for accuracy by comparison with surgical records. All new malignant diagnoses were assessed as to whether symptoms could have been masked by the reason for the index operation (“confounding by indication”) by an experienced general surgeon not related to the investigation. This assessor was instructed to regard doubtful cases as possible confounding by indication.
The risk of contracting a malignant disease within 5 years after surgery was analyzed by means of Cox proportional hazard models. The model included age, sex, TANESTH, TBIS<45, ASA physical status, body mass index, tobacco smoking (defined as daily smoking), type of surgery, and the number of additional operations during follow-up. The primary exposure variable was cumulated TBIS<45, which served as a proxy for profound anesthesia exposure. This analysis was performed with time to first malignancy during follow-up as the end point, and the follow-up started 30 days after surgery. A corresponding calculation was also performed using duration of anesthesia, defined as the time from induction to removal of the endotracheal tube. The anesthesia time variables were considered continuous variables and were categorized into quartiles. Analyses were also repeated using thresholds for BIS of <30, <40, and <50. A Kaplan-Meier curve of time to malignancy in relation to quartile of TBIS<45 was estimated, and differences between these were tested using the log-rank test.
To estimate the cancer risk in the surgery cohort in relation to risk in the general population, standardized incidence ratios (SIRs) were calculated, i.e., the ratio of observed-to-expected number of cancers. The expected number of malignancies was calculated by splitting the person-years of follow-up by attained age, sex, and calendar year and multiplying these by the corresponding cancer rates obtained from the Swedish Cancer Registry. Ninety-five percent confidence intervals (CIs) for SIRs were calculated assuming Poisson distributed number of observed cancers. All analyses were performed using SAS version 9.2 (SAS Institute, Inc., Cary, NC).
In the population of 2977 patients, 5 patients died within 30 days after surgery and were excluded from further analyses. Demographic data on the remaining 2972 surgical patients are shown in Table 1. A concomitant epidural anesthetic was used in 6.4% of patients.
In the cohort of 2972 patients, there were 129 individuals (4.3%) in whom we identified a total of 136 new malignant diagnoses within 5 years after the index operation. There was no association between TANESTH or TBIS<45 and the risk of contracting malignancy during follow-up in the adjusted models (Table 2). Considering various levels of profound exposure to sevoflurane anesthesia, this absence of an association was confirmed when we repeated the analyses with thresholds for BIS of <30, <40, and <50 (Table 3). Table 4 lists the sites of new malignancies and also displays the distribution of the new malignant diagnoses with regard to quartiles of TBIS<45. The Kaplan-Meier plot in Figure 1 shows an overall linear decay of the fraction of patients without new cancer, without any differences (by log-rank test: P=0.90) in the time to a new malignant diagnosis with regard to TBIS<45.
The SIR incidence of new malignant diagnoses was 1.37 (CI, 1.15–1.62), i.e., 37% higher than expected. Table 5 displays the assessment of all 129 patients who were assigned a new malignant disease regarding the possibility of confounding by indication, i.e., whether symptoms could have been masked by the reason for the index operation.
The main finding in this study is that there was no impact of total time with profound sevoflurane anesthesia, nor the total duration of anesthesia, on the development of malignancy during a 5-year follow-up period. The estimated relative risk with respect to quartiles of TBIS<45 and duration of anesthesia do not display any dose response or suggest any threshold effect. A BIS value of 45 was chosen as the threshold in the primary analysis because it has been used in earlier work on adverse effects from anesthesia9; it should be noted that we confirmed our finding by repeating our analyses for various surrogate depths of anesthesia, i.e., thresholds for BIS of <30, <40, and <50. The possibility that we failed to identify a small effect can be estimated by comparing the upper CIs for the relative risk in the highest quartiles with the lowest quartile for TBIS<45 and TANESTH, respectively. Notably, whether the 37% higher than expected incidence of malignant diagnoses found in this study was attributable to selection bias or to reasons of medical significance cannot be determined from our data.
The theory that tumor cells are recognized and destroyed by the immune system was launched a long time ago, and evolved into the concept of immunoediting.2,6 This theory includes the assumption that a population of tumor cells that is not completely destroyed by the immune system may remain in equilibrium for a variable, possibly lifelong period that precludes or delays progression to a clinical disease.
Preclinical data demonstrate that drugs used for general anesthesia may impair the immune response.5 Inhaled anesthetics attenuate the innate immunity, including natural killer cell toxicity and phagocytic cells as well as the acquired immunity mediated by lymphocytes.5 Furthermore, it has been suggested that the inhaled anesthetics, because of a more profound effect on natural killer cell cytotoxicity and lymphocyte function compared with propofol, have a greater potential for compromising the defense against tumor cell proliferation.4,5 Thus, we restricted our analysis to patients anesthetized with an inhaled drug, sevoflurane.
The addition of regional analgesia to a general anesthetic has been suggested to decrease the risk for recurrence of malignancy in 2 nonrandomized human studies, possibly by reducing the need for general anesthetics,10,11 whereas other studies reported equivocal findings,12,13 or failed to confirm an effect from regional anesthesia.14,15 The addition of nitrous oxide was found not to increase the incidence of colon cancer recurrence.16 In a recent nonrandomized study, intraoperative use of ketorolac was associated with a reduced recurrence of breast cancer (from 17% to 6%), possibly by reducing overexpression of cyclooxygenase-2 in tumor cells and, hence, avoiding increased levels of prostaglandin E2.17 However, this result was confounded by the fact that diclofenac was ineffective in offering similar protection.
Thus, previous human data are inconclusive and have mainly focused on attenuating recurrence of cancer with respect to different anesthetic regimens. In the present study, the focus was whether a specific anesthetic, sevoflurane, which from preclinical data may be expected to attenuate the immune response to surgery, would result in any difference in the risk of new malignant disease with regard to the duration and intensity of exposure. Because we primarily investigated the propensity of sevoflurane to promote progression from subclinical malignancy to a clinically identified disease in patients with no previously identified cancer, our results may not be valid in patients with previous malignancy or those undergoing cancer surgery, in whom the relationship between tumor burden and immunocompetence may be different. Another potential limitation of our study is the concept of confounding by indication, meaning that symptoms leading to surgery may mask symptoms from a simultaneous, not yet identified malignant disease that is detected later irrespective of perioperative events. An assessor not related to this investigation estimated this potential confounder and noted that, at most, 26 of the 136 new malignant diagnoses could have been classified in this category; furthermore, we did not identify any accumulation of new malignant diagnoses during the first part of the observational period (Kaplan-Meier plot) that would have been expected if this was a significant confounder in our cohort. In addition to anesthetics, morphine, which is frequently used in the perioperative period, may independently facilitate angiogenesis and promote cancer progression,1 whereas a corresponding effect from the synthetic opioids is less clear.2,4 All patients in our study were frequently given opioids intraoperatively and also postoperatively. The currently limited understanding of how different doses of different opioids given at various time points may affect tumor progression in humans precludes a meaningful assessment of this potential confounder in our study.
Blood transfusion interferes with the immune response,18 and it has been demonstrated in a rat model that transfused blood may promote tumor growth.19 We did not consider blood transfusion as a covariate because of the recognized difficulty in differentiating between adverse effects from extensive surgery itself from adverse effects of concomitant allogenic blood transfusion.
In summary, neither duration of anesthesia nor increased cumulative time with profound sevoflurane anesthesia was associated with an increased risk for new malignant disease within 5 years after surgery in previously cancer-free patients.
Name: Maj-Lis Lindholm, PhD.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Conflicts: Maj-Lis Lindholm reported no conflicts of interest.
Attestation: Maj-Lis Lindholm has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
Name: Fredrik Granath, PhD.
Contribution: This author helped analyze the data and write the manuscript.
Conflicts: Fredrik Granath reported no conflicts of interest.
Attestation: Fredrik Granath has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Lars I. Eriksson, MD, PhD.
Contribution: This author helped write the manuscript.
Conflicts: Lars I. Eriksson received honoraria from Abbott Scandinavia AB, consulted for Abbott Scandinavia AB, received research funding from Abbott Scandinavia AB, received honoraria from Schering-Plough, part of Merck, Inc., consulted for Schering-Plough, part of Merck, Inc., received research funding from Schering-Plough, part of Merck, Inc., and consulted for Alteco Medical AB.
Attestation: Lars I. Eriksson has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Rolf Sandin, MD, PhD.
Contribution: This author helped design the study, analyze the data, and write the manuscript.
Conflicts: Rolf Sandin received honoraria from Abbott Scandinavia AB, Stockholm, Sweden, and consulted for Abbott Scandinavia AB, Stockholm, Sweden. Rolf Sandin has given a 45-minute lecture about awareness at a 2-day postgraduate course in anesthesia sponsored by Abbott Scandinavia AB (the manufacturer of sevoflurane) and received a speaker's fee. Rolf Sandin has received economic compensation for critically evaluating a number of published scientific papers related to sevoflurane and considered to be of interest to the company. This consulting service, which has occurred approximately 5 times over the last 10 years, has ended.
Attestation: Rolf Sandin has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Professor Anders Ekbom, MD, PhD, is gratefully acknowledged for his expert advice regarding cancer epidemiology, and Peter Möller, MD, is gratefully acknowledged for assessing the cases with regard to possible “confounding by indication.”
1. Sessler DI. Long-term consequences of anesthetic management. Anesthesiology 2009;111:1–4
2. Gottschalk A, Sharma S, Ford J, Durieux ME, Tiouririne M. The role of the perioperative period in recurrence after cancer surgery. Anesth Analg 2010;110:1636–43
3. Snyder GL, Greenberg S. Effect of anaesthetic technique and other perioperative factors on cancer recurrence. Br J Anaesth 2010;105:106–15
4. Bovill JG. Surgery for cancer: does anesthesia matter? Anesth Analg 2010;110:1524–6
5. Kurosawa S, Kato M. Anesthetics, immune cells, and immune responses. J Anesth 2008;22:263–77
6. Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: from immunosurveillance to tumor escape. Nature Immunology 2002;3:991–8
7. Ekman A, Lindholm ML, Lennmarken C, Sandin R. Reduction in the incidence of awareness using BIS monitoring. Acta Anaesthesiol Scand 2004;48:20–6
8. Lindholm ML, Träff S, Granath F, Greenwald SD, Ekbom A, Lennmarken C, Sandin RH. Mortality within two years after surgery in relation to low intraoperative BIS values and pre-existing malignant and cardiovascular disease. Anesth Analg 2009;108:508–12
9. Monk TG, Saini V, Weldon BC, Sigl JC. Anesthetic management and one-year mortality after noncardiac surgery. Anesth Analg 2005;100:4–10
10. Exadaktylos AK, Buggy DJ, Moriarty DC, Mascha E, Sessler DI. Can anesthetic technique for primary breast cancer surgery affect recurrence or metastasis? Anesthesiology 2006;4:660–4
11. 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
12. Christopherson R, James KE, Tableman M, Marshall P, Johnson FE. Long-term survival after colon cancer surgery: a variation associated with choice of anesthesia. Anesth Analg 2008;107:325–32
13. Wuethrich PY, Hsu Schmitz SF, Kessler TM, Thalmann GN, Studer UE, Stueber F, Burkhard FC. Potential influence of the anesthetic technique used during open radical prostatectomy on prostate cancer-related outcome: a retrospective study. Anesthesiology 2010;113:570–6
14. Tsui BC, Rashiq S, Schopflocher D, Murtha A, Broemling S, Pillay J, Finucane BT. Epidural anesthesia and cancer recurrence rates after radical prostatectomy. Can J Anaesth 2010;57:107–12
15. Gottschalk A, Ford JG, Regelin CC, You J, Mascha EJ, Sessler DI, Durieux ME, Nemergut EC. Association between epidural analgesia and cancer recurrence after colorectal cancer surgery. Anesthesiology 2010;113:27–34
16. Fleischmann E, Marschalek C, Schlemitz K, Dalton JE, Gruenberger T, Herbst F, Kurz A, Sessler DI. Nitrous oxide may not increase the risk of cancer recurrence after colorectal surgery: a follow-up of a randomized controlled trial. BMC Anesthesiol 2009;9:1
17. Forget P, Vandenhende J, Berliere M, Machiels JP, 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
18. Spahn DR, Moch H, Hofmann A, Isbister JP. Patient blood management: the pragmatic solution for the problems with blood transfusions. Anesthesiology 2008;109:951–3
19. Gupta K, Kshirsagar S, Chang L, Schwartz R, Law PY, Yee D, Hebbel RP. Morphine stimulates angiogenesis by activating proangiogenic and survival-promoting signaling and promotes breast tumor growth. Cancer Res 2002;62:4491–8