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.”
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© 2011 International Anesthesia Research Society
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