General anesthesia, surgery, and related events depress immunocompetent cells and signaling cascades in the perioperative period. These events may affect the risk of recurrence of malignant disease after surgery.1–5 Depression of immunocompetent cells by anesthesia and surgery may be of importance for the ability to prevent subclincal malignancy from proliferation and increasing the risk of recurrent disease after cancer surgery.1–5
We previously found that 4.3% of cancer-free surgical patients developed a malignant disease within 5 years after surgery under sevoflurane anesthesia.6 There was neither an impact of total time with profound sevoflurane anesthesia nor the total duration of anesthesia on the development of malignancy. However, the relationship between tumor burden and immunocompetence may be different in patients with previous malignant disease or in those undergoing cancer surgery. Here we analyze the impact of duration of sevoflurane anesthesia (TANESTH) and also the cumulative time with BIS (Bispectral Index) value under 45 (TBIS <45), a surrogate measure of more intense anesthesia exposure, on identification of malignant disease within 5 years of surgery in patients with previous or prevailing cancer. Patients with persisting malignant disease after surgery may not be assigned any new diagnosis despite tumor progress. Therefore, we also investigated the relation between 5-year survival and TANESTH or TBIS <45. Our primary hypothesis was that there is a significant positive relationship between TBIS <45 and the risk of a new malignant diagnosis within 5 years after surgery or all-cause death. Secondary outcome measures included corresponding relations to TANESTH and correlations by using other thresholds for BIS.
After receiving IRB and The Swedish National Cancer Registry approval, a prospective cohort of 766 surgical patients with previous or prevailing malignant disease at the time of surgery was studied. The patients consented orally to the initial study7 at the time of the first postoperative interview. 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 was done without reference to patient identity that was strictly adhered to. This cohort, collected between January 2001 and May 2002, consisted of patients anesthetized with sevoflurane and was derived from a population with mixed types of anesthesia in which we previously reported the effects of BIS monitoring on the incidence of awareness, postoperative mortality, and risk of new cancer within 5 years in previously cancer-free patients.6–8 The inclusion criteria were age >16 years, exposure to sevoflurane anesthesia including muscle relaxation and/or endotracheal intubation, and previous or prevailing malignant disease. Anesthetic induction was either with propofol or thiopental. General anesthesia was maintained with sevoflurane supplemented with opioids in all patients. Nitrous oxide and a concomitant epidural block were allowed according to institutional clinical guidelines. BIS monitoring (BIS A-2000, BIS index version 3.4; Coviden, Boulder, CO) was recorded in all cases, and 1-minute average values were downloaded by using monitor settings as previously described.7 All other data were manually retrieved from the anesthetic records.
The National Cancer Registry of Sweden was searched for malignant histopathological diagnoses as registered before the index operation, at the index operation, and within the first 5 years after index surgery. All cancer data were manually checked for accuracy by comparison with surgical records.
The risk of contracting a diagnosis of malignant disease within 5 years after surgery was analyzed by using Cox proportional hazard models. The model included age, sex, TBIS <45, ASA physical status, body mass index, and tobacco smoking (defined as daily smoking). Multivariate analyses were made by backward deletion (P > 0.05). Corresponding analyses were also made for overall mortality. The primary exposure variable was cumulated time with BIS below 45, which served as a proxy for profound anesthesia exposure. The 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 by using duration of anesthesia (TANESTH) defined as the time from induction to removal of the endotracheal tube. The continuous variables TBIS <45 and TANESTH were categorized into quartiles (Table 1). Analyses were also repeated by using thresholds for BIS of 30 (categorized into 0, 0.01–0.13, ≥ 0.l3 hours), 40 (≤0.27, 0.28–0.81, 0.82–1.60, ≥1.60 hours), and 50 (≤1.12, 1.13–1.77, 1.78–2.55, ≥2.55 hours). Analyses were performed by using Statistica version 10 (Statistica; StatSoft®, Tulsa, OK).
Demographic data for 766 included patients are shown in Table 1. A concomitant epidural anesthetic was used in 273 (35.6%) patients. The types of preoperative malignancy diagnoses are given in Table 2. Cancer surgery comprised 387 (51%) of the index operations. Two hundred ninety-three (38%) patients died during the 5-year follow-up. The procedure code “explorative laparotomy” alone or combined with the code “biopsy,” possibly indicating uncompleted intended surgery, was assigned to 10 patients who did not survive the study period, and their median duration of anesthesia was 115 minutes.
In the cohort of 766 patients, there were 51 (6.7%) individuals from whom we identified 54 new malignant diagnoses within 5 years after the index operation. Twenty-one (41%) of the 51 patients with a new malignant diagnosis died within the study period.
There was no association between TANESTH or TBIS <45 and the risk of new malignancy during follow-up (hazard ratio [HR] 0.64–1.11 and 0.76–1.30, respectively; Table 3). Two hundred twenty-four of the patients (76 %) who died during follow-up were considered to have died from ongoing malignant disease. Cox regression did not reveal a relation between 5-year survival and TANESTH or TBIS <45 in the entire cohort (HR 0.85–1.05 and 0.94–1.16, respectively; Table 4). Considering the various pharmacodynamic intensities of sevoflurane exposure, no significant correlations were found when we repeated the analyses with thresholds for BIS of <30, <40, and <50 (Tables 3, 34).
Factorial analysis was used to investigate pairwise interactions among all variables in Table 1, and mortality and new cancer, respectively. Separate analyses for all 4 different thresholds for time with BIS (<30, <40, <45 and <50) and duration of anesthesia were done. The only detected significant interaction was between gender and mortality for time with BIS under 30 (TBIS <30) (P < 0.027). All other P were >0.09 (Tables 3 and 4). The significant pairwise interaction between gender and mortality for TBIS <30 was further explored by Kaplan-Meier plots (Appendix 1). Within each of the gender groups, no significant interactions were detected between survival and TBIS <30 (P < 0.21 for women, and < 0.06 for men, respectively). For women, the patients with no TBIS <30 had numerically (albeit not significantly) higher mortality compared with those having longer TBIS <30, whereas for men patients with no TBIS <30 and those with the longest times had numerically (albeit not significantly) lower mortality compared with those with intermediate TBIS <30. Thus, no indication of a gender-dependent relation between intensity of anesthetic exposure and mortality, explaining the significant pairwise relation between gender and mortality for TBIS <30 was found.
Inhaled anesthetic drugs depress natural killer cell cytotoxicity and lymphocyte function and theoretically attenuate the defense against tumor cell proliferation.4,5 Preclinical data have shown that drugs used for general anesthesia may alter the immune response.5 Here, we investigated whether patients with previous or prevailing malignant disease undergoing new surgery are at increased risk for worse outcome regarding prolonged or more intense sevoflurane anesthesia. In this study, there was no impact of cumulated time with profound sevoflurane anesthesia or total duration of anesthesia on the risk for contracting a new malignant diagnosis, nor did we find any impact on the risk of death during a 5-year follow-up period. The absence of any significant relationship agrees with our previous corresponding study in patients without any diagnosis or history of cancer at the time of the index surgery.6 The reason for doing this investigation was that the relationship between tumor burden and immunocompetence may be different in patients with previous malignant disease or in those undergoing cancer surgery compared with cancer-free patients.
We used BIS as a pharmacodynamic measure to mirror the intensity of anesthetic exposure in relation to individual need. A BIS value of 45 was chosen as the threshold in the primary analysis since it has been used in earlier work on adverse effects from anesthesia.9 It should be noted that we confirmed our finding by repeating our analyses for various surrogate depths of anesthesia, that is, thresholds for BIS of <30, <40, and <50. A pairwise interaction between gender and mortality for TBIS <30 was detected, but further exploration revealed no indication of a gender-dependent relation between intensity of anesthetic exposure and mortality, explaining this finding. No other pairwise interactions between investigated variables were found.
Thirty-eight percent of the patients died during follow-up, and in 77% of these cases, malignancy was considered to have contributed to or caused death. While tumor progress cannot be assessed with accuracy in a cohort with mixed malignant diseases, we used its most dire and important consequence, death, in addition to new malignant diagnoses to mirror the potential impact from sevoflurane anesthesia. The reason for a dual end point in this study is that patients with malignant disease before index surgery may not be assigned a new diagnosis despite tumor progress.
It is important to include correct covariates to demonstrate or refute the existence of meaningful relationships. In this clinical study, there are a number of covariates that could be of importance to the risk of new or recurrent malignant disease. Our hypothesis, that TBIS <45 or TANESTH would significantly augment the risk of death or new malignant disease, was rejected. If this negative finding were erroneously due to omission of a truly significant covariate, this covariate must affect BIS and mortality or the risk of new malignant diagnoses in the same direction, that is, an increase in BIS is accompanied by increased mortality and/or new malignancy or vice versa. Apart from anesthetic action, BIS may be affected in a number of situations, but none of those is known to alter the risk of mortality or new malignancy and BIS in the same direction.10 Therefore, we regard it unlikely that the absence of a relationship between TBIS <45 and mortality or new malignant disease is due to improper selection of covariates.
Even if an increasing TANESTH, due to more careful surgical performance, in some cases may lead to improved outcome, there is no general relationship between surgical skillfulness and duration of surgery. A short TANESTH, however, may be due to an unexpectedly advanced disease discovered at surgery precluding the intended procedure and thus being related to increased mortality. This situation is mainly identified by the procedure code “explorative laparotomy.” Because this procedure was assigned, only 10 patients who did not survive the study period and their median duration of anesthesia was 115 minutes; this situation cannot have distorted our result.
Taken together, even if we cannot exclude the possibility, we believe that the likelihood of improper selection of covariates has significantly affected our negative finding regarding TBIS <45, and TANESTH is very low. Albeit not known to affect BIS in a way that could explain our result, there are a number of covariates, possibly related to poor outcome that we for methodological reasons have not assessed.
Morphine, which is frequently used in the perioperative period, may have independently facilitated angiogenesis and promoted cancer progression in preclinical models, while a corresponding effect from the synthetic opioids used intraoperatively is less clear.2,4 Opiates may reduce BIS directly to a minor extent and more importantly by attenuating afferent nervous signaling during surgery.11 All patients in our study were given opioids intraoperatively and frequently 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 a potential promalignant opioid effect in our study.
Blood transfusions are not uncommon during and after surgery and have been associated with various negative effects including increased mortality. Blood transfusion has been known to interfere with the immune response,12 and it has been demonstrated in a rat model that transfused blood may promote tumor growth.13 We abstained from entering blood transfusion as a covariate due to the recognized difficulty to differentiate between adverse effects from extensive surgery and from concomitant allogenic blood transfusion.
Ionizing radiation and chemotherapy may affect tumor progression. We have not retrieved any data on exposure to ionizing radiation or previous or ongoing chemotherapy because we are not aware of any information concerning how to categorize and quantify (cumulated dose, repeated doses, time span, targeted organs, etc.) the information of contribution to the studied outcome measures.
Nonsteroid antiinflammatory drugs, that is, ketorolac but not diclofenac, have been shown to affect breast cancer recurrence.14 Again, there is no current understanding of how different nonsteroid anti-inflammatory drugs given at various time points in the perioperative period, and 5-year follow-up should be categorized as a meaningful covariate.
Thus, a number of potentially important covariates that could be of importance to explain poor outcome have not been included in our calculations due to lack of understanding of how to categorize the information. However, according to our hypothesis, we specifically investigated whether TBIS <45 or TANESTH would significantly augment the risk of death or new malignant disease, not other possible promoting factors. Our hypothesis was rejected, which we consider an important result. If it had been demonstrated that the duration or intensity of anesthetic delivery was coupled to worse outcome in terms of tumor proliferation, this would have called for strategies to minimize anesthetic exposure, albeit with some remaining uncertainty due to possible omission of important promalignant covariates. As an indication of sensitivity, it should be noted that patient age and tobacco smoking, 2 previously identified promalignant covariates, were significantly related to new malignancy in our study.
Considering the results from the present and our previous study,6 we have not found any evidence that the intensity of exposure to sevoflurane anesthesia is related to the risk of cancer proliferation irrespective of cancer status at the time of surgery. Thus, monitoring depth of anesthesia is not expected to alter the risk of cancer proliferation after surgery.
Even if our study does not support a general relation between risk for new or aggravated malignant disease and intensity of exposure to sevoflurane, we cannot definitely exclude an effect in subsets of patients.
In summary, neither duration of anesthesia nor increased cumulative time with profound sevoflurane anesthesia was associated with an increased risk for new malignant disease or death within 5 years after surgery in patients with earlier or existing malignant disease at the time of surgery. Monitoring depth of anesthesia is not expected to alter the risk of cancer proliferation after surgery.
Name: Maj-Lis Lindholm, PhD.
Contribution: This author helped design and conduct the study, analyze the data, and write the manuscript.
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.
Conflicts of Interest: The author has no conflicts of interest to declare.
Name: Lars Brudin, MD, PhD.
Contribution: This author helped design the study, analyze the data, and write the manuscript.
Attestation: Lars Brudin has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Conflicts of Interest: The author has no conflicts of interest to declare.
Name: Rolf H. Sandin, MD, PhD.
Contribution: This author helped design the study, analyze the data, and write the manuscript.
Attestation: Rolf Sandin has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Conflicts of Interest: 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 speakers’ 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 that has occurred approximately 5 times over the last 10 years has ended.
This manuscript was handled by: Sorin J. Brull, MD, FCARCSI (Hon).