Abstract
Background/Aim: A recent preclinical study reported that renal cell carcinoma was more susceptible to sevoflurane-mediated metastatic potentiation, compared to non-small cell lung cancer, suggesting that the effect of anesthetic agents on the metastatic potential varies according to cancer type. Based on this report, we conducted a retrospective cohort study to compare recurrence-free survival after nephrectomy, between renal cell carcinoma patients receiving volatile anesthesia and those receiving intravenous anesthesia. Patients and Methods: We reviewed the electronic medical records of patients who underwent partial or radical nephrectomy for renal cell carcinoma at the Seoul National University Hospital. Patients were divided into two groups according to whether volatile or intravenous anesthesia was used for nephrectomy. A total of 651 patients (582 in the volatile and 69 in the intravenous group) were enrolled in the study. Recurrence-free survival after nephrectomy was compared using Cox proportional hazards regression analysis with inverse probability of treatment weighting. Results: Cox regression analysis with inverse probability of treatment weighting revealed that volatile anesthesia had no impact on recurrence-free survival [hazard ratio (HR)=0.45; 95% confidence interval (CI)=0.07-2.85; p=0.398] or overall survival (HR=1.41; 95% CI=0.31-6.44; p=0.661). Conclusion: We found no significant association between volatile anesthesia and poor outcomes after nephrectomy for renal cell carcinoma. Volatile anesthetic-promoted metastatic potentiation of renal cell carcinoma, shown in a preclinical study, does not seem to be translated in the clinical setting.
Cancer is the major leading cause of death worldwide (1). Although surgical excision is the definite treatment for solid tumors, patients may suffer from cancer recurrence even after surgery. However, the surgical procedure can paradoxically facilitate the metastatic process of cancer cells by activation of stress responses and suppression of immune responses (2).
The choice of anesthetic agents for cancer surgery has also been suggested to affect surgery-induced immune modulation. It has been proposed that there exists an association between anesthesia type and cancer outcomes and that anesthetic agents can affect cancer cell biology and host immunomodulation (3, 4). Recent meta-analyses reported that intravenous anesthesia has potential benefits over volatile anesthesia in long-term survival after cancer surgery (5, 6). However, results among individual studies investigating the effect of anesthetic techniques in various types of cancers, were inconsistent. Although intravenous anesthesia has been associated with better outcomes in patients with esophageal (7), gastric (8), and colon cancers (9), no significant association between anesthesia type and long-term survival has been found in patients with breast (10, 11), rectal (12), lung cancers (13), and urothelial carcinoma (14). This may suggest a differential effect of anesthetic agents on different cancer types.
A recent in vitro study reported that sevoflurane, the most popular volatile anesthetic, can potentiate metastasis of renal cell carcinoma through up-regulation of transforming growth factor-β (TGF-β) and osteopontin signaling, but not that of non-small cell lung cancer (15). Based on this preclinical finding, we conducted a retrospective cohort study to evaluate whether volatile anesthesia is associated with poor postoperative outcomes in patients with renal cell carcinoma compared to intravenous anesthesia in the clinical setting, since there exist limited clinical data on the association between anesthesia type and renal cancer surgery outcome. We hypothesized that patients who received volatile anesthesia would have poor outcomes after nephrectomy for renal cell carcinoma compared to those who received intravenous anesthesia.
Patients and Methods
This retrospective observational study was approved by the Institutional Review Board of the Seoul National University Hospital (No. C-1902-141-1016). Written informed consent was waived by the Institutional Review Board of the Seoul National University Hospital owing to the retrospective design of this study using an electronic database. All methods were carried out in accordance with the Strengthening the reporting of observational studies in epidemiology (STROBE) statement.
Study population. All patients who underwent partial or radical nephrectomy for renal cell carcinoma at the Seoul National University Hospital between January 2010 and December 2012 were included. The exclusion criteria were as follows: 1) patients receiving both volatile and intravenous anesthesia during the study period, 2) those who had been diagnosed with metastatic renal cell carcinoma, 3) those who had been diagnosed with a malignancy other than renal cell carcinoma in pathologic examination, and 4) those who had bilateral nephrectomy.
Patients were divided into two groups according to whether they received volatile or intravenous anesthesia for maintenance during general anesthesia for nephrectomy. The choice of maintenance anesthetic agents was made at the discretion of the attending anesthesiologists. Volatile anesthesia was maintained using sevoflurane or desflurane after induction by a bolus infusion of propofol or thiopental, whereas intravenous anesthesia was induced and maintained with a target-controlled infusion of propofol using a syringe pump (Orchestra® Module DPS, Fresenius Kabi AG, Bad Homburg, Germany). Patients in both groups received a target-controlled infusion of remifentanil for intraoperative analgesia. No patients received regional anesthetic techniques during the perioperative period.
Variables and outcome measurements. The following data were extracted from the electronic medical records: age, sex, height, weight, body mass index, smoking history, American Society of Anesthesiologists (ASA) physical status, operation type (partial or radical nephrectomy; open nephrectomy or laparoscopic surgery), operation time, perioperative red blood cell transfusion, T stage and N stage of tumor-node-metastasis (TNM) staging system, histology of renal cell carcinoma, and Fuhrman Nuclear grade. Comorbidities, including myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular disease, dementia, chronic pulmonary disease, connective tissue disease, peptic ulcer disease, liver disease, diabetes, hemiplegia, chronic kidney disease, solid tumor, leukemia, lymphoma, and acquired immune-deficiency syndrome, were also recorded to calculate the Charlson Comorbidity Index score (16).
The primary endpoint was recurrence-free survival, defined as the time interval between the date of surgery and the date of recurrence of renal cell carcinoma. The recurrence of renal cell carcinoma included local and systemic recurrences confirmed by radiological or histological examination. The secondary endpoint was overall survival, defined as the time interval from the date of surgery to the date of death from any cause. The date of death was obtained from the Statistics Korea on December 31, 2016. Survival was censored at the date of the last follow-up for patients who were lost to follow-up.
Statistical analyses. The sample size was based on available data from all patients who underwent partial or radical nephrectomy for renal cell carcinoma at our Institution during the study period. Continuous variables are presented as mean±standard deviation or median (interquartile range), as appropriate, and categorical variables are presented as number (percentage). Independent sample t-test or Mann-Whitney U-test and Pearson’s Chi-squared test were used to compare continuous and categorical variables, respectively. Body mass index was categorized according to the World Health Organization classification (17).
The primary endpoint was compared using Cox proportional hazards regression analysis with inverse probability of treatment weighting to account for differences in baseline characteristics (18). The propensity score was calculated using logistic regression to the probability of receiving intravenous anesthesia, with covariates, including age, sex, body mass index, smoking history, ASA physical status, Charlson Comorbidity Index score, operation type (partial or radical nephrectomy; open nephrectomy or laparoscopic surgery), operation time, perioperative transfusion, T stage and N stage of TNM staging system, histology of renal cell carcinoma, and Fuhrman Nuclear grade.
To identify potential risk factors for cancer recurrence or all-cause mortality, an additional multivariable Cox regression analysis was performed using the same covariates. The proportional hazard assumption was evaluated using the log–minus–log survival plots. We also constructed the Kaplan-Meier survival curves to estimate recurrence-free survival and overall survival, and the log-rank test was used to compare the two groups.
All analyses were performed using R software version 4.0.2 (R Foundation for Statistical Computing, Vienna, Austria). The function “coxph” in the package “survival” was used for the Cox proportional hazard regression analysis and the argument “weights” for the inverse probability of treatment weighting. We also used the function “ggsurvplot” in the package “ggplot2” to construct the Kaplan-Meier survival curves. A p<0.05 was considered statistically significant.
Results
Of the 825 patients who underwent partial or radical nephrectomy between January 2010 and December 2012 at the Seoul National University Hospital, 174 were excluded due to receiving both types of anesthetics during the study period (n=62), benign disease (n=54), metastatic cancer (n=33), bilateral nephrectomy (n=24), and previous history of nephrectomy (n=1). The remaining 651 patients (582 receiving volatile and 69 receiving intravenous anesthesia) were included in the final analysis.
Patient characteristics are presented in Table I. The median follow-up duration was 72 (59-85) months for all patients, 72 (59-85) months for patients receiving volatile anesthesia and 78 (62-89) months for those receiving intravenous anesthesia.
Patient characteristics for patients included in the study.
Cox proportional hazards regression analysis with inverse probability of treatment weighting revealed that volatile anesthesia was not significantly associated with poor recurrence-free survival [hazard ratio (HR)=0.45; 95% confidence interval (CI)=0.07-2.85; p=0.398] or overall survival (HR=1.41; 95% CI=0.31-6.44; p=0.661).
The results from multivariable Cox regression analyses for recurrence-free survival and overall survival are shown in Table II and Table III, respectively. The multivariable Cox proportional hazards regression analyses also demonstrated that volatile anesthesia was not associated with cancer recurrence (HR=0.84; 95% CI=0.16-4.54; p=0.843) or all-cause mortality (HR=3.58; 95% CI=0.85-15.14; p=0.083).
Multivariable Cox proportional hazard regression analysis for recurrence-free survival.
Multivariable Cox proportional hazard regression analysis for overall survival.
The Kaplan-Meier survival curves after nephrectomy are presented in Figure 1, demonstrating a 5-year recurrence-free survival rate of 94.1% (95% CI=92.1-96.1) in the volatile group and 98.3% (95% CI=95.0-100) in the intravenous group and respective 5-year overall survival rate of 90.4% (95% CI=87.9-92.9) and 95.0% (95% CI=89.7-100). There was no significant difference in recurrence-free survival (p=0.246) or overall survival (p=0.108) between patients receiving volatile anesthesia and those receiving intravenous anesthesia.
Kaplan-Meier survival curves for recurrence-free survival (A) and overall survival (B) after nephrectomy in patients receiving volatile or intravenous anesthesia.
Discussion
In this retrospective cohort study, we found no significant association between the type of anesthetic agent during nephrectomy for renal cell carcinoma and postoperative outcomes. Neither recurrence-free survival nor overall survival was affected by volatile anesthesia in the clinical setting, contrary to a preclinical finding that volatile anesthetic agents can potentiate metastasis of renal cell carcinoma (15). Without an investigation of biological factors, such as TGF-β, which is known to be associated with tumor growth and metastasis, we are not able to propose any mechanism responsible for the discrepancy between our study and the in vitro study (15). Given that there were no significant differences in serum concentrations of cytokines among patients receiving volatile and intravenous anesthesia in recent randomized studies (11, 19), several conditions that did not exist in laboratory studies, such as the use of opioids, may have induced that inconsistency. Opioids have been also suggested to promote growth and migration of cancer cells by inhibiting cell-mediated immunity (20, 21), and it is possible that the use of remifentanil in all patients included in our study may have induced insignificant results.
The association between anesthesia type and postoperative outcomes has been widely investigated in recent years. Many studies tested the hypothesis that volatile anesthesia for cancer surgery may have a deleterious effect on cancer survival in various types of cancers, including breast, gastroesophageal, colorectal, hepatobiliary, and lung cancers (5, 6). However, the negative effect of volatile anesthesia on cancer survival was only observed in patients with esophageal (7), gastric (8), or colon cancers (9), but not in those with other cancer types. This discrepancy may be explained by the differential extent of surgery among each cancer type. Surgery-induced immunosuppression and immunomodulation by volatile anesthetic seem to share common mechanisms, including up-regulation of vascular endothelial growth factor, matrix metalloproteinases, hypoxia-induced factors, and suppression of natural killer cell and T-cell activities (22, 23). Considering that a larger degree of surgical insult promotes cancer metastases via similar mechanisms (24), the effect of different anesthesia types on cancer prognosis may be related to the extent of surgery.
Another possible explanation for the inconsistent results is the differential effects of anesthetic agents on different cancer types. A recent preclinical study addressed this issue, reporting that sevoflurane potentiates metastasis of renal cell carcinoma, but not of non-small cell lung cancer (15). Exposure to sevoflurane up-regulates TGF-β and osteopontin signaling pathway (15), known to be associated with tumorigenesis of renal cell carcinoma (25). In contrast, sevoflurane treatment had little effect on TGF-β signaling in lung adenocarcinoma (15). Since the effect of volatile anesthetics on cellular signaling differs based on cancer cell type, clinical studies comparing prognosis between volatile and intravenous anesthesia after cancer surgery, may also have shown conflicting results related to different cancer types.
Unfortunately, there are few prospective studies on the effect of volatile and intravenous anesthesia on postoperative outcomes in cancer patients. The effect of regional anesthetic techniques on cancer prognosis has been evaluated in several interventional studies, which demonstrated no significant difference in cancer recurrence or survival (26-29). However, only a few randomized studies have investigated the effect of volatile and intravenous anesthesia on immune responses after cancer surgery (11, 19), showing no significant impact on postoperative outcomes. Therefore, we could conclude on the effects of different types of anesthetics on cancer prognosis after the results of ongoing large-scale prospective studies (NCT03034096, NCT04316013, NCT04513808) become available.
Although we conducted Cox regression analyses for cancer recurrence and all-cause mortality, the results of those analyses should be interpreted as an exploratory investigation due to the small number of events. The statistical insignificance in the association between volatile anesthesia and cancer prognosis found in our study also needs to be evaluated in further studies with a larger sample size.
Some limitations should be considered when interpreting our results. First, due to the retrospective observational nature of this study, we could not evaluate any possible mechanisms at the molecular level that were proposed in the previous preclinical study. Second, the sample size was not determined by a prior power analysis in this study, the results are hard to generalize and should be interpreted as preliminarily. Moreover, we were able to recruit only a small number of patients receiving intravenous anesthesia because the use of volatile anesthetic was the main strategy for maintenance at our Institution. Third, other potential risk factors of cancer recurrence, including adherence to standard cancer therapy, such as adjuvant chemotherapy and radiation therapy, were not considered due to the lack of data. Fourth, since the severity of renal cell carcinoma was relatively low in the study population, the small number of events may have impeded the detection of the difference between volatile and intravenous anesthesia. Lastly, since the study period was a decade ago due to the availability of data, advances in surgical techniques, as well as medical treatments, may produce different results from those of our study.
Despite these limitations, our study has a clinically important implication; this is the first clinical study investigating the potential pro-tumorigenic effect of volatile anesthetics on renal cell carcinoma that was revealed in a previous preclinical study. Since the effect of anesthesia types on cancer prognosis is still largely unknown, this topic warrants further laboratory and larger clinical studies.
In this retrospective observational study, volatile anesthesia did not increase the risk of cancer recurrence or death in patients with renal cell carcinoma. However, given the absence of power analysis and the relatively small number of patients receiving intravenous anesthesia compared to those receiving volatile anesthetics, we cannot draw any valid clinical conclusion based on our results. Large-scale prospective randomized studies in progress will be able to better answer the question on the effect of anesthesia type and cancer prognosis.
Acknowledgements
We would like to thank Editage (www.editage.co.kr) for English language editing. This study was supported by Seoul National University (800-20210498).
Footnotes
Authors’ Contributions
SY helped design the study, interpret the data, and draft the manuscript. CWJ helped collect, analyze, and interpret the data and revise the manuscript. HK helped collect and analyze the data and revise the manuscript. YK helped collect and analyze the data and draft the manuscript. MH helped collect and analyze the data and revise the manuscript. YJL helped conceptualize and design the study and revise the manuscript. JTK helped conceptualize and design the study, interpret the data, and revise the manuscript. All Authors read and approved the final version of the manuscript.
Conflicts of Interest
The Authors have no conflicts of interest to declare.
- Received September 13, 2022.
- Revision received October 17, 2022.
- Accepted October 19, 2022.
- Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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