High-grade glioma (HGG) is the most common primary malignant brain tumor, occurring with an incidence of 3 to 5 cases per 100,000 people.1,2 The prognosis remains poor with an overall survival (OS) ranging from 1 to 5 years.1 Surgery reduces tumor burden and intracranial pressure (ICP), but also involves risk for tumor spread and metastasis, which has been reported in colorectal cancer.3,4 Perioperative factors, including volatile anesthetic agents, also contribute to inhibition of host immunity and hence may impact prognosis.3,5 These factors warrant evaluation in HGG patients, particularly the roles of anesthetics which have been suggested in previous studies to impact on prognosis in patients with colorectal and prostate cancer.
Inhalational anesthetics have been reported to increase prostate and renal cancer cell proliferation and migration.6,7 However, the conclusions of in vitro studies across different cancer cell lines are inconsistent.8 A recent retrospective analysis of 378 patients demonstrated that, compared with isoflurane, desflurane was not associated with reduced progression-free or OS in patients with glioblastoma.9 However, anesthesia duration and extent of tumor resection may confound such observations. An analysis of 2838 patients with breast, colon, or rectal cancers found no differences in cumulative 1-year and 5-year survival rates in patients receiving sevoflurane or propofol, although observation time and intraoperative management were potential confounders in this study.10 An observational study of 7030 patients over a 3-year period after elective cancer surgery found that the hazard ratio (HR) for death was 1.46 (95% CI, 1.29-1.66) in patients who received inhalational compared with intravenous anesthesia.11 However, differences in baseline characteristics, cancer type, and maintenance with 2 different volatile anesthetics might have confounded the association. Neither of the latter two studies included patients with brain tumors, including HGG.
This retrospective observational study aimed to investigate the hypothesis that maintenance of anesthesia with sevoflurane worsens progression-free survival and OS in HGG patients undergoing tumor resection compared with propofol.
This study was a retrospective observational study performed at Beijing Tiantan Hospital, Capital Medical University. Following institutional review board approval (ChiECRCT-2016008) we reviewed consecutive patients who underwent elective resection of HGG between January 1, 2012 and April 30, 2016. All participants provided written informed consent.
All patients with a pathologic diagnosis of HGG, in terms of World Health Organization (WHO) pathologic classification III to IV, were recruited for eligibility. Exclusion criteria included: (1) age below 16 years; (2) requirement for emergency surgery for saving patients’ lives or neurological function; (3) infratentorial or intravertebral mass location; (4) presence of other malignant tumors; (5) administration of combined propofol and sevoflurane anesthesia; (6) recurrent tumor or repeat surgery; (7) biopsy procedure; and (8) reoperation for postoperative complications (ventricular-peritoneal shunt or ventriculostomy for hydrocephalus or decompression for hematoma).
Demographic data, including age, sex, body mass index (BMI), preoperative comorbidities, age-adjusted Charlson Comorbidity Index, American Society of Anesthesiologists physical status classification and Karnofsky performance status score were collected from medical records, except for age-adjusted Charlson Comorbidity Index which was calculated afterwards following retrieval of relevant data from the records.
Two groups were identified based on the agent used for maintenance of anesthesia during HGG resection: propofol anesthesia maintenance—defined as the use of propofol for the entire procedure (including induction), and sevoflurane maintenance—defined as sevoflurane administration from immediately after induction of anesthesia (with propofol) to the end of surgery. Neither nitrous oxide nor other volatile anesthetic agents were used in this patient population.
Intraoperative data, including total dose of sufentanil, infusion rate of remifentanil, intraoperative hypertension and hypotension requiring treatment, estimated total blood loss, transfusion of red blood cells or plasma, duration of surgery (from skin incision to closure), and duration of anesthesia (from induction to cessation of anesthetic administration), were recorded. WHO pathologic classification and functional status for tumor resectability were assessed.12,13 A dedicated neuroradiologist evaluated the extent of resection from magnetic resonance imaging at 72 hours postoperatively.13 For early postoperative outcome, the incidence of postoperative complications requiring medications or interventions was obtained from the medical records. Length of hospital stay after surgery was also recorded, and total cost of hospitalization calculated.
All data were obtained from contemporaneous hospital clinical and anesthetic electronic monitoring records. Outcome data after discharge was collected by trained researchers blinded to anesthesia type. All-cause 30-day mortality rate was also documented.
The primary outcomes included progression-free and OS. Progression-free survival was defined as the total period from the day of surgery to the day of first evidence of tumor progression or death. The neurosurgeons evaluated tumor progression using the 2 most recent magnetic resonance images and clinical factors according to the Rano criteria.14 OS was defined as the period from the day of surgery to the day of death or last follow-up, and assessed by telephone interview with patients or their relatives.
All data were analyzed using SPSS Statistics version 20.0 (SPSS, Chicago, IL) and R Studio (R Studio 1.0.153; Boston, MA). The Kolmogorov-Smirnov test was used to test data normality. Normally distributed continuous variables were described as means±SD and compared using independent t tests. Non-normally distributed variables were summarized as medians and interquartile range (IQR) and compared using Mann-Whitney U tests. Categorical variables were described as numbers (n) and percentage (%) and compared using χ2 or Fisher’s exact tests. The Kaplan-Meier method was used to describe the time-to-event data (progression-free survival and OS), and the log-rank test for comparisons. Univariate and multivariate Cox proportional hazard regressions were used for survival analysis. Together with anesthesia type, variables with P<0.1 in the univariate analysis were regarded as candidate variables for the multivariable model. The association between anesthesia maintenance and progression-free survival and OS in different subgroups were analyzed and classified by age-adjusted Charlson Comorbidity Index, Karnofsky performance status score, extent of resection, WHO grade, duration of anesthesia and chemotherapy. About 204 events (deaths) would be required to detect a HR of 1.46 with the power of 80% at a 2-sided level of 5%. A P-value <0.05 was considered statistically significant.
In total, 1408 patients with HGG were reviewed, and 1114 were excluded based on the predefined exclusion criteria. A total of 294 patients (154 and 140 in whom anesthesia was maintained with propofol and sevoflurane, respectively) were included in the final analysis (Fig. 1).
Baseline demographics and clinical characteristics did not differ between patients maintained with propofol and sevoflurane, except for BMI which was higher in the sevoflurane compared with propofol group (25 vs. 24 kg/cm2; P=0.004) (Table 1). The total intraoperative dose of sufentanil was lower (30 vs. 40 μg; P<0.001), whereas the infusion rate of remifentanil was higher (0.15 vs. 0.1 μg/kg/min; P<0.001) in patients maintained with propofol. The number of patients with intraoperative hypertension requiring intervention was higher in patients maintained with propofol (12 vs. 3; P=0.034). Durations of surgery(4.1 vs. 4.7 h; P<0.001) and anesthesia (5.0 vs. 5.5 h; P=0.002) were shorter in patients in whom anesthesia was maintained with propofol compared with sevoflurane (Table 1). Early postoperative complications and outcome were similar between groups (Table 1).
Median progression-free survival was 10 months (IQR, 6 to 18) versus 11 months (IQR, 6 to 20; P=0.674), and median OS was 18 months (IQR, 11 to 39) versus 18 months (IQR, 10 to 44; P=0.759) in patients maintained with propofol and sevoflurane, respectively (Table 1 and Fig. 2). The median follow-up time was similar between patients maintained with propofol and sevoflurane anesthesia (12 [IQR, 10 to 13] vs. 12 [IQR, 12 to 13] mo; P=0.363) (Table 1).
Univariate Cox proportional hazard analysis revealed that age, age-adjusted Charlson Comorbidity Index, duration of anesthesia, Karnofsky performance status score, gross total resection, radiotherapy/chemotherapy, and WHO classification grade were associated with tumor progression or death. However, sevoflurane or propofol maintenance anesthesia did not affect progression-free or OS. The HR for progression-free survival in these voflurane groups was 0.947 (95% CI, 0.735-1.220; P=0.674), and 1.044 (95% CI, 0.793-1.375; P=0.759) for OS. The multivariable Cox proportional hazard model demonstrated that Karnofsky performance status score (HR, 0.984; 95% CI, 0.971-0.998; P=0.025), gross total resection (HR, 0.724, 95% CI, 0.549-0.955; P=0.022), age-adjusted Charlson Comorbidity Index (HR, 1.108, 95% CI, 1.023-1.201; P=0.012), WHO grade (HR, 2.166, 95% CI, 1.137-4.127; P=0.019), duration of anesthesia (HR, 1.165, 95% CI, 1.054-1.228; P=0.003) and chemotherapy (HR, 0.604, 95% CI, 0.452-0.809; P<0.001) significantly affected progression-free survival, while Karnofsky performance status score (HR, 0.983, 95% CI, 0.969-0.997; P=0.019), age-adjusted Charlson Comorbidity Index (HR, 1.150, 95% CI, 1.054-1.253; P=0.002), duration of anesthesia (HR, 1.272, 95% CI, 1.146-1.413; P<0.001) and chemotherapy (HR, 0.581, 95% CI, 0.424-0.796; P=0.001) significantly affected OS (Table 2).
In addition, subgroup analysis was undertaken to assess the association between anesthesia and outcome according to age-adjusted Charlson Comorbidity Index, Karnofsky performance status score, extent of resection, WHO grade, duration of anesthesia and chemotherapy. Sevoflurane increased the HR to 1.661 (95% CI, 1.075-2.565; P=0.022) for death compared with propofol only in the subgroup of patients with a Karnofsky performance status score <80. The interaction effect between anesthesia maintenance and Karnofsky performance status score significantly influenced OS (P=0.035), but other subgroup factors did not significantly influence progression-free or OS (Supplementary Data 1, Supplemental Digital Content 1, http://links.lww.com/JNA/A112). In patients with a Karnofsky performance status score <80, OS was longer in patients with propofol compared with sevoflurane maintenance (15 vs. 11 mo; P=0.017), but there was no difference in progression-free survival. In patients with a Karnofsky performance status score ≥80, progression-free survival and OS were similar in patients maintained with propofol or sevoflurane (Table 3).
This retrospective study of 294 patients with supratentorial HGG undergoing elective craniotomy for tumor resection demonstrated that anesthesia maintenance with sevoflurane did not significantly worsen progression-free survival or OS compared with propofol. However, in patients with a Karnofsky performance status score <80, sevoflurane might decrease OS compared with propofol.
Median progression-free and OS has been reported as 5.5 and 5.6 years, respectively, in patients with WHO grade III tumors.15,16 Most WHO grade IV HGGs are glioblastomas, which have median progression-free survival and OS of 7 months and 12 to 15 months, respectively.17–19 The WHO grade IV class of HGGs accounted for 94% of the tumors in our study; median progression-free and OS were 10 and 18 months, respectively, and in line with those reported previously.
Preclinical studies suggest that inhalational anesthetics may promote tumor progression,20,21 but these effects are dependent on cancer type and concentration and duration of anesthesia exposure. In one study, isoflurane enhanced the invasion of glioblastoma stem cells and augmented vascular endothelial growth factor expression.20 In another, 6 hours of 2% sevoflurane exposure induced HIF upregulation in human glial stem cells.21 Sevoflurane has also been found to favorably suppress the growth and metastasis of lung cancer cells induced by hypoxic conditions of 1% oxygen, but this is incompatible with clinical practice.22 In our study, anesthesia was maintained with 2% sevoflurane and lasted an average duration of 330 minutes in 40% to 60% oxygen-supplemented ambient air. Propofol exhibits antitumor effects by various mechanisms. It promotes peripheral blood T-helper cell activation and differentiation,23 enhances natural killer cell activity in breast cancer patients,24 partially prevents isoflurane-induced malignant characteristics in prostate cancer cells,6 and kills glioblastoma and astrocytoma cells in preclinical studies.25,26 However, our retrospective study found no difference in progression-free survival between patients maintained with propofol and sevoflurane anesthesia.
OS is an important outcome for tumor patients. Laws et al27 demonstrated that age, Karnofsky performance status score, pathologic grade and extent of surgical resection are important risk factors for OS in HGG patients. Our study also found a significant reduction in OS in older patients with higher comorbidity scores (age-adjusted Charlson Comorbidity Index), and in those who did not receive chemotherapy. Moreover, we also confirmed that chemotherapy improved OS, which is consistent with recent report that OS increased from 9.9 to 13.9 months with postoperative chemotherapy28 and 12.1 to 14.6 months following combined radiotherapy and chemotherapy.29 Early chemotherapy is strongly recommended in patients with a satisfactory surgical recovery without neurological deficits, brain edema, infection or coma. Our study also suggests that longer duration of anesthesia is a risk factor for reduced progression-free and OS, a findings previously reported by Oh et al.30 Although we found lower total dose of sufentanil, higher infusion rate of remifentanil, and more hypertension requiring intervention in patients maintained with propofol, these did not affect the outcome.
The association between anesthesia and OS remain controversial. Enlund et al10 found no differences in 1-year or 5-year cumulative mortality rates between propofol and sevoflurane anesthesia in 2838 patients with breast, colon, and rectal cancers. In contrast, Wigmore et al11 found that 1-year mortality was decreased by 6.2% in 7030 cancer patients receiving intravenous anesthesia compared with inhalational anesthesia, but tumor types and pathologic grades were heterogeneous. However, Oh et al30 identified no benefit of propofol-based total intravenous anesthesia relative to inhalational agents for long-term oncologic outcome after 943 cases of non–small cell lung cancer surgery.
In a subgroup analysis of our data, patients with a Karnofsky performance status score <80 whose anesthesia was maintained with propofol seemed to survive longer than those who received sevoflurane anesthesia. Several reasons might account for these findings. Sevoflurane increases cerebral blood flow and ICP, which may threaten surgical exposure and postoperative neurofunction,31 whereas propofol is associated with improved ICP control and cerebral hemodynamics.32,33 Although there was no difference in the preoperative Karnofsky performance status scores between patients having different anesthesia in our study, propofol improved prognosis in those with a Karnofsky performance status score <80. These results support the recommended guidelines for the use of propofol for neurosurgical anesthesia in patients with increased ICP and poor intracerebral compliance.
This study has several limitations. First, because the data were collected retrospectively we were unable to report the impact of potential confounding factors, such as depth of anesthesia and local anesthetic infiltration or scalp block.34,35 Second, selection bias might exist. For example, those patients with higher BMI and expected longer anesthesia duration might tend to have received sevoflurane anesthesia. Third, although we enrolled HGG patients consecutively over >4 years, the sample size was still relatively small and this might account for the negative results. Moreover, in the power analysis we applied a HR from other kinds of solid cancer, which might have resulted in an underestimate of sample size. Finally, patients maintained with sevoflurane also received single bolus propofol for induction of anesthesia and how this might have affected our findings is unknown.
In summary, this observational study highlights the need for large randomized controlled trials to verify any causal relation between choice of general anesthesia maintenance and tumor progression and survival after HGG resection.
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