Study design
This is a single-center, randomized-controlled, and paralleled-group trial being conducted at Beijing Tiantan Hospital, Capital Medical University(Figure 1.). The study was approved by the Ethics Review Committee of China Registered Clinical Trials on March 30, 2020 (number: ChiECRCT-20200049) and updated at www.clinicaltrials.gov on April 1, 2020 (number: NCT02756312). The schedule of enrollment and assessment is shown in the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) (see Figure 2). Written inform consent will be obtained from the legal representatives. Additional consent will be provided for collection and use of participant data and biological specimens in ancillary studies.
Study population
Participants
Patients undergoing selective tumor resection under general anesthesia will be recruited consecutively from neurosurgical wards in Beijing Tiantan Hospital, Capital Medical University from Sept 2020 to December 2023.
Inclusion criteria includes age more than 18 and less than 80 years old, preoperative KPS less than 80, and diagnosis of supratentorial high-grade glioma by preoperative magnetic radiology imaging (MRI). The patients or their relatives agree to provide for collection and use of participant data and biological specimens and sign written informed consent.
Exclusion criteria includes history of other operations after diagnosis of HGG, patients with recurrence and metastasis of gliomas or with malignant tumors of other organs, emergency surgery, ASA physical status of V or higher, pregnant or breastfeeding women, allergic to study drugs, patients who need electrophysiological monitoring during operation, or patients receiving reoperation with different anesthesia methods will be removed. The patients will be withdrawn from the study when postoperative pathological results excluded high-grade glioma.
Randomization and blinding
Block randomization will be conducted via a computer- generated codes by an independent research assistant who will pack the allocation sequence with identical opaque envelopes and distribute to the researcher according to the randomization. Patients will be randomly assigned to the two groups at a 1:1 ratio. The attending anesthesiologists will perform anesthesia and record intraoperative information. Trained follow-up personnel will not participate in the clinical anesthesia and postoperative management, or know the records of other researchers. The researcher assistant, patients and outcome assessors will be blinded to the allocation until the completion of the study analysis unless specific circumstances, such as the occurrence of a serious adverse event (SAE).
Intervention
The enrolled patients will be randomly assigned to the intravenous group or the inhalation group. Propofol will be used for anesthesia maintenance with the initial dose of 5-7mg/kg/h in intravenous group. Sevoflurane will be used for anesthesia maintenance with the initial concentration of 2-3% in inhalation group. During anesthesia, the same depth of anesthesia will be maintained by adjusting the dosage of propofol or sevoflurane, keeping bispectral index (BIS) range between 40 and 60. Inhalation of sevoflurane, or infusion of propofol and remifentanil will be discontinued at the end of surgery. The adherence of intervention will be guaranteed by the common and routine method of anesthesia maintenance administered in the trial.
Concomitant treatment
Routine monitoring will include electrocardiograph, noninvasive blood pressure, pulse oxygen saturation, body temperature and BIS. The BIS electrodes will be placed on the contralateral side to the tumor. Core temperature will be monitored continuously by an esophageal probe. Peripheral venous access will be established before anesthesia induction. Continuous arterial pressure, urine output and end-tidal carbon dioxide partial pressure (PetCO2), minimal alveolar concentration (MAC) of inhalation agent will be monitored after anesthesia induction. All patients will be premedicated with midazolam (0.05 mg/kg) intravenously 5 minutes before anesthesia induction. Anesthesia will be induced with propofol (1-3 mg/kg), sufentanil (0.3 to 0.4 μg/kg), and rocuronium (0.6 mg/kg) or cisatracurium (0.2 mg/kg). After endotracheal intubation, mechanical ventilation will be performed, with a tidal volume 6-8 ml/kg, a respiratory rate of 12-15/min, a 50-70% fraction of inspired oxygen in the air and fresh gas at a flow rate of 1-2 L/min to maintain the PetCO2 between 35 and 40 mmHg.
Before skin incision, 0.1-0.2 μg/kg of sufentanil will be given once, and the dosage of remifentanil and sufentanil will be adjusted according to the signs of blood pressure and heart rate. Local anesthetics infiltration in the scalp will be performed at the time of incision. Muscle relaxants can be added intermittently. Crystal or colloid fluid, the urine volume and blood loss will be monitored. Blood transfusion practice guidelines will be resort to once considering blood transfusion[29]. If necessary, vasoactive drugs can be used perioperatively. Single dose of sufentanil 1 μg/kg, tramadol 100mg and ondersetron 8mg will be given to the patients as dura closure. The patients will be extubated after full recovery from anesthesia and transferred to the post-anesthesia care unit (PACU). The patient-controlled intravenous analgesia will be connected to the patients with sufentanil 100 μg and ondansetron 16 mg in 100 ml 0.9% sodium chloride solution, with background dose 2 ml/h. After pressing the pump button to reduce pain, one single 0.5 ml (0.5 μg) will be infused with 15 minutes locking time.
Outcomes
The primary outcome is OS (by months) within 18 months postoperatively. OS is the duration from the day of surgery to the date of death or last follow-up. The assessment of outcomes will be performed by trained research assessors who are blinded to the group allocation. Researchers assess the OS through telephone interview patients or their relatives every 3 months postoperatively.
Secondary outcomes include:
- PFS is the duration from the surgery day to the day of first evidence of progression or death within postoperative-18 month. PFS will be evaluated by using the latest-two MRI tests and clinical evidence according to the RANO (response assessment in neuro-oncology) criteria (Supplementary Table 1). [30]
- Pain: numerical rating scale (NRS) of pain intensity and sleep quality on postoperative 1 to 3 days will be evaluated. Pain intensity score in NRS is 0 to 10, 0 representing no pain and 10 representing worst pain imaginable. Sleep quality with the NRS (0 = worst sleep, 10 = best sleep) will be used to evaluate the sleep quality at 8 to 10 a.m. every day postoperatively before discharge and every 3 months after discharge.
- Encephaloedema volume will be calculated from MRI assessed by radiologist at 3 to 7 day postoperatively.
- Adverse events or complications will be recorded, including congestive heart failure, arrhythmia, myocardial ischemia or infarction, pulmonary edema, pulmonary embolism, respiratory failure, stroke, encephaloedema, hydrocephalus, pneumocranium, intracranial hematomas or infection, epilepsy, gastrointestinal hemorrhage, liver and kidney dysfunction, etc. (Supplementary Table 2, 3)
- The length and cost effectiveness of hospital stay will be calculated and analyzed.
- Blood sample will be collected before anesthesia, at the end of surgery and 1 to 3 days after the resection.
Data collection and management
After obtaining informed consent, an independent research assistant will initiate baseline information collection one day before surgery. All personal information will be kept strictly confidential for research purposes only. Basic demographic information, including gender, age, vital signs, body mass index, past medical history, family history, smoking and drinking history, allergy history, operation history or anesthesia history, medication history, age-adjusted Charlson comorbidity index, ASA classification, KPS, Glasgow coma scale (GCS) will be collected. Functional classification of tumor (indicating the resectability of tumor) will be evaluated according to the results of preoperative MRI (Supplementary Table 4.) [31,32].
Intraoperative viable include vital sign parameters during anesthesia, total dose or infusion rate of anesthetic agents or other drugs during operation, such as inotropic or vasoactive drugs, estimated blood loss, urine volume, the type and dose of fluid and blood transfusion, duration of surgery and anesthesia. The usage of analgesia pump (dosage, number of compressions and effective compressions) will be recorded.
Postoperative medication will be recorded including sedative, analgesia, glucocorticoids, mannitol and fluid infusion on 1 to 3 day postoperatively. The extent of resection (EOR) will be evaluated by a professional neuro-radiologist according to the results of MRI within 72 hours postoperatively (Supplementary Table 5).
The median follow-up time will be 18 months before the study was terminated. The start points of simultaneous radiotherapy and chemotherapy, patient compliance, adverse events or complications and treatment, the European organization for the research and treatment of cancer on quality of life (EORTCQLQ-C30) and the Karnofsky performance status (KPS) will be evaluated every 3 months postoperatively. Strict data management will be kept including double data entry and establishing range checks for data values.
Sample size calculation and statistical analysis
The sample size is estimated by using PASS 2011 software (NCCS LLC). We calculated the sample size based on the primary outcome. A two-sided Log-rank test with an overall sample size of 196 subjects (98 in intravenous group and 98 in inhalation group) achieves 80.2% power at a 0.05 significance level to detect a hazard ratio of 1.66 when the proportion surviving is 62.3% and 39.2% in intravenous and inhalation group, respectively. The study will last for about 36 months, of which subject accrual (entry) occurs at the first 18 months with the proportion dropping out of the two group is 0.1, respectively.
Analysis will be conducted using SPSS software (version 23.0). The Kolmogorov-Smirnov test will be used to test data normality. Normally distributed continuous variables will be described as the means with standard deviation (SD) and compared using independent t tests. Non-normally distributed variables will be summarized as medians and interquartile range (IQR) and compared by using Mann-Whitney U tests. Categorical variables will be described as numbers (n) and percentage (%) and compared using Chi-square or Fisher’s exact tests.
The Kaplan-Meier method will be used to describe the time-to-event data (OS and PFS), and the log-rank test will be used for comparisons. Univariate and multivariate Cox proportional hazard regressions will be used for survival analysis. Together with the anesthesia type, variables with P<0.1 in the univariate analysis will be regarded as candidate variables for the multivariable model. A significance level of P<0.05 will be used to indicate statistical significance. The imputation method will be used for dealing with missing data. The impact of missing data will be estimated by sensitivity analysis. Additionally, subgroup analysis will be undertaken to assess the association between anesthesia and the outcome according to the aCCI, KPS, EOR, WHO grade, duration of anesthesia and whether chemotherapy or not. No interim analysis will be done or the trial will not early terminate.
Reporting of adverse events
Data monitoring committee is not set up in the trial for the sample size is not very large. However, auditing trial will be conducted twice per year and the process will be independent from investigators and the sponsor. All adverse events (AEs) will be closely monitored until a stable situation has been reached. The chief investigator will be informed of any serious AEs and determine the severity and causality of these events. All AEs associated with this study will be recorded and reported to the Ethics Committee as part of the annual report. The chief investigator will be responsible for collecting the details about causes of AEs, treatment, prognosis, and reporting SAE to the Ethics Committee immediately. The incidence of adverse effects will be described as percentage and frequencies for each group. Chi-square and Fisher’s exact test will be used for comparison between groups. The researcher will have access to the final trial data set.
Protocol Amendment
The chief investigator will be responsible for any decision to amend the protocol. If there is any modification (e.g., changes to eligibility criteria, outcomes or analyses), the principle investigator will report and gain approval from the China Ethics Committee of Registering Clinical Trials prior to implementation, by communicating with relevant other members (e.g., investigators, participants, registries, journals, and regulators).