Study objective
The aim of this study is to compare the efficacy and safety of RT plus TMZ with RT alone for high-risk LGGs. Beyond that, we will focus on molecular features, in addition to histologic classification, to establish a more appropriate treatment modality for certain cohorts.
Study design
This is a multicentre, open-label, prospective RCT. The study has received ethical approval from China Registered Clinical Trial Ethics Committee. The protocol is written in line with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines (see Additional file 1: SPIRIT Checklist). Following informed consent, eligible patients will be allocated to a RT group (control group) or a CRT group (experimental group). The flow diagram of the main procedures is illustrated in Fig.1.
Recruitment and informed consent
A total of two hundred and fifty participants will be recruited from 4 centres in China (see Additional file 2). Registration step can be done at any time after being diagnosed as WHO grade II glioma. And the enrollment period is expected to be completed within 5 years of the beginning of recruitment. Research staff are in charge of screening process to make sure each participant match the inclusion and exclusion criteria. An informed consent form (ICF) describing detailed study procedures and illustrating potential benefits and risks will be provided to all participants, so that they can decide whether or not to volunteer. Written informed consent must be acquired from all patients or their legal representatives prior to participating in this clinical trial.
Eligibility criteria
Inclusion criteria are as follows:
- Newly diagnosed supratentorial WHO grade II gliomas;
- Aged 18 to 39 years without total resection, or aged 40 to 70 years with any extent of resection or biopsy;
- Karnofsky performance score (KPS) ≥ 60;
- No more than moderate neurologic symptoms and signs;
- The interval between surgery and randomization is less than 12 weeks;
- Have signed the consent form.
Exclusion criteria are as follows:
- WHO grade 1 gliomas or high-grade gliomas according to WHO’s grading system;
- Have received prior radiation therapy to the head and neck region;
- Have received prior chemotherapy;
- Synchronous multiple primary malignant tumor excluding carcinoma of the cervix in situ or nonmelanomatous skin cancer;
- Prior malignancy’s disease-free survival less than 5 years;
- Have active infection;
- Patients are pregnant or breast-feeding.
Randomization
Qualified patients will be randomized in a 1:1 ratio using the method of block randomization. The blocked randomization sequence is generated by computer software SPSS, and the block size is determined by statisticians. After the patient has registered and signed the informed consent form, he or she will be allocated to RT group or CRT group by web-based central randomization. The allocation sequence is unavailable to researchers who will enroll participants or assign interventions.
Interventions
Eligible patients will be assigned 1:1 to an experimental group or a control group. In experimental group, patients will be treated with RT combined with adjuvant TMZ with or without concurrent TMZ. And in control group, patients will only have RT treatment. Both groups will receive the same intensity modulated radiation therapy (IMRT). The radiation dose is 50-54 Gy given in 25-30 fractions (1.8-2.0 Gy once daily, 5 days per week). RT treatment volumes will be defined using pre- and postoperative T2 or fluid-attenuated inversion recovery (FLAIR) on MRI. Drug dose adjustments are allowed according to blood counts and adverse reactions. Concurrent chemotherapy is to receive oral TMZ, 75 mg/m2 per day, during radiation therapy. Concurrent TMZ can be used for 42 days continuously if an absolute neutrophil count (ANC) is not less than 1.5x109 cells per L and platelet count not less than 100 x109 cells per L and non-haematological toxicity of grade 0 or 1 (except alopecia, nausea, and vomiting) according to version 4.03 of the National Cancer Institute Common Toxicity Criteria (NCI-CTC). In the case of ANC less than 1.5 x109 cells per L but more than 0.5 x109 cells per L, platelet count less than 100 x109 cells per L but more than 10 x109 cells per L, or non-haematological toxicity of grade 2, concurrent TMZ treatment should suspend until recovery to toxicity of grade 0 or 1. Temozolomide chemotherapy will be terminated when one of the following conditions occurs: ANC<0.5 x109 cells per L, platelet count<10 x109 cells per L, non-haematological toxicity of grade 3 or 4.
Patients who are assigned to adopt adjuvant chemotherapy will be treated with six cycles of TMZ, 150 to 200 mg/m2 per day for five consecutive days, repeated every 4 weeks. There is a 28-day break during RT and adjuvant TMZ. The first cycle dose of adjuvant chemotherapy is 150 mg/m2. A higher dose of 200 mg/m2 is recommended in the subsequent cycles if ANC not less than 1.5x109/L and platelet count not less than 100 x109/L and non-haematological toxicity of grade 0 or 1 (except alopecia, nausea, and vomiting) during the first cycle. The dose will reduce by 50mg/m2 if ANC is less than 1x109 cells per L or platelet count less than 50x109 cells per L or non-haematological toxicity of grade 3 during any period of adjuvant chemotherapy. Patients have to discontinue adjuvant TMZ if grade 4 non-haematological is recorded or the dose of TMZ has reduced to less than 100 mg/m2 or grade 3 non-haematological reoccurs after dose reduction.
Outcomes
Our primary outcome is progression-free survival which is calculated from the date of randomization to the date of first reported disease progression or the date of death caused by any cause. Secondary outcomes are overall survival, adverse events and cognitive function. OS is calculated from the date of randomization until death caused by any cause. Cognitive function will be assessed by Mini-Mental State Examination (MMSE).
Adverse events (AE)
Investigators should explain to participants in detail that they are required to faithfully reflect changes in their condition during and after treatment. Researchers are supposed to pay close attention to adverse events while observing the curative effect. The following information should be recorded in the case report form (CRF): symptom, occurrence time, severity, duration, treatment measures and outcomes. Researchers should evaluate the association between AE and treatment and record them timely and truly with signature and date. The grading of adverse events will accord with CTC-AE v4.03.
Baseline and follow-up visits
After obtaining written informed consent, baseline assessment including physical examination, KPS, complete blood count (CBC), serum biochemistry will be completed within 7 days before interventions. Postoperative head MRI and cognitive function test are allowed to complete within 28 days prior to treatment. During treatment, complete blood count and serum biochemistry (including renal and liver function, electrolyte and lactate dehydrogenase) will be conducted weekly. The first follow-up visit (KPS, head MRI, cognitive function) will be done one month after radiotherapy. Then every 3 months in the first 2 years, every half year from 3 to 5 years and at least annually thereafter. Participants will be followed up to 10 years after the end of treatment for the last patient. The schedule of assessments before, during and after treatment are displayed in Table 1.
Table 1. Study schedule of enrollment, intervention, and assessments.
|
Study Period
|
|
Enrollment
|
Allocation
|
Post-allocation
|
Time point
|
-4 weeks
|
0
|
Week 0-6
|
Week 10
|
Week 11-34
|
Within 2 years
|
3-5 years
|
5-10 years
|
Enrollment:
|
|
|
|
|
|
|
|
|
Eligibility screen
|
X
|
|
|
|
|
|
|
|
Informed consent
|
X
|
|
|
|
|
|
|
|
Randomization
|
X
|
|
|
|
|
|
|
|
Allocation
|
|
X
|
|
|
|
|
|
|
Interventions:
|
|
|
|
|
|
|
|
|
RT
|
|
|
X
|
|
|
|
|
|
Concurrent TMZ
|
|
|
X
|
|
|
|
|
|
Adjuvant
TMZ
|
|
|
|
X
|
X
|
|
|
|
Assessments:
|
|
|
|
|
|
|
|
|
Physical examination
|
|
X
|
|
|
|
every 3 months
|
every 6 months
|
annually
|
KPS
|
|
X
|
|
X
|
|
every 3 months
|
every 6 months
|
annually
|
CBC
|
|
X
|
weekly
|
X
|
weekly
|
|
|
|
Serum biochemistry
|
|
X
|
weekly
|
X
|
weekly
|
|
|
|
Postoperative head MRI
|
X
|
|
|
X
|
|
every 3 months
|
every 6 months
|
annually
|
Cognitive function
|
X
|
|
|
X
|
|
every 3 months
|
every 6 months
|
annually
|
Adverse
events
|
|
|
X
|
X
|
X
|
every 3 months
|
every 6 months
|
annually
|
Abbreviations: RT, radiation therapy; TMZ, temozolomide; KPS, Karnofsky performance score; CBC, complete blood count.
Sample size
This RCT is designed as a superiority trial. Based on literature reports and clinical experience, the median OS of the RT group is 7.8 years and that of chemoradiotherapy group (RT plus TMZ) is 13.3 years. One-sided log-rank test with a significance level of 0.05, a test power of 80%, withdrawal and loss of follow-up rate of 10% is applied in this trial. 10-year follow-up for patient events will be conducted after the end of treatment for the last patient. The sample size estimated by software PASS 11 is 125 subjects per group.
Data collection and management
All relevant information of each subject should be recorded in CRF and inputted in ResMan, an Internet-based electronic data capture, timely and truly by trained research staff. Personal information of each subject is confidential. In order to promote participant retention, researchers will instruct subjects to take the medicine as prescribed. Besides, patients will be informed of the follow-up visit by telephone in advance, and all items will be measured in strict accordance with assessments schedule shown in Table 1. Two data entry staff are needed to input the data independently. After reviewing and confirming that the database is correct, electronic data will be conserved and backup. As original material, CRF should not be changed easily. Researcher has to sign and date when it is necessary to modify. The locked electronic data files are not allowed to make any changes. The database will be statistically analyzed by statistical analysts as required by the statistical plan. Principal investigator has the access to the final dataset, while other investigators are prohibited from entering.. Except for the name-related data, the disclosure of the information to third parties is prohibited. After the completion of the trial, the responsible unit of the study has the right to publish contents related to the experiment in the form of a paper.
Data analysis
Professional statisticians undertake statistical analysis tasks and participate in the whole process from trial design, implementation to analysis and summary. Kaplan-Meier will be used to estimate median PFS and OS, and log-rank test will be used to compare differences between two arms. Furthermore, a COX’s proportional hazards analysis will be done to estimate the hazard ratio (HR) and 95% confidence interval (CI). Regarding prognostic factors, uni-and multi variate analysis including age, histology, treatment method, IDH mutation,1p19q status, and MGMT promoter status will be used to analyze their impact on PFS and OS. Safety analysis, mainly for adverse events, will be done in safety set (SS) population. All effectiveness analysis (PFS, OS, cognitive function) will be done on an intention-to-treat set. ITT analysis will be put to use to handle non-compliance and missing data.
Data monitoring
To ensure the safety and validity of the trial, the data will be overseen by an independent Data Safety Monitoring Board (DSMB) during study period. The board consists of clinicians and statisticians and will monitor all implementation activities including but not limited to the enrollment of each centre, starting time of procedures and drop out. All adverse events and issues concerning interventions will be reported to DSMB in line with requirements. All data entered into the database will be checked by DSMB before being locked, and no changes will be permitted. To ensure data security, data must be backed up in time and irrelevant personnel cannot access and modify data.