Aim
The purpose of this study was to confirm the non-inferiority of radiotherapy as 25 Gy in 5 fractions with concomitant and adjuvant temozolomide over 40 Gy in 15 fractions with concomitant and adjuvant temozolomide in terms of OS in elderly patients with newly diagnosed glioblastoma.
Randomization
The first registration is performed by JCOG Web System to the JCOG Data Center if all eligibility criteria for the first registration are satisfied. Methylation status of the O6-methylguanine-DNA methyltransferase (MGMT) promoter region is examined using surgical specimens before the second registration. After confirming the inclusion criteria for the second registration have been met, the second registration will be made by the JCOG Web System to the JCOG Data Center. Patients will be randomized in a 1:1 ratio into either arm A (standard treatment arm: radiotherapy as 40 Gy in 15 fractions with concomitant and adjuvant temozolomide) or arm B (experimental treatment arm: radiotherapy as 25 Gy in 5 fractions with concomitant and adjuvant temozolomide) using a minimization method with a random component while balancing arms with respect to institution, extent of surgical resection (partial resection + total resection vs. biopsy), Karnofsky performance status (< 70% vs. ≥70%) and methylation status of the MGMT promoter region (methylated vs. unmethylated).
Study setting
A multi-institutional, randomized controlled trial.
Funding
This study is supported by the National Cancer Center Research and Development Fund (2020-J-3) and the Japan Agency for Medical Research and Development (JP20ck0106619).
Endpoints
The primary endpoint is OS, and secondary endpoints are PFS, frequency of adverse events (AEs), proportion of Karnofsky performance status preservation, and proportion of health-related QOL preservation.
OS is defined as the time from registration to death from any cause, censored as of the last day when the patient is known to be alive. PFS is defined as the time from registration to either the first event of tumor progression or death from any cause, censored as of the latest day when the patient is alive without any evidence of progression. Tumor response is evaluated according to the Response Assessment in Neuro-Oncology (RANO) criteria [16]. AEs are evaluated according to the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE 5.0). SAE is defined as any ≥ grade 4 non-hematological toxicity at least possibly related to treatment, unexpected AE requiring hospitalization or prolongation of hospital stay, death from any cause during treatment or within 30 days after a protocol treatment, or treatment-related death. Health-related QOL is measured in accordance with EORTC QLQ-C30 and EORTC QLQ-BN20.
Inclusion criteria
First registration criteria:
-
(1)
Tumor diagnosed as glioblastoma or Grade III glioma (WHO 2016 criteria) in pathological diagnosis during surgery, or histologically proven glioblastoma diagnosed according to WHO 2016 criteria.
-
(2)
Tumor specimen available for analysis of MGMT promoter methylation status.
-
(3)
No history of treatments for glioma except for resection including biopsy; in that case, second resection within 21 days after first resection.
-
(4)
First registration within 21 days after surgery.
-
(5)
Tumor present in the supratentorial region on preoperative contrast-enhanced MRI of the brain.
-
(6)
Preoperative contrast-enhanced MRI of the brain reveals no dissemination.
-
(7)
Presence of a measurable lesion is not mandatory.
-
(8)
Patient 71 years old or older at registration; 71 to 75 years old with resection of less than 90% of contrast-enhanced region.
-
(9)
ECOG performance status (PS) of 0, 1, 2, or 3 due to neurological symptoms caused by the tumor.
-
(10)
No prior chemotherapy or radiation therapy to the brain for any intracranial tumors.
-
(11)
Sufficient organ function.
-
(i)
Neutrophil count ≥1500 /mm3.
-
(ii)
Hemoglobin ≥8.0 mg/dl.
-
(iii)
Platelet count ≥100,000 /mm3.
-
(iv)
AST ≤ 120 U/L.
-
(v)
ALT ≤120 U/L.
-
(vi)
Cr ≤ 1.605 mg/dL for males, or ≤ 1.185 mg/dL for females.
-
(12)
Informed consent provided voluntarily by the patient.
Second registration criteria:
-
(1)
Second registration within 21 days of the first registration.
-
(2)
Histologically proven glioblastoma diagnosed according to WHO 2016 criteria.
-
(3)
Confirmation of methylation or unmethylation in MGMT promoter region.
Exclusion criteria
-
(1)
Synchronous or metachronous malignancies (within the preceding 2 years).
-
(2)
Infections needing systemic treatment at time of registration.
-
(3)
Body temperature above 38 °C at registration.
-
(4)
Severe psychological disease at time of registration.
-
(5)
Continuous systemic corticosteroid or immunosuppressant treatment due to diseases other than brain tumor.
-
(6)
Uncontrollable diabetes mellitus.
-
(7)
Unstable angina pectoris, or history of myocardial infarction within the preceding 6 months.
-
(8)
Interstitial pneumonia, pulmonary fibrosis, or severe emphysema at time of registration.
-
(9)
Gadolinium allergy.
-
(10)
Positive results for HIV antibody.
-
(11)
Positive results for HBs antigen.
Interventions
Arm A:
(1) 40 Gy in 15 daily fractions with temozolomide.
(i) Concomitant phase, temozolomide (75 mg/m2, daily from first to last day of radiation), radiation (2.67 Gy/day, 5 days/week, 15 times and 40 Gy in total)
(ii) Maintenance phase, temozolomide (150–200 mg/m2, days 1–5, every 4 weeks) 12 cycles.
Arm B:
(1) 25 Gy in 5 daily fractions with temozolomide.
(i) Concomitant phase, temozolomide (150 mg/m2, 5 days from first day), radiation (5 Gy/day, 5 days/week, 5 times and 25 Gy in total)
(ii) Maintenance phase, temozolomide (150–200 mg/m2, days 1–5, every 4 weeks) 12 cycles.
Procedures of radiotherapy
Contouring was performed using computed tomography (CT) with a maximum slice thickness of 5 mm. Gross tumor volume (GTV) was defined as residual tumor according to pre- and postoperative contrast-enhanced MRI. Clinical target volume (CTV) was created by adding 1.5-cm margins to the GTV and resection cavity. In addition, CTV included surrounding edema (high-intensity area on T2-weighted or fluid-attenuated inversion recovery images). The margin for the planning target volume was set at 3–5 mm. The same target setting was used for Arms A and B.
Follow-up
All patients will be followed-up for at least 2 years after completion of protocol treatment. Gadolinium-enhanced MRI of the brain will be evaluated at least every 8 weeks until disease progression or death. Tumor response will also be assessed every 8 weeks according to RANO criteria. Physical examination, laboratory tests, and evaluation of AEs according to CTCAE version 5.0 will be carried out at least every 4 weeks during protocol treatment.
Statistical analysis
This study is designed as a multi-institutional, randomized controlled trial to confirm the non-inferiority of radiotherapy of 25 Gy in 5 fractions with concomitant and adjuvant temozolomide over 40 Gy in 15 fractions with concomitant and adjuvant temozolomide in terms of OS in elderly patients with newly diagnosed glioblastoma. The required sample size for randomization is calculated as 264, which will provide 70% power with a hypothesized 1-year survival rate of 37.8% in both arms and a non-inferiority margin of 1.32 using a one-sided alpha of 0.05 to observe 249 deaths. Considering some patients will not be registered due to progression before the second registration, the planned sample size for the first registration is 270 patients in a 4-year accrual period and 2-year follow-up period. Stratified Cox regression analysis with extent of surgical resection, Karnofsky performance status and methylation status of the MGMT promoter region will be performed for primary analysis.
Interim analysis and monitoring
We plan to conduct an interim analysis to judge whether the study should be terminated early due to futility or clear evidence of efficacy. The interim analysis will be conducted after half of the planned number patients have been enrolled. The Lan-DeMets method with an O’Brien and Fleming-type alpha spending function will be used to adjust the multiplicity of the interim analysis and the primary analysis [17].
JCOG Data Center staff will conduct central monitoring issuing a monitoring report twice annually to evaluate and improve study progress, data integrity and patient safety. Futility will be considered at each monitoring report if necessary. For quality assurance, site-visit audits, not for a study-specific basis but for the study group basis, will be performed by the JCOG Audit Committee.