Randomized Trial on the efficacy of Radiotherapy for Cerebral Low-Grade Glioma in the Adult: European Organization for Research and Treatment of Cancer Study 22845 with the Medical Research Council Study BR04: An Interim Analysis

Authors: Karim et al.
Source:Int. J. Radiation Oncology Biol. Phys., Vol. 52, No. 2 pp. 316-32, 2002

Introduction

There is no consensus on the treatment strategy for adult patients with cerebral low-grade glioma. The diagnosis and primary treatment are usually undertaken by surgery. Some investigators doubt the efficacy of postoperative radiotherapy (RT), whereas others advise routine postoperative RT. This study reports the primary results of a multicenter trial to address this discordance; essentially a study of "wait and see" vs. early postoperative RT.

METHODS

Patient selection

• Histopathologic diagnosis of LGG (low-grade gliomas)
  • low-grade astrocytoma, oligodendroglioma, mixed oligo-astrocytoma
• KPS >= 60/WHO <=2 after surgery

Workup

• Clinical exam and pre-op CT, post-op CT advised but not routine
• Neurosurgeons assessed the size/site/type of resection
  • Biopsy/minimal excision: <50% removal
  • Bulk removal: 50-90%
  • Almost total removal: 90-100%

Randomization and study design

• Stratification by institution, histology, amount of tumor removal
• RT within 8 weeks of day of surgery or no postoperative RT
• Followed every 4 months the first 2 years, then annually

Radiation treatment

• Linac or 60Co (16.5%), 54Gy dose in 6 weeks (1.8Gy fx)
  • 5 patients received 56-64.8Gy
• Parallel opposed/angled wedge/multiple fields
• Target volume: 2cm margin to cover contrast-enhanced areas, 1cm margin beyond hypodense areas for non-enhanced
• After 45Gy shrink field by 1cm for remaining 9Gy
• Non-irradiated patients: on progression of tumor, RT with similar technique and dose
• Clinical/neuro exams, CTs advised to detect tumor progression

Statistical Analysis

• Overall endpoints were overall survival and time to progression
• Analysis performed according to intent to treat
• Progression of tumor was defined as clinical-neurologic deterioration confirmed by definitive evidence of tumor activity clinically and on CT or MRI

RESULTS

• 311 patients accrued and randomized from March 1986 to September 1997
• 290 patients were eligible and assessable
• 21 patients were ineligible because of missing data and age/"bad physical condition"
• One patient in treatment arm did not receive immediate RT
• 92 patients have died, 89% of brain tumor (44 in treated arm, 38 in control arm)
• Minor acute reactions of short duration were noted only in a minority of patients.
• Mild to moderate reactions in the form of headache, skin erythema, otitis, and vomiting were recorded in some, but severe reactions were rare.
• The OS was not significantly different (p = 0.49, log-rank test) between irradiated patients and those who were not.
• The estimated risk ratio for the irradiated group was 1.15 (95% confidence interval 0.67–1.74).
• The 5-year estimate of OS was 63% in the treated arm and 66% in the controls. However, the TTP was significantly different (p = 0.02, log-rank test) in favor of early postoperative irradiation.
• The estimated risk ratio for the RT arm was 0.68 (95% confidence interval 0.50–0.94).
• The 5-year estimate of the progression free rate was 44% for the irradiated group and 37% for the nonirradiated control arm of the study. The TTP was 4.8 years in the RT arm and 3.4 years in the control arm.
• In the control arm, the 85 nonirradiated patients with progressive tumor (clinically and on neuroimaging) were treated with: supportive treatment in 14%, chemotherapy only in 5%, surgery only in 11%, and surgery with chemotherapy in 3%.
• Only 62% (n = 53) of the progressing patients received RT. The protocol RT was given in 72% (38 of 53) of those cases. Some of these patients also underwent surgery (18%) or chemotherapy (1%) or both surgery and chemotherapy (8%).
• A subgroup analysis was performed in the 172 patients with confirmed Grade II eligible histologic features. The OS and TTP Kaplan-Meier estimates do not suggest different conclusions than those of the ITT evaluation.

DISCUSSION

This is a prospective randomized multicenter trial to examine the question of early postop RT vs. intervention at progression for LGG. This study builds on the retrospective Mayo Clinic experience (Shaw et al, J. Neurosurg, 1989), and the EORTC 22844 (Karim et al, IJROBP, 1996), and the NCCTG-led Intergroup 86-72-51 (Shaw et al, JCO, 2002) trials. The findings of this study demonstrate that immediate postop radiation improves the time to progression for these patients. However, there is no overall survival benefit with early intervention. There was no assessment of quality of life parameters in this study. The subgroup analysis is likely underpowered and regardless does not suggest different conclusions from the ITT evaluation. The radiation was well tolerated by patients with severe reactions being rare. The authors recommend that routine postoperative and early RT may be advisable for adult patients with cerebral LGG due to the significantly longer time to progression of the patients in the early irradiated group treated with conventional techniques such as were used in this study. However, this study does not convincingly demonstrate the advantage to early postop RT, and there is still controversy between believers and non-believers.