Temozolomide vs Radiotherapy in High-Risk Low-Grade Glioma
In the phase III EORTC (European Organisation for Research and Treatment) 22033-26033 intergroup trial reported in The Lancet Oncology, Baumert et al found no progression-free survival difference between temozolomide chemotherapy and radiotherapy alone in patients with high-risk low-grade glioma. Preliminary evidence of a benefit of radiotherapy was observed in a molecular subtype.
Study Details
In the open-label trial, 477 patients aged ≥ 18 years from 78 clinical centers in 19 countries (Europe, Canada, and Australia) were randomized between December 2005 and December 2012 to receive either conformal radiotherapy (up to 50.4 Gy; 28 doses of 1.8 Gy once daily 5 days per week for up to 6.5 weeks; n = 240) or dose-dense oral temozolomide (75 mg/m2 once daily for 21 days repeated every 28 days in 1 cycle for a maximum of 12 cycles; n = 237).
Patients had low-grade (WHO [World Health Organization] grade II) glioma (astrocytoma, oligoastrocytoma, or oligodendroglioma) and at least one high-risk feature (aged > 40 years, progressive disease, tumor size > 5 cm, tumor crossing the midline, or neurologic symptoms) and were without known HIV (human immunodeficiency virus) infection or chronic hepatitis B or C virus infection. The primary endpoint was progression-free survival in the intent-to-treat population.
At a median follow-up of 48 months, median progression-free survival was 39 months in the temozolomide group vs 46 months in the radiotherapy group (unadjusted hazard ratio [HR] = 1.16, P = .22). Median overall survival had not been reached. At database lock, 25% of patients had died, including 24% of the temozolomide group and 26% of the radiotherapy group, preventing meaningful analysis of overall survival.
Molecular Subgroups
An exploratory analysis among 318 molecularly defined patients showed significantly different progression-free survival among the 3 recently defined molecular subgroups of IDHmt with (IDHmt/codel, 39% of patients) or without (IDHmt/noncodel, 46% of patients) 1p/19q codeletion and IDH wild type (IDHwt, 15% of patients). Median progression-free survival in these 3 groups overall was 62 months, 48 months, and 20 months (P = .013 overall), respectively.
Median progression-free survival for temozolomide vs radiotherapy was 41 vs 51 months among all 318 patients (HR = 1.18, P = .30); median progression-free survival was significantly better with radiotherapy vs temozolomide among patients with IDHmt/noncodel (36 vs 55 months, HR = 1.86, P = .004), with no significant differences observed between groups among those with IDHmt/codel (55 vs 62 months, HR = 1.04, P = .91) or those with IDHwt (24 vs 19 months, HR = 0.67, P = .24; P = .013 for interaction).
Adverse Events
Grade 3 or 4 hematologic adverse events occurred in 14% of the temozolomide group and < 1% of the radiotherapy group, and grade 3 or 4 infection occurred in 3% and 1%. Grade 3 or 4 neurologic symptoms occurred in 17% vs 12%, and grade 3 or 4 constitutional symptoms occurred in 6% vs 4%. Moderate-to-severe fatigue occurred in 7% vs 3%. Four patients died due to treatment-related causes, including two patients in the temozolomide group and two patients in the radiotherapy group.
The investigators concluded: “Overall, there was no significant difference in progression-free survival in patients with low-grade glioma when treated with either radiotherapy alone or temozolomide chemotherapy alone. Further data maturation is needed for overall survival analyses and evaluation of the full predictive effects of different molecular subtypes for future individualised treatment choices.”
Health-Related Quality of Life
As reported in a companion article in The Lancet Oncology by Reijneveld et al, there was little difference in health-related quality of life between the temozolomide and radiotherapy groups in the trial. Health-related quality of lifewas assessed using the EORTC QLQ-C30 (Quality-of-Life Questionnaire-Core 30) and the EORTC Brain Cancer Module (QLQ-BN20), and global cognitive functioning was assessed using the Mini-Mental State Examination (MMSE).
No significant difference in health-related quality of lifebetween the groups was found during 36 months of follow-up (mean between group difference averaged over all time points = 0.06, P = 0.98). At baseline, impaired cognitive function on the MMSE was present in 14% of the temozolomide group and 13% of the radiotherapy group. After randomization, impaired cognitive function occurred in 6% of 54 temozolomide patients and 8% of 63 radiotherapy patients followed for 36 months. There was no significant difference between the groups in change in MMSE scores during 36 months of follow-up.
The investigators concluded: “The effect of temozolomide chemotherapy or radiotherapy on [health-related quality of life] or global cognitive functioning did not differ in patients with low-grade glioma. These results do not support the choice of temozolomide alone over radiotherapy alone in patients with high-risk low-grade glioma.”
The studies were supported by Merck Sharpe & Dohme-Merck & Co, the Canadian Cancer Society, the Swiss Cancer League, the UK National Institutes of Health, the Australian National Health and Medical Research Council, the U.S. National Cancer Institute, Cancer Research UK, and the EORTC of Cancer Cancer Research Fund.
Brigitta G. Baumert, MD, of the EORTC, Brussels, and Jaap C. Reijneveld, MD, of the VU University Medical Center, Amsterdam, are the corresponding authors of The Lancet Oncology articles.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
