No Progression-Free Survival Difference With Temozolomide vs Radiotherapy in High-Risk Low-Grade Glioma



Temozolomide vs Radiotherapy in Low-Grade Glioma

  • No significant progression-free survival difference was observed between temozolomide and radiotherapy in patients with high-risk low-grade glioma.
  • No differences in health-related quality of life or global cognitive function were observed.

In a phase III intergroup trial reported in The Lancet Oncology, Brigitta G. Baumert, MD, of the European Organisation for Research and Treatment of Cancer (EORTC), Brussels, and colleagues found no progression-free survival difference between temozolomide chemotherapy and radiotherapy alone in patients with high-risk low-grade glioma.1 Preliminary evidence of a benefit of radiotherapy was observed in a molecular subtype.

Study Details

In the open-label EORTC 22033-26033 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 for 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).


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.
— Brigitta G. Baumert, MD, and colleagues

Patients had low-grade (World Health Organization grade II) glioma (astrocytoma, oligoastrocytoma, or oligodendroglioma) and at least one high-risk feature (age > 40 years, progressive disease, tumor size > 5 cm, tumor crossing the midline, or neurologic symptoms) and were without known HIV infection or chronic hepatitis B or C virus infection. The primary endpoint was progression-free survival in the intent-to-treat population.

Progression-Free Survival

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 1p/19q codeletion (IDHmt/codel, 39% of patients) or without 1p/19q codeletion (IDHmt/noncodel, 46% of patients) and IDH wild type (IDHwt, 15% of patients). Median progression-free survival in these three groups overall was 62 months, 48 months, and 20 months (P = .013 overall). 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%, respectively. 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


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.
— Jaap C. Reijneveld, MD, and colleagues

As reported in a companion article in The Lancet Oncology by Jaap C. Reijneveld, MD, of VU University Medical Centre, Amsterdam, and colleagues, there was little difference in health-related quality of life between the temozolomide and radiotherapy groups in the trial.2 Health-related quality of life was assessed using the EORTC Quality-of-Life Questionnaire-Core 30 (EORTC QLQ-C30) and the EORTC Brain Cancer Module (QLQ-BN20), and global cognitive functioning was assessed using the Mini–Mental State Examination.

No significant difference in health-related quality of life between the groups was found during 36 months of follow-up (mean between group difference averaged over all time points = 0.06, P = .98). At baseline, impaired cognitive function on the Mini–Mental State Examination 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 Mini–Mental State Examination 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.” ■

Disclosure: For full disclosures of the authors of these studies, visit www.thelancet.com.

References

1. Baumert BG, Hegi ME, van den Bent MJ, et al: Temozolomide chemotherapy versus radiotherapy in high-risk low-grade glioma (EORTC 22033-26033): A randomised, open-label, phase 3 intergroup study. Lancet Oncol. September 26, 2016 (early release online).

2. Reijneveld JC, Taphoorn MJ, Coens C, et al: Health-related quality of life in patients with high-risk low-grade glioma (EORTC 22033-26033): A randomised, open-label, phase 3 intergroup study. Lancet Oncol. September 26, 2016 (early release online).



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