Best Treatment for High-Risk, Low-Grade Glioma Is Still Radiotherapy

In a large, international, randomized trial, initial radiotherapy was compared to temozolomide chemotherapy for low-grade glioma treatment. A statistically significant difference between the two treatment strategies was not observed for progression-free survival, although radiotherapy was statistically favored. However, molecular tumor characterization may allow the treatment approach to be personalized and one or the other treatment modality to be selected.

The findings of the EORTC trial 22033-26033 were presented in June 2013 at the annual meeting of the American Society of Clinical Oncology (ASCO), held in Chicago (IL, USA), by the coordinator of the study Brigitta Baumert, MD, PhD, of the radiation oncology department, Maastricht University (MAASTRO; The Netherlands) and recently appointed deputy head of the radiotherapy department of the MediClin Robert-Janker Clinic (Bonn, Germany), clinical cooperation unit neurooncology, and University of Bonn Medical Center (Germany). In this trial, 477 patients from 18 countries were randomized (after molecular stratification for 1p-status) between radiotherapy (240 patients) and chemotherapy with temozolomide (237 patients), a drug that has been shown to have an activity in low-grade glioma. The trial findings revealed that first-line treatment with temozolomide compared to radiotherapy does not improve progression-free survival in these high-risk, low-grade glioma patients.

Dr. Baumert stated, “This is the first study in primary brain tumor to prospectively evaluate molecular markers. In the future, diagnosis of low-grade glioma will be substituted by a more differentiated molecular tumor characterization upon which treatment strategies will depend. The data are preliminary—as median overall survival has not yet been reached. Good wine needs aging….”

Patient outcome with low-grade glioma varies widely. In earlier randomized trials, the EORTC and others have shown that treatment can be deferred in patients without additional risk factors. For higher risk patients, radiotherapy might be of useful. EORTC trial 22033-26033 was designed for patients with a prognostic profile that indicated a poor outcome and investigated whether primary chemotherapy as compared to conventional radiotherapy would prolong progression-free and overall survival.

The study’s goal was also to identify prognostic molecular factors that might help in making treatment decisions. At the time of study beginning, the prognostic significance for tumor response to treatment in the presence of a chromosomal deletion on the short arm of chromosome 1 was known, and consequently patients were stratified before randomization. Other markers will be studied now that the study is complete and will clarify why some patients have a much better disease outcome than others. “This is a very important study in our quest to personalize treatment strategies. The ongoing molecular tumor characterization will identify individual characteristics guiding future treatment decisions—be it intensifying therapy for some, or withholding therapy for others,” said Roger Stupp, director of the Zurich University Cancer Center (Switzerland), president of the EORTC (European Organization for Research and Treatment of Cancer; Brussels, Belgium), and one of the lead investigators of the study.

At a median follow-up of 45.5 months and after the tumors of 246 patients had progressed, there was no statistical difference in progression-free survival, the primary endpoint. Overall toxicity was mild. Grade 3 hematologic toxicity was seen in 9% of the temozolomide-treated patients.

Secondary analyses included overall survival and the impact of 1p status. Median overall survival is not yet reached, but 1p deletion was confirmed to be a positive prognostic factor with either treatments (p-value stratified by treatment, progression-free survival: p = 0.0003; HR = 0.59, 95% CI (0.45-0.78), overall survival: p = 0.002; HR = 0.49; 95% CI (0.32-0.77). Although the interaction test was not significant, for patients treated with temozolomide, there was a trend for inferior progression-free survival in patients who had 1p intact, and overall survival may be better for patients who had the 1p deletion. The survival analyses require additional maturation and more molecular data to additionally differentiate the responders to temozolomide therapy and guide treatment decision. Analyses of molecular profiles, neurocognition, and quality-of-life are ongoing.

This Intergroup trial was coordinated by the EORTC Radiation Oncology and Brain Tumor Groups in collaboration with Medical Research Council Clinical Trial Unit (London, UK), the National Cancer Institute of Canada Clinical Trial Group (Kingston, ON, Canada), and Trans-Tasman Radiation Oncology Group (New Lambton, NSW, Australia).

Related Links:
Maastricht University
MediClin Robert-Janker Clinic
European Organization for Research and Treatment of Cancer