Temozolomide chemotherapy versus radiotherapy in high-risk low-grade glioma (EORTC 22033-26033): a randomised, open-label, phase 3 intergroup study

Summary

Background

Outcome of low-grade glioma (WHO grade II) is highly variable, reflecting molecular heterogeneity of the disease. We compared two different, single-modality treatment strategies of standard radiotherapy versus primary temozolomide chemotherapy in patients with low-grade glioma, and assessed progression-free survival outcomes and identified predictive molecular factors.

Methods

For this randomised, open-label, phase 3 intergroup study (EORTC 22033-26033), undertaken in 78 clinical centres in 19 countries, we included patients aged 18 years or older who had a low-grade (WHO grade II) glioma (astrocytoma, oligoastrocytoma, or oligodendroglioma) with at least one high-risk feature (aged >40 years, progressive disease, tumour size >5 cm, tumour crossing the midline, or neurological symptoms), and without known HIV infection, chronic hepatitis B or C virus infection, or any condition that could interfere with oral drug administration. Eligible patients were randomly assigned (1:1) 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) or dose-dense oral temozolomide (75 mg/m² once daily for 21 days, repeated every 28 days [one cycle], for a maximum of 12 cycles). Random treatment allocation was done online by a minimisation technique with prospective stratification by institution, 1p deletion (absent vs present vs undetermined), contrast enhancement (yes vs no), age (<40 vs ≥40 years), and WHO performance status (0 vs ≥1). Patients, treating physicians, and researchers were aware of the assigned intervention. A planned analysis was done after 216 progression events occurred. Our primary clinical endpoint was progression-free survival, analysed by intention-to-treat; secondary outcomes were overall survival, adverse events, neurocognitive function (will be reported separately), health-related quality of life and neurological function (reported separately), and correlative analyses of progression-free survival by molecular markers (1p/19q co-deletion, MGMT promoter methylation status, and IDH1/IDH2 mutations). This trial is closed to accrual but continuing for follow-up, and is registered at the European Trials Registry, EudraCT 2004-002714-11, and at ClinicalTrials.gov, NCT00182819.

Findings

Between Sept 23, 2005, and March 26, 2010, 707 patients were registered for the study. Between Dec 6, 2005, and Dec 21, 2012, we randomly assigned 477 patients to receive either radiotherapy (n=240) or temozolomide chemotherapy (n=237). At a median follow-up of 48 months (IQR 31–56), median progression-free survival was 39 months (95% CI 35–44) in the temozolomide group and 46 months (40–56) in the radiotherapy group (unadjusted hazard ratio [HR] 1·16, 95% CI 0·9–1·5, p=0·22). Median overall survival has not been reached. Exploratory analyses in 318 molecularly-defined patients confirmed the significantly different prognosis for progression-free survival in the three recently defined molecular low-grade glioma subgroups (IDHmt, with or without 1p/19q co-deletion [IDHmt/codel], or IDH wild type [IDHwt]; p=0·013). Patients with IDHmt/non-codel tumours treated with radiotherapy had a longer progression-free survival than those treated with temozolomide (HR 1·86 [95% CI 1·21–2·87], log-rank p=0·0043), whereas there were no significant treatment-dependent differences in progression-free survival for patients with IDHmt/codel and IDHwt tumours. Grade 3–4 haematological adverse events occurred in 32 (14%) of 236 patients treated with temozolomide and in one (<1%) of 228 patients treated with radiotherapy, and grade 3–4 infections occurred in eight (3%) of 236 patients treated with temozolomide and in two (1%) of 228 patients treated with radiotherapy. Moderate to severe fatigue was recorded in eight (3%) patients in the radiotherapy group (grade 2) and 16 (7%) in the temozolomide group. 119 (25%) of all 477 patients had died at database lock. Four patients died due to treatment-related causes: two in the temozolomide group and two in the radiotherapy group.

Interpretation

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.

Funding

Merck Sharpe & Dohme-Merck & Co, Canadian Cancer Society, Swiss Cancer League, UK National Institutes of Health, Australian National Health and Medical Research Council, US National Cancer Institute, European Organisation for Research and Treatment of Cancer Cancer Research Fund.

Introduction

Low-grade glioma encompasses a diverse group of diffusely infiltrative, slowly growing, glial brain tumours that most frequently affect adults in their third or fourth decade of life. The natural history of these tumours varies greatly and optimum management remains controversial. Treatment options include watchful waiting, radical surgery, radiotherapy, chemotherapy, or a combination thereof.¹ Individual management decisions depend on clinical and molecular prognostic factors, extent of neurological symptoms, estimated risk of malignant transformation, and risk of acute and late treatment-associated toxicity.² We previously derived a prognostic score with estimated median survival times varying from 3·2 years (95% CI 3·0–4·0) to 7·8 years (6·8–8·9).³ Age 40 years or older, astrocytic histology, tumour size of 6 cm or larger, tumours crossing the midline of the brain, and the presence of neurological deficits were all associated with a shortened life expectancy.³ In the past 10 years, molecular characteristics, especially co-deletion of chromosomal arms 1p and 19q, which are associated with oligodendroglial histology and mutations of isocitrate dehydrogenase genes 1 (IDH1) and 2 (IDH2), have been associated with a more favourable prognosis and better response to both chemotherapy and radiotherapy compared with people without these alterations.4, 5

Research in context

Evidence before this study

The optimum treatment modality and sequence of patients with low-grade glioma is highly controversial, aiming to balance a favourable effect on progression-free survival versus long-term toxicity in this overall young patient population (median <45 years). We searched PubMed between June 1, 1993, and April 30, 2016, using the search terms “randomized”, “low grade glioma”, “chemotherapy”, and “radiotherapy”. We identified only four conclusive trials (EORTC 22844, EORTC 22845/MRC BR04, NCCTG/RTOG/ECOG, and RTOG 9802), including reports on delaying treatment initiation, or the optimal dose of radiotherapy. The latest report of RTOG 9802 shows an impressive 5·5-year improvement in median overall survival with radiotherapy followed by up to six cycles of adjuvant procarbazine, lomustine, and vincristine chemotherapy, compared with standard radiotherapy alone. However, no data are available for the prognostically highly relevant molecular subtype displaying 1p/19q co-deletion. The absence of this molecular information and the availability of less toxic drugs hinder the translation of molecularly stratified treatment into clinical practice.

Added value of this study

Our study aimed to use data after central histological confirmation and molecular characterisation, and an additional stratification by molecular subtype before randomisation. We therefore had tumour tissue available for most patients, allowing us to confirm the prognostic value of identified molecular subgroups that are now an integral part of the 2016 revised WHO classification of low-grade glioma. To our knowledge, our study is the largest trial of prospectively treated patients with low-grade glioma, allowing for molecular tumour characterisation and analysis of its association with outcome. Although overall no significant difference in progression-free survival was shown between the two treatment groups, our results show the value of molecular characterisation and subgrouping of the disease. Patients with an IDH mutation without 1p/19q co-deletion had a significantly longer progression-free survival when treated with radiotherapy versus chemotherapy, whereas those with wild-type IDH mutation belonged to different categories of glioma often with a much more aggressive course.

Implications of all the available evidence

In future clinical trials, treatment strategies should be adapted to the risk of tumour progression or recurrence based on molecular subgroups of low-grade gliomas. Ultimately this change in strategy should lead to individually-adapted and risk-adapted treatments. Ongoing exploratory analyses might allow for identification of putative predictive molecular markers for further refinement of the prognostic value of the molecular subtyping, and, importantly, might identify novel therapeutic targets in low-grade glioma.

Radiotherapy has been the standard treatment for progressive and inoperable low-grade glioma for more than three decades, established at a time when neither modern imaging technology nor alternative treatment modalities were available.3, 6, 7, 8, 9 Temozolomide (Merck & Co, White House Station, NJ, USA), an alkylating drug, was specifically developed to have chemical properties that allow it to cross the blood–brain barrier and in 1999 was the first drug to be approved by the US Food and Drug Administration for the treatment of recurrent anaplastic astrocytoma.¹⁰ High sensitivity to chemtherapy had been shown for oligodendroglioma with 1p/19q co-deletion, and uncontrolled trials11, 12, 13, 14 suggested that temozolomide also had activity against low-grade glioma. Dose-dense regimens allowing for increased doses and prolonged exposure were viewed as conceptually attractive, especially for slow-proliferating tumours such as low-grade glioma.15, 16, 17

In this European Organisation for Research and Treatment of Cancer (EORTC) 22033-26033 intergroup study, we investigated whether initial temozolomide chemotherapy confers an advantage in patient survival, toxicity, and quality-of-life outcomes compared with standard radiotherapy. We report the survival outcomes and toxicity findings in this paper. Neurocognitive outcomes and quality-of-life results are reported separately.¹⁸