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

Abstract

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.

Figure 1

Consort statement. The numbers of patients registered, eligibility and allocation per treatment arms, including reasons for exclusion per treatment arm. At the date of database lock, 51 registered patients did not meet the criteria to be eligible for randomization.

Figure 2

Progression-free survival per treatment group. The difference between per log rank test was not significant (HR: 1.16; 95 percent confidence interval, 0.9 to 1.5; P=0.22).

Figure 3

Molecular subgroups, PFS and treatment. Kaplan-Meier curves are shown for the 3 molecular subgroups, IDH mutated and 1p/19q co-deleted (IDHmt/codel), IDHmt/non-codel, and IDH wild-type (IDHwt). (A) prognostic value of the molecular subgroups is observed. Pairwise comparisons of the two treatment arms RT and TMZ are shown by molecular subtype: IDHmt/non-codel (B), IDHmt/codel (C), and IDHwt (D).

Figure 3

Molecular subgroups, PFS and treatment. Kaplan-Meier curves are shown for the 3 molecular subgroups, IDH mutated and 1p/19q co-deleted (IDHmt/codel), IDHmt/non-codel, and IDH wild-type (IDHwt). (A) prognostic value of the molecular subgroups is observed. Pairwise comparisons of the two treatment arms RT and TMZ are shown by molecular subtype: IDHmt/non-codel (B), IDHmt/codel (C), and IDHwt (D).

Figure 3

Molecular subgroups, PFS and treatment. Kaplan-Meier curves are shown for the 3 molecular subgroups, IDH mutated and 1p/19q co-deleted (IDHmt/codel), IDHmt/non-codel, and IDH wild-type (IDHwt). (A) prognostic value of the molecular subgroups is observed. Pairwise comparisons of the two treatment arms RT and TMZ are shown by molecular subtype: IDHmt/non-codel (B), IDHmt/codel (C), and IDHwt (D).

Figure 3

Molecular subgroups, PFS and treatment. Kaplan-Meier curves are shown for the 3 molecular subgroups, IDH mutated and 1p/19q co-deleted (IDHmt/codel), IDHmt/non-codel, and IDH wild-type (IDHwt). (A) prognostic value of the molecular subgroups is observed. Pairwise comparisons of the two treatment arms RT and TMZ are shown by molecular subtype: IDHmt/non-codel (B), IDHmt/codel (C), and IDHwt (D).