Fast track — ArticlesNomograms for predicting survival of patients with newly diagnosed glioblastoma: prognostic factor analysis of EORTC and NCIC trial 26981-22981/CE.3
Introduction
A randomised trial published by the European Organisation for Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada (NCIC) Clinical Trials Group (trial 26981-22981/CE.3) showed that addition of temozolomide to radiotherapy for the treatment of patients with newly diagnosed glioblastoma significantly improved survival.1 Radiotherapy plus concomitant and adjuvant temozolomide has rapidly become the new standard of care in Europe and North America. New strategies are now being developed that build on this treatment of glioblastoma. Despite this progress, the overall outcome of patients with glioblastoma remains unsatisfactory, and prognosis is highly variable in various categories of patients. Previous studies have identified several clinical factors that help to explain the variability of outcome in patients with glioblastoma. Age, performance status, and extent of surgical resection are the most consistently reported prognostic factors.2, 3, 4, 5, 6, 7 In particular, a recursive partitioning analysis (RPA) undertaken by the Radiation Therapy Oncology Group (RTOG) has identified four risk classes for glioblastoma (classes III, IV, V, and VI) based on patients' ages, Karnofsky performance status, neurological function, mental status, and extent of surgery.2, 3 Additionally, the effect of tumour location has been described in several published studies, and includes, in particular, the unfavourable effect of midline cranial shift involvement and of deep seated tumours, and the possible favourable prognosis of a frontal location.4, 5, 6, 7, 8, 9, 10
The unfavourable prognostic effect of an abnormal mental status was first reported by Curran and colleagues2 in the original report of the RPA classification, although a formal definition of abnormal mental status was not provided. In a study of prognosis in high-grade gliomas, the Folstein Mini-Mental State Examination (MMSE) was retained in an RPA together with age and grade.11 Similarly, Brown and co-workers12 identified MMSE as a prognostic factor in patients with low-grade and high-grade gliomas. In another study,13 the group also suggested increased fatigue as an independent predictor of poorer survival.
Decreased expression of the O6-methylguanine-DNA methyltransferase (MGMT) repair enzyme makes tumours sensitive to alkylating chemotherapy. Molecular analysis of the tumour tissue of a large subgroup of patients showed that the benefit of temozolomide chemotherapy might be restricted to patients who have a silenced MGMT gene by promoter methylation.14, 15
The main aim of this study was to confirm or identify new prognostic factors for survival in patients with glioblastoma and to derive nomograms, ie, graphical representations of statistical models that predict patient prognosis. Nomograms have been used for other cancer sites, especially urological cancers, but so far have not been applied to neuro-oncology,
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Patients and procedures
573 patients with newly diagnosed glioblastoma (WHO astrocytoma grade IV) were randomly assigned treatment in the EORTC and NCIC trial.1 Eligibility criteria were: age 18 to 70 years; WHO performance status less than or equal to 2; no more than 6 weeks since diagnostic surgery or biopsy; adequate haematological, renal, and hepatic function (absolute neutrophil count of ≥1500×106 cells per L, platelet count of ≥100×109 cells per L, serum creatinine concentration ≤1·5 times the upper limit of
Results
Data from 573 patients with newly diagnosed glioblastoma who were randomised in the EORTC and NCIC trial were included in this subanalysis. Table 1 shows the characteristics of the patients. In the population of all randomised patients (population 1), overall, MMSE was missing in 22 patients (4%). Except for the MGMT promoter methylation status, fewer than six patients (1%) had data missing for the other factors. The dataset was found to be representative of the population of patients with
Discussion
A proper understanding of prognostic factors is important for the counselling of individual patients, to select patients for specific treatments, and for the design and interpretation of clinical trials. The EORTC and NCIC trial 26981-22981/CE.3 showed that treatment with concurrent and adjuvant temozolomide in addition to radiotherapy improved the overall outcome compared with treatment with radiotherapy alone.1 The companion prognostic factor analysis reported here has identified treatment
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