Nomograms for predicting survival of patients with newly diagnosed glioblastoma: prognostic factor analysis of EORTC and NCIC trial 26981-22981/CE.3

doi:10.1016/S1470-2045(07)70384-4

The Lancet Oncology

Volume 9, Issue 1, January 2008, Pages 29-38

https://doi.org/10.1016/S1470-2045(07)70384-4 Get rights and content

Summary

Background

Methods

Data from 573 patients with newly diagnosed glioblastoma who were randomly assigned to radiotherapy alone or to the same radiotherapy plus temozolomide in the EORTC and NCIC trial were included in this subanalysis. Survival modelling was done in three patient populations: intention-to-treat population of all randomised patients (population 1); patients assigned temozolomide and radiotherapy (population 2, n=287); and patients assigned temozolomide and radiotherapy who had assessment of MGMT promoter methylation status and who had undergone tumour resection (population 3, n=103). Cox proportional hazards models were fitted with and without O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. Nomograms were developed to predict an individual patient's median and 2-year survival probabilities. No nomogram was developed in the radiotherapy-alone group because combined treatment is now the new standard of care.

Findings

Independent of the MGMT promoter methylation status, analysis in all randomised patients (population 1) identified combined treatment with temozolomide, more extensive tumour resection, younger age, Mini-Mental State Examination (MMSE) score of 27 or higher, and no corticosteroid treatment at baseline as independent prognostic factors correlated with improved survival outcome. In patients assigned temozolomide and radiotherapy (population 2), younger age, better performance status, more extensive tumour resection, and MMSE score of 27 or higher were associated with better survival. In patients who had tumours resected, who were assigned temozolomide and radiotherapy, and who had available MGMT promoter methylation status (population 3), methylated MGMT, better performance status, and MMSE score of 27 or higher were associated with improved survival. Nomograms were developed and are available at http://www.eortc.be/tools/gbmcalculator.

Interpretation

MGMT promoter methylation status, age, performance status, extent of resection, and MMSE are suggested as eligibility or stratification factors for future trials in patients with newly diagnosed glioblastoma. Stratifying by MGMT promoter methylation status should be mandatory in all glioblastoma trials that use alkylating chemotherapy. Nomograms can be used to predict an individual patient's prognosis, and they integrate pertinent molecular information that is consistent with a paradigm shift towards individualised patient management.

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,

Section snippets

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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Fast track — ArticlesNomograms for predicting survival of patients with newly diagnosed glioblastoma: prognostic factor analysis of EORTC and NCIC trial 26981-22981/CE.3

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Patients and procedures

Results

Discussion

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Semin Oncol

Int J Radiat Oncol Biol Phys

Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma

N Engl J Med

Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials

J Natl Cancer Inst

The role of tumor resection in the treatment of glioblastoma multiforme in adults

Cancer

Multivariate analysis of clinical prognostic factors in patients with glioblastoma multiforme treated with a combined modality approach

J Cancer Res Clin Oncol

Multivariate analysis of prognostic factors in patients with glioblastoma

Strahlenther Onkol

Prognostic factors for survival of patients with glioblastoma: recursive partitioning analysis

Neuro Oncol

Clinical prognostic factors in patients treated with malignant glioma treated with combined modality approach

Am J Clin Oncol

Prospective study of quality of life in adults with newly diagnosed high-grade gliomas

J Neurooncol

Fast track — Articles
Nomograms for predicting survival of patients with newly diagnosed glioblastoma: prognostic factor analysis of EORTC and NCIC trial 26981-22981/CE.3