New prognostic factors and calculators for outcome prediction in patients with recurrent glioblastoma: A pooled analysis of EORTC Brain Tumour Group phase I and II clinical trials

Abstract

Background

Prognostic models have been developed to predict survival of patients with newly diagnosed glioblastoma (GBM). To improve predictions, models should be updated with information at the recurrence. We performed a pooled analysis of European Organization for Research and Treatment of Cancer (EORTC) trials on recurrent glioblastoma to validate existing clinical prognostic factors, identify new markers, and derive new predictions for overall survival (OS) and progression free survival (PFS).

Methods

Data from 300 patients with recurrent GBM recruited in eight phase I or II trials conducted by the EORTC Brain Tumour Group were used to evaluate patient’s age, sex, World Health Organisation (WHO) performance status (PS), presence of neurological deficits, disease history, use of steroids or anti-epileptics and disease characteristics to predict PFS and OS. Prognostic calculators were developed in patients initially treated by chemoradiation with temozolomide.

Results

Poor PS and more than one target lesion had a significant negative prognostic impact for both PFS and OS. Patients with large tumours measured by the maximum diameter of the largest lesion (⩾42 mm) and treated with steroids at baseline had shorter OS. Tumours with predominant frontal location had better survival. Age and sex did not show independent prognostic values for PFS or OS.

Conclusions

This analysis confirms performance status but not age as a major prognostic factor for PFS and OS in recurrent GBM. Patients with multiple and large lesions have an increased risk of death. With these data prognostic calculators with confidence intervals for both medians and fixed time probabilities of survival were derived.

Introduction

The prognosis of patients with glioblastoma (GBM) remains dismal despite substantial therapeutic improvement provided by chemoradiation with temozolomide (TMZ) at the initial diagnosis.¹ As yet, there is still no universally accepted standard treatment at the first recurrence, many patients being treated with nitrosoureas (e.g. lomustine [CCNU]) or with bevacizumab or considered for experimental therapy within clinical trials.² Clinical trials of new treatments or novel approaches aiming at improving outcome after disease recurrence are urgently needed. In order to identify a real sign of activity of investigational treatments, reliable end-points for phase II trials are required. Probabilities of progression-free survival at 6 months (PFS6) and of overall survival at 1 year (OS12) are both recognised end-points for clinical trials to assess the outcome of patients with recurrent GBM.³ The identification of accurate prognostic factors is an important issue to guide therapeutic decisions and patient management.⁴ In a previous report, we reviewed the prognostic importance of clinicobiological factors for predicting survival in newly diagnosed GBM. We showed that combined and concomitant radio and TMZ chemotherapy (TMZ/Radiotherapy (RT) → TMZ), O⁶-methylguanine-DNA methyltransferase (MGMT) promoter methylation status, extent of primary surgery, age, World Health Organization (WHO) performance status (PS), Mini-Mental State Examination (MMSE) and administration of corticosteroids at the baseline strongly impacted on patient’s survival.⁵ At the time of tumour progression other prognostic factors may be relevant. Patients commonly have an altered performance status, and will require more frequent corticosteroids administration. Furthermore, treatment specific molecular alterations may be selected for in the recurrent tumour, such as inactivation of mismatch repair pathway constituents in TMZ treated patients.⁶ The New Approaches to Brain Tumor Therapy Central Nervous System (NABTT CNS) Consortium performed a Recursive Partitioning Analysis (RPA) for overall survival in recurrent high-grade gliomas. They identified histology, age, Karnofsky’s index (KPS), tumour localisation and corticosteroids at the baseline as important prognostic factors.⁷ Joint North Central Cancer Treatment Group (NCCTG) and North America Brain Tumor Coalition (NABTC) analyses found grade, age, PS, baseline steroids and time since initial diagnosis (Wu et al., 2010) as most influential factors for survival.⁸

Dempsey et al. showed that a large tumour by volumetric measurement had a detrimental effect on survival in a group of malignant gliomas. They also identified older age and male sex as risk factors for survival.⁹ Age was not identified as an independent prognostic factor for survival in two previous reports.10, 11

We have pooled the data from phase I and phase II clinical trials on recurrent GBM conducted by the European Organization for Research and Treatment of Cancer (EORTC) Brain Tumour Group (BTG) in order to further assess prognostic factors for clinical outcome and to develop prognostic models. We have derived prognostic calculators providing estimates with confidence intervals for both medians and fixed time probabilities of survival.