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
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.
Section snippets
Patient selection
Between 1999 and 2010, the EORTC has conducted eight prospective multicentre phase 1 and phase 2 clinical trials investigating safety and activity of novel therapeutic agents in recurrent malignant glioma.12, 13, 14, 15, 16, 17, 18, 19 Agents under study in dose finding phase I trials were SCH66336 (lonafarnib) and LY317615 (enzastaurin). The phase II trials involved XR5000 (DACA, Xenova®), D19575 (glufosfamide), RFS 2000, STI571 (imatinib, Glivec®), OSI 774 (erlotinib, Tarceva®) and ZK219477
Statistical considerations
Categorical data were tabulated with frequencies and percentages. Medians and ranges (minimum–maximum) were used to summarise continuous variables. The significance of the association between categorical factors was assessed by the Fisher Exact test (nominal) or the Jonckheere-Terpstra test (ordinal). Between continuous variables, significance was computed based on a specific student’s statistic for testing the null hypothesis of no association. For the association between continuous and
Patients characteristics and correlation analyses
Four hundred eleven patients were recruited in the eight trials, 300 had a local histopathological diagnosis of GBM (astrocytoma grade IV according to WHO). Central pathology review was available for 155 patients (52%), in 149 patients (96%) GBM was confirmed. Baseline characteristics are summarised in Table 1. One hundred thirty eight patients had received TMZ/RT → TMZ as first-line therapy. One hundred fifty eight patients received standard fractionated RT to the equivalent of approximately 60
Discussion
In this report, baseline characteristics and outcome data were available for 300 patients diagnosed with GBM by the local pathologist. In all pooled phase II trials, the last dose of radiotherapy had to be administered more than 3 months from the time of recruitment thus making the chance of pseudoprogression less likely.26, 27 One hundred thirty eight had received TMZ/RT → TMZ at initial diagnosis. We have shown that tumour load measured by the maximum diameter of the largest target lesion and
Conflict of interest statement
Thierry Gorlia, Mario M. Campone, Pierre Fumoleau, Eric Raymond, Roy R. Rampling, Chris C. Twelves and Denis Lacombe had no conflict of interest. The research institute directed by Christian Dittrich has received unrestricted research Grants from Novartis, Basel, Switzerland and MSD/Merck & Co. (formerly Schering-Plough), North Wales, PA, USA. Martin van den Bent provided consultancy for Roche Pharma, Basel, Switzerland, Novartis, Basel, Switzerland and Bayer HealthCare Pharma (formerly
Acknowledgements
This publication was supported by Grants number 5U10 CA11488-29 through 2U10 CA011488-41 from the National Cancer Institute (Bethesda, Maryland, USA) and by a donation from the ‘Vlaamse Liga Tegen Kanker’ from Belgium through the EORTC Charitable Trust. Its content is solely the responsibility of the authors and does not necessarily reflect the official views of the National Cancer Institute.
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