ReviewTherapeutic options in recurrent glioblastoma—An update
Introduction
Despite advances in the understanding of its biology, glioblastoma, the most common malignant brain tumor, remains a devastating disease. Median overall survival (OS) in population-based studies in the US was 8.1 months in the period of 2000–2003 and 9.7 months from 2005 to 2008 (Johnson and O’Neill, 2012). In 2005, the current standard of care in newly diagnosed glioblastoma was established based on the trial of the European Organisation for Research and Treatment of Cancer (EORTC)/National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) showing prolonged median OS of 14.6 months by addition of temozolomide (TMZ) during and after radiotherapy compared to radiotherapy alone (12.1 months) (Stupp et al., 2005). Promoter methylation of the O6-methylguanine-DNA methyltransferase (MGMT) gene was established as a predictive biomarker for benefit from TMZ in newly diagnosed glioblastoma (Hegi et al., 2005). For elderly patients, e.g., older than 65–70 years, the standard of care for newly diagnosed glioblastoma without MGMT promoter methylation or unknown MGMT status is radiotherapy alone (Keime-Guibert et al., 2007). In contrast, elderly patients with glioblastoma with MGMT promoter methylation should receive TMZ without or with radiotherapy (Wick et al., 2012, Malmstrom et al., 2012, Weller et al., 2014).
Tumor recurrence occurs in almost all patients. Currently, no standard of care is established in recurrent or progressive glioblastoma (Weller et al., 2014). Despite numerous clinical trials, the identification of effective therapies is complicated by the lack of appropriate control arms, selection bias, small sample sizes and disease heterogeneity (Weller et al., 2013).
Section snippets
Scope and objectives
Here, we review clinical efficacy data for the treatment of patients with recurrent (=progressive) glioblastoma with focus on prospective and randomized clinical trials published in PubMed or as ASCO abstract reports until June 2015. Phase I or retrospective studies were only included in case of lack of prospective data, or for historical or innovative importance. We discuss the current status of diagnosis of tumor response and progression. The therapeutic value of repeat surgery and
Diagnosis of progression and response
Criteria for response and progression in glioblastoma have remained a matter of debate for the past decades. Still, MRI imaging every 2–3 months remains the gold standard for diagnosis of response or progression in glioblastoma. However, several concerns have been raised regarding the Macdonald criteria, being the standard tool for response evaluation until 2010 (Macdonald et al., 1990). Limitations included the observation of “pseudoprogression” as a transient increase of contrast-enhancing
Summary and conclusion
Despite a plethora of clinical trials in recurrent glioblastoma, there are no established standards of care beyond alkylating chemotherapy or bevacizumab. The future role of bevacizumab is uncertain since the EORTC 26101 trial failed to demonstrate superiority for OS of lomustine plus bevacizumab over lomustine alone (Wick et al., 2015). Many single-arm trials are difficult to interpret because of the lack of a controlled and randomized design and heterogeneous cohorts. Stratification of
Conflicts of interest
KS has received honoraria from Roche for advisory board participation.
WW has received research grants from Apogenix, Boehringer Ingelheim, Eli Lilly, immatics, MSD and Roche as well as honoraria for lectures or advisory board participation from MSD and Roche. WW is or has been the coordinating investigator for sponsored clinical trials evaluating APG101 (Apogenix), bevacizumab (Roche), galunisertib (Eli Lilly), temozolomide (MSD) and temsirolimus (Pfizer).
MW has received research grants from
Katharina Seystahl, MD works as a Physician-Scientist at the Department of Neurology at the University Hospital Zurich. Research interests include clinical and molecular neuro-oncology with focus on antiangiogenic therapies and involvement of TGF-β in the pathogenesis of glioblastoma.
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Katharina Seystahl, MD works as a Physician-Scientist at the Department of Neurology at the University Hospital Zurich. Research interests include clinical and molecular neuro-oncology with focus on antiangiogenic therapies and involvement of TGF-β in the pathogenesis of glioblastoma.
Wolfgang Wick, MD, is Chairman of the Neurology Clinic at the University Hospital Heidelberg, Germany and Division Head at the German Cancer Research Center. His research focus is on precision medicine and immunotherapies for brain tumor patients. He chairs the Neurooncology Working Group (NOA) of the German Cancer Society.
Michael Weller, MD is Chairman of the Department of Neurology at the University Hospital Zurich. His research interests include brain tumor immunology and clinical trials in neuro-oncology. He serves as the Chairman of the Brain Tumor Group of the European Organisation for Research and Treatment of Cancer (EORTC).