Review
Therapeutic options in recurrent glioblastoma—An update

https://doi.org/10.1016/j.critrevonc.2016.01.018Get rights and content

Highlights

  • Standards of care are incompletely defined in recurrent glioblastoma.

  • The evidence for repeat surgery or reirradiation is limited.

  • Alkylating chemotherapy (nitrosourea, temozolomide) is a widely accepted therapeutic option.

  • Bevacizumab has clinical activity, but an effect on overall survival is uncertain.

  • Individualized treatment concepts should consider age, performance status, MGMT promoter methylation status, response to and type of previous regimens and quality of life.

Abstract

Introduction

Standards of care are not yet defined in recurrent glioblastoma.

Methods

We reviewed the literature on clinical trials for recurrent glioblastoma available in PubMed and American Society of Clinical Oncology (ASCO) abstracts until June 2015.

Results

Evidence is limited due to the paucity of randomized controlled studies. Second surgery or re-irradiation are options for selected patients. Alkylating chemotherapy such as nitrosoureas or temozolomide and the vascular endothelial growth factor (VEGF) antibody, bevacizumab, exhibit comparable single agent activity. Phase III data exploring the benefit of combining bevacizumab and lomustine are emerging. Novel approaches in the fields of targeted therapy, immunotherapy, and tumor metabolism are coming forward. Several biomarkers are being explored, but, except for O6-methylguanine DNA methyltransferase (MGMT) promoter methylation, none has assumed a role in clinical practice.

Conclusion

Proper patient selection, development of predictive biomarkers and randomized controlled studies are required to develop evidence-based concepts for recurrent glioblastoma.

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.

References (146)

  • T.T. Batchelor et al.

    Phase III randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma

    J. Clin. Oncol.

    (2013)
  • A. Berrocal et al.

    Extended-schedule dose-dense temozolomide in refractory gliomas

    J. Neurooncol.

    (2010)
  • O. Bloch et al.

    Impact of extent of resection for recurrent glioblastoma on overall survival: clinical article

    J. Neurosurg.

    (2012)
  • O. Bloch et al.

    Heat-shock protein peptide complex-96 vaccination for recurrent glioblastoma: a phase II, single-arm trial

    Neuro Oncol.

    (2014)
  • D. Bonekamp et al.

    Association of overall survival in patients with newly diagnosed glioblastoma with contrast-enhanced perfusion MRI: comparison of intraindividually matched T1 – and T2 (*) – based bolus techniques

    J. Magn. Reson. Imaging

    (2015)
  • M. Brada et al.

    Temozolomide versus procarbazine, lomustine, and vincristine in recurrent high-grade glioma

    J. Clin. Oncol.

    (2010)
  • A.A. Brandes et al.

    Temozolomide as a second-line systemic regimen in recurrent high-grade glioma: a phase II study

    Ann. Oncol.

    (2001)
  • A.A. Brandes et al.

    Temozolomide in patients with glioblastoma at second relapse after first line nitrosourea-procarbazine failure: a phase II study

    Oncology

    (2002)
  • A.A. Brandes et al.

    How effective is BCNU in recurrent glioblastoma in the modern era? A phase II trial

    Neurology

    (2004)
  • A.A. Brandes et al.

    First-line chemotherapy with cisplatin plus fractionated temozolomide in recurrent glioblastoma multiforme: a phase II study of the Gruppo Italiano Cooperativo di Neuro-Oncologia

    J. Clin. Oncol.

    (2004)
  • A.A. Brandes et al.

    Second-line chemotherapy with irinotecan plus carmustine in glioblastoma recurrent or progressive after first-line temozolomide chemotherapy: a phase II study of the Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO)

    J. Clin. Oncol.

    (2004)
  • A.A. Brandes et al.

    Temozolomide 3 weeks on and 1 week off as first-line therapy for recurrent glioblastoma: phase II study from gruppo italiano cooperativo di neuro-oncologia (GICNO)

    Br. J. Cancer

    (2006)
  • A.A. Brandes et al.

    Fotemustine as second-line treatment for recurrent or progressive glioblastoma after concomitant and/or adjuvant temozolomide: a phase II trial of Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO)

    Cancer Chemother. Pharmacol.

    (2009)
  • A.A. Brandes et al.

    A phase II study of galunisertib monotherapy or galunisertib plus lomustine compared to lomustine monotherapy in recurrent glioblastoma

    J. Clin. Oncol.

    (2015)
  • M.C. Chamberlain et al.

    A phase 2 trial of verubulin for recurrent glioblastoma: a prospective study by the Brain Tumor Investigational Consortium (BTIC)

    J. Neurooncol.

    (2014)
  • D.T. Chan et al.

    Temozolomide in the treatment of recurrent malignant glioma in Chinese patients

    Hong Kong Med. J.

    (2005)
  • S.L. Chua et al.

    Phase 2 study of temozolomide and Caelyx in patients with recurrent glioblastoma multiforme

    Neuro Oncol.

    (2004)
  • S.E. Combs et al.

    Radiotherapeutic alternatives for previously irradiated recurrent gliomas

    BMC Cancer

    (2007)
  • S.E. Combs et al.

    Generation and validation of a prognostic score to predict outcome after re-irradiation of recurrent glioma

    Acta Oncol.

    (2013)
  • A. Desjardins et al.

    Bevacizumab and daily temozolomide for recurrent glioblastoma

    Cancer

    (2012)
  • F. Dhermain et al.

    Role of radiotherapy in recurrent gliomas

    Bull. Cancer

    (2004)
  • J.F. de Groot et al.

    Phase II study of aflibercept in recurrent malignant glioma: a North American Brain Tumor Consortium study

    J. Clin. Oncol.

    (2011)
  • B.M. Ellingson et al.

    Pretreatment ADC histogram analysis is a predictive imaging biomarker for bevacizumab treatment but not chemotherapy in recurrent glioblastoma

    AJNR Am. J. Neuroradiol.

    (2014)
  • B.M. Ellingson et al.

    Consensus recommendations for a standardized brain tumor imaging protocol in clinical trials

    Neuro Oncol.

    (2015)
  • M. Esteller et al.

    Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents

    N. Engl. J. Med.

    (2000)
  • M.G. Fabrini et al.

    A multi-institutional phase II study on second-line fotemustine chemotherapy in recurrent glioblastoma

    J Neurooncol

    (2009)
  • K.M. Field et al.

    Randomized phase 2 study of carboplatin and bevacizumab in recurrent glioblastoma

    Neuro Oncol.

    (2015)
  • M. Flieger et al.

    Re-irradiation and bevacizumab in recurrent high-grade glioma: an effective treatment option

    J. Neurooncol.

    (2014)
  • S.E. Fogh et al.

    Hypofractionated stereotactic radiation therapy: an effective therapy for recurrent high-grade gliomas

    J. Clin. Oncol.

    (2010)
  • E. Franceschi et al.

    The effect of re-operation on survival in patients with recurrent glioblastoma

    Anticancer Res.

    (2015)
  • B.B. Friday et al.

    Phase II trial of vorinostat in combination with bortezomib in recurrent glioblastoma: a north central cancer treatment group study

    Neuro Oncol.

    (2012)
  • H.S. Friedman et al.

    Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma

    J. Clin. Oncol.

    (2009)
  • E. Galanis et al.

    Phase II trial of vorinostat in recurrent glioblastoma multiforme: a north central cancer treatment group study

    J. Clin. Oncol.

    (2009)
  • E. Galanis et al.

    Phase II study of bevacizumab in combination with sorafenib in recurrent glioblastoma (N0776): a north central cancer treatment group trial

    Clin. Cancer Res.

    (2013)
  • E. Galanis et al.

    NCCTG N0872 (Alliance): a randomized placebo-controlled phase II trial of bevacizumab plus dasatinib in patients with recurrent glioblastoma (GBM)

    J. Clin. Oncol.

    (2015)
  • N. Galldiks et al.

    Diagnosis of pseudoprogression in patients with glioblastoma using O-(2-[18F]fluoroethyl)-l-tyrosine PET

    Eur. J. Nucl. Med. Mol. Imaging

    (2015)
  • H. Gan et al.

    A phase 1 study evaluating ABT-414 in combination with temozolomide (TMZ) for subjects with recurrent or unresectable glioblastoma (GBM)

    J. Clin. Oncol.

    (2015)
  • P. Gaviani et al.

    Combined chemotherapy with temozolomide and fotemustine in recurrent glioblastoma patients

    J. Neurooncol.

    (2011)
  • A. Ghiaseddin et al.

    Phase II study of bevacizumab and vorinostat for recurrent glioblastoma

    J. Clin. Oncol.

    (2015)
  • M.R. Gilbert et al.

    RTOG 0625: a phase II study of bevacizumab with irinotecan in recurrent glioblastoma (GBM)

    J. Clin. Oncol.

    (2009)
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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).

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