Success and Failures of Combined Modalities in Glioblastoma Multiforme: Old Problems and New Directions

https://doi.org/10.1016/j.semradonc.2016.06.003Get rights and content

Glioblastoma multiforme (GBM) is an aggressive intracranial tumor characterized by local and distant brain relapse despite aggressive therapy. Current standard treatment includes surgical resection followed by radiation with concurrent and adjuvant temozolomide as part of a combined modality approach. In this review, the historical basis for the current standard treatment is discussed as well as other recent combined modality successes and failures. An overview of emerging combined modality therapies for GBM is presented including immunotherapy, and rationally designed radiosensitizers. Unanswered questions facing the oncology community regarding the treatment of GBM are also discussed.

Introduction

The therapeutic management of glioblastoma multiforme (GBM) and many other brain tumors is complicated by a unique set of challenges that are rarely seen in combination at other extracranial sites. These challenges consist of (1) extent of resection: tumors arising in many regions of the brain and the brainstem are unresectable because of unacceptable levels of morbidity and mortality, and the infiltrative nature of these tumors makes it virtually impossible to resect all viable tumor cells; (2) blood-brain barrier (BBB) penetration: many therapeutic agents, regardless of their tumor selectivity and potency, cannot cross the BBB, and in many cases, tumor penetration can be predicted but has not been confirmed in situ; (3) tissue sensitivity: cytotoxic agents, especially radiation therapy (RT) and many systemic DNA damaging chemotherapies, can induce significant acute toxicities in brain tissue, as well as profound late effects including cognitive dysfunction, and finally (4) therapeutic resistance: although controversial and not necessarily limited to GBMs, these cancers appear to contain substantial radio-resistant and chemo-resistant populations of tumor cells, as well as significant intratumoral heterogeneity at the molecular level. Because of these challenges, it is likely that any significant advance in overall survival (OS) for GBM requires an intensive, combined modality strategy, which addresses a heterogeneous and treatment-refractory disease at the primary site and at distant areas in the brain. Much like Sun Tzu’s advice above, a variety of unique tactics are required for this strategy to be successful. In this review, we define and summarize the key elements of combined modality therapy for the treatment of GBM. We then present selected examples of successes and failures along the path to enhance OS for this disease, followed by a discussion of emerging opportunities for new therapy combinations. Finally, we present a series of open questions for consideration in the future for the design of new treatment regimens.

Section snippets

Clinical Case

We begin with a clinical case of GBM that highlights the aggressive and insidious nature of GBM, and why this disease has proved so resistant to treatment. Patient G.S. was initially diagnosed with a left frontal lobe GBM after presenting with several brief episodes of speech impairment in May of 2013. The patient was treated at our center, and the chronological magnetic resonance imaging (MRI) images for this patient are shown in the Figure. Because of the tumor’s location near Broca area, he

Overview of Combined Modality Therapy and Its Relevance in GBM

Before we can discuss successes and failures in GBM combined modality therapy, it is important to review the concept and the tools that are utilized for treatment in GBM. While the concept of combined modality therapy and its application in GBM may seem obvious to this particular audience, our field is rapidly evolving and we are witnessing a significant increase in the types of novel therapies that are available. With each new advance, there is an opportunity to de-emphasize, or to simply

Successes and Failures in GBM Combined Modality Therapy

Here, we focus on 2 successes and 2 failures in combined modality therapy for GBM. The 2 successes were chosen to highlight the existing backbones of therapy and promising approaches that have recently matured in clinical trials, both of which would be important components in future combined modality strategies. Importantly, both successes were built on the thoughtful integration of the new modality into the existing treatment regimen from GBM. The 2 failures were chosen as a means to highlight

Emerging Combined Modality Therapy Opportunities for GBM

In the back-drop of successes and failures presented above, there a number of promising new therapeutic strategies for GBM that are in development. The 2 examples are, (A) rationally designed radiosensitizers and (B) immune checkpoint modulation. The first example largely has been driven by the recent development of clinically viable drugs that target the DNA damage response. In contrast to their precursor molecules, these agents demonstrate extraordinary selectivity and potency for various DNA

Hypofractionation—Better or Worse for Combined Modality Therapy?

The standard radiation dose regimen for glioblastoma is based on the Stupp regimen, which involves a total dose of 60 Gy in 2 Gy fractions.40 Hypofractionated treatment has been shown to provide similar outcomes to standard fractionation in elderly patients with GBM who receive radiation alone.204, 205 Recently, short-course therapy delivered over 1 week was compared to the more commonly used hypofractionated regimen of 40 Gy in 2.67 Gy fractions in elderly patients, and showed no difference in OS

Conclusions

In summary, despite decades of disappointing clinical trial results with little change in OS for GBM, new developments in multiple therapeutic realms hold great promise for the treatment of GBM. It is likely that the combination of a variety of therapeutic strategies are necessary to substantially improve OS for this disease, as history has taught us that no single agent can control this disease. We return to the quotation from Sun Tzu for guidance, which still remains true to this day. As our

Acknowledgments

We wish to acknowledge Drs David Reardon, Minesh Mehta, Martin Van Den Bent, and Skip Grossman for insightful comments and critical review of the article.

References (229)

  • L. Souhami et al.

    Randomized comparison of stereotactic radiosurgery followed by conventional radiotherapy with carmustine to conventional radiotherapy with carmustine for patients with glioblastoma multiforme: Report of Radiation Therapy Oncology Group 93-05 protocol

    Int J Radiat Oncol Biol Phys

    (2004)
  • J.G. Douglas et al.

    [F-18]-fluorodeoxyglucose positron emission tomography for targeting radiation dose escalation for patients with glioblastoma multiforme: Clinical outcomes and patterns of failure

    Int J Radiat Oncol Biol Phys

    (2006)
  • J.R. Castro et al.

    A phase I-II trial of heavy charged particle irradiation of malignant glioma of the brain: A Northern California Oncology Group Study

    Int J Radiat Oncol Biol Phys

    (1985)
  • J.R. Castro et al.

    Neon heavy charged particle radiotherapy of glioblastoma of the brain

    Int J Radiat Oncol Biol Phys

    (1997)
  • T. Pickles et al.

    Pion radiation for high grade astrocytoma: Results of a randomized study

    Int J Radiat Oncol Biol Phys

    (1997)
  • H. Suit et al.

    Proton vs carbon ion beams in the definitive radiation treatment of cancer patients

    Radiother Oncol

    (2010)
  • V.A. Levin et al.

    Superiority of post-radiotherapy adjuvant chemotherapy with CCNU, procarbazine, and vincristine (PCV) over BCNU for anaplastic gliomas: NCOG 6G61 final report

    Int J Radiat Oncol Biol Phys

    (1990)
  • M.D. Prados et al.

    Radiation therapy and hydroxyurea followed by the combination of 6-thioguanine and BCNU for the treatment of primary malignant brain tumors

    Int J Radiat Oncol Biol Phys

    (1998)
  • E.C. Halperin et al.

    A phase III randomized prospective trial of external beam radiotherapy, mitomycin C, carmustine, and 6-mercaptopurine for the treatment of adults with anaplastic glioma of the brain. CNS Cancer Consortium

    Int J Radiat Oncol Biol Phys

    (1996)
  • S.M. O'Reilly et al.

    Temozolomide: A new oral cytotoxic chemotherapeutic agent with promising activity against primary brain tumours

    Eur J Cancer

    (1993)
  • E.S. Newlands et al.

    The Charing Cross Hospital experience with temozolomide in patients with gliomas

    Eur J Cancer

    (1996)
  • K. Yoshioka et al.

    ATR kinase activation mediated by MutSalpha and MutLalpha in response to cytotoxic O6-methylguanine adducts

    Mol Cell

    (2006)
  • J. van Rijn et al.

    Survival of human glioma cells treated with various combination of temozolomide and X-rays

    Int J Radiat Oncol Biol Phys

    (2000)
  • S.E. Combs et al.

    In vitro responsiveness of glioma cell lines to multimodality treatment with radiotherapy, temozolomide, and epidermal growth factor receptor inhibition with cetuximab

    Int J Radiat Oncol Biol Phys

    (2007)
  • K.A. van Nifterik et al.

    Differential radiosensitizing potential of temozolomide in MGMT promoter methylated glioblastoma multiforme cell lines

    Int J Radiat Oncol Biol Phys

    (2007)
  • B.L. Carlson et al.

    Radiosensitizing effects of temozolomide observed in vivo only in a subset of O6-methylguanine-DNA methyltransferase methylated glioblastoma multiforme xenografts

    Int J Radiat Oncol Biol Phys

    (2009)
  • A.R. Dix et al.

    Immune defects observed in patients with primary malignant brain tumors

    J Neuroimmunol

    (1999)
  • A. Waziri

    Glioblastoma-derived mechanisms of systemic immunosuppression

    Neurosurg Clin N Am

    (2010)
  • C.R. Kelsey et al.

    Combined-modality therapy for early-stage Hodgkin lymphoma: Maintaining high cure rates while minimizing risks

    Oncology (Williston Park)

    (2012)
  • C.J. Tsai et al.

    Outcomes after multidisciplinary treatment of inflammatory breast cancer in the era of neoadjuvant HER2-directed therapy

    Am J Clin Oncol

    (2015)
  • S. Mallick et al.

    Shifting paradigm in the management of anal canal carcinoma

    J Gastrointest Cancer

    (2015)
  • C.D. Corso et al.

    Role of chemoradiotherapy in elderly patients with limited-stage small-cell lung cancer

    J Clin Oncol

    (2015)
  • J.R. Park et al.

    Children’s Oncology Group’s 2013 blueprint for research: Neuroblastoma

    Pediatr Blood Cancer

    (2013)
  • G.G. Steel et al.

    Exploitable mechanisms in combined radiotherapy-chemotherapy: The concept of additivity

    Int J Radiat Oncol Biol Phys

    (1979)
  • M. Lacroix et al.

    A multivariate analysis of 416 patients with glioblastoma multiforme: Prognosis, extent of resection, and survival

    J Neurosurg

    (2001)
  • N. Sanai et al.

    An extent of resection threshold for newly diagnosed glioblastomas

    J Neurosurg

    (2011)
  • W.E. Dandy

    Removal of right cerebral hemisphere for certain tumors with hemiplegia: Preliminary report

    J Am Med Assoc

    (1928)
  • A.P. Andersen

    Postoperative irradiation of glioblastomas. Results in a randomized series

    Acta Radiol Oncol Radiat Phys Biol

    (1978)
  • M.D. Walker et al.

    Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery

    N Engl J Med

    (1980)
  • M.D. Walker et al.

    Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. A cooperative clinical trial

    J Neurosurg

    (1978)
  • F.H. Hochberg et al.

    Assumptions in the radiotherapy of glioblastoma

    Neurology

    (1980)
  • B.C. Liang et al.

    Malignant astrocytomas: Focal tumor recurrence after focal external beam radiation therapy

    J Neurosurg

    (1991)
  • B.J. Gebhardt et al.

    Patterns of failure for glioblastoma multiforme following limited-margin radiation and concurrent temozolomide

    Radiat Oncol

    (2014)
  • R.J. Coffey et al.

    Survival after stereotactic biopsy of malignant gliomas

    Neurosurgery

    (1988)
  • C.H. Chang et al.

    Comparison of postoperative radiotherapy and combined postoperative radiotherapy and chemotherapy in the multidisciplinary management of malignant gliomas. A joint Radiation Therapy Oncology Group and Eastern Cooperative Oncology Group study

    Cancer

    (1983)
  • D.F. Nelson et al.

    Combined modality approach to treatment of malignant gliomas—Re-evaluation of RTOG 7401/ECOG 1374 with long-term follow-up: A joint study of the Radiation Therapy Oncology Group and the Eastern Cooperative Oncology Group

    NCI Monogr

    (1988)
  • J.L. Chan et al.

    Survival and failure patterns of high-grade gliomas after three-dimensional conformal radiotherapy

    J Clin Oncol

    (2002)
  • S. Rieken et al.

    Proton and carbon ion radiotherapy for primary brain tumors delivered with active raster scanning at the Heidelberg Ion Therapy Center (HIT): Early treatment results and study concepts

    Radiat Oncol

    (2012)
  • D. Schardt et al.

    Heavy-ion tumor therapy: Physical and radiobiological benefits

    Rev Mod Phys

    (2010)
  • R.M. Anderson et al.

    Effect of linear energy transfer (LET) on the complexity of alpha-particle-induced chromosome aberrations in human CD34+ cells

    Radiat Res

    (2007)

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