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Treatment of Glioma in the 21st Century: An Exciting Decade of Postsurgical Treatment Advances in the Molecular Era

      Abstract

      The past decade has brought about major changes in the way we classify and have begun to approach patients with high-grade glioma. As we trend toward personalized medicine, we are now able to utilize the molecular characteristics of each individual's tumor in order to tailor their treatment, particularly if the patient is elderly or has a poor performance status at baseline. We address the state of the practice as of 2016 in regard to chemotherapy, immunotherapy, and tumor-treating fields. The goal of this review is to enhance readers’ understanding of the nuances that are allowing clinicians to tailor the treatment of high-grade glioma more specifically.

      Abbreviations and Acronyms:

      EORTC (European Organisation for Research and Treatment of Cancer), FDA (Food and Drug Administration), GBM (glioblastoma multiforme), GFR (growth factor receptor), IDH (isocitrate dehydrogenase gene), KPS (Karnofsky Performance Status), MGMT (O6-methylguanine-DNA methyltransferase gene), PCV (procarbazine, lomustine [CCNU], and vincristine), RT (radiotherapy), RTOG (Radiation Therapy Oncology Group), TMZ (temozolomide), TTF (tumor-treating field), VEGF (vascular endothelial growth factor), WHO (World Health Organization)
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      Learning Objectives: On completion of this article, you should be able to (1) identify molecular markers that play a role in the understanding of response to therapy in patients with high-grade glioma; (2) contrast the treatment options available and their efficacy in patients with high-grade glioma and various molecular signatures; and (3) recognize the larger clinical trials that have shaped the current management of high-grade glioma.
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      In their editorial and administrative roles, William L. Lanier, Jr, MD, Terry L. Jopke, Kimberly D. Sankey, and Nicki M. Smith, MPA, have control of the content of this program but have no relevant financial relationship(s) with industry. Dr Uhm has received honoraria from Novocure, manufacturer of the Optune tumor-treating field device that is discussed in this article.
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      Questions? Contact [email protected] .
      The past decade has seen remarkable research advances in glioblastoma that have culminated in tremendous improvements in patient outcome, with extensions in overall survival that have never been seen previously. Whereas 2-year survival for patients with glioblastoma remained stagnant for decades at a dismal 10%, it nearly tripled to 27% with the advent of temozolomide (TMZ) and increased almost 5-fold for patients whose tumors harbor a specific genetic alteration (O6-methylguanine-DNA methyltransferase gene [MGMT] promoter methylation) in a pivotal study just over 10 years ago.
      • Uhm J.H.
      Chemotherapy and antineoplastic agents.
      • Stupp R.
      • Mason W.P.
      • van den Bent M.J.
      • et al.
      European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group
      Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma.
      • Hegi M.E.
      • Diserens A.C.
      • Gorlia T.
      • et al.
      MGMT gene silencing and benefit from temozolomide in glioblastoma.
      The publication of that pivotal study a decade ago was the beginning of one advance after another, each documenting improvements in survival for patients with gliomas. Through advances in the identification of molecular signatures found in these tumors, new directions have been identified that are guiding treatment options in the field. Such new directions include the key role of genetic alterations that will inevitably replace the standard diagnostic procedures based on microscopy (histology/grade). These genetic alterations help to better match specific treatment modalities with a tumor based on its biologic features. This article will highlight several key advances in chemotherapy that have occurred over the past decade that, in turn, direct us toward an even brighter future for our patients.

      Chemotherapeutic Extension of Survival in Patients With Glioblastoma: TMZ and the Identification of MGMT as a Molecular Marker

      As the field of neuro-oncology was approaching the end of the 20th century, we had amassed a wealth of information about the molecular biology of glioma cells, which, in turn, identified many potential targets for therapeutics. Figure 1 illustrates the signal transduction pathways that drive glioma growth, with several principal components: the growth factor receptor (GFR) at the cell surface functioning as a “docking station” for growth signals; secondary messenger systems within the cells that are activated by GFRs; the DNA as a common convergence point for many signal transduction pathways to activate expression of cancer-associated genes (oncogenes); and the protein products of those oncogenes that then define the malignant phenotype (cell cycle progression/mitosis, angiogenesis, tumor invasiveness).
      • Uhm J.H.
      Chemotherapy and antineoplastic agents.
      Each component of this molecular diagram is an ongoing or potential target for therapeutics. Despite numerous drugs developed to inhibit the new molecular targets of signal transduction, in the end it was targeting DNA—the archetypal target in most cancers—that led to the first chemotherapy breakthrough with the advent of TMZ.
      • Stupp R.
      • Mason W.P.
      • van den Bent M.J.
      • et al.
      European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group
      Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma.
      • Hegi M.E.
      • Diserens A.C.
      • Gorlia T.
      • et al.
      MGMT gene silencing and benefit from temozolomide in glioblastoma.
      Figure thumbnail gr1
      Figure 1Signal transduction pathways in glioma. AKT = protein kinase B or serine/threonine kinase; mTOR = mechanistic target of rapamycin; PKC = protein kinase C; PTEN = phosphatase and tensin homolog; p53 = tumor protein 53; TF = transcription factor; VEGF = vascular endothelial growth factor. ∗ Indicates targets for chemotherapy.
      The benefit of TMZ is summarized in Table 1. For decades, the dogma held that surgery
      • Sanai N.
      • Polley M.Y.
      • McDermott M.W.
      • Parsa A.T.
      • Berger M.S.
      An extent of resection threshold for newly diagnosed glioblastomas.
      and radiotherapy (RT)
      • Omuro A.
      • DeAngelis L.M.
      Glioblastoma and other malignant gliomas: a clinical review.
      were the only 2 therapeutic modalities that improved survival of patients with glioblastoma multiforme (GBM), with only 10% of patients surviving 2 years. A pivotal European/Canadian study by Stupp et al
      • Stupp R.
      • Mason W.P.
      • van den Bent M.J.
      • et al.
      European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group
      Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma.
      described the addition of a well-tolerated oral chemotherapeutic agent, TMZ, which alkylates DNA (adds methyl group—hence the term alkylation—to guanine residue of DNA) (since termed the Stupp protocol). The Stupp protocol includes TMZ at 75 mg/m2 on days 1 through 42 with concomitant RT, followed by TMZ on days 1 through 5 of 28 for 6 consecutive months as adjuvant therapy at a dose of 150 to 200 mg/m2. This regimen led to an improvement in 2-year survival to 27%. Furthermore, the presence of a specific alteration—methylation of the MGMT gene promoter—improved 2-year survival to 47%, a 5-fold increase compared with RT alone.
      • Hegi M.E.
      • Diserens A.C.
      • Gorlia T.
      • et al.
      MGMT gene silencing and benefit from temozolomide in glioblastoma.
      The MGMT gene product repairs the DNA modification caused by alkylators such as TMZ, and therefore, silencing of the MGMT gene by promoter methylation is thought to confer increased sensitivity to TMZ. As a result of these 2 back-to-back publications in 2005, RT combined with TMZ became the long-awaited new standard of care in newly diagnosed glioblastoma and MGMT the key molecular marker in our field.
      Table 1Impact of Temozolomide and MGMT Promoter Methylation on Survival in Patients With Glioblastoma
      Treatment modality2-Year survival
      RT only10%
      RT + TMZ27%
      RT + TMZ + MGMT promoter methylation47%
      MGMT = O6-methylguanine-DNA methyltransferase gene; RT = radiotherapy; TMZ = temozolomide.

      Tailoring the Stupp Regimen for the Elderly Patient Population

      MGMT promoter methylation thus became an important prognostic marker in neuro-oncology. Given that the benefit of TMZ is most apparent when this gene alteration is present, MGMT methylation may also be a marker that guides therapy choices. The role of MGMT in helping to guide therapy was highlighted in a series of reports pertaining to optimization of treatment for the elderly population with high-grade glioma.
      Table 2 summarizes the evolution of treatment—in particular, the trimming of the Stupp regimen—for the elderly patient population. The French study
      • Keime-Guibert F.
      • Chinot O.
      • Taillandier L.
      • et al.
      Association of French-Speaking Neuro-Oncologists
      Radiotherapy for glioblastoma in the elderly.
      found that a standard 6-week course of RT (6000 cGy over 6 weeks) improves survival compared with palliative care alone. However, the standard RT course was poorly tolerated by many patients in the study, leading to a decrease in Karnofsky Performance Status (KPS) score, increased utilization of corticosteroids, and decreased quality of life, raising the question as to whether the standard RT course is suitable for all elderly patients. Particular concern is given to those with poor KPS score because these patients are at greatest risk for poor tolerance of RT and may be unable to complete the full course of therapy. The Canadian study
      • Roa W.
      • Brasher P.M.
      • Bauman G.
      • et al.
      Abbreviated course of radiation therapy in older patients with glioblastoma multiforme: a prospective randomized clinical trial.
      addressed this concern and documented that RT could be abbreviated to 3 weeks without compromising survival and that this regimen was, as anticipated, better tolerated. Nonetheless, the question remained as to whether RT could be omitted altogether and the patient be treated with the well-tolerated oral TMZ alone. In this regard, the subsequent German
      • Wick W.
      • Platten M.
      • Meisner C.
      • et al.
      NOA-08 Study Group of Neuro-oncology Working Group (NOA) of German Cancer Society
      Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial.
      and Scandinavian
      • Malmström A.
      • Grønberg B.H.
      • Marosi C.
      • et al.
      Nordic Clinical Brain Tumour Study Group (NCBTSG)
      Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial.
      studies found that for patients with MGMT methylation, treatment with TMZ alone was not inferior (or perhaps was even superior) to RT. These aforementioned studies evaluated specific RT schedules (without chemotherapy) or TMZ alone but did not evaluate the question of combining RT with chemotherapy. That question was addressed by the European Organisation for Research and Treatment of Cancer (EORTC)/National Cancer Information Center study
      • Perry J.R.
      • Laperriere N.
      • O'Callaghan C.J.
      • et al.
      A phase III randomized controlled trial of short-course radiotherapy with or without concomitant and adjuvant temozolomide in elderly patients with glioblastoma (CCTG CE.6, EORTC 26062-22061, TROG 08.02, NCT00482677) [abstract].
      comparing abbreviated (3 weeks) RT used alone or in combination with TMZ, the latter being a “trimmed down” version of the original Stupp protocol. In a recent report, the study results were positive, with the addition of TMZ to RT improving overall survival, especially in patients with MGMT methylation.
      Table 2Evolution of Treatment Options for Elderly Patients
      StudyQuestion/study/results
      Keime-Guibert et al,
      • Keime-Guibert F.
      • Chinot O.
      • Taillandier L.
      • et al.
      Association of French-Speaking Neuro-Oncologists
      Radiotherapy for glioblastoma in the elderly.
      2007
      Question: Does radiation matter?

      Study: Randomized study of standard RT (up to 6000 cGy over 6 wk) vs palliative care (patients ≥70 y)

      Results: Yes. RT improved OS, but there was poor tolerance of 6-wk RT in many patients
      Roa et al,
      • Roa W.
      • Brasher P.M.
      • Bauman G.
      • et al.
      Abbreviated course of radiation therapy in older patients with glioblastoma multiforme: a prospective randomized clinical trial.
      2004
      Question: Can RT be abbreviated?

      Study: 4000 cGy for 3 wk vs 6000 cGy for 6 wk; patients ≥60 y

      Results: Yes. Abbreviated RT is not inferior to standard 6-wk course; the shortened course of RT was better tolerated as well
      Wick et al,
      • Wick W.
      • Platten M.
      • Meisner C.
      • et al.
      NOA-08 Study Group of Neuro-oncology Working Group (NOA) of German Cancer Society
      Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial.
      2012
      Question: Can RT be omitted and TMZ used alone?

      Study: 6000 cGy for 6 wk vs TMZ alone; pts >65 y

      Results: Yes. In MGMT methylated patients, TMZ was not inferior (perhaps even superior) to RT
      Malmström et al,
      • Malmström A.
      • Grønberg B.H.
      • Marosi C.
      • et al.
      Nordic Clinical Brain Tumour Study Group (NCBTSG)
      Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial.
      2012
      Question: How does TMZ alone compare to RT 6 wks vs 3 wks?

      Study: Comparison of 6 wk of RT vs 3 wk of RT vs TMZ alone

      Results: Abbreviated RT was not inferior to 6 wk of RT; if tumor is MGMT methylated, using TMZ alone is an option
      Perry et al,
      • Perry J.R.
      • Laperriere N.
      • O'Callaghan C.J.
      • et al.
      A phase III randomized controlled trial of short-course radiotherapy with or without concomitant and adjuvant temozolomide in elderly patients with glioblastoma (CCTG CE.6, EORTC 26062-22061, TROG 08.02, NCT00482677) [abstract].
      2016
      Question: Is there any benefit of adding TMZ to the abbreviated RT?

      Study: 3 wk of RT with or without TMZ; patients ≥65 y

      Results: Yes. TMZ extends survival when added to 3-wk course of RT; benefits all groups, but benefit is most apparent in MGMT methylated patients
      EORTC = European Organisation for Research and Treatment of Cancer; MGMT = O6-methylguanine-DNA methyltransferase gene; NCIC = National Cancer Information Center; NOA = Neuro-oncology Working Group; OS = overall survival; RT = radiotherapy; TMZ = temozolomide.
      There is no doubt that these recent reports reflect tremendous advances in our treatment options for the elderly patient population. But the results also raise important questions. For one, what age group should be defined as elderly? The patients in the aforementioned studies ranged from 60 years or older to 70 years or older. Also, what matters more—chronological age or biological age? Should all patients over a certain age be barred from a 6-week standard course of RT (which would bar them from many clinical studies)? Despite the questions raised, these recent advances arm the clinician with choices. For example, for the patient whose neurologic/performance status is somewhat compromised, a 3-week course of RT (with TMZ) is a viable option because it is likely to be better tolerated than 6 weeks of RT. For the patient whose KPS score is quite poor but treatment is still desired, then perhaps TMZ alone could be considered (if the tumor is MGMT methylated). Such diversity of choices was not previously available to this growing patient population in which adverse effects of treatment are all the more apparent than in younger age groups. Undoubtedly, incorporation of other genetic markers (see “A Decade of Advances in Genetics and Chemotherapy: Is Immuno-oncology the Next Frontier?” section) will further advance our understanding and tailoring of therapy for not only elderly patients but patients of all ages.

      Can We Further Improve Outcome by Adding Another Treatment to the RT-TMZ Combination?

      Although the demonstration of extended survival with TMZ for patients with GBM was a tremendously welcome and long-awaited advance, we need to continue to build on this foundation. Many of the extracellular and intracellular targets illustrated in Figure 1 have been subjected to drug targeting. To date, no one drug has been found to add another layer of benefit to the RT-TMZ regimen for newly diagnosed GBM.
      In the current model for clinical trials for newly diagnosed GBM, promising agents are first tested in the setting of recurrent glioma (see “When Up-front Therapies Fail: Treatment Options for Recurrent Glioma” section) and if there is evidence of activity (for example, prolongation of progression-free survival), the drug is brought to the frontline setting for evaluation in newly diagnosed patients. In that regard, the monoclonal antibody (bevacizumab) that inhibits angiogenesis by binding and neutralizing a tumor-derived paracrine angiogenic protein (vascular endothelial growth factor [VEGF]) produced impressive results in the recurrent glioma setting.
      • Vredenburgh J.J.
      • Desjardins A.
      • Herndon II, J.E.
      • et al.
      Bevacizumab plus irinotecan in recurrent glioblastoma multiforme.
      • Friedman H.S.
      • Prados M.D.
      • Wen P.Y.
      • et al.
      Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma.
      However, when tested in conjunction with RT-TMZ in newly diagnosed GBM in 2 large prospective, randomized studies,
      • Gilbert M.R.
      • Dignam J.J.
      • Armstrong T.S.
      • et al.
      A randomized trial of bevacizumab for newly diagnosed glioblastoma.
      • Chinot O.L.
      • Wick W.
      • Mason W.
      • et al.
      Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma.
      no benefit was seen compared with placebo added to RT-TMZ. Although these results were disappointing, some degree of optimism remains regarding bevacizumab for this patient population. Molecular analysis of patient tumor samples by microarray-based gene expression profile analysis has revealed that patients whose tumor harbors the proneural expression profile live longer when treated with bevacizumab.
      • Sandmann T.
      • Bourgon R.
      • Garcia J.
      • et al.
      Patients with proneural glioblastoma may derive overall survival benefit from the addition of bevacizumab to first-line radiotherapy and temozolomide: retrospective analysis of the AVAglio trial.
      Such findings underscore the importance of incorporating molecular markers into clinical trials that provide additional layers of data stratified by genetic alterations.
      While the search continues for drugs or antibodies to improve outcome for patients with newly diagnosed GBM, exciting results have emerged by way of a medical device. Described as a fourth modality of therapy (the 3 conventional modalities being surgery, RT, and chemotherapy), the tumor-treating field (TTF) device was found in an open-label prospective randomized study to increase survival, boosting the 2-year survival from 29% with RT-TMZ alone to 43% when the TTF device was added in the adjuvant treatment phase in patients with a good performance status.
      • Stupp R.
      • Taillibert S.
      • Kanner A.A.
      • et al.
      Maintenance therapy with tumor-treating fields plus temozolomide vs temozolomide alone for glioblastoma: a randomized clinical trial.
      The TTF-based device consists of a battery/power source that is connected to adhesive pads containing arrays that generate a high-frequency alternating electric field. The proposed mechanism of action is that such a device applied to the patient’s shaved head interferes with the formation of microtubules required to separate DNA during mitosis. During mitosis, tubulin monomers must undergo polymerization to form microtubules, but in the presence of the TTF generated by the device, this polymerization is disrupted as the intrinsic electric dipole of each tubulin monomer leads it to align in the direction of the device-generated electric field,
      • Gutin P.H.
      • Wong E.T.
      Noninvasive application of alternating electric fields in glioblastoma: a fourth cancer treatment modality.
      leading to disruption of glioma cell mitosis. After its approval by the US Food and Drug Administration (FDA) in late 2015, the TTF device modality is finding its place in our armamentarium of glioma therapeutics.

      When Up-front Therapies Fail: Treatment Options for Recurrent Glioma

      The aforementioned advances of TMZ added to RT (Stupp regimen), tailoring of RT-TMZ to the elderly population, and abrogation of mitosis by electric fields have changed the landscape of glioma therapy. Nonetheless, for the great majority of patients with GBM, the tumor does ultimately break through frontline therapies. To date, bevacizumab remains the only treatment that has gained widespread acceptance for nonsurgical treatment of recurrent glioma. There are 2 important points about the journey leading to bevacizumab approval for recurrent glioma.
      First, innumerable clinical studies evaluating drugs that target GFRs and secondary messenger system components (illustrated in Figure 1) have failed dismally. These failures are due to a myriad of reasons, including poor delivery and redundancy in the signaling system. Delivery of many of these drugs, which are often hydrophilic/polar in nature, is severely impeded by the blood-brain barrier,
      • Oberoi R.K.
      • Parrish K.E.
      • Sio T.T.
      • Mittapalli R.K.
      • Elmquist W.F.
      • Sarkaria J.N.
      Strategies to improve delivery of anticancer drugs across the blood-brain barrier to treat glioblastoma.
      and hence, effective drug concentrations often cannot be attained.
      • Holdhoff M.
      • Supko J.G.
      • Gallia G.L.
      • et al.
      Intratumoral concentrations of imatinib after oral administration in patients with glioblastoma multiforme.
      • Pitz M.W.
      • Desai A.
      • Grossman S.A.
      • Blakeley J.O.
      Tissue concentration of systemically administered antineoplastic agents in human brain tumors.
      Moreover, even if a drug were able to traverse the blood-brain barrier and neutralize its intended GFR target, the tumor cell may not be affected because other GFRs that are also overexpressed continue to drive tumor growth.
      • Stommel J.M.
      • Kimmelman A.C.
      • Ying H.
      • et al.
      Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies.
      • Mellinghoff I.K.
      • Lassman A.B.
      • Wen P.Y.
      Signal transduction inhibitors and antiangiogenic therapies for malignant glioma.
      Second, given the poor experience in targeting specific signaling pathway components in glioma, would better results be attained by targeting an aspect of tumor biology that is not unique to gliomas but shared across most, if not all, tumor types? Such an extrapolation led to the evaluation of angiogenesis inhibitors in patients with brain tumors, and studies before evaluation in glioma reported exciting results of bevacizumab in many cancer types. Initial studies in glioma
      • Vredenburgh J.J.
      • Desjardins A.
      • Herndon II, J.E.
      • et al.
      Bevacizumab plus irinotecan in recurrent glioblastoma multiforme.
      • Vredenburgh J.J.
      • Desjardins A.
      • Herndon II, J.E.
      • et al.
      Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma.
      were generalized from the colorectal carcinoma literature, in which bevacizumab (antibody that neutralizes the principal angiogenic protein, VEGF) was used in combination with irinotecan. These earlier promising reports then led to a randomized study comparing bevacizumab combined with irinotecan vs bevacizumab alone that revealed no significant advantage conferred by irinotecan, hence leading to FDA approval in 2009 of single-agent bevacizumab for treatment of recurrent high-grade glioma.
      • Friedman H.S.
      • Prados M.D.
      • Wen P.Y.
      • et al.
      Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma.
      Despite the widespread use of bevacizumab since FDA approval, there still exists no conclusive data that this therapy improves overall survival. In fact, the median time to resistance to bevacizumab is a disappointing 4 months, with tumor cells escaping bevacizumab control due to (1) utilization of alternate angiogenic pathways (eg, platelet-derived growth factor, fibroblast growth factor, mesenchymal stem cells) that are independent of bevacizumab’s target VEGF
      • Lu-Emerson C.
      • Duda D.G.
      • Emblem K.E.
      • et al.
      Lessons from anti-vascular endothelial growth factor and anti-vascular endothelial growth factor receptor trials in patients with glioblastoma.
      and (2) induction of an evasive phenotype in which tumor cells may take on a more infiltrative/metastatic behavior after exposure to bevacizumab.
      • Lu K.V.
      • Bergers G.
      Mechanisms of evasive resistance to anti-VEGF therapy in glioblastoma.
      • Wick W.
      • Wick A.
      • Weiler M.
      • Weller M.
      Patterns of progression in malignant glioma following anti-VEGF therapy: perceptions and evidence.
      • de Groot J.F.
      • Fuller G.
      • Kumar A.J.
      • et al.
      Tumor invasion after treatment of glioblastoma with bevacizumab: radiographic and pathologic correlation in humans and mice.
      As a result, many trials have tested other drugs—often the very same small molecule inhibitors that were already known to be ineffective as single agents—and to date, all studies have had negative results. The addition of lomustine, a nitrosourea, to bevacizumab in a phase 2 study increased progression-free and overall survival in the classic subtype of patients with recurrent glioblastoma,
      • Taal W.
      • Oosterkamp H.M.
      • Walenkamp A.M.
      • et al.
      Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial.
      and this regimen may show promise in phase 3 studies. Increased understanding of the various angiogenic pathways (especially those not involving VEGF) in glioma growth will then hopefully lead to ways by which we can overcome resistance to current angiogenesis inhibitors.

      Learning From the Past: Older Studies Bearing Fruit Decades Later

      Thus far, we have reviewed promising clinical trial data in high-grade gliomas arising from studies initiated in the early 2000s or later. Similarly, results from studies initiated in the 1990s that have only recently matured have made a huge impact in the care of patients with low- and intermediate-grade gliomas. Two groups asked the same question: Does chemotherapy add benefit to RT in patients with intermediate- and low-grade glioma? Both studies yielded positive results with a doubling of life expectancy and, moreover, led to further underscoring the importance of molecular markers in treatment planning.

      Intermediate-Grade Glioma

      The Radiation Therapy Oncology Group (RTOG) 9402 study, hence named because it was initiated in 1994, evaluated the 3-drug regimen consisting of procarbazine, lomustine [CCNU], and vincristine (PCV) in addition to RT in the treatment of patients with World Health Organization (WHO) grade III/anaplastic oligodendroglial tumors. When initial results were reported in 2006,
      • Cairncross G.
      • Berkey B.
      • Shaw E.
      • et al.
      Phase III trial of chemotherapy plus radiotherapy compared with radiotherapy alone for pure and mixed anaplastic oligodendroglioma: Intergroup Radiation Therapy Oncology Group Trial 9402.
      concurrently with results of a similar study done in Europe by the EORTC,
      • van den Bent M.J.
      • Carpentier A.F.
      • Brandes A.A.
      • et al.
      Adjuvant procarbazine, lomustine, and vincristine improves progression-free survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: a randomized European Organisation for Research and Treatment of Cancer phase III trial.
      both studies found no difference between the treatment arms. When the data matured 6 years later, the survival curves split specifically for the patients whose tumors harbored a deletion of chromosome segments 1p and 19q (termed 1p/19q codeletion). Both studies reported essentially the same findings—the addition of chemotherapy doubled survival from approximately 8 years (RT alone) to 15 years or longer.
      • Cairncross G.
      • Wang M.
      • Shaw E.
      • et al.
      Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402.
      • van den Bent M.J.
      • Brandes A.A.
      • Taphoorn M.J.
      • et al.
      Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC Brain Tumor Group study 26951.
      In the absence of 1p/19q codeletion, the presence of a mutation in the isocitrate dehydrogenase gene (IDH) was also predictive of survival benefit from PCV therapy.
      • Cairncross J.G.
      • Wang M.
      • Jenkins R.B.
      • et al.
      Benefit from procarbazine, lomustine, and vincristine in oligodendroglial tumors is associated with mutation of IDH.
      Both genetic alterations (1p/19q codeletion and IDH mutations) were not identified until well after these studies had been initiated, but thanks to the foresight of the RTOG and EORTC study teams, archival tumor tissue from study participants could be located and assessed for these key genetic determinants, which yielded practice-altering results guided by molecular variables.

      Low-Grade Glioma

      As indicated by its name, the RTOG 9802 study was initiated in 1998. This study, like the one described previously, evaluated the role of adding PCV chemotherapy to RT but this time in the context of low-grade (WHO grade II) gliomas of both oligodendroglial and astrocytic cell types.
      • Buckner J.C.
      • Shaw E.G.
      • Pugh S.L.
      • et al.
      Radiation plus procarbazine, CCNU, and vincristine in low-grade glioma.
      For patients in the higher-risk category (any patient >40 years of age or any patient regardless of age who had residual tumor after biopsy/surgery), chemotherapy improved overall survival. But similar to the study with grade III oligodendrogliomas, the oligodendroglial tumors as well as tumors harboring the IDH mutation derived the most apparent benefit from the chemotherapy. The relatively small number of patients whose tumors were available for 1p/19q analysis made it difficult to determine if that gene alteration was predictive of chemotherapy benefit.
      As such, both the intermediate- and low-grade glioma studies discussed herein determined that the oligodendroglial cell type as well as the presence of IDH mutation portends a better outcome with chemotherapy. The experience of these pivotal studies of low- and intermediate-grade glioma is somewhat ironic in that advances in tumor genetics led to a rekindled interest in a chemotherapy regimen (PCV) that was believed to be a thing of the past. Controversy remains regarding whether PCV is superior to TMZ in this setting. Perhaps there is no such thing as “old drugs,” but rather simply drugs that have yet to be matched to the appropriate patient population.

      A Decade of Advances in Genetics and Chemotherapy: Is Immuno-Oncology the Next Frontier?

      The past decade has indeed been eventful, marked by a number of important clinical advances. We can improve survival in low-, intermediate-, and high-grade gliomas by adding chemotherapy to RT, and now for all 3 conditions, the combined therapy is the new standard of care. In all 3 grades of glioma, specific genetic alterations serve as not only prognostic but also predictive markers because they identify which patient population would best benefit from chemotherapy. However, although the overall life expectancy has increased substantially, treatment resistance is too often an occurrence, largely stemming from 2 major hindrances to therapy—tumor heterogeneity and barriers to drug delivery.
      Although a schematic of a single tumor cell as depicted in Figure 1 may be accurate for that one individual tumor cell, the reality is that a patient’s tumor mass is composed of millions of cells, each cell with its potential to diverge and evolve its own molecular alterations, thereby generating extensive intratumoral heterogeneity. In such a system in which, for example, EGFRvIII alteration can be seen in one area of the tumor but not in another, the possible permutations of this and other genetic alterations from one cell to another in a large tumor mass can be endless.
      • Suzuki H.
      • Aoki K.
      • Chiba K.
      • et al.
      Mutational landscape and clonal architecture in grade II and III gliomas.
      Herein lies the challenge of finding a curative treatment—how to treat such an incredible diversity of tumor cells with just 1, 2, or 3 drugs. The future may lie in immunologic therapies.
      Figure 2 and Table 3 illustrate the therapeutic challenges as well as potential solutions presented by immunologically based therapies. The tumor mass (“A” in Figure 2) presents the challenge of the tremendous heterogeneity of cells, each cell harboring antigens distinct from other cells within the mass. These tumor antigens are processed by the dendritic cells, which present the antigens to T cells (“B” in Figure 2), thereby converting naive T cells to their activated forms. There are several checkpoints in this pathway whose function is to dampen T-cell activation in order to avoid an overzealous immune reaction that could lead to autoimmune conditions. Such immunosuppressive checkpoints exist at the point of antigen presentation (interaction between dendritic cell and naive T cells; “B” in Figure 2) and in the tumor microenvironment (“D” in Figure 2) and are amenable to therapy with checkpoint inhibitors (Table 3).
      Figure thumbnail gr2
      Figure 2Therapeutic challenges and potential solutions presented by immunologically based therapies. A = tumor mass; B = tumor antigens are processed by the dendritic cells, which present the antigens to T cells, thereby converting naive T cells to their activated forms; C = activated T cells are capable of entering the central nervous system via expression of specific cell surface molecules; D = tumor microenvironment; EGFR = epidermal growth factor receptor; red triangles = blood-brain barrier.
      Table 3Immunotherapeutic Approaches to Address Challenges in Brain Tumor Treatment in Immuno-oncological Therapies
      Challenge to treatmentPossible solution/approach
      • Tumor heterogeneity
        •  In “A” on Figure 2, heterogeneity is illustrated by different colored cells (each cell representing a distinct set of molecular alterations and antigens)
      • Dendritic cell vaccine
        •  Antigen-presenting cells or dendritic cells process and present innumerable tumor antigens to T cells to generate activated antitumor T cells
        •  Resected tumor serves as a rich source of numerous tumor antigens to be targeted by T cells, thereby addressing the issue of tumor heterogeneity
      Antigen presentation by dendritic cells (“B” on Figure 2) is dampened by cell-cell interactions between dendritic cells and T cells. This dampening of antigen presentation serves as a checkpoint to suppress T-cell activation
      • Checkpoint inhibitor
        •  Monoclonal antibodies to disrupt the immunosup-pressive cell-cell signaling (example: ipilimumab, a checkpoint inhibitor)
      Blood-brain barrier hindering entry of drugs into brain and tumor (“C” on Figure 2)Activated T cells are capable of entering the central nervous system via expression of specific cell surface molecules
      • Immunosuppressive factors in tumor microenvironment (“D” on Figure 2)
        •  PD-L1 expressed by tumor cells (red triangles on Figure 2) bind to PD-1 receptor on approaching T cells, inducing apoptotic death of T cells
      • Checkpoint inhibitor
        •  Monoclonal antibodies to disrupt interaction between PD-L1 and PD-1
        •  (example: nivolumab)
      • Immunosuppression by tumor
        •  Effectively cloaks tumor cells to avoid detection by T cells and antigen-presenting cells
      Dendritic cell vaccine. Patient’s dendritic cells are exposed to tumor antigens extracted from resected tumor to drive T-cell activation

      Radiotherapy, oncolytic viruses kill a portion of tumor → tumor cell death releases tumor antigens that then drive antigen presentation → recruitment of activated T cells to area of radiotherapy or oncolytic virus injection to augment tumor kill

      The Molecular Era of Neuro-Oncology: Updated Map for Future Advances

      Undoubtedly, the past decade has been a remarkable one, with many advances in treatment options. In regard to chemotherapy, our field has gone from having no clear role for chemotherapy in the treatment of glioma to chemotherapy being able to as much as double life expectancy in the case of low- and intermediate-grade gliomas. Moreover, not only prognosis but also treatment choices can be guided by the tumor’s molecular/genetic alterations as summarized in Table 4.
      Table 4Molecular/Genetic Markers in Glioma and Their Clinical Relevance—a Road Map for Future Advances in Treatment
      Molecular alteration in gliomaClinical relevance
      MGMT promoter methylationSensitivity to alkylator chemotherapy (eg, TMZ)
      TERT mutationNegative prognostic marker when present alone
      • Eckel-Passow J.E.
      • Lachance D.H.
      • Molinaro A.M.
      • et al.
      Glioma groups based on 1p/19q, IDH, and TERT promoter mutations in tumors.
      Cancer Genome Atlas Research Network
      Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas.
      ; however, the prognostic/predictive benefit of MGMT methylation may require TERT mutation
      1p/19q CodeletionPositive prognostic marker. Identifies subgroup of gliomas responsive to alkylator-based chemotherapy as well as RT
      IDH mutationPositive prognostic marker. Identifies subgroup of patients with 1p/19q nondeleted oligodendroglioma who may benefit from alkylator chemotherapy
      1p/19q Codeletion + IDH mutation + TERT mutationThis combination identifies one of the best prognostic categories for glioma patients
      Proneural gene expression profileIdentifies subgroup of patients with GBM who may benefit from bevacizumab added to RT-TMZ
      EGFR variant 3 (EGFRvIII)Identifies subgroup that may benefit from EGFRvIII-directed vaccine therapies
      • Schuster J.
      • Lai R.K.
      • Recht L.D.
      • et al.
      A phase II, multicenter trial of rindopepimut (CDX-110) in newly diagnosed glioblastoma: the ACT III study.
      PD-L1Activated T cells express PD-1; when PD-L1 (expressed by tumor cells) binds to its receptor PD-1 on T cells, these T cells undergo apoptotic death (hence, mechanism of immune evasion). Target for nivolumab (PD-L1 inhibitor)
      • Berghoff A.S.
      • Kiesel B.
      • Widhalm G.
      • et al.
      Programmed death ligand 1 expression and tumor-infiltrating lymphocytes in glioblastoma.
      CD155Receptor for infection by oncolytic poliovirus
      • Brown M.C.
      • Gromeier M.
      Cytotoxic and immunogenic mechanisms of recombinant oncolytic poliovirus.
      CD46Receptor for infection by oncolytic measles virus
      • Allen C.
      • Paraskevakou G.
      • Liu C.
      • et al.
      Oncolytic measles virus strains in the treatment of gliomas.
      Overactive RasPermits replication of modified oncolytic reovirus
      • Wilcox M.E.
      • Yang W.
      • Senger D.
      • et al.
      Reovirus as an oncolytic agent against experimental human malignant gliomas.
      EGFR = epidermal growth factor receptor; GBM = glioblastoma multiforme; IDH = isocitrate dehydrogenase gene; MGMT = O6-methylguanine-DNA methyltransferase gene; RT = radiotherapy; TERT = telomerase reverse transcriptase gene; TMZ = temozolomide.
      With the ever-growing importance of genetic alterations to determine prognosis and treatment choices, the diagnostic labels that we ascribe to tumors is shifting from the standard WHO grades II, III, and IV to one of molecularly based diagnoses. This transition toward molecular classification of gliomas has been evolving over the past 10 to 15 years and reached a tipping point in 2015 when 3 groups (Mayo Clinic/University of California, San Francisco,
      • Eckel-Passow J.E.
      • Lachance D.H.
      • Molinaro A.M.
      • et al.
      Glioma groups based on 1p/19q, IDH, and TERT promoter mutations in tumors.
      the Cancer Genome Atlas Network (TCGA) group,
      Cancer Genome Atlas Research Network
      Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas.
      and the Japanese group led by Suzuki et al
      • Suzuki H.
      • Aoki K.
      • Chiba K.
      • et al.
      Mutational landscape and clonal architecture in grade II and III gliomas.
      ) concurrently published their findings that converged on the same conclusion: that molecularly based diagnosis is superior to diagnosis based on conventional histologic and morphological features of tumor cells. For example, although we would typically expect the prognosis to be grade dependent, exceptions to this general rule are often encountered—eg, a patient with a grade IV/high-grade tumor may have a much longer life expectancy than one who has a grade III/intermediate-grade or even grade II/low-grade tumor. Furthermore, there can be considerable variability in histology-based diagnosis among neuropathologists because of the relatively subjective nature of interpreting cell morphology, nuclear atypia, number of mitotic figures, and other morphological characteristics that determine tumor type and grade. This issue is in contrast to the more binary nature of interpreting genetic tests—for example, 1p/19q alleles are either codeleted or they are not. Along these lines, the aforementioned 3 articles published in 2015 reveal that patients with brain tumors can be grouped into diagnostic clusters based on genetic alterations in which a tumor harboring triple positivity (1p/19q deletion, IDH mutation, TERT [telomerase reverse transcriptase gene]/telomerase mutation) presents one of the best prognostic groups. Conversely, a tumor harboring none of the alterations portends a prognosis similar to grade IV astrocytoma (glioblastoma) even if the histology may be grade II or III. As such, the 2016 WHO classification of central nervous system tumors has been extensively revised to incorporate genetic alterations.
      • Louis D.N.
      • Perry A.
      • Reifenberger G.
      • et al.
      The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary.
      This more accurate classification scheme will also influence future clinical studies, in which eligibility for a specific clinical study will be based more on molecular genetic alterations.

      Conclusion

      The shift of the neuro-oncology field toward individualized medicine represents a molecular revolution built on a steadfast evolution and accumulation of many years of rigorous basic and translational research. The past decade that has seen tremendous advances in treatments that prolong life for patients with brain tumors was the product of many preceding years of research. As we look ahead, we rely on the exponential increase in our understanding of glioma biology to serve as fuel for an even better future for our patients. If the numerous scientific advances listed in Table 4 serve in any way as an indicator of what lies ahead, then we can be optimistic.

      Supplemental Online Material

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