- Department of Neuro-oncology, Roger Salengro Hospital, University Hospital, Lille, and Neurology, Department of Medical Oncology, Oscar Lambret Center, Lille, France, Inserm U-1192, Laboratoire de Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM), Lille 1 University, Villeneuve D’Ascq, France
- Neurology, Mazarin and Radiation Oncology, Pitié Salpétrière Hospital, University Pierre et Marie Curie, Paris VI, Paris, France
- Department of Neurology and Neurological Surgery, University of Washington, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
Correspondence Address:
Marc C. Chamberlain
Department of Neurology and Neurological Surgery, University of Washington, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
DOI:10.4103/2152-7806.151331
Copyright: © 2015 Le Rhun E. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.How to cite this article: Rhun EL, Taillibert S, Chamberlain MC. The future of high-grade glioma: Where we are and where are we going. Surg Neurol Int 13-Feb-2015;6:
How to cite this URL: Rhun EL, Taillibert S, Chamberlain MC. The future of high-grade glioma: Where we are and where are we going. Surg Neurol Int 13-Feb-2015;6:. Available from: http://sni.wpengine.com/surgicalint_articles/the-future-of-high-grade-glioma-where-we-are-and-where-are-we-going/
Abstract
High-grade glioma (HGG) are optimally treated with maximum safe surgery, followed by radiotherapy (RT) and/or systemic chemotherapy (CT). Recently, the treatment of newly diagnosed anaplastic glioma (AG) has changed, particularly in patients with 1p19q codeleted tumors. Results of trials currenlty ongoing are likely to determine the best standard of care for patients with noncodeleted AG tumors. Trials in AG illustrate the importance of molecular characterization, which are germane to both prognosis and treatment. In contrast, efforts to improve the current standard of care of newly diagnosed glioblastoma (GB) with, for example, the addition of bevacizumab (BEV), have been largely disappointing and furthermore molecular characterization has not changed therapy except in elderly patients. Novel approaches, such as vaccine-based immunotherapy, for newly diagnosed GB are currently being pursued in multiple clinical trials. Recurrent disease, an event inevitable in nearly all patients with HGG, continues to be a challenge. Both recurrent GB and AG are managed in similar manner and when feasible re-resection is often suggested notwithstanding limited data to suggest benefit from repeat surgery. Occassional patients may be candidates for re-irradiation but again there is a paucity of data to commend this therapy and only a minority of selected patients are eligible for this approach. Consequently systemic therapy continues to be the most often utilized treatment in recurrent HGG. Choice of therapy, however, varies and revolves around re-challenge with temozolomide (TMZ), use of a nitrosourea (most often lomustine; CCNU) or BEV, the most frequently used angiogenic inhibitor. Nevertheless, no clear standard recommendation regarding the prefered agent or combination of agents is avaliable. Prognosis after progression of a HGG remains poor, with an unmet need to improve therapy.
Keywords: Anaplastic glioma, anti-angiogenic agents, bevacizumab, chemotherapy, glioblastoma, high grade glioma, immunotherapy, nitrosourea, temozolomide, targeted therapy
INTRODUCTION
High-grade glioma (HGG) are the most frequent malignant primary brain tumor, which account for 80% of all gliomas in the United States, and are encountered with an annual incidence of 5.26 per 100,000 population, or 17,000 new cases diagnosed per year.[
ANAPLASTIC GLIOMA
Histological and molecular data
According to the WHO classification, which is based on morphological criteria, three histological subtypes of AG are described: Anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), and anaplastic oligoastrocytoma also called mixed anaplastic glioma (AOA).[
Different molecular subtypes are present within each histologic subtype of AG.[
Molecular markers are becoming increasingly important in the management of AG, and may at times asssit in the determination of diagnosis. Additionally molecular markers have prognostic value and help to resolve the discrepancy between WHO classification and clinical outcomes. Lastly, they may be predictive with response to treatment. The molecular markers that currently are most informative with respect to either treatment or prognosis include 1p19q codeletion status (determined by fluorescence in situ hybridization [FISH]), IDH1/2 mutation (determined by immunohistochemistry [IHC]), O-6 methylguanine-DNA-methyltransferase (MGMT) promoter methylation (determined by polymerase chain reaction [PCR]), and ATRX mutation (determined by IHC).[
In the NOA-4 trial of AG (radiation therapy [RT] vs. CT), 1p/19q codeletion was detected in 40.9% of AG (14.9% of patients with AA, 77.4% of patients with AO, and 58.7% of patients with AOA).[
The IDH1 gene, a cytosolic enzyme, functions as a tumor suppressor that when mutationally inactivated contributes to tumorigenesis in part through induction of the hypoxia inducible factor-1 pathway.[
Expression of the DNA repair protein MGMT results in resistance of gliomas to alkylating and methylating agents.[
ATRX loss has been reported to be rare in oligodendroglial tumors[
Recent studies have evaluated the genetic landscape of AG by exome sequencing and identified frequent markers as IDH1 mutation, ATRX loss, TP53 in addition to mutations in the Notch pathway genes.[
The best characterized epigenetic event in cancer is DNA methylation at gene promoter regions. Cancers are frequently characterized by specific methylation patterns. Abberant methylation is usually associated with silencing and loss of function of the concerned genes.[
In conclusion, molecular classification represents a major advance in prognostication of AG.[
Upfront treatment of anaplastic glioma
Since the early 1990s, initial therapy for newly diagnosed AO was PCV with or without RT.[
Figure 2
NO 04-design. n Number of patients, R: Randomization; PD: Progression disease; TMZ: Temozolomide; PCV: Lomustine, vincristine, procarbazine. PCV: Lomustine 110 mg/m2 on day1, vincristine 2 mg on days 8 and 29, and procarbazine 60 mg/m2 on days 8 through 21 TMZ: 200 mg/m2 on days 1 through 5, every 28 days
The long-term results of the two randomized phase III studies (RTOG 9402 and EORTC 26951) changed the managment of newly diagnosed anaplastic oligodendroglial tumors. The aim of both studies was to determine the role of the addition of neoadjuvant or adjuvant CT with PCV to RT in the initial treatment as compared with RT only. In the RTOG 9402 trial, patients with newly diagnosed AO or AOA were randomly assigned to 4 cycles of neoadjuvant intensive PCV plus RT versus RT only.[
In the EORTC 26951 trial, patients with newly diagnosed AO or AOA were randomly assigned to either RT or RT followed by 6 cycles of adjuvant PCV [
In both the RTOG and EORTC trials, the addition of PCV to RT significantly improved the survival, especially in the population of 1p/19q codeleted anaplastic oligodendroglial tumors and currently represents the SOC. The results of both studies suggest that neither the timing of PCV administration (immediatly before or after RT) nor the dose-intensity of the PCV schedule matter.[
An important question regarding QoL is the respective roles of TMZ and PCV as they impact QoL in the initial treatment of AG. PCV CT has been reported as being more effective than TMZ in a large retrospective study,[
Until now, limited data regarding best upfront treatment is avaliable in uni- or nondeleted AG. In the cohort of AO or AOA, Lassman reported a longer median time to progression (TTP) following CT + RT (concurrent CT-RT, RT followed by CT or CT followed by RT) (3.1 years) than CT alone (TMZ or PCV) (0.9 years, P = 0.0124) or RT (1.1 years, P < 0.0001). OS was also better in the CT + RT group of patients (5.0 years) than CT (2.2 years, P = 0.02) or RT (1.9 years, P < 0.0001).[
The CATNON trial (concurrent and adjuvant TMZ CT in non-1p/19q codeleted AG; EORTC 26053-22054) is an ongoing phase III multicenter trial (Europe, Australia, and North America), which will inform as to the contribution of TMZ and RT in patients with nondeleted AG tumors. This study is comparing the efficacy of OS of RT only to RT + TMZ (concomitant and adjuvant) to RT followed by adjuvant TMZ to RT with concomitant TMZ in patients with non-1p/19q deleted newly diagnosed AG. The design of CATNON is detailed in
In conclusion, in the population of newly diagnosed AG and in patients with 1p/19q codeletion, the SOC is currently RT + PCV.[
Treatment of recurrent anaplastic glioma
The treatment of recurrent AG requires a consideration of patient age and PS, the magnetic resonance imaging (MRI) characteristic of the glioma at progression (local, diffuse, eloquent location or not), response to initial treatment, and time between initial treatment and first progression. When feasible re-resection is often suggested notwithstanding limited data to suggest benefit from repeat surgery. Occasional patients may be candidates for re-irradiation but again there is a paucity of data to commend this therapy and only a minority of selected patients are eligible for this approach. Consequently systemic therapy continues to be the most often utilized treatment in recurrent HGG.
No SOC regarding choice of CT is universally agreed upon for the treatment of recurrent AG. In NOA-4, patients initially treated with TMZ or PCV received RT at first progression. In patients initially treated with RT, at first progression patients were treated with either TMZ or PCV.[
In the EORTC 26972, a phase II prospective nonrandomized trial, the role of TMZ in recurrent AO and AOA after prior PCV CT and RT was investigated. Twenty-eight evaluable patients, enrolled following first recurrence after prior adjuvant RT + PCV or adjuvant RT followed by PCV administered at first recurrence, received TMZ for 12 cycles. In patients with proven anaplastic oligodendroglial pathology, the response rate was 25% (7/28; 95% CI 11–45%). Median time to progression for responding patients was 8.0 months. Of the 24 patients evaluable for response to prior PCV CT, 12 (50%) had initially responded to PCV (5 complete response and 7 partial responses). No difference was observed in response rate to TMZ regardless of prior PCV response.[
The role of BEV in the treatment of recurrent AG remains to be determined. The available data for patients with AG treated with BEV are derived primarily from retrospective studies that demonstrate response rates from 15% to 79%, median PFS from 5.0 to 13.4 months, and median OS from 6.8 to 12.6 months[
GLIOBLASTOMA
Histological data and molecular data
GB is considered by the WHO classification as a single histological entity including described variants such as gliosarcoma, GB with oligodendroglial features, and small cell GB. Nonetheless considerable variability in the response to treatment and in prognosis is observed.[
MGMT is a single enzyme DNA repair protein that removes alkylation or methylation adducts from the O6 position of guanine, a cytotoxic lesion induced by alkylating agents. Methylation of the MGMT gene promoter results in epigenetic translational silencing of the methyltransferase, resulting in increased tumor senstivity to alkylator-induced genotoxic injury. MGMT promoter is methylated in 32–45% in newly diagnosed GB.[
Although primary and secondary GBs are histomorphologically identical, these tumors develop though different genetic pathways. The status of the IDH 1/2 (mutation or wild type) distinguish between primary (IDH wild type) and secondary GB (IDH mutated). Point mutations at codon 132 of IDH1 and codon 172 of the IDH2 gene occur in more than 80% of low-grade gliomas and secondary GB, which represent a minority of all GB (<8%).[
Other markers are of interest in GB include the ATRX mutation, which is observed in 57% of the secondary GB.[
Verhaak et al. using The Cancer Genome Atlas (TCGA) data, defined a novel gene-expression-based molecular classification of GB that includes classical, mesenchymal, proneural, and neural subtypes. Aberrations and gene expression of EGFR, Neurofibromin 1 gene (NF1), and platelet-derived growth factor receptor A (PDGFR-A)/IDH1 each define the classical, mesenchymal, and proneural subtypes, respectively. The classical subtype is characterized by EGFR amplification and the absence of p53 mutations and PDGFR-A amplification. The mesenchymal subtype is characterized by deletions or mutation of NF1. The proneural subtype is characterized by IDH1 and p53 mutations and PDGFRA amplification. The neural subtype was typified by the expression of neuronal markers. The molecular subtypes have been shown to be associated with differing survival and varying response to therapy with the best outcome seen in the proneural subtype.[
Upfront treatment of glioblastoma
Standard of care
The current SOC for patients with newly diagnosed GB is maximum safe surgical resection followed by concurrent TMZ (75 mg/m2/day for 6 weeks) and RT (60 Gy in 30 fractions) and then 6 maintenance cycles of post-RT adjuvant TMZ (150–200 mg/m2/day for consecutive 5 days therapy every 28 days, standard 5/28 TMZ [sdTMZ]) according to the results of the pivotal trial by the EORTC/National Cancer Institute of Canada (NCIC) Clinical Trials Group, in which both PFS and OS were improved with combination therapy (RT + TMZ) relative to RT only.[
Elderly glioblatoma
The elderly, defined as individuals aged >65 years, comprise at least 20% of newly diagnosed GB patients.[
Importantly this group of patients were not evaluated in the above-mentioned EORTC/NCIC trial as inclusion criteria mandated age to be <71 years, consequently the value of RT + TMZ has never been prospectively evaluated.[
Two French studies evaluated treatment options in elderly GB patients with a poor PS. In the first single arm multi-institutional phase 2 study, patients with GB, age >70 years, 90% biopsy only and KPS <70, sdTMZ only treatment resulted in a median OS of 6 months.[
Dose of temozolomide
Dose dense schedules of TMZ (ddTMZ; alternating 7-days-on, 7-days-off [7/14] and 21-days on 7 off [21/28]) have been designed to deplete tumor MGMT levels and thereby improve activity of TMZ particularly in the MGMT unmethylated GB cohort. Nonrandomized studies in progressive or recurrent disease first reported treatment efficacy that compared favorably with the established sdTMZ schedule without an increase in treatment-related toxicity.[
The RTOG 0525 phase III trial prospectively compared the sdTMZ schedule and the ddTMZ schedules in the post-RT adjuvant setting. A total of 833 patients were initially treated with RT (60 Gy administered in 2 Gy fractions) and concomitant TMZ. After completion of concomitant chemoradiotherapy, patients were randomly assigned to sdTMZ (n = 411) or ddTMZ (75–100 mg/m2 days 1 through 21 of a 28-day cycle) (n = 422) for 6–12 cycles. The median OS (16.6 vs. 14.9 months, P = 0.63) and the median PFS (5.5 vs. 6.7 months, P = 0.06) were not significantly different between the two arms of treatment. As mentioned above, patients with a MGMT promoter methylated tumor had improved OS (21.2 vs 14 months, P < 0.001) and PFS (8.7 vs. 5.7 months, P < 0.001), but without any significant difference between the two post-RT TMZ treatment arms. Treatment was interrupted for toxicity or intercurrent illness in 49 patients (12%) on the sdTMZ and 94 patients (22%) on the ddTMZ arm. There was increased grade ≥3 toxicity in ddTMZ arm (34% vs. 53%, P < 0.001).[
Length of post-RT TMZ treatment
The defined length of the TMZ adjuvant phase is 6 months based on the results of the EORTC/NCICC trial wherein only 47% of patients were able to complete the prescribed 6-month post-RT TMZ treatment.[
Gliadel (carmustine) implantable wafers
Biodegradable carmustine (BCNU) wafers, implanted into the tumor bed after near or complete tumor resection, has been approved by the US Food and Drug Administration (FDA) for first-line treatment of GB and AG. Nevertheless, the use of carmustine wafers remains controversial due to the questionable survival benefit and potential adverse events.[
In a review of the literature by Bregy, 19 studies with 795 patients were evaluated in whom carmustine wafters were used in conjunction with RT + TMZ. Survival appeared modestly improved and varied from 8.7 to 22.8 months, with a mean of 16.2 months. An adverse event ratio was calculated by computing the number of adverse events in the study per patient receiving carmustine wafers. In this review, the rate of complications was 42.7% suggesting that Gliadel wafers should be used with caution.[
Bevacizumab in newly diagnosed GB
BEV, a monoclonal antibody that targets vascular endothelial growth factor (VEGF) when used for recurrent GB, has resulted in the best response and 6-month PFS (PFS-6) rates when compared with previously used therapies as discussed below.[
Two single institution phase II trials evaluated the role of BEV in newly diagnosed GB. In the study by Lai (concomitant RT, TMZ, and BEV followed by adjuvant TMZ and BEV) the median PFS was 13.6 months and the median OS was 19.6 months. In the study by Vredenburgh (concomitant RT, TMZ, and BEV followed by adjuvant TMZ, BEV, and IRI), the median PFS was 14.2 months and the median OS was 21.2 months.[
Three prospective randomized trials of upfront BEV have been completed and replicate the findings of the above-mentioned single arm phase II trials [
The RTOG 0825 study was a randomized phase III double-blind placebo-controlled trial evaluating BEV with or without SOC in patients with newly diagnosed GB. The co-primary objectives were OS and PFS. The secondary objectives included a comparison of toxicity, symptom burden, health-related (QoL) and neurocognitive function. The study design is detailed in
Health-related QoL was explored by deterioration-free survival (DFS), including progressive disease as an event and time to deterioration (TTD) not including progressive disease as an event. In both cases, the global health status (QLQ-C30 and BN20) was better preserved in the BEV arm (P < 0.0001 and P = 0.0041 for DFS and TTD, respectively). The functional status (PS) was also better preserved in the BEV arm (P < 0.0001 and P = 0.0153 for DFS and TTD, respectively). The median time to corticosteroid initiation in patients off corticosteroids at baseline was shorter in the group without BEV (3.7 vs. 12.3 months, P = 0.0018). The rate of corticosteroid discontinuation in patients on steroids at baseline was 45% in the placebo group and 61% in the BEV arm. The neurocognitive function (as assessed by mini-mental status) did not differ between arms. AVAglio concluded the addition of BEV significantly improved PFS, with better preservation of QoL but the final OS analysis did not reach statistical significance.[
The two trials, RTOG 0825 and AVAglio, were similar in design, patient characteristics, and the primary end points of PFS and OS.[
In both trials, the PFS was prolonged by 3–4 months in the BEV arms, but no difference was observed in OS.[
The prognosis of unresectable GB is particularly poor, with a median survival of 6–10 months.[
Other systemic agents in newly diagnosed GB
Cilengitide, a selective αvβ3-αvβ5-integrin inhibitor, had shown promising results in phase II trials,[
The CORE study was an open-label controlled randomized phase II study evaluating Cilengitide in combination with standard treatment for patients with newly diagnosed GB with unmethylated MGMT promoter. Patients were randomized 1:1 to a control-group (75 mg/m2/day)/RT (30 × 2 Gy) followed up by TMZ (150–200 mg/m2 5 days/28 × 6 cycles), Cilengitide-group (same standard regimen plus Cilengitide 2000 mg iv, 2×/week) or intensive Cilengitide group (same standard regimen plus Cilengitide 5×/week during TMZ/RT [weeks 1–6] and 2×/week in week -1 and >6 weeks).
A total of 265 patients were randomized (89 in the control group, 88 in the Cilengitide, and 88 in the intensive Cilengitide group). Median OS was 13.4 months in the control group, 16.3 months in the Cilengitide group (P = 0.033 vs. control), and 14.5 months in the intensive group (P = 0.38 vs. control). Median PFS per independent reviewer assessment was 4.1 months with control, 5.6 months with Cilengitide (P = 0.23 vs. control), and 5.9 months with intensive cliengitide (iP = 0.16 vs. control). Safety results were in line with the known Cilengitide safety profile. Cilengitide combination treatment showed a nonsignificant trend only in increasing OS in GB patients with unmethylated MGMT promoter, a finding that replicated the failure of Cilengitide to improve OS seen in the CENTRIC trial.[
CENTRIC and CORE trials determined that there is no survival advantage for adding anti-αvβ3-αvβ5-integrin therapy (Cilengitide) to SOC for patients with newly diagnosed GB. Nevertheless, other integrin inhibitors (β1, β8…) may represent another promising strategy.[
Enzastaurin, a potent inhibitor of protein kinase C-beta, an angiogenenic inhibitor and with direct cytotoxic activity against glioma cells, was evaluated before and concomitant with RT, followed by enzastaurin maintenance therapy in patients with newly diagnosed GB without MGMT promoter methylation in a multicenter open-label uncontrolled phase II (EORTC 26981/22981 NCIC CE.3). The PFS-6 was 53.6%. The median OS was 15.0 months for all patients, 3.9 months for patients with biopsy, 15.4 months for patients with partial resection, and 18.9 months for patients with complete resection. The safety profile in this study was as seen in previous trials and therapy was well tolerated. In this trial, PFS-6 of >55% was the prespecified endpoint and consequently failed to achieve its primary planned outcome.[
The results of a phase II open label trial (NCT01019434) evaluating RT and temsirolimus, a mTOR inhibitor, in patients with newly diagnosed GB without methylation of the MGMT gene promoter should soon be avaliable. In arm 1, standard treatment with TMZ (75 mg/m2/day)/RT (30 × 2 Gy) followed up by TMZ (150–200 mg/m2 5 days/28 days) administered up to 12 cycles is given. In arm 2, temsirolimus was given once one week before RT and then once every week (25 mg iv) concomitanty with RT. After completion of chemoradiotherapy, patients receive maintenance temsirolimus once weekly in the absence of disease progression and unacceptable toxicity. The primary outcome is OS at 1 year and the secondary outcomes were safety, PFS at 6 and 12 months, OS at 2 years, and correlative biomarkers.
Immunotherapy
A variety of vaccination strategies based on either whole GB tumor lysate or tumor-specific antigens (TSAs) have shown consistent safety as well as preliminary and encouraging immunogenicity and efficacy.[
The most common EGFR mutation in GB is EGFRvIII, which results from an in-frame deletion of 267 amino acids in the extracellular domain.[
Rindopepimut (PEPvIII-KLH; CDX-110; Celldex Therapeutics, Phillipsburg, NJ), is a peptide vaccine that elicits humoral and cellular immune responses.[
Another approach utilizes a DC vaccine, DCVax-L. The vaccine is manufacturated using the patient's autologous DCs loaded with a tumor cell lysate prepared from surgically resected primary tumor tissue. The DCs are collected by leukapheresis. Different methods to activate DC have been explored.[
In conclusion, avaliable data regarding vaccine therapy for GB – whether utilizing whole cell lysates or synthetic antigens, suggest a therapy with excellent tolerance, that is, minimal toxicity and preliminary evidence of tumor immunogenicity and antitumor efficacy. Nevertheless, several issues need to be considered. First, immunotherapies have to date demonstraterd very little activity in other solid tumor cancers including metastatic melanoma. Second, a selection bias is observed in all studies to date as patients are required to have minimal residual disease following first surgery as well as after completing chemoradiotherapy, a subgroup of patients in which there is no well-defined survival data when treated with SOC. Third, all studies to date have enrolled a small number of patients with highly favorable prognostic features and been performed as single institution trials. Currently there are no identified biomarkers that predict for response or serve as surrogates for response to immunotherapy. Currently response to immunotherapies utilizes the same assessment criteria as with systemic CT. There is a theoretical possibility that immune response specific criteria may be required as witnessed with ipilimumab therapy for metastatic melanoma.[
Heat-shock proteins (HSPs), which function as intracellular chaperones, can be used to deliver a variety of tumor antigens to antigen presenting cells for immune stimulation.[
Immune check point inhibitors such an anti-VLTA4 and antiprogrammed cell death 1 (anti-PD1) monoclonal antibodies are just begining clinical trials in GB. These targeted agents represent a novel immune therapy that has shown success in metastatic melanoma as well as nonsmall cell lung cancer. A trial using nivolumab (anti-PD1 antibody) with or without ipilimumab (anticytotoxic T lymphocyte antigen-4 [CTLA4] antibody) in recurrent GB has recently commenced (NCT02017717).
NOVOCURE trial
Alternating electric fields (AEF) have been shown to inhibit by an antimicrotubule mechanism of action, cancer cell growth in vitro and in vivo when applied at low intensity and intermediate frequency[
Viral-based therapy
Viral therapies can be divided into two categories. Replication-deficient viral vectors are used as delivery vehicles for therapeutic genes with antitumor activities. Alternatively, replication-competent oncolytic viruses specifically infect and replicate in cancer cells and thereby, kill their tumor cell hosts sparing normal tissue, spread throughout the tumor, and thus have the potential to amplify themselves in situ and spread throughout the tumor. Additionally, tumor cell kill is also mediated by antitumor immune activation and disruption of tumor blood supply.[
The role of the cytomegalovirus (CMV) in GB remains controversial. CMV DNA and proteins are expressed in several types of human cancers[
Treatment of recurrent glioblastoma
The treatment of GB at recurrence depends on several factors, including age of the patient, PS of the patient, extent and location of disease at recurrence, response to initial treatment, time between initial treatment and first recurrence, and prior treatment.[
Chemotherapy
A variety of alkylator-based CT regimens (Carmustine [BCNU], Lomustine [CCNU], Fotemustine, TMZ in TMZ-naive patients, TMZ in TMZ-pretreated patients) have been evaluated at recurrence of GB and constitute the current SOC.[
In an attempt to improve on TMZ only therapy, a variety of agents both cytotoxic and targeted have been combined with TMZ including BEV, nitrosoureas, alpha-interferon, IRI, cisplatin in more than 12 phase I or II studies. None of these combinations have proved superior to TMZ alone.[
Bevacizumab
In 2005, Stark Vance presented the first results of BEV in recurrent HGG using the combination of BEV/IRI in 21 patients. Patients received 6-week cycles with BEV (5 mg/kg, every other week) and IRI (125 mg/m2 every 4 weeks), followed by a 2-week rest. Toxicities included neutropenia, diarrhea, epistaxis, emesis, and asthenia. One patient died of an intracranial hemorrhage and one patient died of complications of gastrointestinal perforation. One complete response, 8 partial responses, and 11 stable diseases were observed, suggesting a possible role for BEV in recurrent HGG.[
A variety of retrospective and prospective studies have evaluated combining BEV with various agents including IRI, etoposide, TMZ, carboplatin, cetuximab, erlotinib, and to date none have proved more effective than BEV only [
The BELOB phase II study (Landelijke Werkgroep Neuro-Oncologie [LWNO] trial 0901) compared BEV alone versus BEV plus Lomustine versus Lomustine alone in patients with a first recurrence of GB. The initial design of BELOB consisted in a 2-arm study, evaluating BEV versus BEV plus Lomustine in recurrent GB. The primary endpoint was 6-PFS. After the negative ruling of EMA in Europe on the use of BEV at first recurrence for GB, the trial was amended to include three arms. The new protocol was thus a three-arm randomized open label controlled phase II study with a primary endpoint of OS at 9 months. The treatment arms were Lomustine alone (110 mg/m2 every 6 weeks for 6 cycles), Lomustine (90 mg/m2 every 6 weeks for 6 cycles) + BEV (10 mg/kg every 2 weeks until progression), and BEV alone (10 mg/kg every 2 weeks until progression). Initially Lomustine was administered at 110 mg/m2, but due to hematological toxicity, the dose of Lomustine was reduced. A total of 148 eligible patients were enrolled: 50 patients were assigned to BEV alone, 46 patients to Lomustine alone, and 52 patients to the combined group. Treatment was interrupted for toxicity for two patients in BEV alone arm and five patients in the combination arm. The most frequent adverse events were hypertension and fatigue. The 9 months OS was 43% (range, 29–57%), 38% (range 25–51%), and 63% (range, 49–75%) in the Lomustine arm, in the BEV arm, and in the combination arm, respectively. The median OS was 8 months in either the Lomustine only or BEV alone arms, and 12 months in the BEV + Lomustine arm. The PFS at 6 months was 13% (range, 5–24%), 18% (7–27%) and 42% (range, 29–55%) in the Lomustine arm, the BEV arm and in the combination arm, respectively.[
EORTC 26101 (NCT01290939) was recently modified as a three-arm phase III adressing results of BELOB. This trial will determine whether the combination of BEV and Lomustine in patients with first reccurence of GB is superior to BEV or Lomustine only. The primary endpoint is the OS, and the secondary outcomes are median PFS, PFS at 6 and 12 months, OS at 9, 12, and 24 months, response rate and duration of response and progression parttern, safety, clinical DFS, steroid use, QoL and development of cognitive deterioration, and identification of biomarkers that hopefully will translate into advances in screening, diagnosis, treatment, and monitoring patients with recurrent GB. In arm 1, patients will recieve Lomustine (90–110 mg/m2 every 6 weeks) plus BEV (10 mg/kg every 2 weeks). In arm 2, patients will receive Lomustine as single agent (110 mg/m2 every 6 weeks). At progression, treatment is at the discretion of the investigator.
BEV when used for recurrent GB is usually administrated intravenously at 10 mg/kg every 2 weeks. Other schedules of BEV have been evaluated in small cohorts of patients with recurrent GB.[
The median OS after progression on BEV is usually poor (average 3–4.6 months) nothwithstanding attempted further treatment.[
Nonbevacizumab angiogenic inhibitors
Other antiangiogenic agents have been evaluated in recurrent GB. Median PFS-6 was 25.8% with cediranib (vascular endothelial growth factor receptor 2 [VEGFR2] inhibitor, 31 patients), 7.7% with aflibercept (n = 42 patients; VEGF ligand decoy) and 15% with cilengitide (n = 40 patients; antiintegrin inhibitor).[
A phase III open label study compared the efficacy and safety of enzastaurin versus Lomustine in patients with recurrent GB. A total of 266 patients were randomly assigned (2:1) to receive 6-week cycles of enzastaurin 1125–500 mg/d (n = 174) or Lomustine (100–130 mg/m2, day 1) (n = 92). Median PFS (1.5 vs. 1.6 months, P = 0.08), OS (6.6 vs. 7.1 months, P = 0.25), and 6-month PFS rate (11.1% vs. 19%, P = 0.13) did not differ significantly between enzastaurin and Lomustine, respectively. Stable disease occurred in 38.5% and 35.9% of patients and objective response occurred in 2.9% and 4.3% of patients, respectively. Time to deterioration of physical and functional well-being and symptoms did not differ between arms (P = 0.54). Four patients discontinued enzastaurin because of drug-related serious adverse events (AEs). Grade 3 to 4 hematologic toxicities were significantly higher with Lomustine than with enzastaurin (P ≤ 0.001). In this study, enzastaurin was not superior to Lomustine in patients with recurrent GB.[
REGAL was a randomized phase III placebo controlled partially blinded trial to determine the efficacy of cediranib, an oral pan-VEGF receptor tyrosine kinase (RTK) inhibitor, either as monotherapy or in combination with Lomustine versus Lomustine only in patients with recurrent GB.[
This study did not meet its primary end point of PFS prolongation with cediranib either as monotherapy or in combination with Lomustine versus Lomustine in patients with recurrent GB, but did confirm the benefit of Lomustine similar to the conclusions of the enzastaurin trial mentioned above.
Molecular targeted therapy
The anaplastic lymphoma kinase (ALK) and the hepatocyte growth factor receptor (HGFR or, more commonly MET) are both members of the RTK family and included within the insulin-like receptor superfamily. This signaling pathway has a role in modulating mitosis, migration, and survival in cancer cells.[
BRAF mutations, another uncommon mutation in GB, may represent another druggable target using specific BRAF inhibitors such as vemurafenib or dabrafenib. BRAF V600E mutations have been identified in a less than 5% of adult GB and when seen are mostly observed in epithelioid-GB, a tumor subtype seen in pediatric and young adults.[
Vaccine-based immunotherapy
ReACT (NCT01498328) a phase II trial with granulocyte-macrophage colony-stimulating facto (GM-CSF) and KLH in combination with the EGFRvIII peptide vaccine rindopepimut, is evaluating vaccine-based therapy in patients with recurrent EGFRvIII-positive GB. Group 1 are patients who have never been treated with BEV and will be randomly assigned to receive either rindopepimut/GM-CSF + KLH vaccine and BEV or BEV only in conjunction with a non-EGFRvIII peptide containing vaccine. Treatment assignment for Group 1 will be blinded. Group 2 patients are refractory to BEV (recurrence or progression of GB while on BEV or within 2 months of discontinuing BEV). These patients will receive rindopepimut/GM-CSF vaccine in conjunction with BEV. The primary objective is PFS in Groups 1 and 2 and objective response rate in the Group 2. The secondary outcome measures are safety and tolerability, antitumor activity and EGFRvIII-specific immune response.
Gliadel trial
A total of 222 patients with recurrent GB who underwent reoperation were randomized in a phase III study comparing resection + carmustine wafers (Gliadel) (n = 110) versus resection + placebo wafers (n = 112). The median OS were 31 versus 23 weeks (P = 0.006) in the carmustine wafer and placebo arm, respectively.[
Convection-enhanced delivery
Convection-enhanced delivery (CED) was designed to improve the delivery of drugs that would normally not cross the blood–brain barrier. Agents are delivered through one to several catheters placed stereotactically within the tumor or in brain surrounding tumor. Different classes of drugs are amenable to this technology including standard chemotherapeutics or novel experimental targeted drugs. Nevertheless, trials have failed to demonstrate a success when utilizing CED as means of drug delivery.[
Alternating electric fields or tumor treating fields
Two clinical trials have assessed the effect of AEF using the NovoTTF-100A device (Novocure Ltd, Haifa, Israël) in the recurrent setting. In the first trial, a small pilot study of 10 patients, the device was used continuously for a minimum of 18 h/day and used until disease progression. Median OS was 62.2 weeks, 6-month PFS rate was 50%, TTP was 6.1 months. These results compared favorably with historical controls that showed a median OS of 29.3 weeks, a 6-month PFS rate of 15.3%, and a TTP of 9.5 weeks. Tolerance profile was excellent with dermatitis beneath the electrodes being the most frequent side effect.[
CONCLUSION
Molecular markers and gene expression profiles increasingly assist in determining prognosis and response to treatment in HGG, and particularly in AG, in which, treatment is dependent upon the 1p/19q status. In the GB population, the molecular markers and classification does not currently influence treatment except in elderly patients. Potentially and recently identified mutations markers may be druggable (cMET, ALK, BRAF, EGFRvIII, IDH…) and reprent new treatment strategies. HGG when feasible are first treated with maximum safe surgery, followed by RT and/or systemic CT. The standard treatment of newly diagnosed 1p19q codeleted AG has changed after publication of the long-term results of the RTOG 9402 and EORTC 26951 trials, and now includes RT + PCV, with PCV administered either immediately before or after RT. The role of TMZ in lieu of PCV, which is less toxic than PCV, remains to be determined and is the primary hypothesis in the currently on going trial CODEL. In the 1p/19q noncodeleted AG population, there is insufficient data to recommend concomitant RT + TMZ and in this population, the standard initial treatment remains RT or CT alone based on the NOA-04 trial. Results of CATNON are awaited, which will hopefully inform as to the role of TMZ in the first-line treatment of nondeleted AG.
The addition of BEV to the SOC of newly diagnosed GB has shown no impact on OS and consequently cannot be commended for use in GB except at recurrence. Similarly there is no evidence that Cilengitide adds addional benefit to the initial treatment of GB. The role of vaccine-based immunotherapy in the upfront treatment of GB will be determined upon completion of two large Phase 3 trials, ACT 4 and DCvax. New targeted agents, such as inhibitors of BRAF, cMET, or ALK, are currently exploratory and may be applicable to a small select subpopulation. Vaccines directed at HSP and IDH1 may be another promising approach.
There continues to be SOC identified in recurrent HGG. Several factors should be taken into account such as age and PS of the patient, extent and location of disease at recurrence, response to initial treatment, time between initial treatment and first recurrence, and prior treatment. Both recurrent GB and AG are managed in a similar manner. Re-resection or re-irradiation may be options in a minority of select patients. Systemic treatment remains the most often utilized option for recurrent HGG. Re-challenge with TMZ or alternative use of a nitrosourea (most often Lomustine) are one of standard options. BEV alone has also shown an improvment of PFS-6 in the GB population. The role of combination therapy with BEV and Lomustine recently was suggested to be more effective (BELOB trial) and is currently being examined in an EORTC phase III trial in recurrent GB. The use of immune check point inhibitors such as anti-PD1 monoclonal antibodies is just commencing and is a potential new stratgey for recurrent HGG. Nevertheless, there is no clear standard recommendation regarding the prefered agent or combination of agents for recurrent HGG. Prognosis after progression remains poor, with an unmet need to improve therapy.
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