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      Efficacy and safety of long-term therapy for high-grade glioma with temozolomide: A meta-analysis

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          Abstract

          Further treatments are warranted in preventing recurrence or progression for high-grade glioma (HGG) patients having achieved stable disease with tolerable toxicity after the Stupp regimen (6 cycles of temozolomide). This meta-analysis aims to extensively evaluate the safety, feasibility, and efficacy of long-term therapy with temozolomide (>6 cycles) for these patients. We systematically searched the pubmed, Embase and Chinese Biomedical (CBM) databases using the strategy of combination of free-text words and MeSH terms. The efficacy indicators are hazard ratio (HR) for the pooled analysis of overall survival (OS) and progression free survival (PFS). The safety indicator is risk ratio (RR) for the pooled analysis of adverse effects. Six studies comprising a total number of 396 patients met all inclusion and exclusion criteria were included. No heterogeneity and publication bias were observed across each study. It was found that patients could obtain benefits from long-term administration of temozolomide both in OS (HR 2.39, 95% CI 1.82–3.14) and PFS (HR 2.12, 95% CI 1.56–2.89). In addition, the results showed that the patients receiving long-term administration of temozolomide did not experience additional toxicity over that of the Stupp regimen (6 cycles of temozolomide). It could be concluded that it's efficacious and safe for HGG patients to receive long-term therapy with temozolomide. Nevertheless, more randomized controlled trials (RCTs) should be carried out to verify this conclusion.

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          Most cited references25

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          Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas.

          Published data on prognostic and predictive factors in patients with gliomas are largely based on clinical trials and hospital-based studies. This review summarizes data on incidence rates, survival, and genetic alterations from population-based studies of astrocytic and oligodendrogliomas that were carried out in the Canton of Zurich, Switzerland (approximately 1.16 million inhabitants). A total of 987 cases were diagnosed between 1980 and 1994 and patients were followed up at least until 1999. While survival rates for pilocytic astrocytomas were excellent (96% at 10 years), the prognosis of diffusely infiltrating gliomas was poorer, with median survival times (MST) of 5.6 years for low-grade astrocytoma WHO grade II, 1.6 years for anaplastic astrocytoma grade III, and 0.4 years for glioblastoma. For oligodendrogliomas the MSTwas 11.6 years for grade II and 3.5 years for grade III. TP53 mutations were most frequent in gemistocytic astrocytomas (88%), followed by fibrillary astrocytomas (53%) and oligoastrocytomas (44%), but infrequent (13%) in oligodendrogliomas. LOH 1p/19q typically occurred in tumors without TP53 mutations and were most frequent in oligodendrogliomas (69%), followed by oligoastrocytomas (45%), but were rare in fibrillary astrocytomas (7%) and absent in gemistocytic astrocytomas. Glioblastomas were most frequent (3.55 cases per 100,000 persons per year) adjusted to the European Standard Population, amounting to 69% of total incident cases. Observed survival rates were 42.4% at 6 months, 17.7% at one year, and 3.3% at 2 years. For all age groups, survival was inversely correlated with age, ranging from an MST of 8.8 months ( 80 years). In glioblastomas, LOH 10q was the most frequent genetic alteration (69%), followed by EGFR amplification (34%), TP53 mutations (31%), p16INK4a deletion (31%), and PTEN mutations (24%). LOH 10q occurred in association with any of the other genetic alterations, and was the only alteration associated with shorter survival of glioblastoma patients. Primary (de novo) glioblastomas prevailed (95%), while secondary glioblastomas that progressed from low-grade or anaplastic gliomas were rare (5%). Secondary glioblastomas were characterized by frequent LOH 10q (63%) and TP53 mutations (65%). Of the TP53 mutations in secondary glioblastomas, 57% were in hot-spot codons 248 and 273, while in primary glioblastomas, mutations were more evenly distributed. G:C-->A:T mutations at CpG sites were more frequent in secondary than primary glioblastomas, suggesting that the acquisition of TP53 mutations in these glioblastoma subtypes may occur through different mechanisms.
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            Temozolomide preferentially depletes cancer stem cells in glioblastoma.

            The prognosis of patients suffering from glioblastoma (GBM) is dismal despite multimodal therapy. Although chemotherapy with temozolomide may contain tumor growth for some months, invariable tumor recurrence suggests that cancer stem cells (CSC) maintaining these tumors persist. We have therefore investigated the effect of temozolomide on CD133(+) and CD133(-) GBM CSC lines. Although differentiated tumor cells constituting the bulk of all tumor cells were resistant to the cytotoxic effects of the substance, temozolomide induced a dose- and time-dependent decline of the stem cell subpopulation. Incubation with sublethal concentrations of temozolomide for 2 days completely depleted clonogenic tumor cells in vitro and substantially reduced tumorigenicity in vivo. In O(6)-methylguanine-DNA-methyltransferase (MGMT)-expressing CSC lines, this effect occurred at 10-fold higher doses compared with MGMT-negative CSC lines. Thus, temozolomide concentrations that are reached in patients were only sufficient to completely eliminate CSC in vitro from MGMT-negative but not from MGMT-positive tumors. Accordingly, our data strongly suggest that optimized temozolomide-based chemotherapeutic protocols might substantially improve the elimination of GBM stem cells and consequently prolong the survival of patients.
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              Prospective Longitudinal Analysis of 2-Hydroxyglutarate Magnetic Resonance Spectroscopy Identifies Broad Clinical Utility for the Management of Patients With IDH-Mutant Glioma.

              Purpose Proton magnetic resonance spectroscopy (MRS) of the brain can detect 2-hydroxyglutarate (2HG), the oncometabolite produced in neoplasms harboring a mutation in the gene coding for isocitrate dehydrogenase ( IDH). We conducted a prospective longitudinal imaging study to determine whether quantitative assessment of 2HG by MRS could serve as a noninvasive clinical imaging biomarker for IDH-mutated gliomas. Patients and Methods 2HG MRS was performed in 136 patients using point-resolved spectroscopy at 3 T in parallel with standard clinical magnetic resonance imaging and assessment. Data were analyzed in patient cohorts representing the major phases of the glioma clinical course and were further subgrouped by histology and treatment type to evaluate 2HG. Histologic correlations were performed. Results Quantitative 2HG MRS was technically and biologically reproducible. 2HG concentration > 1 mM could be reliably detected with high confidence. During the period of indolent disease, 2HG concentration varied by less than ± 1 mM, and it increased sharply with tumor progression. 2HG concentration was positively correlated with tumor cellularity and significantly differed between high- and lower-grade gliomas. In response to cytotoxic therapy, 2HG concentration decreased rapidly in 1p/19q codeleted oligodendrogliomas and with a slower time course in astrocytomas and mixed gliomas. The magnitude and time course of the decrease in 2HG concentration and magnitude of the decrease in tumor volume did not differ between oligodendrogliomas treated with temozolomide or carmustine. Criteria for 2HG MRS were established to make a presumptive molecular diagnosis of an IDH mutation in gliomas technically unable to undergo a surgical procedure. Conclusion 2HG concentration as measured by MRS was reproducible and reliably reflected the disease state. These data provide a basis for incorporating 2HG MRS into clinical management of IDH-mutated gliomas.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                1 August 2017
                24 April 2017
                : 8
                : 31
                : 51758-51765
                Affiliations
                1 Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
                2 Brain Research Institute, Zhejiang University, Hangzhou, Zhejiang, China
                3 Collaborative Innovation Center for Brain Science, Zhejiang University, Hangzhou, Zhejiang, China
                Author notes
                [*]

                These authors have contributed equally to this work as co-first authors

                Correspondence to: Jianmin Zhang, zhangjianmin2016@ 123456163.com
                Article
                17401
                10.18632/oncotarget.17401
                5584285
                28881684
                5b5e0467-20ba-450e-bb77-13bbc711356d
                Copyright: © 2017 Xu et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 7 March 2017
                : 4 April 2017
                Categories
                Meta-Analysis

                Oncology & Radiotherapy
                long-term,glioma,temozolomide,meta-analysis
                Oncology & Radiotherapy
                long-term, glioma, temozolomide, meta-analysis

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