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ORIGINAL ARTICLE
Year : 2015  |  Volume : 11  |  Issue : 6  |  Page : 196-201

Radiotherapy with temozolomide provides better survival in the newly diagnosed glioblastoma multiforme: A meta-analysis


1 Department of Neurology, Beijing Tian Tan Hospital, Capital Medical University, Beijing 100050, China
2 Biotech Center for Viral Disease Emergency, National Institute for Disease Control and Prevention, Chinese Disease Control and Prevention, Beijing 102206, China
3 Department of Clinical Medicine, Harbin Medical University, Harbin 150081, China
4 Department of Cardiology, -Japan Union Hospital of Jilin University, Changchun 130033, China

Date of Web Publication26-Oct-2015

Correspondence Address:
Zhe An
Department of Cardiology, China-Japan Union Hospital of Jilin University, Changchun 130033
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.168184

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 > Abstract 

Background: The optimal treatment for patients with newly diagnosed glioblastoma multiforme (GBM) remains controversial. The purpose of this meta-analysis was to systematically evaluate radiotherapy/temozolomide (TMZ) versus radiotherapy for treating newly diagnosed GBM.
Materials and Methods: Six electronic databases (PubMed, EMBASE, MEDLINE, Web of Science, Cochrane Library, and CNKI) were searched for relevant publications up to November 05, 2014. RevMan version 5.2 software was used for statistical analysis.
Results: A total of 9 studies were identified in this analyses, which included 986 patients. The summary risk ratio (RR) for overall survival and the progression-free survival (PFS) was the measure of interest. Results revealed that the addition of TMZ to radiotherapy resulted in a statistically significant survival benefit in poor prognosis patients with newly diagnosed glioblastoma (RR = 2.93 [95% confidence interval (CI) 2.29, 3.75], P < 0.00001). Moreover, radiotherapy plus TMZ was more beneficial than radiotherapy alone in improving PFS (RR = 3.52, [95% CI 2.53, 4.89], P < 0.00001). However, certain grade 3–4 hematological toxicities were significantly more common with TMZ.
Conclusions: This meta-analysis suggests that radiotherapy/TMZ provides better survival than radiotherapy alone in treating GBM.

Keywords: Glioblastoma multiforme, meta-analysis, radiotherapy, temozolomide


How to cite this article:
Wang C, Zhu N, Wang L, An Z. Radiotherapy with temozolomide provides better survival in the newly diagnosed glioblastoma multiforme: A meta-analysis. J Can Res Ther 2015;11, Suppl S2:196-201

How to cite this URL:
Wang C, Zhu N, Wang L, An Z. Radiotherapy with temozolomide provides better survival in the newly diagnosed glioblastoma multiforme: A meta-analysis. J Can Res Ther [serial online] 2015 [cited 2021 Jul 30];11:196-201. Available from: https://www.cancerjournal.net/text.asp?2015/11/6/196/168184


 > Introduction Top


Glioblastoma multiforme (GBM) is the most common primary tumor of the central nervous system [1],[2] with there being approximately 10,000 new cases per year in the United States.[3] GBM is associated with a particularly poor prognosis, rapidly progressive, and resistant to therapy.[4] Median survival is generally <1-year from the time of diagnosis, and even in the most favorable situations, most patients die within 2 years.[5],[6] Clearly, optimizing currently available treatment options are essential for improving patient survival.

Current treatment of GMB includes surgery followed by radiotherapy and chemotherapy.[1],[5] A meta-analysis published in 2002[7] including many different chemotherapeutic regimes has pointed out that the association of chemotherapy is, in general, more effective than radiotherapy alone in prolonging survival, and in delaying recurrences in glioma patients. These evidences encouraged research with new chemotherapeutic agents.

Temozolomide (TMZ) is a novel, an oral chemotherapy drug that has demonstrated activity in malignant gliomas. TMZ has nearly 100% bioavailability and readily crosses the blood-brain barrier.[8],[9],[10] Gil-Salú et al.[11] firstly conducted a survival analysis following the addition of TMZ to surgery and radiotherapy in patients with GBM. So far, a number of other randomized and nonrandomized trials have examined the efficacy and safety of radiotherapy and chemotherapy with TMZ versus radiotherapy alone for the treatment of GBM.

As such, we felt a meta-analysis of the current literature to provide an updated perspective on radiotherapy plus TMZ versus radiotherapy alone for the treatment of newly diagnosed GBM.


 > Materials and Methods Top


Search strategy

We systematically searched PubMed (http://www.ncbi.nlm.nih.gov/pubmed/], EMBASE (http://www.elsevier.com/solutions/embase), the Cochrane Library (http://www.thecochranelibrary.com), MEDLINE (http://www.medline.com), Web of Science (http://apps.webofknowledge.com), and China National Knowledge Infrastructure (CNKI, http://www.cnki.net/) using combinations of the following terms: "GBM/glioblastoma, newly diagnosed," "temozolomide/TMZ," and "radiation therapy (RT)/radiotherapy." The reference lists of retrieved articles and previous meta-analysis [12] were also reviewed to search for additional trials. No language restrictions were set for the search, and it was up-to-date on November 05, 2014.

Study selection

Studies were included if (i) they were the randomized clinical trials or nonrandomized designs with parallel controlled design; (ii) the objects of study were surgical patients who had not received prior radiotherapy or chemotherapy; and (iii) specific outcomes were mentioned. We excluded studies if (i) they did not report an adequate statistical analysis; (ii) reviews or case reports. Two reviewers determined the eligibility of each article independently. The disagreement was resolved by discussion.

Data extraction

For each study, we extracted details onfirst author, publication year, number of participants, age of participants, study design, median survival, survival rate, median progression-free survival (PFS), PFS rate, and adverse outcomes.

Statistical analysis

The summary risk ratio (RR) for overall survival (OS) and PFS was the measure of interest. The heterogeneity assumption was assessed by Q statistic test [13] and I2-test.[14] When significant heterogeneity (P < 0.10, I2 > 50%) was found, random effects model was used. Otherwise, fixed effects model was used. RevMan 5 software (version 5.2, Australasian Cochrane Centre)[15] was used for the statistical analysis. It was considered statistical significant when P < 0.05.


 > Results Top


Search results

The initial search yielded 787 potentially relevant references. After removing duplicates, review and papers that were less related according to the titles and abstracts, there were 45 studies left. Then reading the full text of these studies and excluding the studies which had other interventions, 9 trials met the inclusion criteria and were selected as appropriate for inclusion in this meta-analysis [Figure 1]. The included trials were 7 randomized clinical trials [16],[17],[18],[19],[20],[21],[22] and 2 nonrandomized clinical trials [23],[24] and were published between 2005 to November 2014. The sample size varied from 38 to 573, reaching a total of 986.
Figure 1: Flow diagram of trial selection process

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Study characteristics

The characteristics of the selected trials are presented in [Table 1]. Note: Two of the articles reported results from the same study population. However, results in different time are presented in each article; hence, all were included in the meta-analysis.
Table 1: The characteristics of studies included in the meta-analysis

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Risk of bias and publication bias assessment

Although seven of all eligible trials reported that the participants were randomized into different treatment arms, none of them provided details about random sequence generation, which may lead to selection bias. But that was inevitable effectively on oncotherapy. Outcome measures (essentially everything apart from OS) including PFS and adverse events were an objective index. All eligible trials conducted efficacy analysis on an intention-to-treat basis except one.[16] All trials had independent persons who performed the outcome assessment. We believe that the outcomes were unlikely to have been affected in these instances. No significant publication bias was detected for any of the measured outcomes by funnel plots.

Overall survival

OS analysis was divided into: 0.5-year, 1-year, 2-year, 3-year, 4-year, and 5-year, pooled RRs were demonstrated in [Figure 2]. Using a random effects model in [Figure 2]a, a meta-analysis indicated that no statistically significant improvement was shown in 0.5-year OS [four studies, 786 total patients; RR 1.12, 95% confidence interval (CI) 0.99–1.27, P = 0.07; χ2 = 6.49, P = 0.09, I2 = 54%; [Figure 2]a, but RT + TMZ treatment showed a modest but statistically significant improvement in 1-year OS [five studies, 856 total patients; RR 1.47, 95% CI 1.07–2.03, P = 0.02; [Figure 2]a. Moreover, subgroup analysis according to survival time showed a statistically significant improvement in OS in radiotherapy with TMZ treatment patients the [2-year OS analysis RR = 2.27 (95% CI 1.67,3.09), P < 0.00001; the 3-year OS analysis RR = 3.53 (95% CI 1.95,6.38), P < 0.0001; the 4-year OS analysis RR = 3.88 (95% CI 1.90,7.91), P = 0.0002; the 5-year OS analysis RR = 5.58 (95% CI 2.19,14.25), P = 0.0003 [Figure 2]b. Overall this meta-analysis showed a longer OS in patients who received a combination of radiotherapy and chemotherapy TMZ treatment, especially in the long time.
Figure 2: Forest plot of subgroup analysis for overall survival. (a) The analysis for 0.5-year and 1-year OS: Random-effects model. (b) Subgroup analysis for OS with fixed-effects model

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Progression free survival

Two studies were included in the PFS analyses, using a random effect model in [Figure 3]a and a fixed effects model in [Figure 3]b, respectively. No significant difference was shown in 0.5-year PFS between the radiotherapy plus TMZ group and the radiotherapy group [RR = 4.29, (95% CI 0.34, 53.85), P = 0.26; [Figure 3]a. However, subgroup analysis demonstrated significant improvements in PFS in 1- or 2 -year. [the 1-year PFS analysis RR = 3.07 (95% CI 2.17,4.34), P < 0.00001; the 2-year PFS analysis RR = 7.47 (95% CI 2.67,20.94), P = 0.0001 [Figure 3]b.
Figure 3: Forest plot of subgroup analysis for progression-free survival. (a) The analysis for 0.5-year PFS: Random-effects model. (b) Subgroup analysis for PFS with fixed-effects model

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Adverse events

Data for the grade 3 or 4 adverse events were available in seven studies, and chemotherapy-related hematological adverse events (HAEs) were the major safety concerns. The results indicated an increased risk of grade 3–4 (G3–4) HAEs in the radiotherapy plus TMZ groups [RR 16.90, 95% CI 7.69–37.15, P < 0.00001; [Table 2], but most of these side effects could be managed by delaying the next cycle or reducing the dose. Notably, the incidence of HAEs might also be in part related to the dose intensification and careful monitoring, particularly for the older. However, nonhematological toxicities such as infections, liver enzyme elevation, seizures, and so on were similar between the groups.
Table 2: A toxicity comparison between the TMZ and RT groups

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 > Discussion Top


In this meta-analysis, we examined the OS and PFS of radiotherapy and TMZ versus radiotherapy alone for the treatment of newly diagnosed GBM. A total of nine unique prospective (randomized or nonrandomized) studies,[16],[17],[18],[19],[20],[21],[22],[23],[24] involving 986 participants, were included. In general, TMZ is effective compared with radiotherapy alone when used in a concomitant and adjuvant manner. It prolongs the OS and PFS particularly obvious in the long time but with an increased risk of early adverse events. Our findings are consistent with those reported in a recent meta-analysis of randomized controlled trials.[25]

Except the study reported by Kocher et al.,[19] the others included in our meta-analysis reveal better median survival, survival rate, median PFS, and PFS rate outcomes when treating with radiotherapy and TMZ than radiotherapy alone. The negative result may be a consequence of the small sample size due to the early closure of the study. The reason for these conflicting results may also stem from the numerous factors that influence the response of malignant glioma cells to TMZ. So this study was not sufficiently powered.

The present meta-analysis has some limitations. First, due to limited data, we were unable to perform a pooled analysis according to ethnicity. To explore a high heterogeneity level in total OS, PFS, we conducted subgroup analysis according to dominant ethnicity. What's more, MGMT promoter methylation has been proposed as a means of predicting those who respond best to TMZ. Methylation of the MGMTpromoter precludes transcription, that is, production of MGMT, which may result in the lack of repair in TMZ-alkylated DNA, and may, therefore, lead to greater efficacy of TMZ and longer survival of patients with gliomas.[26],[27] Data on MGMT promoter methylation status is not all available, so we don't do an analysis of the relevance of MGMT. However, a recent meta-analysis [28] has confirmed the predictive significance of this biomarker, which could be utilized to identify subgroups of older patients for optimal individualized treatment.

Taken together, evidence for OS and PFS suggest that the use of TMZ concomitantly and adjuvantly to radiotherapy results in extended survival when compared with radiotherapy alone. But the prognosis for these patients is still extremely poor, and this treatment strategy was more toxic. Therefore, continued investigation of other regimens, such as the optimal TMZ schedules, hypofractionated radiation,[29],[30] and addition of other agents (e.g., bevacizumab) to standard RT and TMZ [31],[32] is warranted to further improve treatment for GBM.


 > Conclusion Top


The administration of TMZ before during and after radiotherapy for newly diagnosed GBM results in a clinically and statistically significant improvement of OS, PFS compared with patients receiving RT alone, but there are possibly more adverse events with temozolomide.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 > References Top

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Athanassiou H, Synodinou M, Maragoudakis E, Paraskevaidis M, Verigos C, Misailidou D, et al. Randomized phase II study of temozolomide and radiotherapy compared with radiotherapy alone in newly diagnosed glioblastoma multiforme. J Clin Oncol 2005;23:2372-7.  Back to cited text no. 16
    
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