Comprehensive Analysis of Temozolomide Treatment for Patients with Glioma

Gliomas are the most common malignant brain tumors in Chinese adults (Cheng et al., 2013; Ge et al., 2013; Jiang et al., 2013; Liang et al., 2013; Yu et al., 2013; Wang et al., 2013; Luo et al., 2013; Zhu et al., 2013). Previous report revealed a statistically significant survival benefit for patients with gliomas treated with radiotherapy (RT) plus concomitant and adjuvant temozolomide (TMZ) chemotherapy, which currently represents the standard of care for newly diagnosed gliomas (Stupp et al., 2005; Stupp et al., 2007; Stupp et alk., 2009). However, despite surgery, RT and TMZ, patients with gliomas always relapse and ultimately develop terminal disease. TMZ is used in the treatment of glioma and is associated with an improvement of the prognosis (Khasraw et al., 2009). TMZ is an orally administered chemotherapeutic drug that methyl¬ates DNA in a way that prevents tumor cell proliferation, and is a second-generation alkylating agent approved by the Food and Drug Administration in 1999 (Stupp et al., 2002; Stupp et al., 2005; Khasraw et al., 2009). After Stupp reported the efficacy and toxicity of TMZ, it be¬came a common and standard regimen in the chemotherapy of malignant gliomas (Stupp et al., 2005). Since 2006, it has been approved for the standard treatment of newly diagnosed glioblastoma in con¬junction with radiotherapy for Chinese patients. However, no comprehensive analysis on TMZ in treating


Introduction
Gliomas are the most common malignant brain tumors in Chinese adults (Cheng et al., 2013;Ge et al., 2013;Jiang et al., 2013;Liang et al., 2013;Yu et al., 2013;Luo et al., 2013;Zhu et al., 2013). Previous report revealed a statistically significant survival benefit for patients with gliomas treated with radiotherapy (RT) plus concomitant and adjuvant temozolomide (TMZ) chemotherapy, which currently represents the standard of care for newly diagnosed gliomas Stupp et al., 2007;Stupp et alk., 2009). However, despite surgery, RT and TMZ, patients with gliomas always relapse and ultimately develop terminal disease. TMZ is used in the treatment of glioma and is associated with an improvement of the prognosis (Khasraw et al., 2009). TMZ is an orally administered chemotherapeutic drug that methyl¬ates DNA in a way that prevents tumor cell proliferation, and is a second-generation alkylating agent approved by the Food and Drug Administration in 1999 (Stupp et al., 2002;Khasraw et al., 2009). After Stupp reported the efficacy and toxicity of TMZ, it be¬came a common and standard regimen in the chemotherapy of malignant gliomas . Since 2006, it has been approved for the standard treatment of newly diagnosed glioblastoma in con¬junction with radiotherapy for Chinese patients. However, no comprehensive analysis on TMZ in treating patients with glioma was conducted. According to this background, we hypothesize that TMZ originated regimen could be established as an optimal schedule for patients with glioma. And we should conduct this analysis.

Search strategy
We searched PUBMED, by using the following search term: (glioma) and (temozolomide). All clinical studies evaluating the impact of temozolomide on the response or survival and side effects for glioma published in English prior to July 1st of 2014 were identified. If samples of two studies overlap, only the latest one was included. Additional articles were obtained from references within the articles identified by the electronic search. We did not consider meeting abstracts or unpublished reports.

Inclusion and exclusion criteria
We reviewed abstracts of all citations and retrieved studies. The following criteria were used to include published studies: (a) clinical studies, with temozolomide; (b) The study was performed in accordance with the Helsinki Declaration (1964, amended in 1975 and 1983) of the World Medical Association. Eligibility criteria included histologically verified with glioma, the presence of at least one bidimensionally measurable lesion, a performance status (WHO) 2, age 18 years. Studies were excluded if one of the following existed: (a) duplicate data; (b) no sufficient data were reported.

Data collection and analysis
Selection of trials and data extraction: The titles and abstracts of publications identified according to the above search strategy were assessed independently for inclusion by two authors, the full text was selected for further assessment if the abstract suggests relevance. Disagreement was resolved by discussion. Data was extracted by independent authors. The following recorded data were extracted: author, publication data, and country of the first or corresponding author, the number of patients.

Results
There were 152 papers relevant to the search words by the end of July, 2014. Via steps of screening the title and reading the abstract, 5 studies were identified (Verhoeff et al., 2010;Zustovich et al., 2009;Quinn et al., 2009;Tosoni et al., 2008;Brandes et al., 2006) when TMZ was used in chemotherapy. These studies had been carried out in Europe countries, and the United States. The following outcomes were presented in all studies and extracted for combined analysis: response rate, including the rate of complete or partial response (CR or PR) and toxicities.
Characteristics of TMZ as a component of chemotherapy, studies included in this study are presented as short-term outcomes: the response rate of Verhoeff JJ et al. was 20%,of Zustovich F et al. was  Observation on toxicities: Nausea and vom¬iting, were exceedingly common. Grade 3/4 toxicities included neutropenia, thrombocytopenia, and anemia (graded according to the World Health Organization grading system). No treatment related death occurred in TMZ based treatment.

Discussion
According to 2007 World Health Organization classification on tumors of central nervous system, glioma is divided into grades I-IV. Grade I and II are defined as low grade and grade III and IV as high grade. The incidence of the tumor in China is 1-4/100, 000 (Zhou et al., 2012). Treatment strategies for malignant glioma include removing the local lesion by surgery followed by adjuvant radiation and chemotherapy (Chen et al., 2013;Yang et al., 2013). Despite considerable efforts, however, the prognosis for patients with glioma is still poor. Resistance to radiation and chemotherapy is the main reason in treatment failure of malignant glioma. On this background, chemotherapy plays an important role in this settings. Currently, concomitant radiochemotherapy with TMZ, an alkylating agent, is widely used in China, and is reported to reduce the risk of recurrence and prolong patient survival (Strik et al., 2012;Yang et al., 2013). However, clinical studies of TMZ on malignant glioma in Chinese patients is not well documented. Thus, we conduct this comprehensive analysis on efficacy, side reactions, and clinical application of TMZ in the treatment of glioma. Compared with common used chemotherapeutic agents, effect of TMZ in treating malignant glioma is significantly improved. It was suggested that complete response and partial response rates are approximately 30% with TMZ versus only 10% with common used chemotherapeutic agents (Shen et al., 2012). Two-year survival rate is improved from 10.4% to 26.5% with the use of TMZ when the efficacy of TMZ was compared with lomustine (Shen et al., 2012;Qian et al., 2009). In a previous report, when patients were randomly divided into TMZ group and lomustine group, the response rate in TMZ and lomustine group was 35.7% and 9.1%, and clinical benefit rate was 90.5% and 75.0%, respectively. Yan evaluated the efficacy of TMZ in the treatment of recurrent glioma, the treatment effect of TMZ was modest (Yan et al., 2007). Thus they concluded that patients who were treated first with TMZ had significantly higher rates of response and 6-month progression-free survival than patients retreated with previous chemotherapy. Much of the relevant data generated in China is similar to that for studies performed in other countries, and shows that the therapeutic effect of TMZ is more effective than that of traditional chemotherapy regimens with regard to progression-free survival, overall survival, complete response rate, and clinical benefit rate in patients with malignant glioma (Yan et al., 2007). Silvani et al.  analyzed the activity and safety of procarbazine and fotemustine combination in the treatment of TMZ-refractory glioblastoma patients. They obtained a low rate of toxicity: only 2% of patients had grades 3-4 haematologic toxicity and no patients required dose reduction. They demonstrated the results of efficacy: median PFS and OS were 19.3 and 28.7 weeks, respectively. The association of TMZ and fotemustine in TMZ -refractory glioblastoma was also unsuccessful in previous study due to the important toxicity of the combination ; in fact, this study was stopped for relevant side-effects that occurred in the first 20 patients: 13 patients did not complete the third cycle because of grades 3-4 thrombocytopenia and 7 of 13 patients had grade 4 granulocytopenia .
In recent years, Bevacizumab, an anti-VEGF antibody, was approved by the US Food and Drug Administration in 2009 for patients with recurrent gliomas who have failed previous TMZ and radiation therapy based on prior studies (Vredenburgh et al., 2007;Friedman et al., 2009). This is because gliomas are highly vascularised brain tumors and are attractive targets for antiangiogenic therapies. Moreover, a recent clinical trial showed encouraging evidence of bevacizumab activity as well as acceptable safety among patients with recurrent grade III malignant glioma (Reardon et al., 2011). It is demonstrated that during bevacizumab therapy tumors may evade the inhibition of VEGF signaling and so the association of a cytotoxic drug might lead to more effective treatment. This could be the reason why bevacizumab would enhance the delivery of an active cytotoxic drug. But bevacizumab is very expensive and not yet covered by medical insurance in China, thus not available for most of patients.
We analyzed the efficacy and toxicity of TMZ by a comprehensive assessment on TMZ when treating patients with glioma. The response rate of Verhoeff JJ et al. was 20%,of Zustovich F et al. was 29.4%,19% for Quinn JA et al,30% for Tosoni A et al,and 9% for Brandes AA et al. Totally,152 patients were enrolled and 32 patients achieved CR or PR, the pooled response rate thus was 21% (32/152). Although TMZ is associated with a set of toxicities, most of the toxicities were grade 1 or 2 and were tolerable to patients. How¬ever, gastrointestinal troubles, e.g. nausea and vom¬iting, were exceedingly common. Thus, our systemic analysis suggests that TMZ based regimens are associated with mild response rate and accepted toxicities for treating patients with glioma.