| Background:As the most common primary malignant brain tumor, even in modern times of high-precision brain surgery and irradiation, glioblastoma (GBM) is always associated with a poor prognosis. For decades, the mainstay of treatment for malignant glioma has been radiotherapy (RT) followed by alkylating agents such as the nitrosoureas, pro-carbazine, and, more recently, temozolomide. Initially temozolomide was approved for the treatment of recurrent high-grade glioma at a dose of 150-200 mg/m2/day for 5 days every 28-day cycle (i.e., standard 5-day regimen).This clinical dosing regimen was determined based on preclinical studies conducted by Stevens and colleagues in the late 1980s showing schedule-dependent activity and phase I clinical studies conducted by Newlands and colleagues in the early 1990s. Subsequently, Brock et al demonstrated that a continuous daily regimen at a dose of 75 mg/m2/day was active and well tolerated for periods up to 6 or 7 weeks. This study began a very fruitful period of investigation into the clinical activity of a variety of alternative temozolomide dosing regimens.The cytotoxicity of temozolomide, like many other alkylating agents, manifests primarily by methylation of the 06 position of guanine. Although these DNA adducts represent,9% of the total DNA methylation events caused by temozolomide, 06-methylguanine induces DNA mismatch repair, which is unable to successfully Repair the lesion, and the resulting double-strand breaks ultimately drive the cell to undergo apoptosis. In contrast, N7-methylguanine and N3-methyladenine, which constitute approximately 80% of the total methylation events, are readily repaired by the base excision repair pathway and are generally not cytotoxic. Therefore, generation of O6-methylguanine and a functional DNA mismatch repair pathway are both critical to the cytotoxic potential of temozolomide. The only cellular mechanism capable of repairing these adducts is the enzyme 06-methylguanine DNA methyltransferase (MGMT). Consequently, the cellular levels of MGMT can affect the cytotoxicity of temozolomide and other alkylating agents, and the amount of MGMT in tumor cells is often regulated by epigenetic silencing of the gene via hyper methylation of CpG islands within the MGMT gene promoter. Tumor cells with a methylated MGMT promoter produce less MGMT protein. This is particularly relevant in light of recent studies showing that MGMT promoter methylation correlates with the clinical benefit of alkylating agents, particularly temozolomide. Recently, temozolomide was shown to significantly improve survival in patients with newly diagnosed glioblastoma (GBM) when administered concomitantly with RT and as maintenance therapy thereafter.3,13 A randomized, phase III trial jointly conducted by the European Organization for Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada (NCIC) Clinical Trials Group analyzed standard RT (60 Gy) alone compared with RT plus concomitant temozolomide (75 mg/m2/day 36 weeks) followed by up to six cycles of maintenance temozolomide using the standard 5-day schedule.3 Median survival was 12.1 months with RT alone versus 14.6 months for patients treated with RT plus temozolomide (p<0.001), and 2-year survival was 27% in the temozolomide group compared with 10% in the control group.3 This trial also showed that methylation of the MGMT promoter correlated with improved survival in patients treated with RT plus temozolomide, suggesting that tumors presumably with low levels of MGMT protein caused by epigenetic gene silencing may respond better to temozolomide than do tumors with high MGMT levels. These data also indicated that GBM with an unmethylated MGMT promoter may show only a marginal response to temozolomide. The retrospective MGMT promoter methylation analysis performed in the context of this large, randomized trial confirmed previous reports from several smaller studies and provided further evidence to support the hypothesis that MGMT promoter methylation status can profoundly affect sensitivity to alkylating agents. The growing body of evidence demonstrating the clinical importance of MGMT has generated considerable interest in the exploration of strategies to overcome MGMT-mediated resistance to alkylating agents. Research efforts have focused on either disabling the enzyme using inhibitors such as O6-benzylguanine (O 6-BG) or depleting MGMT enzyme activity in tumor cells.When MGMT repairs O 6-methylguanine lesions, it transfers the alkyl group from guanine to a cysteine moiety in its active site, thereby repairing the DNA. In the process, however, MGMT is irreversibly inactivated such that new MGMT protein synthesis is required for recovery of MGMT activity. In theory, it may be possible to exploit this feature to overcome chemo-resistance. If the number of O 6-methylguanine DNA adducts formed were to exceed the synthesis of cellular MGMT, then MGMT activity could be depleted, thus increasing the cytotoxic potential of the alkylating agent. However, MGMT is also depleted in normal cells, particularly hematopoietic stem cells, resulting in hematologic toxicity. The therapeutic window is largest when tumor cells have lower levels of MGMT activity relative to normal tissue. This is often the case in tumor cells with a hyper-methylated MGMT promoter, which effectively silences the gene. Epigenetic gene silencing of the MGMT promoter is found in 45%-70% of high-grade gliomas. This reflects a general mechanism whereby tumor cells turn off many genes that might otherwise act to reduce mutations, to slow cell division, or to induce apoptosis in response to DNA damage or mutations.The concept of MGMT depletion was validated in peripheral blood by Tolcher et a14 during treatment with temozolomide for 7 consecutive days every 14 days (2100 mg/m2/circle) or 21 consecutive days every 28 days (2100 mg/m2/circle).The cumulative dose was nearly twice as much as the standard dosing of 200 mg/m2 1-5/28 (1000 mg/m2/circle) and the metronomic schedule with 50 mg/m2/day (1400 mg/m2/circle).However, it is still unclear whether a regimen with a higher cumulative Tmz dose per cycle can deplete MGMT in tumors and overcome MGMT-mediated resistance. Additionally, the efficacy and safety of such a TMZ treatment plan is the subject of much controversy.This study is a meta-analysis to systematically evaluate the 7-14- and 21-28-day schedule (2100 mg/m2/circle) versus the standard or metronomic schedule (1000 mg/m2/circle) in GBM patients. The objective of this study was to verify whether a double cumulative dose per cycle can achieve a better survival benefit without an increasing incidence and severity of toxicity profile.Method:IncludedType of studiesAll studies included are RCTs.Type of participantsAll patients had histologically confirmed GBM.Type of interventionsSchedules with different cumulative doses (Figure 1) of TMZ per cycle after conventional radiation planning are compared.Type of outcomesPrimary outcome:Overall Survival (OS), defined as the time from diagnosis or randomization to the date of death or last follow up.Secondary outcomes:(1) PFS:the time from diagnosis or randomization to the date of progression defined by the Macdonald criteria 5, death or the last follow-up without progression.(2) Toxicity is defined according to the National Cancer Institute Common Terminology Criteria (NCI-CTC).Literature searchAll searchings were conducted carefully in Cochrane library, Science Direct, PubMed Databases were searched by two independent investigators with the following search strings:(1) "glioma", "glioblastoma", "malignant glioma", and "high grade glioma", (2) "dose-dense", "treatment schedule" and "regimen" (3) "temozolomide", "temozolomide", and "Temodar". The flow diagram of study selection is presented.Study selection and data extractionAll studies included met the following criteria:1. Must be random, prospective clinical RCTs.2. No language restriction was applied, and the nationality and race of research subjects were not restricted.3. Must compare two different Tmz schedules. They must include the Tmz regimen with a lower cumulative dose per cycle for the control group and the dose of the comparison group (s) per cycle must be higher than the control group.4. The primary endpoint was OS, and secondary endpoints were time to tumor progression (PFS) and overall response rate (ORR).Studies containing the following criteria have been excluded:1. The study did not meet the inclusion criteria;2. The research failed to provide the required information, such as the total number of patients, the median OS time, ORR, and 1-year survival rate.3. Poor quality, serious bias, too little literature information. Assessing the risk of bias in the eligible studiesThe risk of bias was assessed at time-to-event outcome level by two independent investigators (Hao.S and GX Liao) using the domain-based Cochrane Collaboration’s tool 6. Disagreements were resolved through consensus.Statistical analysisThe hazard ratios (HRs) for OS and PFS were statistically pooled to evaluate the efficacy, with a value<1 favoring the regimen with a higher cumulative dose (HCD) per cycle. If the HR was not given directly, then the value was calculated based on the Kaplan-Meier survival curves.For the safety analysis, the risk ratio (RR) was utilized to compare NCD and HCD, with a value>1 indicating an increased risk of adverse events in the HCD group.The inverse-variance (HR pooling) and the Mantel-Haenszel (RR pooling) methods were utilized to combine the data from each study, and either the fixed-effect model or the random-effect model was applied based on the heterogeneity of the included studies.Sensitivity analyses were conducted by considering the risk of bias of the studies and variables that were not closely related to our topic.Publication bias was described by the funnel plots and by analytic methods (e.g., Egger’s test 7)All of the analyses were performed by Review Manager V5.3 (The Cochrane Collaboration, Software Update, and Oxford, UK).Result:1. Characteristics of the studiesAccording to the inclusion criteria, we identified three RCTs that compared the NCD and the HCD groups with GBM (2 phase II RCTs:Jennifer Clarke, Michael Brada,1 phase III RCTs:Mark R. Gilbert 10) and comprised1141 patients. The characteristics of these RCTs are summarized.Among the three RCTs, the schedule of the NCD group is 50 mg/m2 1-28 days (1400 mg/m2) compared with the HCD with 150 mg/m2 1-7 and 15-21 days (2100 mg/m2) in the study by Jennifer Clarke and colleagues 8, and Tmz 200 mg/m2 1-5 days (1000 mg/m2) compared with Tmz 100 mg/m21-21 days (2100 mg/m2) in the Michael Brada et al and Mark R. Gilbert et al trials.The risk of bias in the included studies was assessed using the standard Cochrane Collaboration’s tool. All three randomized controlled trials with straight random principle were suggested to have low risk despite no performance of double-blinding, which is considered to not bias the assessment of OS and PFS. The individual prognostic factors (e.g., age, gender, performance status, and extent of surgery) were all well balanced within these studies.2. OSThere was no heterogeneity (x2=3.14, P=0.21, P=36%) among the three RCTs (Figure 3a), therefore the HR and 95% CI were calculated by the fixed effects model. (1141 total patients; HR 1.07,95% CI 0.94-1.22, P=0.31). This meta-analysis does not suggest a significant reduction in the risk of death in the HCD regimen. On the contrary, the standard regimen with higher peak Tmz concentration during short-term treatment (daily doses≥150 mg/m2 within 7 days or less per cycle) seemed to be more effective according to the statistic. To verify whether the peak drug concentration is the main reason for improvement in treatment effect, we swapped the control and the experimental group of the Clarke et al study 8 to keep consistent with the HR [Low peak drug concentration Vs High peak drug concentration] of the Gilbert and Brada9,10 before we calculated a new pooled HR. The new analysis yielded a new pooled HR of 1.10 with a 95% CI of 0.96- 1.25(P=0.17) [HR with value>1 prefer the regimen with High peak drug concentration].Unfortunately, there is no conclusive evidence for the superiority of the peak Tmz concentration regimens.3. PFSTwo studies 9,10 were included for the PFS analyses due to the lack of statistics in the study by Clarke et al 8 (Figure 4). The HR was calculated using the random-effect model (1056 total patients, HR 1.08,95% CI 0.69-1.69, P=0.31). No therapeutic benefits on PFS were detected for the HCD regimen.4. Adverse outcomesSafety data were collected among all these three studies and are demonstrated. Chemotherapy-related hematological adverse events (HAEs) such as Anemia/hemoglobin, Leukopenia/WBC toxicity, Neutropenia and Thrombocytopenia were the major safety concerns. The results did not indicate an increased risk of grade 3-4 (G3-4) HAEs among the patients with the HCD regimen except for Lymphopenia (RR 1.53,95%CI [0.81,2.89], P=0.009). Other non-hematological toxicity like Fatigue, Nausea/Vomiting, and Amino Transferases were similar between the groups.Therefore, our study demonstrate that the HCD regimen would lead to increased risk for Lymphopenia during the treatment period. No significant difference in non-hematological toxicities, such as fatigue/asthenia, nausea/vomiting and amino transferases, were observed.Conclusion:This meta-analysis has demonstrated the inferiority of the HCD regimen to the standard 1000 mg/m2 per cycle to some extent. Furthermore, the HCD regimen may be associated with increased risk for Lymphopenia for patients. The results of this meta-analysis suggest that regimens aiming to prolong exposure to Tmz or to increase cumulative dose cannot replace the standard 5-day regimen in clinical practice. Future trials should be designed to examine schedules using a higher daily dose with intensification to achieve higher peak concentrations. |
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