BCNU wafer placement with temozolomide (TMZ) in the immediate postoperative period after tumor resection followed by radiation therapy with TMZ in patients with newly diagnosed high grade glioma: final results of a prospective, multi-institutional, phase II trial

Abstract

Temozolomide (TMZ) and BCNU have demonstrated anti-glioma synergism in preclinical models. We report final data from a prospective, multi-institutional study of BCNU wafers and early TMZ followed by radiation therapy with TMZ in patients with newly diagnosed malignant glioma. 65 patients were consented in 4 institutions, and 46 patients (43 GBM, 3 AA) were eligible for analysis. After resection and BCNU wafer placement, TMZ began on day four postoperatively. Radiation and TMZ (RT/TMZ) were then administered, followed by monthly TMZ at 200 mg/m2 for the first 26 patients, which was reduced to 150 mg/m2 for the remaining 20 patients. Non-hematologic toxicities were minimal. Nine of 27 patients (33 %) who received 200 mg/m2 TMZ, but only 1 of 20 (5 %) who received 150 mg/m2, experienced grade 3/4 thrombocytopenia. Median progression free survival (PFS) and overall survival (OS) period was 8.5 and 18 months, respectively. The 1-year OS rate was 76 %, which is a significant improvement compared with the historical control 1-year OS rate of 59 % (p = 0.023). However, there was no difference in 1-year OS compared with standard RT/TMZ (p = 0.12) or BCNU wafer followed by RT/TMZ (p = 0.87) in post hoc analyses. Early post-operative TMZ can be safely administered with BCNU wafers following resection of malignant glioma at the 150 mg/m2 dose level. Although there was an OS benefit compared to historical control, there was no indication of benefit for BCNU wafers and early TMZ in addition to standard RT/TMZ or early TMZ in addition to regimens of BCNU wafers followed by RT/TMZ.

Up‐regulation of miR‐497 confers resistance to temozolomide in human glioma cells by targeting mTOR/Bcl‐2

“…It has become the current standard chemotherapeutic drug in the treatment for glioma. However, the development of inherent or acquired TMZ resistance limits its clinical application, and the mechanisms of TMZ resistance are not fully understood . Thus, identification of new molecular targets is urgently required to fight against TMZ resistance in glioma.…”

Gliadel wafer implantation combined with standard radiotherapy and concurrent followed by adjuvant temozolomide for treatment of newly diagnosed high-grade glioma: a systematic literature review

“…Burri et al included an immediate postoperative 5-day cycle of TMZ beginning on day 4 ± 1, dosed at 150–200 mg/m 2 per day [29]. Concurrent TMZ at 75 mg/m 2 then began at day 33 ± 1 with RT; after completion of concurrent treatment, adjuvant TMZ was begun and administered at 150–200 mg/m 2 per day for 5 days per 28-day cycle for up to 10 cycles or until progression or patient intolerance [29]. Because the Burri et al trial was a multisite phase II study, it was included in the analysis.…”

“…Only two of the trials in this systematic review reported MGMT analysis. Burri et al reported MGMT promoter methylation status for 22 of 43 patients with GBM (out of 46 patients total in the study) [29]. In the study by Noel et al, MGMT promoter methylation status was reported for all 65 patients: 24 patients were methylated, 27 patients were unmethylated, and 14 patients were not analyzed [34].…”

“…In the Burri et al clinical trial, patients with unmethylated MGMT ( n  = 19) experienced shorter median OS but longer median PFS than patients with methylated MGMT ( n  = 14) (18.2 vs 27.3 months for median OS; 8.9 vs 7.4 months for median PFS) [29]. …”

“…However, Bock et al noted that after introducing a risk-management strategy to address patient selection, surgical techniques, and follow-up schedules, the incidence of implantation-site-related complications dropped significantly [40]. In the phase II clinical trial by Burri et al, in which 39 adverse events were reported, adjuvant TMZ was administered at a dose of 150–200 mg/m 2 [29]. The investigators reported that nine of the patients receiving 200 mg/m 2 of TMZ experienced one or more episodes of grade 3 or 4 thrombocytopenia after the initial pre-radiotherapy cycle of adjuvant TMZ.…”