O⁶‐methylguanine‐DNA methyltransferase (MGMT) promoter methylation and low MGMT‐encoded protein expression as prognostic markers in glioblastoma patients treated with biodegradable carmustine wafer implants after initial surgery followed by radiotherapy with concomitant and adjuvant temozolomide

Abstract

BACKGROUND: O 6 -methylguanine-DNA methyltransferase (MGMT) promoter methylation status was proposed as a prognostic biomarker for patients with glioblastoma. However, the prognostic impact of MGMT in patients with newly diagnosed glioblastoma who receive carmustine-releasing wafers (Gliadel) along with temozolomide (TMZ) is still unknown. METHODS: MGMT promoter methylation status and protein expression were analyzed in formalin-fixed, paraffin-embedded tumor specimens obtained from 111 French patients with newly diagnosed glioblastoma. Patients received the Gliadel wafers followed by radiotherapy plus concomitant and adjuvant TMZ chemotherapy while they were enrolled in a French multicenter prospective study. RESULTS: For the whole cohort, the median overall survival (OS) was 17.5 months, and the progression-free survival was 10.3 months. Patients with tumors that harbored MGMT methylation had a significantly longer OS compared with patients who had wild-type MGMT (21.7 months vs 15.1 months; P ¼ .025). Similarly, patients who had low MGMT protein expression ( 15%) had a significantly improved OS compared with patients who had high MGMT expression (27.0 months vs 15.1 months; P ¼ .021). The extent of resection was the strongest clinical predictor of outcome. In multivariate Cox models that were adjusted for sex, performance status, and extent of surgery, both MGMT methylation and protein expression were identified as independent prognosticators, and the finding was validated internally using a bootstrap resampling technique. Discrepancies were identified between protein expression and MGMT methylation status, thus suggesting that the 2 assays probably assess different biologic features. CONCLUSIONS: MGMT promoter methylation status and low MGMT expression both were identified as positive prognosticators in patients with newly diagnosed glioblastoma who underwent surgical resection and received Gliadel wafer implants followed by adjuvant radiotherapy and concomitant oral TMZ chemotherapy (the Stupp protocol).

Rapid regression of glioblastoma following carmustine wafer implantation: A case report

“…A pharmacokinetic analysis indicated that exposure of the tissue area to carmustine under a concentration-time curve achieved by polymeric delivery was 4-1,200-fold higher compared with that produced by intravenous administration of a higher dose; however, the MGMT status should be considered as the main factor that limits the efficacy of carmustine wafers (12). Indeed, in patients with newly diagnosed GB who underwent surgical resection and received carmustine wafer implants followed by adjuvant radiotherapy and concomitant oral TMZ chemotherapy, MGMT promoter methylation status and low MGMT expression were identified as positive prognostic factors (10). In the present case, the tumor was highly responsive to carmustine wafers, and also exhibited genetic characteristics conferring sensitivity to alkylating agents.…”

“…Consequently, carmustine wafers may be implanted concomitantly with these combined standard treatments. The rationale underlying this type of local therapy is to fill the gap between surgery and adjuvant treatments to maintain alkylating treatment pressure on residual tumor cells (10). However, in the present case, carmustine wafers were so effective that the residual tumor had markedly regressed when systemic TMZ chemotherapy was initiated, indicating that the outcome of adjuvant therapy was mainly affected by the carmustine wafers.…”

Intracranial microcapsule chemotherapy delivery for the localized treatment of rodent metastatic breast adenocarcinoma in the brain

“…Release kinetics were controlled by the diameter of device orifices, the number of orifices, and the solubility of the drug. The inner volume of the reservoir measured 1.5 mL, which allowed for higher drug loading per device volume compared with previous drug delivery devices (10,32). One important innovation in this work was the use of the injection molding process for high-precision device production, which gave reliable and consistent results, including very small tolerances in volume.…”

“…Localized drug delivery devices provide high drug concentrations to the tumor site while preventing drug degradation and clearance until its release (7,8). The efficacy of current intracranial drug delivery, such as Carmustine wafers, has promise, with a doubling of median survival from 9 to 20 mo in the case of Carmustine wafers (6,9,10). Phase III trial data indicated a 2-to 3-mo survival advantage in Carmustine wafers-treated patients (11), and Carmustine wafers continue to have a role combined with radiation and oral temozolomide (TMZ).…”

Safety and efficacy of Gliadel wafers for newly diagnosed and recurrent glioblastomas

“…With regard to this multimodal treatment, the interesting data recently published in Cancer [9] about the prognostic impact of MGMT in patients with newly diagnosed glioblastoma who receive carmustine-releasing wafers (Gliadel) along with temozolomide must be emphasized. Patients with tumors that harbored MGMT methylation had a significantly longer OS compared with patients who had wild-type MGMT (21.7 months vs. 15.1 months; P00.025).…”