Temozolomide rechallenge in recurrent malignant glioma by using a continuous temozolomide schedule

Abstract

BACKGROUND. Despite advances in first‐line therapy, there are few data on treatment of glioblastoma multiforme (GBM) at recurrence. Temozolomide (TMZ) is well tolerated and may have activity despite prior TMZ exposure if novel dose schedules are used. METHODS. The authors reviewed their experience with a continuous TMZ schedule (50 mg/m2 daily), given at progression after conventional 5‐day TMZ. Patients were reported in 3 groups: 1) GBM after progression on conventional TMZ; 2) GBM at first recurrence after completion of standard concomitant and adjuvant TMZ; and 3) patients with other anaplastic gliomas at second relapse on conventional TMZ. RESULTS. In Group 1, 21 patients with a median age of 54 years (range, 33 years‐68 years) received a median of 3 cycles (range, 2‐12 cycles) of continuous TMZ at 50 mg/m2. Overall clinical benefit (complete response, partial response, and stable disease) was 47%, with 6‐month progression‐free survival (PFS) of 17%. In Group 2, 14 patients with GBM, median age 52 years (range, 38 years‐62 years) received continuous TMZ at progression after initial TMZ/radiotherapy (RT) and adjuvant TMZ. The median interval after adjuvant TMZ was 3 months (range, 2 months‐10 months). A median of 5 cycles of TMZ was given, and 6‐month PFS was 57%. In Group 3, 14 patients with a median age of 49 years (range, 34 years‐56 years) received continuous TMZ; 2 partial responses and 6 with stable disease were seen, with a 6‐month PFS of 42%. Toxicities were mild and well tolerated; lymphopenia was common but no serious opportunistic infections were identified. CONCLUSIONS. Although retrospective, our results demonstrate that continuous daily administration of TMZ is an active regimen despite prior TMZ therapy. The excellent tolerability of this regimen may allow future combination with other alkylating agents or with novel therapies. Cancer 2008. © 2008 American Cancer Society.

Combined therapy of temozolomide and ZD6474 (vandetanib) effectively reduces glioblastoma tumor volume through anti-angiogenic and anti-proliferative mechanisms

“…It was developed as a DNA alkylating agent that directly damages tumor cells (5)(6)(7). TMZ is stable in acidic conditions, but breaks down to 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (MTIC) and forms methyldiazonium ions in alkaline conditions, such as the blood.…”

“…Temozolomide (TMZ) is the most widely used chemotherapy for GBM and is orally administered (5). TMZ is a small-molecule DNA alkylating agent that easily penetrates the blood-brain barrier and elicits DNA methylation to effect tumor cell death (6,7).…”

MGMT promoter methylation in malignant gliomas: ready for personalized medicine?

“…[51][52][53] In vivo evidence for the direct involvement of MGMT in the response of glioblastoma to alkylating agents has been provided by The Cancer Genome Atlas. 54 The value of temozolomide in the setting of recurrent glioblastoma, including its relationship with MGMT promoter methylation status, must now to be determined in patients who have already been exposed to temozolomide in the first-line setting, 55,56 as is being pursued in the DIRECTOR trial (http://clinicaltrials.gov, NCT00941460).…”

Pharmacists Perspective on Management of GBM

“…Although TMZ does not have US Food and Drug Administration (FDA) approval for use in recurrent GBM, smaller studies of dose-dense regimens have shown some efficacy with its use for this indication [14][15][16]. The theory behind dose-dense TMZ regimens is that they more effectively deplete MGMT, so that the affected DNA cannot be repaired, allowing the tumor cells to be more susceptible to the antitumor activity of the alkylating agent [11,17].…”