Rechallenge with temozolomide in patients with recurrent gliomas

Abstract

Temozolomide (TMZ) is the standard of care for patients with newly diagnosed glioblastoma (GBM) as well as those with recurrent anaplastic glioma (AG) and GBM. It has become common practice to re-expose patients to TMZ who had been previously treated with TMZ, or to switch patients to alternative dosing regimens of TMZ when there are signs of relapse or progress on standard TMZ therapeutic regimens. To date, however, there is a scarcity of data on the efficacy of this therapeutic strategy, currently referred to as TMZ rechallenge. We have conducted a retrospective review of patients with recurrent glioma rechallenged with TMZ. Patients experiencing progressive disease (PD) during TMZ therapy who were rechallenged with alternative TMZ regimens and patients rechallenged after stable disease in a TMZ-free interval were evaluated separately. A total of 90 rechallenges were identified in 80 patients. The progression-free survival at 6 months (PFS-6) was 48% in patients with AG (12/25) and 27.7% in those with GBM (14/47). The PFS-6 was 16.7% in AG and 26.3% in GBM for patients switched during TMZ and 57.9 and 28.6% in patients rechallenged after a TMZ-free interval of at least 8 weeks. Relevant hematological toxicity (NCI-CTC grade 3-5) was observed in 22 of 90 rechallenges, and relevant non-hematological in ten of 90 rechallenges. Temozolomide was well tolerated and generated promising PFS-6 in patients who had previously failed TMZ, regardless if they progressed during TMZ treatment, or if they were rechallenged after a TMZ-free interval. These results suggest that the TMZ rechallenge strategy warrants further investigation in a prospective randomized trial.

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).…”

Canadian Recommendations for the Treatment of Recurrent or Progressive Glioblastoma Multiforme

“…At entry, 22 patients were chemotherapy-naïve, 30 had received prior nimustine-teniposide, 3 had received procarbazine-lomustine-vincristine (pcv), and 9 had received lomustine-temozolomide. A retrospective review by the same authors reported a 6-month pfs of 27.7% for gbm patients rechallenged with temozolomide 70 , results that are comparable to those seen with the continuous low-dose temozolomide regimen.…”

Stereotactic laser ablation of high-grade gliomas

“…1,5,16,26,30,55 A randomized, double-blind, placebo-controlled control trial also supported the implantation of carmustine (BCNU) wafers in tumor cavities after repeat operation. 10 Although salvage temozolomide had previously been used for recurrent GBM, 9,56,80 recent Level II evidence clinical studies in patients with recurrent GBM have demonstrated that salvage chemotherapy combining bevacizumab, an antiangiogenic agent, with cytotoxic drugs can extend progression-free survival and overall survival to 6.1 and 9.2 months, respectively. 21,75,82 Finally, emerging agents that target tumorigenesis pathways, such as new angiogenesis inhibitors and other novel agents, show promise as therapeutic options.…”