Dose-dense temozolomide for recurrent high-grade gliomas: a single-center retrospective study

Abstract

There are limited treatment modalities after high-grade gliomas recurrence. MGMT depletion modulated by dose-dense temozolomide (ddTMZ) remains a debated therapy for initial TMZ responders. Patients were selected retrospectively from our practice with diagnosis of high-grade gliomas (WHO grade III or IV), and were followed since the start of ddTMZ until death or change of therapy. Twenty-one patients were reviewed, with a median age of 47 (25-61) years and a median of 5.8 (1.5-38.8) cycles of ddTMZ. The majority were males (71.4%). Sixty-six percent received 21 on/28 off ddTMZ schedule, 28.6% daily, and 1 patient received a 7 days on/7 days off schedule. IDH mutation status was available for 18 (85.7%) patients, with 7 (33.3%) IDH mutant and 11 (52.5%) IDH wild type. MGMT methylation was assessed in 6 (28.6%) of the patients, being MGMT methylated in 3 (14.3%) patients, and non-methylated in 3 (14.3%) patients. The majority of patients (57.1%) were receiving ddTMZ in addition to other forms of therapy, including either bevacizumab (38.1%) or tumor-treating fields (TTFields) (19.1%). Overall ddTMZ was well tolerated, with few adverse events reported. The estimated median overall survival after ddTMZ start was 11 months. Median progression-free survival (PFS) was 6 months. Outcomes did not vary between patients receiving ddTMZ alone or those using TTFields or bevacizumab as concomitant therapy, but there was a trend to longer survival with the use of concomitant TTFields. Our results demonstrate benefit of ddTMZ after previous treatment with standard TMZ dosing with no apparent increase in treatment-related toxicities. In summary, ddTMZ should be considered in TMZ responsive patients and warrants further investigation.

The efficacy and adverse events of bevacizumab combined with temozolomide in the treatment of glioma: a systemic review and meta-analysis of randomized controlled trials

“…TMZ inhibits the growth of tumor cells by inhibiting cellular DNA replication, but it also damages the DNA of normal cells, resulting in normal cell death ( 38 , 39 ). And the metabolites of TMZ are small in size, easily absorbed, and have high blood–brain barrier permeability, which may be a relevant mechanism leading to the development of adverse events ( 40 ). Although BEV as an antiangiogenic agent combined with TMZ can significantly reduce the growth of tumor cells, it also interferes with the blood metabolism of normal tissues, and its clinical application value is still controversial ( 41 ).…”

Challenges and Perspectives of Standard Therapy and Drug Development in High-Grade Gliomas

“…The standard dose (75 mg/m 2 /day) and concurrent administration of Tmz in recurrent anaplastic astrocytoma patients demonstrated 6-month progression-free survival and overall survival of around 46% and 13.6 months, respectively [62][63][64]. The continuous dose-dense Tmz for recurrent anaplastic astrocytoma can help overcome the drug resistance by decreasing MGMT activity with anti-angiogenic properties [62,65,66]. In contrast, anaplastic oligodendroglioma patients are responsive to various chemotherapy such as PCV (procarbazine, vincristine, lomustine) and Tmz [62,67].…”