Long-term daily temozolomide with dose-dependent efficacy in MGMT promotor methylation negative recurrent high-grade astrocytoma

Abstract

Temozolomide (TMZ) for malignant gliomas is traditionally dosed in 5 out of a 28-day cycle, however alternative regimens exist, including dose-dense. Continuous daily dosing is available, but the acceptable dose and duration of therapy is unknown. We document a 40-year-old male with recurrent anaplastic astrocytoma, IDH mutant and MGMT promotor methylation negative, who has well-tolerated continuous daily TMZ for 20 months at 100 mg per day for nearly the length of this period. A trial at 80 mg per day demonstrated disease progression with response upon return to 100 mg per day. Prior to the daily TMZ, the patient underwent three surgical resections, radiation therapy with concurrent TMZ according to the EORTC-NCIC protocol, and subsequently bevacizumab in combination with use of the Optune device. Long-term survival of patients with recurrent malignant gliomas is uncommon, and currently no standard treatment strategies exist for these patients. We present this case to demonstrate the tolerability and dose dependency of prolonged daily TMZ dosing as a therapeutic option for recurrent anaplastic astrocytomas.

Combination Chemoradiotherapy with Temozolomide, Vincristine, and Interferon-β Might Improve Outcomes Regardless of O6-Methyl-Guanine-DNA-Methyltransferase (MGMT) Promoter Methylation Status in Newly Glioblastoma

“…A meta-analysis has indicated that long-term treatment is more bene cial in terms of both OS and PFS [34]. In addition, according to one study, MGMT-mediated TMZ resistance may be attenuated by continuous therapy [35]. Certainly, long-term administration of TMZ would enhance the accumulation of TMZ in the body, and may have the same signi cance as the use of dose-dense TMZ, which depletes MGMT.…”

Combination chemoradiotherapy with temozolomide, vincristine, and interferon-β might improve outcomes regardless of O6-methyl-guanine-DNA-methyltransferase (MGMT) promoter methylation status in newly glioblastoma

“…A meta-analysis has indicated that long-term treatment is more beneficial in terms of both OS and PFS [41]. In addition, according to one study, MGMTmediated TMZ resistance may be attenuated by continuous therapy [42]. Certainly, long-term administration of TMZ would enhance the accumulation of TMZ in the body, and may have the same significance as the use of dose-dense TMZ, which depletes MGMT.…”

PI3Kγ inhibition suppresses microglia/TAM accumulation in glioblastoma microenvironment to promote exceptional temozolomide response

“…Of those tested, only interleukin 11 (IL11) exhibited the anticipated survival association. In the TCGA dataset, high IL11 mRNA expression was associated with 9 poor survival ( Fig. 2D).…”

“…First, while glioblastomas harboring isocitrate dehydrogenase (IDH) mutations are generally associated with improved survival (3), such mutations are not required for long-term survivorship (4,5). Second, in independent studies, clinical specimens from long-term survivors are more likely to harbor promoter methylation attenuating the expression of O6-methylguanine-DNA-methyltransferase (MGMT), a DNA repair protein that confers TMZ resistance (6)(7)(8)(9).…”