In the Journals

Metronomic temozolomide extends PFS, OS in EGFR-amplified glioblastoma

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March 16, 2015

Patients with epidermal growth factor receptor-amplified and -overexpressing glioblastomas demonstrated a significant benefit from metronomic temozolomide-based therapies, according to retrospective study results.

“Glioblastoma represents the most frequent primary malignant brain tumor in adults, with a median survival of only 14.6 months,” Pietro Luigi Poliani, MD, of the pathology unit of the department of molecular and translational medicine at the University of Brescia Medical School, and colleagues wrote. “Temozolomide responsiveness remains difficult to predict, mainly because of the lack of robust predictive biomarkers, other than MGMT promoter methylation, and patients living longer than 3 years are rarely seen.”

Poliani and colleagues evaluated data collected from 70 patients (median age, 57.5 years) with newly diagnosed glioblastoma. All patients underwent surgery followed by standard concomitant radiation therapy and chemotherapy.

Forty patients then received a standard schedule of temozolomide (Temodar, Schering-Plough), which consisted of 150-mg/m2 to 200-mg/m2 doses for 5 days in 28-day cycles. The other 30 patients received treatment on a metronomic schedule, which consisted of 75 mg/m2 doses daily until tumor progression.

Results indicated patients who received the metronomic schedule achieved significantly prolonged PFS when they had tumors with high vs. low EGFR expression (20 months vs. 11 months; HR = 0.28; 95% CI, 0.11-0.72). EGFR amplification or overexpression also was significantly associated with improved median OS in patients who received the metronomic schedule (34 months vs. 14 months; HR = 0.22; 95% CI, 0.09-0.55).

The improved outcomes associated with EGFR expression and metronomic temozolomide persisted in patients independent of MGMT promoter methylation (PFS, P = .005; OS, P ˂ .0005) and EGFRvIII status (PFS and OS, P ˂ .0005).

Among patients with EGFR-amplified glioblastoma, those with PTEN loss demonstrated particularly significant improvements in PFS (HR = 0.15; 95% CI, 0.05-0.39) and OS (HR = 0.06; 95% CI, 0.02-0.2) with metronomic temozolomide.

In vitro assays of human-derived glioblastoma cancer stem cells indicated response to temozolomide is mediated through inhibition of nuclear factor-κB (NF- κB) activation. Specimens from recurrent metronomic-treated, EGFR-overexpressing patients demonstrated a reduction in EGFR-amplified cells and a decrease in NF- κB/p65 expression.

“Some limitations of our study are the retrospective non-randomized nature of the analysis and the limited numbers of the patient cohorts,” Poliani and colleagues wrote. “Nevertheless, because up to 40% of newly diagnosed glioblastomas are characterized by EGFR amplification/overexpression, our observations might hold important implications for glioblastoma treatment that require prospective validation in a well-designed clinical trial.” – by Cameron Kelsall

Disclosure: The researchers report no relevant financial disclosures.

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