Hydroxyurea for recurrent surgery and radiation refractory high-grade meningioma

Abstract

Hydroxyurea (HU), an orally administered chemotherapy, has become the de facto standard chemotherapeutic agent in patients with surgically and radiation refractory meningiomas based on a limited literature. A retrospective case series of 35 patients with recurrent WHO Grade 2 (n = 22) or 3 (n = 13) meningioma treated with HU following progression after surgery and radiotherapy was collated with primary study objectives of overall response rate, median and progression free survival (PFS) at 6-months. Thirty-five patients (25 women; 10 men: median age 63 years, range 34-86) with recurrent high-grade meningioma were treated with HU (1,000 mg/m(2) orally divided twice per day; one cycle operationally defined as 4 weeks of daily HU). Patients had progressed radiographically after prior therapy with surgery (35/35) and radiotherapy (35/35: external beam radiotherapy 35/35; stereotactic radiotherapy 35/35). No patient received prior chemotherapy or targeted therapy before instituting HU. Patients received 0.5-7 cycles (median 2.0) of HU with modest toxicity (28.5% all grades and 8.5% grade 3+ anemia or fatigue). There were no radiographic responses, 43% of patients had stable disease and 57% manifested progressive disease at first evaluation. The overall PFS was 3.0% at 6 months (median PFS 2.0 months; 95% CI 1.6-2.4). The majority of patients (80%) following progression on HU were subsequently treated on an investigational trial. In this retrospective series, HU though well tolerated and convenient appeared to have very limited activity, raise questions of what constitutes effective salvage therapy and indicates an unmet need for alternative treatments for recurrent high-grade meningiomas.

Kinetics of tumor size and peritumoral brain edema before, during, and after systemic therapy in recurrent WHO grade II or III meningioma

“…A recent systematic analysis proposed a PFS-6 rate of 26% as the benchmark for historical comparisons. 14 Considering this benchmark, hydroxyurea, octreotide analogues, gefitinib, and erlotinib were deemed ineffective, 4,13,16 while anti-angiogenic drugs, including bevacizumab, vatalanib, and sunitinib showed potential activity, with PFS-6 rates of 37.5% to 64.3%. 11,14,17 -19 Interestingly, our data support a potential role of anti-angiogenic treatment in recurrent WHO grades II and III meningioma, as the most pronounced decrease of tumor growth rates was observed in patients put on bevacizumab therapy.…”

Recent developments in chemotherapy for meningiomas: a review

“…9 A follow-up retrospective study of 35 patients with WHO Grade II and Grade III meningiomas showed 57% progression of disease at 6 months. 6 These results suggest that although hydroxyurea is generally well tolerated with limited toxicity, it appears to have very limited activity in tumor control. Investigators are currently looking at the role of hydroxyurea as an adjunct to other therapies, such as radiation or calcium channel blockers.…”

“…Larger, more recent studies have also failed to demonstrate significant clinical efficacy. 6,9 In a recent large-scale trial that included 60 patients, progression of disease occurred in 65% of participants despite hydroxyurea therapy. 9 A follow-up retrospective study of 35 patients with WHO Grade II and Grade III meningiomas showed 57% progression of disease at 6 months.…”

An evidence-based treatment algorithm for the management of WHO Grade II and III meningiomas

“…Pa-tients with these refractory tumors typically have a median overall survival of only 6-33 months. 9,38,56 Modern trials have looked at the possible utility of receptor tyrosine kinase (RTK) inhibitors. Gefitinib, erlotinib, and imatinib, which target platelet-derived growth factor receptor (PDGFR) and epidermal growth factor receptor (EGFR), respectively, have generally been ineffective for AM and MM.…”