A Phase 2 Study of Neo-adjuvant Metformin and Temozolomide followed by Hypofractionated Accelerated RadioTherapy (HART) with Concomitant and Adjuvant Metformin and Temozolomide (TMZ) in Patients with Glioblastoma

Abstract

Metformin inhibits the proliferation of glioblastoma (GBM) cancer stem cells through stimulation of AMPK, lowers glucose levels, insulin, and IGF-1. The purpose was to assess the feasibility of post-op neo-adjuvant metformin and TMZ, followed by HART with concomitant and adjuvant TMZ/metformin. Neo-adjuvant metformin (850 mg BID) and TMZ (75 mg/m2 QD) were started within 4 weeks from surgery, for 14 days prior to starting radiotherapy. HART was delivered using IMRT simultaneous boost technique. The CTV included surgical resection cavity and post-operative residual contrast enhancing lesion. The PTV_60 included CTV+3-5 mm margin, while PTV_40 included CTV + 15 mm. A dose of 60 Gy was delivered to PTV_60 while a dose of 40 Gy was delivered to PTV_40 in 20 daily fractions. Concomitant and adjuvant TMZ were administered as per the Stupp’s schedule with concomitant metformin. Thirty-three patients, 19 females and 14 males were included. Median age was 54 years, median ECOG score was 1 At a median follow-up of 20.3 months (range 2.0-55.8) for patients at risk, the median survival was 38.2 months (95% CI, 12-59), with 20 out of 33 patients alive at the date of this report. At 2 years the overall survival was 65.5%, and 50.5 % at 3 years. Median PFS was 15.4 months (95% CI, 10-36). For 27 patients with gross total resection, median survival was 38.84 months compared to 16.8 months for 6 patients with partial resection (p = 0.02). The median survival of patients aged < 60 years was 38.8 months and 17.1 for patients > 60 years (p = 0.16). The median survival for 12 patients with methylated MGMT was not reached compared to 38.2 months for 21 patients with unmethylated MGMT (p = 0.12). Adjuvant TMZ/Metformin was discontinued in 2 patients, one with disease progression, and another one following prolonged grade 4 thrombocytopenia. There were no unexpected severe adverse events. Thirteen patients were re-operated for findings suggestive of disease progression. Six patients of the 13 re-operated patients had treatment-related necrosis with no viable residual GBM. Two of these 6 patients later developed disease progression. Eighty-one percent and 70.9% of the patients were free from treatment-related necrosis at 2 and 3 years, respectively. Neo-adjuvant metformin and TMZ followed by concurrent TMZ/metformin and HART and adjuvant TMZ/metformin is feasible and safe, and the results compare favorably to current GBM literature, especially for patients with unmethylated MGMT.