Comparison of Two Phase II Trials of Neoadjuvant Temozolomide Followed with Concomitant and Adjuvant Temozolomide and Hypofractionated Accelerated Radiotherapy with or without Metformin in Patients with Newly Diagnosed Glioblastoma

Abstract

<h3>Purpose/Objective(s)</h3> Metformin (MTF) inhibits the proliferation of Glioblastoma (GBM) cells by activating adenosine monophosphate-activated protein kinase (AMPK), and mTOR, with subsequent sensitization to ionizing radiation and Temozolomide (TMZ). Furthermore, MTF reduces blood glucose levels and growth factors including insulin and insulin-growth factors. <h3>Materials/Methods</h3> Each trial consisted of 50 adults with newly diagnosed GBM. Within 4-5 weeks from surgery patients received either: (1) neo-adjuvant TMZ (75 mg/m²PO QD) for 2 weeks prior to Hypofractionated Accelerated Radiotherapy (HART) (60 Gy in 20 daily fractions over 4 weeks) given with concomitant and adjuvant TMZ given for 6 cycles at 150–200 mg/m² (N-HART) trial ClinicalTrials.gov NCT # NCT01702610; or (2) neo-adjuvant TMZ (75 mg/m²PO QD) + MTF (850 mg PO BID) for 2 weeks prior to HART with concomitant and adjuvant MTF + TMZ. Adjuvant TMZ + MTF were given for 6 cycles ClinicalTrials.gov NCT # 02780024. Survival analyses were done according to the Kaplan-Meier methods and Log-rank statistics. <h3>Results</h3> The median follow up for patients at risk was 107.9 months for the N-HARTT, and 34.3 months for the M-HARTT trials. The 2 cohorts were balanced for age and ECOG status. Gross total resection was performed in 54% of N-HARTT versus 84% in M-HARTT cohort. MGMT-gene promoter was methylated in 48% in N-HARTT trial compared to 32% in the M-HARTT trial. The median overall survival (OS) and PFS were 22.3 months, and 13.7 months, respectively for the N-HARTT trial compared with 29.5 months, and 13.7 months for the M-HARTT cohort [p=0.22 HR 0.91 (95% CI 0.56-1.47)]. Patients with unmethylated MGMT tumors had a median OS of 15 months in the N-HARTT trial compared to 24 months for patients with unmethylated MGMT tumors treated on the M-HARTT trial [(p=0.07 HR 0.64 (CI 95% 0.35-1.17)]. Patients with methylated MGMT tumors had 46.3 months median OS versus 50 months for patients with methylated MGMT tumors treated on N-HARTT and M-HARTT trials, respectively [(p=0.25 HR 1.37 (CI 95% 0.88-2.15)]. In a sub-group analysis of the M-HARTT trial, we observed that the median OS of patients with an average blood glucose levels of < 5 mmol/L has not been reached versus a median OS of 25.7 months for patients with blood glucose levels ≥ 5 mmol/L, (p=0·03 HR 0·30 95%CI, 0·13–0.67 Log-rank) <h3>Conclusion</h3> The addition of MTF in the M-HART trial resulted in an encouraging improvement of the median OS compared with N-HART trial. The main impact was observed in patients with unmethylated MGMT tumors. Furthermore, the results are suggestive for a potential role for glycemic control on outcomes.