Safety of Tumor Treating Fields and Concomitant Radiation Therapy for Newly Diagnosed Glioblastoma in a Pilot Study

Abstract

Tumor Treating Fields (TTFields) are a non-invasive, loco- regional, anti-mitotic treatment based on low intensity alternating electric fields. Efficacy of TTFields in newly diagnosed glioblastoma (ndGBM) has been shown in the EF14 study of TTFields plus maintenance temozolomide (TMZ) (Stupp R., et al., JAMA 2017). TTFields/TMZ showed significant survival improvement versus TMZ alone (HR, 0.63; p<0.001). Preclinical data show that TTFields increase proportion of glioma cells undergoing cellular death following radiotherapy (RT) by inhibiting DNA-damage repair through the homologous recombination pathway. This suggests that TTFields may have a radiosensitizing effect. The current study was the first to test TTFields concomitant to RT in ndGBM patients. Patients with ndGBM (n=10, KPS ≥70) enrolled in this single-arm trial between April and December 2017 had all recovered from maximal debulking surgery or biopsy. Patients started TTFields prior to or at the time of RT, and were on stable or decreasing doses of corticosteroids for 7 days pre-enrollment. TTFields (200 kHz) were delivered 18 hours/day with daily removal of the transducer arrays during RT delivery. TMZ (75 mg/m2 daily) was given for 6 weeks and RT at a total dose of 60 Gy. The primary endpoint was safety of the combined therapies. Median age was 59 (range 42-71 years), median KPS was 90 (range 80-100) and 8 (80%) of patients were male. Five patients (50%) underwent gross total resection while rest had biopsy only. Median dose of RT was 60 Gy (range 52-60 Gy). Six patients (60%) reported adverse events (AEs) to-date. The most common AE was TTFields-related skin toxicity, reported in 4 (40%) patients. These were not severe. All other AEs occurred in a single patient possibly due to underlying disease or chemotherapy. Two serious AEs were reported – seizures and general deterioration, assessed as unrelated to TTFields. TTFields-related skin toxicity (40%) in this study was similar to that reported for the 466 patients treated with TTFields in the phase III study (52%), where patients started TTFields > 4 weeks after RT. No other TTFields-related toxicities were reported, nor was there an increase in RT- or TMZ-related toxicities from combining TTFields with RT or TMZ. TTFields show a high safety profile when combined with other therapies in ndGBM.