Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma: A Randomized Clinical Trial.

Tumor-treating fields (TTFields) is an antimitotic treatment modality that interferes with glioblastoma cell division and organelle assembly by delivering low-intensity alternating electric fields to the tumor. To investigate whether TTFields improves progression-free and overall survival of patients with glioblastoma, a fatal disease that commonly recurs at the initial tumor site or in the central nervous system. In this randomized, open-label trial, 695 patients with glioblastoma whose tumor was resected or biopsied and had completed concomitant radiochemotherapy (median time from diagnosis to randomization, 3.8 months) were enrolled at 83 centers (July 2009-2014) and followed up through December 2016. A preliminary report from this trial was published in 2015; this report describes the final analysis. Patients were randomized 2:1 to TTFields plus maintenance temozolomide chemotherapy (n = 466) or temozolomide alone (n = 229). The TTFields, consisting of low-intensity, 200 kHz frequency, alternating electric fields, was delivered (≥ 18 hours/d) via 4 transducer arrays on the shaved scalp and connected to a portable device. Temozolomide was administered to both groups (150-200 mg/m2) for 5 days per 28-day cycle (6-12 cycles). Progression-free survival (tested at α = .046). The secondary end point was overall survival (tested hierarchically at α = .048). Analyses were performed for the intent-to-treat population. Adverse events were compared by group. Of the 695 randomized patients (median age, 56 years; IQR, 48-63; 473 men [68%]), 637 (92%) completed the trial. Median progression-free survival from randomization was 6.7 months in the TTFields-temozolomide group and 4.0 months in the temozolomide-alone group (HR, 0.63; 95% CI, 0.52-0.76; P < .001). Median overall survival was 20.9 months in the TTFields-temozolomide group vs 16.0 months in the temozolomide-alone group (HR, 0.63; 95% CI, 0.53-0.76; P < .001). Systemic adverse event frequency was 48% in the TTFields-temozolomide group and 44% in the temozolomide-alone group. Mild to moderate skin toxicity underneath the transducer arrays occurred in 52% of patients who received TTFields-temozolomide vs no patients who received temozolomide alone. In the final analysis of this randomized clinical trial of patients with glioblastoma who had received standard radiochemotherapy, the addition of TTFields to maintenance temozolomide chemotherapy vs maintenance temozolomide alone, resulted in statistically significant improvement in progression-free survival and overall survival. These results are consistent with the previous interim analysis. clinicaltrials.gov Identifier: NCT00916409

Tumor treating fields (TTFields) on healthrelated quality of life (HRQoL) in ndGBM: An exploratory analysis of the EF-14 phase I-II trial

TTFields are a novel treatment modality based on homeuse medical device which continuously delivers alternating electric fields to the region of the tumor. These fields selectively interfere with a number of cellular processes during the mitotic cycle, such as the assembly of the mitotic spindle, leading to apoptosis. In the EF-14 phase I-II study in newly diagnosed glioblastoma, TTFields added to maintenance temozolomide led to a significant increase in overall survival, as well as in the 5-year survival rate compared to patients treated with temozolomide alone. It was previously reported that the addition of TTFields to maintenance temozolomide did not negatively impact nine prespecified HRQoL scales except for an expected increase in itchy skin, and in addition resulted in a significant delay in the increase of HRQoL pain assessment. Here we present an exploratory analysis of the remaining EORTC QLQ C30 and BN-20 HRQoL scales. Methods HRQoL was a predefined secondary endpoint in the EF-14 study, measured by collecting the EORTC QLQ-C30 and BN-20 questionnaires at baseline and every 3 months thereafter. HRQoL was assessed for the remaining HRQoL scales except for the prespecified and previously reported nine preselected scales: global health, physical, cognitive, role, social and emotional functioning, itchy skin, pain, and leg weakness. Mean changes from baseline scores were evaluated, as well as significant changes in scores over time (\u3e10 points) using a repeated measures test. Moreover, deterioration-free survival and time to deterioration in HRQoL were assessed for each scale, as well as the percentage of patients with stable/improved HRQoL compared to baseline. Results No statistically or clinically significant decline in any of the exploratory HRQoL scales was seen in the repeated measures analysis or in time to deterioration. A significantly larger proportion of patients treated with TTFields compared to control patients reported stable/improved bladder control (63.6% Vs. 46.8%, p=0.001) and diarrhea (60.6% vs. 43.7%, p=0.001) compared to baseline. The deterioration-free survival for diarrhea, future uncertainty and headaches was significantly delayed in TTFields/temozolomide treated patients compared to those treated with temozolomide alone (HR 0.68, 0.71 and 0.67, respectively, p\u3c0.001). Conclusions The delay in deterioration free survival and increase in percentage of patients with stable/improved HRQoL in several of the additional HRQoL scales may be attributed in part to the longer progression-free survival observed in TTFields/temozolomide treated patients on the EF-14 trial. No negative impact of HRQoL was seen in any of the exploratory analysis. These results further support the addition of TTFields to standard therapy in newly diagnosed glioblastoma patients

The Impact of Tumor Treating Fields on Glioblastoma Progression Patterns.

Tumor-treating fields (TTFields) are an antimitotic treatment modality that interfere with glioblastoma (GBM) cell division and organelle assembly by delivering low-intensity, alternating electric fields to the tumor. A previous analysis from the pivotal EF-14 trial demonstrated a clear correlation between TTFields dose density at the tumor bed and survival in patients treated with TTFields. This study tests the hypothesis that the antimitotic effects of TTFields result in measurable changes in the location and patterns of progression of newly diagnosed GBM. Magnetic resonance images of 428 newly diagnosed GBM patients who participated in the pivotal EF-14 trial were reviewed, and the rates at which distant progression occurred in the TTFields treatment and control arm were compared. Realistic head models of 252 TTFields-treated patients were created, and TTFields intensity distributions were calculated using a finite element method. The TTFields dose was calculated within regions of the tumor bed and normal brain, and its relationship with progression was determined. Distant progression was frequently observed in the TTFields-treated arm, and distant lesions in the TTFields-treated arm appeared at greater distances from the primary lesion than in the control arm. Distant progression correlated with improved clinical outcome in the TTFields patients, with no such correlation observed in the controls. Areas of normal brain that remained normal were exposed to higher TTFields doses compared with normal brain that subsequently exhibited neoplastic progression. Additionally, the average dose to areas of the enhancing tumor that returned to normal was significantly higher than in the areas of the normal brain that progressed to enhancing tumor. There was a direct correlation between TTFields dose distribution and tumor response, confirming the therapeutic activity of TTFields and the rationale for optimizing array placement to maximize the TTFields dose in areas at highest risk of progression, as well as array layout adaptation after progression

EFFECT OF TUMOR TREATING FIELDS (TTFIELDS) ON HEALTH-RELATED QUALITY OF LIFE (HRQoL) IN NEWLY DIAGNOSED GLIOBLASTOMA. RESULTS OF THE EF-14 RANDOMIZED PHASE III TRIAL

Neurolog

Influence of Treatment With Tumor-Treating Fields on Health-Related Quality of Life of Patients With Newly Diagnosed Glioblastoma: A Secondary Analysis of a Randomized Clinical Trial.

Tumor-treating fields (TTFields) therapy improves both progression-free and overall survival in patients with glioblastoma. There is a need to assess the influence of TTFields on patients' health-related quality of life (HRQoL). To examine the association of TTFields therapy with progression-free survival and HRQoL among patients with glioblastoma. This secondary analysis of EF-14, a phase 3 randomized clinical trial, compares TTFields and temozolomide or temozolomide alone in 695 patients with glioblastoma after completion of radiochemotherapy. Patients with glioblastoma were randomized 2:1 to combined treatment with TTFields and temozolomide or temozolomide alone. The study was conducted from July 2009 until November 2014, and patients were followed up through December 2016. Temozolomide, 150 to 200 mg/m2/d, was given for 5 days during each 28-day cycle. TTFields were delivered continuously via 4 transducer arrays placed on the shaved scalp of patients and were connected to a portable medical device. Primary study end point was progression-free survival; HRQoL was a predefined secondary end point, measured with questionnaires at baseline and every 3 months thereafter. Mean changes from baseline scores were evaluated, as well as scores over time. Deterioration-free survival and time to deterioration were assessed for each of 9 preselected scales and items. Of the 695 patients in the study, 639 (91.9%) completed the baseline HRQoL questionnaire. Of these patients, 437 (68.4%) were men; mean (SD) age, 54.8 (11.5) years. Health-related quality of life did not differ significantly between treatment arms except for itchy skin. Deterioration-free survival was significantly longer with TTFields for global health (4.8 vs 3.3 months; P < .01); physical (5.1 vs 3.7 months; P < .01) and emotional functioning (5.3 vs 3.9 months; P < .01); pain (5.6 vs 3.6 months; P < .01); and leg weakness (5.6 vs 3.9 months; P < .01), likely related to improved progression-free survival. Time to deterioration, reflecting the influence of treatment, did not differ significantly except for itchy skin (TTFields worse; 8.2 vs 14.4 months; P < .001) and pain (TTFields improved; 13.4 vs 12.1 months; P < .01). Role, social, and physical functioning were not affected by TTFields. The addition of TTFields to standard treatment with temozolomide for patients with glioblastoma results in improved survival without a negative influence on HRQoL except for more itchy skin, an expected consequence from the transducer arrays. clinicaltrials.gov Identifier: NCT00916409