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

Abstract

Importance: 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.

Objective: 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.

Design, setting, and participants: 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.

Interventions: 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).

Main outcomes and measures: 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.

Results: 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.

Conclusions and relevance: 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.

Trial registration: clinicaltrials.gov Identifier: NCT00916409.

Figure 1.. Recruitment and Inclusion of Patients in the Study

^aTen patients were out of randomization window; 8 had low platelet counts; 17, infratentorial disease; 4, elevated liver enzymes; 3, programmable shunts; 10, pacemakers or defibrillators.

Figure 2.. Kaplan-Meier Survival Curves for Patients Included in the Final Analysis in the Intent-to-Treat Population

A, Median progression-free survival from randomization for the tumor-treating fields (TTFields) plus temozolomide group was 6.7 months and was 4.0 months for the temozolomide-alone group (hazard ratio [HR], 0.63; 95% CI, 0.52-0.76; P < .001). B, Median survival from randomization was 20.9 for the TTFields plus temozolomide group vs 16.0 months for the temozolomide-alone group (HR, 0.63; 95% CI, 0.53-0.76; P < .001). Median follow up was 44 months (range, 25-91 months) in both groups.

Figure 3.. Overall Survival for Each Prognostic Patient Subgroup of Patients Treated With Tumor-Treating Fields Plus Temozolomide vs Temozolomide Alone

Data points represent Cox hazard ratios of overall survival in each subgroup of patients treated with tumor-treating fields (TTFields) plus temozolomide compared with temozolomide alone and were adjusted for the other subgroups. Error bars represent 95% CIs of the hazard ratios. The Karnofsky performance score is measured from 0 to 100 in 10-point increments, with higher scores indicating better the patient performance status. IQR, indicates interquartile range; MGMT, O⁶-methylguanine-DNA methyltransferase promotor region methylation status.

Figure 4.. Overall Survival by Patient Age and by MGMT Promotor Region Methylation Status

A, In comparing tumor-treating fields (TTFields) plus temozolomide vs temozolomide alone among patients younger than 65 years the hazard ratio (HR) was 0.67 (95% CI, 0.55-0.82). B, In comparing the 2 treatments among patients 65 years or older, the HR was 0.51 (95% CI, 0.22-0.77). C, In comparing the treatments among patients with O-methylguanine-DNA methyltransferase MGMT promotor region methylation, the HR was 0.62 (95% CI, 0.43-0.88). D, In comparing the treatments among patients without the MGMT promotor region methylation, the HR was 0.66 (95% CI, 0.49-0.85). The median follow-up of patients was 44 months (range, 25-91 months) in all groups.