Tumor Treating Fields (TTFields) are approved for glioblastoma based on improved overall survival (OS) and progression-free survival (PFS) in the phase 3 EF-14 trial of newly diagnosed glioblastoma. ...To test the hypothesis that increasing TTFields dose at the tumor site improves patient outcomes, we performed a simulation-based study investigating the association between TTFields dose and survival (OS and PFS) in patients treated with TTFields in EF-14.
EF-14 patient cases (N = 340) were included. Realistic head models were derived from T1-contrast images captured at baseline. The transducer array layout on each patient was obtained from EF-14 records; average compliance (fraction of time patient was on active treatment) and average electrical current delivered to the patient were derived from log files of the TTFields devices used by patients. TTFields intensity distributions and power densities were calculated using the finite element method. Local minimum dose density (LMiDD) was defined as the product of TTFields intensity, tissue-specific conductivities, and patient compliance. The average LMiDD within a tumor bed comprising the gross tumor volume and the 3-mm-wide peritumoral boundary zone was calculated.
The median OS and PFS were significantly longer when the average LMiDD in the tumor bed was ≥0.77 mW/cm3: OS was 25.2 versus 20.4 months (P = .003, hazard ratio HR = 0.611) and PFS was 8.5 versus 6.7 months (P = .02, HR = 0.699). The median OS and PFS were longer when the average TTFields intensity was >1.06 V/cm: OS was 24.3 versus 21.6 months (P = .03, HR = 0.705) and PFS was 8.1 versus 7.9 months (P = .03, HR = 0.721).
In this study we present the first reported analysis demonstrating patient-level dose responses to TTFields. We provide a rigorous definition for TTFields dose and set a conceptual framework for future work on TTFields dosimetry and treatment planning.
Coronaviruses are the causative agents of several recent outbreaks, including the COVID-19 pandemic. One therapeutic approach is blocking viral binding to the host receptor. As binding largely ...depends on electrostatic interactions, we hypothesized possible inhibition of viral infection through application of electric fields, and tested the effectiveness of Tumor Treating Fields (TTFields), a clinically approved cancer treatment based on delivery of electric fields. In preclinical models, TTFields were found to inhibit coronavirus infection and replication, leading to lower viral secretion and higher cell survival, and to formation of progeny virions with lower infectivity, overall demonstrating antiviral activity. In a pilot clinical study (NCT04953234), TTFields therapy was safe for patients with severe COVID-19, also demonstrating preliminary effectiveness data, that correlated with higher device usage.
Abstract
INTRODUCTION
Tumor Treating Fields (TTFields) are a novel treatment modality that continuously delivers alternating electric fields to the tumor region. TTFields interfere with the assembly ...of the mitotic spindle leading to apoptosis. In the EF-14 phase III study in newly diagnosed glioblastoma, TTFields plus temozolomide (TTFields/TMZ) showed significant increase in overall and 5-year survival rates compared to temozolomide. TTFields/TMZ did not negatively impact nine prespecified HRQoL scales (global health, physical, cognitive, role, social and emotional functioning, itchy skin, pain, and leg weakness) except for increased itchy skin. We present an exploratory analysis of the remaining 17 EORTC QLQ C-30 and BN-20 HRQoL scales.
METHODS
HRQoL was measured by the EORTC QLQ-C30 and BN20 questionnaires at baseline and every 3 months thereafter. Mean changes from baseline as well as significant changes in scores over time (>10 points) were evaluated using a repeated measures test. Deterioration-free survival and time-to-deterioration in HRQoL were assessed for each scale, as well as % patients with stable/improved HRQoL versus 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. Significantly more patients treated with TTFields/TMZ versus TMZ reported stable/improved bladder control (63.6% versus 46.8%, p=0.001) and diarrhea (60.6% versus 43.7%, p=0.001) compared to baseline. The deterioration-free survival for diarrhea, future uncertainty and headaches was significantly delayed in TTFields/TMZ treated patients compared to TMZ alone (HR 0.68, 0.71 and 0.67, respectively, p<0.001). CONCLUSIONS: No negative impact of HRQoL was seen in any of the exploratory scales between patients treated with temozolomide only or TTFields and TMZ. Adding TTFields to standard therapy in newly diagnosed glioblastoma does not appear to negatively impact QoL.
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.
Abstract
INTRODUCTION: Tumor Treating Fields (TTFields) are low intensity (1-3V/cm), intermediate frequency (100–300 KHz) alternating electrical fields approved for glioblastoma (GBM). In the EF-14 ...phase 3 study, TTFields showed a significant overall and progression-free survival benefit for patients with newly diagnosed GBM in combination with Temozolomide (TMZ). TTFields were not associated with systemic toxicity. At recurrence, patients continued TTFields with second line therapies. We analyzed the safety and feasibility of TTFields + lomustine (CCNU) combination.
Methods
Patients in the EF-14 trial received TTFields until second progression, or for 24 months. Change in chemotherapy regimen was allowed in both groups after tumor progression. We compared patients who received lomustine as second-line chemotherapy in combination with TTFields (n=134) to patients who received lomustine as monotherapy after first progression (n=39). We compared baseline characteristics and the adverse event profile between the two groups.
RESULTS
Baseline characteristics were well balanced; there were less female patients in the lomustine only group (7.7% vs. 22.4%). Median age in the TTFields/lomustine group was 55.5 years (29–83) versus 50.0 years (19–71) for lomustine alone. The addition of TTFields to lomustine therapy was not associated with any significant increase in rates of systemic adverse events compared to lomustine therapy alone (number of patients with ≥ 1 SAE 30 % vs. 31 %) and the distribution, severity and overall incidence of adverse events were not statistically different in patients in the two treatment groups. CONCLUSION: The combination of TTFields and lomustine is safe and feasible. This analysis emphasizes again the strong safety profile of TTFields and the high potential of combining TTFields with other therapy modalities. This data is especially important in light of the recently presented promising data from a small randomized trial that tested the combination of lomustine plus TMZ in newly diagnosed (MGMT promotor-methylated only) GBM patients.
Abstract
INTRODUCTION: TTFields are low intensity, intermediate frequency, alternating electric fields. The significant overall and progression-free survival benefit, shown in the EF-14 phase 3 study ...was seen in all patient-subgroups, independent of e.g. MGMT-promotor methylation-status or age. TTFields were not associated with additional systemic toxicity. At recurrence, patients were allowed to continue TTFields with second-line therapies. Here, we analyzed the safety data of TTFields + lomustine (CCNU) to evaluate safety and feasibility of this combination.
METHODS
Patients in the EF-14 trial received TTFields until second progression, or for 24 months. Change in chemotherapy regimen was allowed after tumor progression. We compared the patients who received lomustine as second-line chemotherapy in combination with TTFields (n=134) to the patients who received lomustine as monotherapy after first progression (n=39). We compared baseline characteristics and the adverse event profile between the groups.
RESULTS
Baseline characteristics were well balanced except for less female patients in the lomustine only group (7.7% vs. 22.4%). Median age in the TTFields/lomustine group was 55.5 years (29–83) compared to 50.0 years (19–71) for lomustine alone. The addition of TTFields to lomustine therapy was not associated with any significant increase in systemic adverse events compared to lomustine therapy alone (number of patients with 1 SAE 30 % vs. 31 %) and the distribution, severity and overall incidence of adverse events were not statistically different in patients in the two treatment groups. CONCLUSION: The data show that the combination of TTFields and lomustine is safe and feasible. This analysis emphasizes again the strong safety profile of TTFields and the high potential of combining TTFields with other modalities. This data is especially important in light of the recently presented, promising data from a small randomized trial that tested the combination of lomustine + TMZ in newly diagnosed (MGMT promotor-methylated only) glioblastoma patients.
Abstract
AIMS
Tumour Treating Fields (TTFields) are electric fields that disrupt processes required for cancer cell viability and tumour progression. TTFields therapy gained FDA approval and CE ...accreditation for newly diagnosed glioblastoma (ndGBM) following the EF-14 study (NCT00916409). We aimed to determine the real-world survival benefit of TTFields therapy.
METHOD
Survival data from clinical studies in TTFields therapy-treated patients with ndGBM were identified using a literature search and analysed. The Cochran Q test and Higgins I2 statistic were used to assess and quantify inter-study heterogeneity. Survival curves were pooled using a distribution-free random-effects method.
RESULTS
Among studies evaluating the clinical effcacy of TTFields therapy in ndGBM, six studies were identified which compared the addition of TTFields therapy to standard of care (SOC) vs SOC alone. The meta-analysis showed a significant improvement in OS for TTFields therapy-treated patients vs SOC alone (P < 0.001). The pooled effect was robust and independent of any individual study. In post-approval studies, the pooled median OS was 22.2 months (95% CI, 17.3–42.6) and 17.3 months (95% CI, 13.6–22.0) for TTFields therapy-treated patients and SOC, respectively. Rates of gross total resection were generally higher in the real-world setting, irrespective of TTFields therapy use. Average device usage of ≥75% was associated with prolonged survival vs <75% usage (pooled HR: 0.63; 95% CI, 0.48–0.83; P = 0.001).
CONCLUSIONS
Data suggest a significant survival benefit when TTFields therapy is added to SOC for patients with ndGBM. Usage of ≥75% may be meaningful in the real-world setting.
Abstract
INTRODUCTION
The pivotal EF-14 trial showed that Tumor Treating Fields (TTFields) extend Progression Free Survival (PFS) in newly Diagnosed Glioblastoma (ndGBM) patients. This leads to the ...hypothesis that TTFields therapy leads to local control of tumors, yielding a significant decrease in tumor growth rates. Here we present an analysis testing this hypothesis in biopsy-only patients who participated in the EF-14 trial.
METHODS
Biopsy patients of the EF-14 trial who exhibited radiological progression were included in this study (treatment: N=37/60, control: N=12/29). Volumes of enhancing tumor were segmented on T1c MRIs at baseline and at progression. Tumor growth rate was calculated as: growth_rate=(ln(v0)-ln(v1))/dt. (v0- tumor volume at baseline), v1- Tumor volume at progression, dt- days to progression), which models tumor volume as increasing exponentially over time. Median growth rates in the treatment and control arms were compared.
RESULTS
The median growth rate was lower in the treatment arm than in the control. (control: 0.14±0.12 mL/month, TTFields -0.011±0.11 mL/month, p< 0.008 Wilcoxon rank-sum)
DISCUSSION AND CONCLUSIONS
This study shows that tumor growth rates are slower in patients treated with TTFileds+Temozolomide (TMZ) than in patients treated with TMZ alone. This analysis was restricted to biopsy-only patients since the definition of tumor volume is ambiguous in patients that underwent resection since a large portion of the tumor has been removed. The negative median growth rate for patients in the treatment arm may indicate that a significant number of TTFields-treated patients a decrease in tumor volume was observed, suggesting that TTFields enhances local tumor control. References: 1 Stupp, Roger, et al. Jama 318.23 (2017): 2306–2316.2 Stensjøen, Anne Line, et al. Neuro-oncology 17.10 (2015): 1402–1411.
Purpose
Tumor Treating Fields (TTFields) therapy, an electric field-based cancer treatment, became FDA-approved for patients with newly diagnosed glioblastoma (GBM) in 2015 based on the randomized ...controlled EF-14 study. Subsequent approvals worldwide and increased adoption over time have raised the question of whether a consistent survival benefit has been observed in the real-world setting, and whether device usage has played a role.
Methods
We conducted a literature search to identify clinical studies evaluating overall survival (OS) in TTFields-treated patients. Comparative and single-cohort studies were analyzed. Survival curves were pooled using a distribution-free random-effects method.
Results
Among nine studies, seven (N = 1430 patients) compared the addition of TTFields therapy to standard of care (SOC) chemoradiotherapy versus SOC alone and were included in a pooled analysis for OS. Meta-analysis of comparative studies indicated a significant improvement in OS for patients receiving TTFields and SOC versus SOC alone (HR: 0.63; 95% CI 0.53–0.75;
p
< 0.001). Among real-world post-approval studies, the pooled median OS was 22.6 months (95% CI 17.6–41.2) for TTFields-treated patients, and 17.4 months (95% CI 14.4–21.6) for those not receiving TTFields. Rates of gross total resection were generally higher in the real-world setting, irrespective of TTFields use. Furthermore, for patients included in studies reporting data on device usage (N = 1015), an average usage rate of ≥ 75% was consistently associated with prolonged survival (
p
< 0.001).
Conclusions
Meta-analysis of comparative TTFields studies suggests survival may be improved with the addition of TTFields to SOC for patients with newly diagnosed GBM.
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