Dataset Information

Increased compliance with tumor treating fields therapy is prognostic for improved survival in the treatment of glioblastoma: a subgroup analysis of the EF-14 phase III trial.

ABSTRACT:

Background

Tumor treating fields (TTFields) is a non-invasive, antimitotic therapy. In the EF-14 phase 3 trial in newly diagnosed glioblastoma, TTFields plus temozolomide (TTFields/TMZ) improved progression free (PFS) and overall survival (OS) versus TMZ alone. Previous data indicate a ≥ 75% daily compliance improves outcomes. We analyzed compliance data from TTFields/TMZ patients in the EF-14 study to correlate TTFields compliance with PFS and OS and identify potential lower boundary for compliance with improved clinical outcomes.

Methods

Compliance was assessed by usage data from the NovoTTF-100A device and calculated as percentage per month of TTFields delivery. TTFields/TMZ patients were segregated into subgroups by percent monthly compliance. A Cox proportional hazard model controlled for sex, extent of resection, MGMT methylation status, age, region, and performance status was used to investigate the effect of compliance on PFS and OS.

Results

A threshold value of 50% compliance with TTFields/TMZ improved PFS (HR 0.70, 95% CI 0.47-1.05) and OS (HR 0.67, 95% CI 0.45-0.99) versus TMZ alone with improved outcome as compliance increased. At compliance > 90%, median survival was 24.9 months (28.7 months from diagnosis) and 5-year survival rate was 29.3%. Compliance was independent of gender, extent of resection, MGMT methylation status, age, region and performance status (HR 0.78; p = 0.031; OS at compliance ≥ 75% vs. < 75%).

Conclusion

A compliance threshold of 50% with TTFields/TMZ correlated with significantly improved OS and PFS versus TMZ alone. Patients with compliance > 90% showed extended median and 5-year survival rates. Increased compliance with TTFields therapy is independently prognostic for improved survival in glioblastoma.

SUBMITTER: Toms SA

PROVIDER: S-EPMC6342854 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Publications

Increased compliance with tumor treating fields therapy is prognostic for improved survival in the treatment of glioblastoma: a subgroup analysis of the EF-14 phase III trial.

Toms S A SA Kim C Y CY Nicholas G G Ram Z Z

Journal of neuro-oncology 20181201 2

<h4>Background</h4>Tumor treating fields (TTFields) is a non-invasive, antimitotic therapy. In the EF-14 phase 3 trial in newly diagnosed glioblastoma, TTFields plus temozolomide (TTFields/TMZ) improved progression free (PFS) and overall survival (OS) versus TMZ alone. Previous data indicate a ≥ 75% daily compliance improves outcomes. We analyzed compliance data from TTFields/TMZ patients in the EF-14 study to correlate TTFields compliance with PFS and OS and identify potential lower boundary fo ...[more]

PMID: 30506499

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Project description:BackgroundUnderstudied elderly patients comprise a large segment of high-risk patients with glioblastoma (GBM) that are challenging to treat. Tumor Treating Fields (TTFields) is a locoregional, noninvasive, antimitotic therapy delivering low-intensity, intermediate-frequency alternating electric fields to the tumor. In the phase 3 EF-14 clinical trial, TTFields (200 kHz) improved median progression-free survival (PFS) and median overall survival (OS) in patients with newly diagnosed GBM (ndGBM) when added concomitantly to maintenance temozolomide (TMZ). This EF-14 subgroup analysis evaluated the safety and efficacy of TTFields in elderly patients.MethodsAll 134 patients who are ≥65 years of age were included (TTFields/TMZ combination, n=89; TMZ monotherapy, n=45; 2:1 ratio of randomization). PFS and OS were analyzed using Kaplan-Meier methodology (α=0.05). Health-related quality-of-life (HRQoL) was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) quality-of-life questionnaire QLQ-C30 supplemented with the brain tumor module (QLQ-BN20). Adverse events (AEs) were evaluated using Common Terminology Criteria for AEs (CTCAE) v4.0.ResultsThe PFS was 6.5 months in patients randomized to the treatment group with TTFields/TMZ combination versus 3.9 months in patients treated with TMZ monotherapy (HR, 0.47; 95% CI, 0.30-0.74; P=0.0236). The OS was 17.4 months in patients treated with TTFields/TMZ combination versus 13.7 months in patients treated with TMZ monotherapy (HR, 0.51; 95% CI, 0.33-0.77; P=0.0204). Annual survival rates with TTFields/TMZ versus TMZ monotherapy were 39% (95% CI, 29-50%) versus 27% (95% CI, 15-41%; P=0.072) at 2 years, 19% (95% CI, 11-29%) versus 11% (95% CI, 4-23%; P=0.135) at 3 years, and 15% (95% CI, 7-25%) versus 0% at 5 years, respectively. There were no significant differences between groups in the preselected items of HRQoL assessment. Grade ≥3 systemic AEs were 46% in the TTFields/TMZ group versus 40% in the TMZ monotherapy group, without statistically significant difference between the two groups. The only TTFields-related AEs were reversible scalp skin reactions, with grades 1-2 and grade 3 skin reactions reported by 51% and 2% of patients, respectively.ConclusionsCombining TTFields with maintenance TMZ significantly improved PFS and OS in elderly patients with ndGBM in the phase 3 EF-14 clinical trial, without significant increases in systemic toxicity or negatively affecting patient HRQoL. TTFields-related skin AEs were low-grade and manageable.Clinical trial registrationhttps://clinicaltrials.gov/ct2/show/NCT00916409, identifier: NCT00916409.

Project description:Glioblastoma is the most common yet most lethal of primary brain cancers with a one-year post-diagnosis survival rate of 65% and a five-year survival rate of barely 5%. Recently the U.S. Food and Drug Administration approved a novel fourth approach (in addition to surgery, radiation therapy, and chemotherapy) to treating glioblastoma; namely, tumor treating fields (TTFields). TTFields involves the delivery of alternating electric fields to the tumor but its mechanisms of action are not fully understood. Current theories involve TTFields disrupting mitosis due to interference with proper mitotic spindle assembly. We show that TTFields also alters cellular membrane structure thus rendering it more permeant to chemotherapeutics. Increased membrane permeability through the imposition of TTFields was shown by several approaches. For example, increased permeability was indicated through increased bioluminescence with TTFields exposure or with the increased binding and ingress of membrane-associating reagents such as Dextran-FITC or ethidium D or with the demonstration by scanning electron microscopy of augmented number and sizes of holes on the cellular membrane. Further investigations showed that increases in bioluminescence and membrane hole production with TTFields exposure disappeared by 24 h after cessation of alternating electric fields thus demonstrating that this phenomenom is reversible. Preliminary investigations showed that TTFields did not induce membrane holes in normal human fibroblasts thus suggesting that the phenomenom was specific to cancer cells. With TTFields, we present evidence showing augmented membrane accessibility by compounds such as 5-aminolevulinic acid, a reagent used intraoperatively to delineate tumor from normal tissue in glioblastoma patients. In addition, this mechanism helps to explain previous reports of additive and synergistic effects between TTFields and other chemotherapies. These findings have implications for the design of combination therapies in glioblastoma and other cancers and may significantly alter standard of care strategies for these diseases.

Dataset Information

Increased compliance with tumor treating fields therapy is prognostic for improved survival in the treatment of glioblastoma: a subgroup analysis of the EF-14 phase III trial.

Background

Methods

Results

Conclusion

Publications

Increased compliance with tumor treating fields therapy is prognostic for improved survival in the treatment of glioblastoma: a subgroup analysis of the EF-14 phase III trial.

Similar Datasets

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