Correlation of Tumor Treating Fields Dosimetry to Survival Outcomes in Newly Diagnosed Glioblastoma

A Large-Scale Numerical Simulation-Based Analysis of Data from the Phase 3 EF-14 Randomized Trial

Matthew Ballo, Noa Urman, Gitit Lavy-Shahaf, Jai Grewal, Ze'ev Bomzon, Steven Toms

Research output: Contribution to journalArticle

Abstract

Introduction: 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. Methods and Materials: 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. Results: 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). Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)1106-1113
Number of pages8
JournalInternational Journal of Radiation Oncology Biology Physics
Volume104
Issue number5
DOIs
StatePublished - Aug 1 2019

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Glioblastoma
dosimeters
tumors
Survival
Neoplasms
Disease-Free Survival
simulation
progressions
dosage
hazards
beds
Patient Compliance
Tumor Burden
Transducers
image contrast
files
Compliance
layouts
planning
density distribution

All Science Journal Classification (ASJC) codes

  • Radiation
  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

Cite this

@article{838cfce6c425455aad50dfb3407d122d,
title = "Correlation of Tumor Treating Fields Dosimetry to Survival Outcomes in Newly Diagnosed Glioblastoma: A Large-Scale Numerical Simulation-Based Analysis of Data from the Phase 3 EF-14 Randomized Trial",
abstract = "Introduction: 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. Methods and Materials: 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. Results: 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). Conclusions: 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.",
author = "Matthew Ballo and Noa Urman and Gitit Lavy-Shahaf and Jai Grewal and Ze'ev Bomzon and Steven Toms",
year = "2019",
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language = "English (US)",
volume = "104",
pages = "1106--1113",
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T1 - Correlation of Tumor Treating Fields Dosimetry to Survival Outcomes in Newly Diagnosed Glioblastoma

T2 - A Large-Scale Numerical Simulation-Based Analysis of Data from the Phase 3 EF-14 Randomized Trial

AU - Ballo, Matthew

AU - Urman, Noa

AU - Lavy-Shahaf, Gitit

AU - Grewal, Jai

AU - Bomzon, Ze'ev

AU - Toms, Steven

PY - 2019/8/1

Y1 - 2019/8/1

N2 - Introduction: 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. Methods and Materials: 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. Results: 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). Conclusions: 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.

AB - Introduction: 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. Methods and Materials: 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. Results: 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). Conclusions: 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.

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