Martin Glas1, Matthew T Ballo2, Ze'ev Bomzon3, Noa Urman3, Shay Levi3, Gitit Lavy-Shahaf3, Suriya Jeyapalan4, Terence T Sio5, Paul M DeRose6, Martin Misch7, Sophie Taillibert8, Zvi Ram9, Andreas F Hottinger10, Jacob Easaw11, Chae-Yong Kim12, Suyash Mohan13, Roger Stupp14. 1. Division of Clinical Neurooncology, Department of Neurology and German Cancer Consortium (DKTK) Partner Site, University Hospital Essen, University Duisburg-Essen, Essen, Germany. 2. Department of Radiation Oncology, West Cancer Center and Research Institute, Memphis, Tennessee. Electronic address: mballo@westclinic.com. 3. NovoCure Ltd, Haifa, Israel. 4. Tufts Medical Center, Boston, Massachusetts. 5. Department of Radiation Oncology, Mayo Clinic, Phoenix, Arizona. 6. Department of Radiation Oncology, Methodist Dallas Medical Center, Dallas, Texas. 7. Department of Neurosurgery, University Hospital Charité, Berlin, Germany. 8. Department of Neurology, Hôpital Pitié-Salpêtrière, APHP, University Pierre et Marie Curie Paris VI, Paris, France. 9. Department of Neurosurgery, Tel Aviv Medical Center and Tel Aviv University School of Medicine, Tel Aviv, Israel. 10. Departments of Clinical Neurosciences and Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. 11. Cross Cancer Institute, Edmonton, Alberta, Canada. 12. Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seoul, Korea. 13. Division of Neuroradiology, Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. 14. Lou and Jean Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Departments of Neurological Surgery, Neurology, and Medicine (Hem/Onc), Northwestern Medicine, Chicago, Illinois.
Abstract
PURPOSE: 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. METHODS AND MATERIALS: 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. RESULTS: 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. CONCLUSIONS: 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.
PURPOSE: 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. METHODS AND MATERIALS: 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. RESULTS: 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. CONCLUSIONS: 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.