Roger Stupp1, Sophie Taillibert2, Andrew A Kanner3, Santosh Kesari4, David M Steinberg5, Steven A Toms6, Lynne P Taylor7, Frank Lieberman8, Antonio Silvani9, Karen L Fink10, Gene H Barnett11, Jay-Jiguang Zhu12, John W Henson13, Herbert H Engelhard14, Thomas C Chen15, David D Tran16, Jan Sroubek17, Nam D Tran18, Andreas F Hottinger19, Joseph Landolfi20, Rajiv Desai21, Manuela Caroli22, Yvonne Kew23, Jerome Honnorat24, Ahmed Idbaih2, Eilon D Kirson25, Uri Weinberg25, Yoram Palti25, Monika E Hegi19, Zvi Ram3. 1. University Hospital Zurich and University of Zurich, Zurich, Switzerland2Lausanne University Hospital (CHUV), Lausanne, Switzerland. 2. Assistance Publique des Hôpitaux de Paris, La Pitié-Salpétrière-University Hospital, Pierre and Marie Curie University, Paris, France. 3. Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel. 4. University of California, San Diego. 5. Tel Aviv University, Tel Aviv, Israel. 6. Geisinger Health System, Danville, Pennsylvania. 7. Tufts Medical Center, Boston, Massachusetts. 8. University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. 9. Istituto Nazionale Neurologico Carlo Besta, Milan, Italy. 10. Baylor University Medical Center, Dallas, Texas. 11. Cleveland Clinic Foundation, Cleveland, Ohio. 12. Baylor University Medical Center, Dallas, Texas13University of Texas Health Science Center, Houston. 13. Swedish Neuroscience Institute, Seattle, Washington. 14. University of Illinois, Chicago. 15. University of Southern California, Los Angeles. 16. Washington University Barnes-Jewish Hospital, St Louis, Missouri. 17. Na Homolce Hospital, Prague, Czech Republic. 18. Moffitt Cancer Center, Tampa, Florida. 19. Lausanne University Hospital (CHUV), Lausanne, Switzerland. 20. New Jersey Neuroscience Institute, Edison. 21. Maine Medical Center, Portland. 22. Fondazione Ospedale Maggiore Policlinico, Milan, Italy. 23. Houston Methodist Hospital, Houston, Texas. 24. Hospices Civils de Lyon, University Claude Bernard Lyon 1, Lyon, France. 25. Novocure, Haifa, Israel.
Abstract
IMPORTANCE: Glioblastoma is the most devastating primary malignancy of the central nervous system in adults. Most patients die within 1 to 2 years of diagnosis. Tumor-treating fields (TTFields) are a locoregionally delivered antimitotic treatment that interferes with cell division and organelle assembly. OBJECTIVE: To evaluate the efficacy and safety of TTFields used in combination with temozolomide maintenance treatment after chemoradiation therapy for patients with glioblastoma. DESIGN, SETTING, AND PARTICIPANTS: After completion of chemoradiotherapy, patients with glioblastoma were randomized (2:1) to receive maintenance treatment with either TTFields plus temozolomide (n = 466) or temozolomide alone (n = 229) (median time from diagnosis to randomization, 3.8 months in both groups). The study enrolled 695 of the planned 700 patients between July 2009 and November 2014 at 83 centers in the United States, Canada, Europe, Israel, and South Korea. The trial was terminated based on the results of this planned interim analysis. INTERVENTIONS: Treatment with TTFields was delivered continuously (>18 hours/day) via 4 transducer arrays placed on the shaved scalp and connected to a portable medical device. Temozolomide (150-200 mg/m2/d) was given for 5 days of each 28-day cycle. MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival in the intent-to-treat population (significance threshold of .01) with overall survival in the per-protocol population (n = 280) as a powered secondary end point (significance threshold of .006). This prespecified interim analysis was to be conducted on the first 315 patients after at least 18 months of follow-up. RESULTS: The interim analysis included 210 patients randomized toTTFields plus temozolomide and 105 randomized to temozolomide alone, and was conducted at a median follow-up of 38 months (range, 18-60 months). Median progression-free survival in the intent-to-treat population was 7.1 months (95% CI, 5.9-8.2 months) in the TTFields plus temozolomide group and 4.0 months (95% CI, 3.3-5.2 months) in the temozolomide alone group (hazard ratio [HR], 0.62 [98.7% CI, 0.43-0.89]; P = .001). Median overall survival in the per-protocol population was 20.5 months (95% CI, 16.7-25.0 months) in the TTFields plus temozolomide group (n = 196) and 15.6 months (95% CI, 13.3-19.1 months) in the temozolomide alone group (n = 84) (HR, 0.64 [99.4% CI, 0.42-0.98]; P = .004). CONCLUSIONS AND RELEVANCE: In this interim analysis of 315 patients with glioblastoma who had completed standard chemoradiation therapy, adding TTFields to maintenancetemozolomide chemotherapy significantly prolonged progression-free and overall survival. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00916409.
RCT Entities:
IMPORTANCE: Glioblastoma is the most devastating primary malignancy of the central nervous system in adults. Most patients die within 1 to 2 years of diagnosis. Tumor-treating fields (TTFields) are a locoregionally delivered antimitotic treatment that interferes with cell division and organelle assembly. OBJECTIVE: To evaluate the efficacy and safety of TTFields used in combination with temozolomide maintenance treatment after chemoradiation therapy for patients with glioblastoma. DESIGN, SETTING, AND PARTICIPANTS: After completion of chemoradiotherapy, patients with glioblastoma were randomized (2:1) to receive maintenance treatment with either TTFields plus temozolomide (n = 466) or temozolomide alone (n = 229) (median time from diagnosis to randomization, 3.8 months in both groups). The study enrolled 695 of the planned 700 patients between July 2009 and November 2014 at 83 centers in the United States, Canada, Europe, Israel, and South Korea. The trial was terminated based on the results of this planned interim analysis. INTERVENTIONS: Treatment with TTFields was delivered continuously (>18 hours/day) via 4 transducer arrays placed on the shaved scalp and connected to a portable medical device. Temozolomide (150-200 mg/m2/d) was given for 5 days of each 28-day cycle. MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival in the intent-to-treat population (significance threshold of .01) with overall survival in the per-protocol population (n = 280) as a powered secondary end point (significance threshold of .006). This prespecified interim analysis was to be conducted on the first 315 patients after at least 18 months of follow-up. RESULTS: The interim analysis included 210 patients randomized to TTFields plus temozolomide and 105 randomized to temozolomide alone, and was conducted at a median follow-up of 38 months (range, 18-60 months). Median progression-free survival in the intent-to-treat population was 7.1 months (95% CI, 5.9-8.2 months) in the TTFields plus temozolomide group and 4.0 months (95% CI, 3.3-5.2 months) in the temozolomide alone group (hazard ratio [HR], 0.62 [98.7% CI, 0.43-0.89]; P = .001). Median overall survival in the per-protocol population was 20.5 months (95% CI, 16.7-25.0 months) in the TTFields plus temozolomide group (n = 196) and 15.6 months (95% CI, 13.3-19.1 months) in the temozolomide alone group (n = 84) (HR, 0.64 [99.4% CI, 0.42-0.98]; P = .004). CONCLUSIONS AND RELEVANCE: In this interim analysis of 315 patients with glioblastoma who had completed standard chemoradiation therapy, adding TTFields to maintenance temozolomide chemotherapy significantly prolonged progression-free and overall survival. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00916409.
Authors: Donald M O'Rourke; MacLean P Nasrallah; Arati Desai; Jan J Melenhorst; Keith Mansfield; Jennifer J D Morrissette; Maria Martinez-Lage; Steven Brem; Eileen Maloney; Angela Shen; Randi Isaacs; Suyash Mohan; Gabriela Plesa; Simon F Lacey; Jean-Marc Navenot; Zhaohui Zheng; Bruce L Levine; Hideho Okada; Carl H June; Jennifer L Brogdon; Marcela V Maus Journal: Sci Transl Med Date: 2017-07-19 Impact factor: 17.956
Authors: Xiao-Tang Kong; Nhung T Nguyen; Yoon J Choi; Guicheng Zhang; HuyTram N Nguyen; Emese Filka; Stacey Green; William H Yong; Linda M Liau; Richard M Green; Tania Kaprealian; Whitney B Pope; P Leia Nghiemphu; Timothy Cloughesy; Andrew Lassman; Albert Lai Journal: Int J Radiat Oncol Biol Phys Date: 2018-01-06 Impact factor: 7.038
Authors: Alison Roos; Harshil D Dhruv; Sen Peng; Landon J Inge; Serdar Tuncali; Michael Pineda; Nghia Millard; Zachary Mayo; Jennifer M Eschbacher; Joseph C Loftus; Jeffrey A Winkles; Nhan L Tran Journal: Mol Cancer Res Date: 2018-05-03 Impact factor: 5.852