title: Maintenance Therapy With Tumor-Treating Fields Plus Temozolomide vs Temozolomide Alone for Glioblastoma: A Randomized Clinical Trial.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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
  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.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00916409.
authors.affiliation: University Hospital Zurich and University of Zurich, Zurich, Switzerland2Lausanne University Hospital (CHUV), Lausanne, Switzerland.
authors.forename: Roger
authors.initials: R
authors.lastname: Stupp
authors.affiliation: Assistance Publique des Hôpitaux de Paris, La Pitié-Salpétrière-University Hospital, Pierre and Marie Curie University, Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Taillibert
authors.affiliation: Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Kanner
authors.affiliation: University of California, San Diego.
authors.forename: Santosh
authors.initials: S
authors.lastname: Kesari
authors.affiliation: Tel Aviv University, Tel Aviv, Israel.
authors.forename: David M
authors.initials: DM
authors.lastname: Steinberg
authors.affiliation: Geisinger Health System, Danville, Pennsylvania.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Toms
authors.affiliation: Tufts Medical Center, Boston, Massachusetts.
authors.forename: Lynne P
authors.initials: LP
authors.lastname: Taylor
authors.affiliation: University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
authors.forename: Frank
authors.initials: F
authors.lastname: Lieberman
authors.affiliation: Istituto Nazionale Neurologico Carlo Besta, Milan, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Silvani
authors.affiliation: Baylor University Medical Center, Dallas, Texas.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Fink
authors.affiliation: Cleveland Clinic Foundation, Cleveland, Ohio.
authors.forename: Gene H
authors.initials: GH
authors.lastname: Barnett
authors.affiliation: Baylor University Medical Center, Dallas, Texas13University of Texas Health Science Center, Houston.
authors.forename: Jay-Jiguang
authors.initials: JJ
authors.lastname: Zhu
authors.affiliation: Swedish Neuroscience Institute, Seattle, Washington.
authors.forename: John W
authors.initials: JW
authors.lastname: Henson
authors.affiliation: University of Illinois, Chicago.
authors.forename: Herbert H
authors.initials: HH
authors.lastname: Engelhard
authors.affiliation: University of Southern California, Los Angeles.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Chen
authors.affiliation: Washington University Barnes-Jewish Hospital, St Louis, Missouri.
authors.forename: David D
authors.initials: DD
authors.lastname: Tran
authors.affiliation: Na Homolce Hospital, Prague, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Sroubek
authors.affiliation: Moffitt Cancer Center, Tampa, Florida.
authors.forename: Nam D
authors.initials: ND
authors.lastname: Tran
authors.affiliation: Lausanne University Hospital (CHUV), Lausanne, Switzerland.
authors.forename: Andreas F
authors.initials: AF
authors.lastname: Hottinger
authors.affiliation: New Jersey Neuroscience Institute, Edison.
authors.forename: Joseph
authors.initials: J
authors.lastname: Landolfi
authors.affiliation: Maine Medical Center, Portland.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Desai
authors.affiliation: Fondazione Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Caroli
authors.affiliation: Houston Methodist Hospital, Houston, Texas.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Kew
authors.affiliation: Hospices Civils de Lyon, University Claude Bernard Lyon 1, Lyon, France.
authors.forename: Jerome
authors.initials: J
authors.lastname: Honnorat
authors.affiliation: Assistance Publique des Hôpitaux de Paris, La Pitié-Salpétrière-University Hospital, Pierre and Marie Curie University, Paris, France.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Idbaih
authors.affiliation: Novocure, Haifa, Israel.
authors.forename: Eilon D
authors.initials: ED
authors.lastname: Kirson
authors.affiliation: Novocure, Haifa, Israel.
authors.forename: Uri
authors.initials: U
authors.lastname: Weinberg
authors.affiliation: Novocure, Haifa, Israel.
authors.forename: Yoram
authors.initials: Y
authors.lastname: Palti
authors.affiliation: Lausanne University Hospital (CHUV), Lausanne, Switzerland.
authors.forename: Monika E
authors.initials: ME
authors.lastname: Hegi
authors.affiliation: Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Zvi
authors.initials: Z
authors.lastname: Ram
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000401:mortality / Q000628:therapy*; D002170:Canada; D002330:Carmustine / Q000627:therapeutic use; D059248:Chemoradiotherapy; D003131:Combined Modality Therapy / Q000009:adverse effects / Q000379:methods; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018450:Disease Progression; D018572:Disease-Free Survival; D057239:Early Termination of Clinical Trials; D004599:Electric Stimulation Therapy / Q000009:adverse effects / Q000379:methods*; D005060:Europe; D005260:Female; D005909:Glioblastoma / Q000401:mortality / Q000628:therapy*; D006801:Humans; D007557:Israel; D060046:Maintenance Chemotherapy / Q000379:methods*; D008297:Male; D008875:Middle Aged; D056910:Republic of Korea; D000077204:Temozolomide; D014481:United States; D055815:Young Adult
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D002330:Carmustine; D000077204:Temozolomide