Maintenance therapy with tumor-Treating fields plus temozolomide vs temozolomide alone for glioblastoma a randomized clinical trial

Roger Stupp, Sophie Taillibert, Andrew A. Kanner, Santosh Kesari, David M. Steinberg, Steven A. Toms, Lynne P. Taylor, Frank Lieberman, Antonio Silvani, Karen L. Fink, Gene H. Barnett, Jay Jiguang Zhu, John W. Henson, Herbert H. Engelhard, Thomas C. Chen, David D. Tran, Jan Sroubek, Nam D. Tran, Andreas F. Hottinger, Joseph LandolfiRajiv Desai, Manuela Caroli, Yvonne Kew, Jerome Honnorat, Ahmed Idbaih, Eilon D. Kirson, Uri Weinberg, Yoram Palti, Monika E. Hegi, Zvi Ram

Research output: Contribution to journalArticle

548 Scopus citations

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 glioblastomawere 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 700patients betweenJuly2009andNovember2014 at83centers in the United States, Canada,Europe, Israel, and South Korea. The trialwas 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 (150-200mg/m2/d) was given for 5 days of each 28-day cycle. MAIN OUTCOMES AND MEASURES The primary end pointwas 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.

Original languageEnglish (US)
Pages (from-to)2535-2543
Number of pages9
JournalJAMA - Journal of the American Medical Association
Volume314
Issue number23
DOIs
StatePublished - Dec 15 2015

ASJC Scopus subject areas

  • Medicine(all)

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