European Journal of Cancer 2012 48 2192 2202 Available at www sciencedirect com journal homepage www ejconline com NovoTTF 100A versus physician s choice chemotherapy in recurrent glioblastoma A randomised phase III trial of a novel treatment modality Roger Stupp a Eric T Wong b Andrew A Kanner c David Steinberg d Herbert Engelhard e Volkmar Heidecke f Eilon D Kirson g Sophie Taillibert h Frank Liebermann i Vladimir Dbaly j Zvi Ram c J Lee Villano e Nikolai Rainov f Uri Weinberg g David Schi k Lara Kunschner l Je rey Raizer m Jerome Honnorat n Andrew Sloan o Mark Malkin p Joseph C Landol q Franz Payer r Maximilian Mehdorn s Robert J Weil t Susan C Pannullo u Manfred Westphal v Martin Smrcka w Lawrence Chin x Herwig Kostron y Silvia Hofer z Je rey Bruce aa Rees Cosgrove ab Nina Paleologous ac Yoram Palti g Philip H Gutin ad a Centre Hospitalier Universitaire Vaudois University of Lausanne Lausanne Switzerland Harvard Medical School Beth Israel Deaconess Medical Center Boston MA United States c Tel Aviv Medical Center Tel Aviv Israel d Department of Biostatistics Tel Aviv University Tel Aviv Israel e University of Illinois at Chicago Chicago IL United States f Augsburg Clinic Augsburg Germany g Novocure Ltd Haifa Israel h Hospital de la Pitie Salpetriere Paris France i University of Pittsburgh Medical Center Pittsburgh PA United States j Na Homolce Hospital Prague Czech Republic k University of Virginia Charlottesville VA United States l Allegheny Neurological Brain Tumor Center Pittsburgh PA United States m Northwestern University Chicago IL United States n Department of Neuro Oncology Hospices Civils de Lyon Universite Claude Bernard Lyon France o University Hospitals of Cleveland Case Western Reserve University School of Medicine Cleveland OH United States p Medical College of Wisconsin Milwaukee WI United States q New Jersey Neuroscience Institute at JFK Medical Center Edison NY United States r University Graz Graz Austria s University of Kiel Kiel Germany t The Cleveland Clinic Foundation Taussig Cancer Center Cleveland OH United States u New York Presbyterian Hospital Weill Cornell Medical Center New York NY United States v University of Hamburg Hamburg Germany w Brno University Hospital Brno Czech Republic x Boston Medical Center Boston MA United States b Corresponding author Address Department of Neurosurgery Centre Hospitalier Universitaire Vaudois CHUV 46 rue du Bugnon Lausanne 1011 Switzerland Tel 41 21 314 0156 fax 41 21 314 0737 E mail address Roger Stupp chuv ch R Stupp 0959 8049 see front matter 2012 Elsevier Ltd All rights reserved http dx doi org 10 1016 j ejca 2012 04 011 R Stupp et al European Journal of Cancer 48 2012 2192 2202 2193 y University of Innsbruck Austria University Hospital Zurich Switzerland aa Columbia University Medical Center New York NY United States ab Lahey Clinic Boston MA United States ac NorthShore University Health System Evanston IL United States ad Memorial Sloan Kettering Cancer Center New York NY United States z Available online 18 May 2012 KEYWORDS Glioblastoma Brain tumour Chemotherapy Randomised trial Abstract Purpose NovoTTF 100A is a portable device delivering low intensity intermediate frequency electric elds via non invasive transducer arrays Tumour Treatment Fields TTF a completely new therapeutic modality in cancer treatment physically interfere with cell division Methods Phase III trial of chemotherapy free treatment of NovoTTF 20 24 h day versus active chemotherapy in the treatment of patients with recurrent glioblastoma Primary endpoint was improvement of overall survival Results Patients median age 54 years range 23 80 Karnofsky performance status 80 range 50 100 were randomised to TTF alone n 120 or active chemotherapy control n 117 Number of prior treatments was two range 1 6 Median survival was 6 6 versus 6 0 months hazard ratio 0 86 95 CI 0 66 1 12 p 0 27 1 year survival rate was 20 and 20 progression free survival rate at 6 months was 21 4 and 15 1 p 0 13 respectively in TTF and active control patients Responses were more common in the TTF arm 14 versus 9 6 p 0 19 The TTF related adverse events were mild 14 to moderate 2 skin rash beneath the transducer arrays Severe adverse events occurred in 6 and 16 p 0 022 of patients treated with TTF and chemotherapy respectively Quality of life analyses favoured TTF therapy in most domains Conclusions This is the rst controlled trial evaluating an entirely novel cancer treatment modality delivering electric elds rather than chemotherapy No improvement in overall survival was demonstrated however ef cacy and activity with this chemotherapy free treatment device appears comparable to chemotherapy regimens that are commonly used for recurrent glioblastoma Toxicity and quality of life clearly favoured TTF 2012 Elsevier Ltd All rights reserved 1 Background Glioblastoma is the most prevalent primary malignant brain tumour in adults Median survival with optimal therapy is only 15 months from diagnosis and most tumours recur within 9 months of initial treatment 1 At the time of disease recurrence treatment options for glioblastoma patients are limited Repeat surgery may be considered in approximately 20 of patients 2 4 and re irradiation is possible in rare circumstances For most patients chemotherapy is indicated at disease recurrence with the choice of drug varying greatly In the United States bevacizumab has been provisionally approved for recurrent glioblastoma while the European Medicines Agency EMEA rejected the application in the absence of a controlled trial 5 6 Cytotoxic agents most frequently used are alkylating agents like nitrosoureas e g lomustine CCNU or carmustine BCNU 7 procarbazine8 or re treatment with temozolomide 9 10 Response rates are below 10 progression free survival rates at 6 months 20 7 8 In the absence of an established and satisfactory standard treatment bevacizumab alone and in combination with irinotecan and experimental treatments are commonly used 11 13 Overall survival OS from recurrence is commonly short and without e ective therapy rarely exceeds 3 5 months 14 19 In a randomised trial of repeat surgery with implantation of carmustine wafers versus placebo median survival was 6 5 versus 4 7 months 20 With active therapy a median survival of 7 months range 5 9 2 months 7 10 12 13 21 24 has been reported A recent randomised comparison of enzastaurin versus lomustine at rst recurrence demonstrated a median survival of 7 1 months with 19 of patients
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