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Phase II Study of Temozolomide in Relapsed or Refractory High-Risk Neuroblastoma: A Joint Société Française des Cancers de l’Enfant and United Kingdom Children Cancer Study Group–New Agents Group Study

Hervé Rubie, Julia Chisholm, Anne Sophie Defachelles, Bruce Morland, Caroline Munzer, Dominique Valteau-Couanet, Véronique Mosseri, Christophe Bergeron, Clare Weston, Carole Coze, Anne Auvrignon, Latifa Djafari, Rachel Hobson, Christiane Baunin, Fiona Dickinson, Hervé Brisse, Kieran McHugh, Lorenzo Biassoni, Francesco Giammarile, Gilles Vassal

From the Unités d’Hémato-Oncologie et de Radiologie, Hôpital des Enfants, Toulouse; Département d’Oncologie Pédiatrique, Centre Oscar Lambret, Lille; Départements de Statistiques, d’Oncologie Pédiatrique et de Radiologie, Institut Curie, Paris; Départements d’Oncologie Pédiatrique et de Médecine Nucléaire, Centre Léon Bérard, Lyon; Service d’Oncologie Pédiatrique, Hôpital d’Enfants de la Timone, Marseille; Service d’Hémato-Oncologie, Hôpital Trousseau, Paris; Département d’Oncologie Pédiatrique, Institut Gustave Roussy, Villejuif; Schering Plough, Levallois, France; Departments of Paediatric Oncology and Radiology, Great Ormond St Hospital; Leicester Royal Infirmary, London; Oncology Department, Children’s Hospital, Birmingham; Royal Marsden Hospital, Sutton; and the United Kingdom Children’s Cancer Study Group Data Centre, Leicester, United Kingdom

Address reprint requests to Hervé Rubie, MD, Unité d’Hémato-Oncologie - Hôpital des Enfants - 330 avenue de Grande Bretagne, BP 3119 - TSA 70034 - 31059 Toulouse cedex 9 - France; e-mail: rubie.h{at}chu-toulouse.fr

Purpose To determine the response rate (RR) of neuroblastoma (NB) in children to temozolomide (TMZ), and evaluate the duration of response and tolerance of the drug in this patient population.

Patients and Methods A multicenter, phase II evaluation of an oral, daily schedule of TMZ (200 mg/m²/d x 5 days every 28 days) was undertaken in children with refractory or relapsed high-risk NB (metastatic or localized with Myc-N amplification). Response assessment was based on imaging with two-dimentional measurement of disease and meta-iodobenzylguanidine (MIBG) score. Activity was defined by a reduction in lesion size or isotope uptake at anytime. Methodology included a two-step design using Fleming’s method with a first step of 15 patients and a second of 10 additional patients if two to four responses had been observed in the first cohort. All data was centrally reviewed by a panel.

Results Twenty-five assessable patients were recruited over a 14-month period in 14 centers and received 94 cycles of chemotherapy. Twenty-three patients had metastatic NB either refractory (n = 9) or in relapse (n = 14). Grade 3 or 4 thrombocytopenia was the most frequent toxicity (16% of cycles). Myelosuppression resulted in treatment delays and dose reductions (24% and 21% of cycles, respectively). Response (complete response, very good partial response, or partial response) was observed in five patients (RR = 20% ± 8%) with a median duration of 6 months and an objective or mixed response in five additional patients.

Conclusion Temozolomide shows activity in heavily pretreated patients with NB, and deserves further evaluation in combination with another drug.

Supported by a grant from Schering Plough, Cent pour Sang la Vie, Agence Française de Sécurité Sanitaire des Produits de Santé, Voeux d’Artistes, and the Direction Régionale à la Recherche Clinique des Hôpitaux de Toulouse.

Presented in part at the 36th Annual Meeting of the International Society of Pediatric Oncology, September 16-19, 2004, Oslo, Norway; and the 42nd Annual Meeting of the American Society of Clinical Oncology June 2-6, 2006, Atlanta, GA.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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