title: Phase II study of temozolomide in combination with topotecan (TOTEM) in relapsed or refractory neuroblastoma: a European Innovative Therapies for Children with Cancer-SIOP-European Neuroblastoma study.
abstract: OBJECTIVE
  To assess objective response rate (ORR) after two cycles of temozolomide in combination with topotecan (TOTEM) in children with refractory or relapsed neuroblastoma.
  
  
  METHODS
  This multicenter, non-randomised, phase II study included children with neuroblastoma according to a two-stage Simon design. Eligibility criteria included relapsed or refractory, measurable or metaiodobenzylguanidine (mIBG) evaluable disease, no more than two lines of prior treatment. Temozolomide was administered orally at 150mg/m(2) followed by topotecan at 0.75mg/m(2) intravenously for five consecutive days every 28days. Tumour response was assessed every two cycles according to International Neuroblastoma Response Criteria (INRC), and reviewed independently.
  
  
  RESULTS
  Thirty-eight patients were enroled and treated in 15 European centres with a median age of 5.4years. Partial tumour response after two cycles was observed in 7 out of 38 evaluable patients [ORR 18%, 95% confidence interval (CI) 8-34%]. The best ORR whatever the time of evaluation was 24% (95% CI, 11-40%) with a median response duration of 8.5months. Tumour control rate (complete response (CR)+partial response (PR)+mixed response (MR)+stable disease (SD)) was 68% (95% CI, 63-90%). The 12-months Progression-Free and Overall Survival were 42% and 58% respectively. Among 213 treatment cycles (median 4, range 1-12 per patient) the most common treatment-related toxicities were haematologic. Grade 3/4 neutropenia occurred in 62% of courses in 89% of patients, grade 3/4 thrombocytopenia in 47% of courses in 71% of patients; three patients (8%) had febrile neutropenia.
  
  
  CONCLUSIONS
  Temozolomide-Topotecan combination results in very encouraging ORR and tumour control in children with heavily pretreated recurrent and refractory neuroblastoma with favourable toxicity profile.
authors.affiliation: Institut Gustave Roussy, Université Paris-Sud, 114 Rue Edouard Vaillant, 94805 Villejuif, France.
authors.forename: Angela
authors.initials: A
authors.lastname: Di Giannatale
authors.affiliation: Institut Gustave Roussy, Université Paris-Sud, 114 Rue Edouard Vaillant, 94805 Villejuif, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Dias-Gastellier
authors.affiliation: Sophia Children's Hospital/Erasmus MC Rotterdam, 60 Dr. Molewaterplein, 3015 GJ Rotterdam, The Netherlands.
authors.forename: Annick
authors.initials: A
authors.lastname: Devos
authors.affiliation: Great Ormond Street Hospital, 34 Great Ormond Street, Bloomsbury, London WC1N 3JH, United Kingdom.
authors.forename: Kieran
authors.initials: K
authors.lastname: Mc Hugh
authors.affiliation: Centre Hospitalier Universitaire Vaudois, 46 Rue du Bugnon, 1011 Lausanne, Switzerland.
authors.forename: Ariane
authors.initials: A
authors.lastname: Boubaker
authors.affiliation: Institut Claudius Regaud, 20-24 Rue du pont Saint-Pierre, 31052 Toulouse Cedex, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: Courbon
authors.affiliation: Hôpital de la Timone, 264 Rue Saint Pierre, 13385 Marseille Cedex 5, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Verschuur
authors.affiliation: Centre Hospitalier Pellegrin Hôpital des Enfants, Place Amélie Raba-Léon, 33076 Bordeaux, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Ducassoul
authors.affiliation: Institut Gustave Roussy, Université Paris-Sud, 114 Rue Edouard Vaillant, 94805 Villejuif, France.
authors.forename: Katty
authors.initials: K
authors.lastname: Malekzadeh
authors.affiliation: Fondazione IRCCS Istituto Nazionale Tumori, 1 Via Venezian, 20133 Milano, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Casanova
authors.affiliation: Istituto Giannina Gaslini, 5 Via Gerolamo Gaslini, 16147 Genova, Italy.
authors.forename: Loredana
authors.initials: L
authors.lastname: Amoroso
authors.affiliation: Hôpital Brabois enfants, 5 Allée du Morvan 54511 Nancy, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Chastagner
authors.affiliation: Sophia Children's Hospital/Erasmus MC Rotterdam, 60 Dr. Molewaterplein, 3015 GJ Rotterdam, The Netherlands.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Zwaan
authors.affiliation: Hôpital des Enfants, 330 Avenue de Grande Bretagne, 31059 Toulouse Cedex 9, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Munzer
authors.affiliation: Universita Cattolica, Gemelli, Largo A. Gemelli 8, 00168 Roma, Italy.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Aerts
authors.affiliation: Institut Curie, 26 Rue d'Ulm, 75248 Paris Cedex 05, France.
authors.forename: Judith
authors.initials: J
authors.lastname: Landman-Parker
authors.affiliation: Hôpital d'Enfants Armand-Trousseau, 26 Avenue du Docteur Arnold Netter, 75571 Paris, France.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Riccardi
authors.affiliation: Institut Gustave Roussy, Université Paris-Sud, 114 Rue Edouard Vaillant, 94805 Villejuif, France.
authors.forename: Marie-Cecile
authors.initials: MC
authors.lastname: Le Deley
authors.affiliation: Institut Gustave Roussy, Université Paris-Sud, 114 Rue Edouard Vaillant, 94805 Villejuif, France.
authors.forename: Birgit
authors.initials: B
authors.lastname: Geoerger
authors.affiliation: Hôpital des Enfants, 330 Avenue de Grande Bretagne, 31059 Toulouse Cedex 9, France. Electronic address: rubie.h@chu-toulouse.fr.
authors.forename: Hervé
authors.initials: H
authors.lastname: Rubie
mesh_terms: D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000473:pathology; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D012008:Recurrence; D000077204:Temozolomide; D019772:Topotecan / Q000008:administration & dosage / Q000009:adverse effects; D055815:Young Adult
chemical_list: D003606:Dacarbazine; D019772:Topotecan; D000077204:Temozolomide
keywords: Neuroblastoma; Paediatrics; Phase II; Temozolomide; Topotecan