title: Omission of doxorubicin from the treatment of stage II-III, intermediate-risk Wilms' tumour (SIOP WT 2001): an open-label, non-inferiority, randomised controlled trial.
abstract: BACKGROUND
  Before this study started, the standard postoperative chemotherapy regimen for stage II-III Wilms' tumour pretreated with chemotherapy was to include doxorubicin. However, avoidance of doxorubicin-related cardiotoxicity effects is important to improve long-term outcomes for childhood cancers that have excellent prognosis. We aimed to assess whether doxorubicin can be omitted safely from chemotherapy for stage II-III, histological intermediate-risk Wilms' tumour when a newly defined high-risk blastemal subtype was excluded from randomisation.
  
  
  METHODS
  For this international, multicentre, open-label, non-inferiority, phase 3, randomised SIOP WT 2001 trial, we recruited children aged 6 months to 18 years at the time of diagnosis of a primary renal tumour from 251 hospitals in 26 countries who had received 4 weeks of preoperative chemotherapy with vincristine and actinomycin D. Children with stage II-III intermediate-risk Wilms' tumours assessed after delayed nephrectomy were randomly assigned (1:1) by a minimisation technique to receive vincristine 1·5 mg/m(2) at weeks 1-8, 11, 12, 14, 15, 17, 18, 20, 21, 23, 24, 26, and 27, plus actinomycin D 45 μg/kg every 3 weeks from week 2, either with five doses of doxorubicin 50 mg/m(2) given every 6 weeks from week 2 (standard treatment) or without doxorubicin (experimental treatment). The primary endpoint was non-inferiority of event-free survival at 2 years, analysed by intention to treat and a margin of 10%. Assessment of safety and adverse events included systematic monitoring of hepatic toxicity and cardiotoxicity. This trial is registered with EudraCT, number 2007-004591-39, and is closed to new participants.
  
  
  RESULTS
  Between Nov 1, 2001, and Dec 16, 2009, we recruited 583 patients, 341 with stage II and 242 with stage III tumours, and randomly assigned 291 children to treatment including doxorubicin, and 292 children to treatment excluding doxorubicin. Median follow-up was 60·8 months (IQR 40·8-79·8). 2 year event-free survival was 92·6% (95% CI 89·6-95·7) for treatment including doxorubicin and 88·2% (84·5-92·1) for treatment excluding doxorubicin, a difference of 4·4% (95% CI 0·4-9·3) that did not exceed the predefined 10% margin. 5 year overall survival was 96·5% (94·3-98·8) for treatment including doxorubicin and 95·8% (93·3-98·4) for treatment excluding doxorubicin. Four children died from a treatment-related toxic effect; one (<1%) of 291 receiving treatment including doxorubicin died of sepsis, three (1%) of 292 receiving treatment excluding doxorubicin died of varicella, metabolic seizure, and sepsis during treatment for relapse. 17 patients (3%) had hepatic veno-occlusive disease. Cardiotoxic effects were reported in 15 (5%) of 291 children receiving treatment including doxorubicin. 12 children receiving treatment including doxorubicin, and ten children receiving treatment excluding doxorubicin, died, with the remaining deaths from tumour recurrence.
  
  
  CONCLUSIONS
  Doxorubicin does not need to be included in treatment of stage II-III intermediate risk Wilms' tumour when the histological response to preoperative chemotherapy is incorporated into the risk stratification.
  
  
  BACKGROUND
  See Acknowledgments for funders.
authors.affiliation: Cancer Section, University College London Institute of Child Health, London, UK. Electronic address: k.pritchard-jones@ucl.ac.uk.
authors.forename: Kathy
authors.initials: K
authors.lastname: Pritchard-Jones
authors.affiliation: Department of Paediatric Haemato-Oncology, Centre Léon Bérard, Lyon, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Bergeron
authors.affiliation: Paediatric Haemato-Oncology Program, Research Center, Instituto Nacional do Cancer, Rio de Janeiro, Brazil.
authors.forename: Beatriz
authors.initials: B
authors.lastname: de Camargo
authors.affiliation: Princess Màxima Center for Paediatric Oncology, Utrecht, Netherlands.
authors.forename: Marry M
authors.initials: MM
authors.lastname: van den Heuvel-Eibrink
authors.affiliation: Unidad de Oncología Pediátrica, Hospital Materno-Infantil Carlos Haya, Malaga, Spain.
authors.forename: Tomas
authors.initials: T
authors.lastname: Acha
authors.affiliation: Department of Paediatric Surgery, Marciniak Hospital, Wroclaw, Poland.
authors.forename: Jan
authors.initials: J
authors.lastname: Godzinski
authors.affiliation: Department of Radiotherapy, Academic Medical Centre, Amsterdam, Netherlands.
authors.forename: Foppe
authors.initials: F
authors.lastname: Oldenburger
authors.affiliation: Department of Paediatric Pathology, University Hopital Armand Trousseau, Paris, France.
authors.forename: Liliane
authors.initials: L
authors.lastname: Boccon-Gibod
authors.affiliation: Kiel Paediatric Tumour Registry, Department of Paediatric Pathology, University Hospital of Schleswig-Holstein, Kiel, Germany.
authors.forename: Ivo
authors.initials: I
authors.lastname: Leuschner
authors.affiliation: Department of Paediatric Pathology, Institute of Cancer & Genetics, Cardiff University, Cardiff, UK.
authors.forename: Gordan
authors.initials: G
authors.lastname: Vujanic
authors.affiliation: Childhood Cancer Research Unit, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Sandstedt
authors.affiliation: Department of Pediatric Haemato-Oncology, Academic Medical Centre, Amsterdam, Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: de Kraker
authors.affiliation: Department of Biostatistics, Netherlands Cancer Institute, Amsterdam, Netherlands.
authors.forename: Harm
authors.initials: H
authors.lastname: van Tinteren
authors.affiliation: Department of Paediatric Haemato-Oncology, University of Saarland, Homburg, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Graf
mesh_terms: D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D017024:Chemotherapy, Adjuvant / Q000009:adverse effects / Q000379:methods; D002648:Child; D002675:Child, Preschool; D003609:Dactinomycin / Q000008:administration & dosage / Q000009:adverse effects; D004317:Doxorubicin / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006801:Humans; D007223:Infant; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D008297:Male; D020360:Neoadjuvant Therapy / Q000009:adverse effects / Q000379:methods; D009367:Neoplasm Staging; D009392:Nephrectomy; D016896:Treatment Outcome; D014750:Vincristine / Q000008:administration & dosage / Q000009:adverse effects; D009396:Wilms Tumor / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery
chemical_list: D003609:Dactinomycin; D014750:Vincristine; D004317:Doxorubicin