Kathy Pritchard-Jones1, Christophe Bergeron2, Beatriz de Camargo3, Marry M van den Heuvel-Eibrink4, Tomas Acha5, Jan Godzinski6, Foppe Oldenburger7, Liliane Boccon-Gibod8, Ivo Leuschner9, Gordan Vujanic10, Bengt Sandstedt11, Jan de Kraker12, Harm van Tinteren13, Norbert Graf14. 1. Cancer Section, University College London Institute of Child Health, London, UK. Electronic address: k.pritchard-jones@ucl.ac.uk. 2. Department of Paediatric Haemato-Oncology, Centre Léon Bérard, Lyon, France. 3. Paediatric Haemato-Oncology Program, Research Center, Instituto Nacional do Cancer, Rio de Janeiro, Brazil. 4. Princess Màxima Center for Paediatric Oncology, Utrecht, Netherlands. 5. Unidad de Oncología Pediátrica, Hospital Materno-Infantil Carlos Haya, Malaga, Spain. 6. Department of Paediatric Surgery, Marciniak Hospital, Wroclaw, Poland. 7. Department of Radiotherapy, Academic Medical Centre, Amsterdam, Netherlands. 8. Department of Paediatric Pathology, University Hopital Armand Trousseau, Paris, France. 9. Kiel Paediatric Tumour Registry, Department of Paediatric Pathology, University Hospital of Schleswig-Holstein, Kiel, Germany. 10. Department of Paediatric Pathology, Institute of Cancer & Genetics, Cardiff University, Cardiff, UK. 11. Childhood Cancer Research Unit, Karolinska Institutet, Stockholm, Sweden. 12. Department of Pediatric Haemato-Oncology, Academic Medical Centre, Amsterdam, Netherlands. 13. Department of Biostatistics, Netherlands Cancer Institute, Amsterdam, Netherlands. 14. Department of Paediatric Haemato-Oncology, University of Saarland, Homburg, Germany.
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 ofpreoperative chemotherapy with vincristine and actinomycinD. 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. FINDINGS: 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 includingdoxorubicin, and 292 children to treatment excludingdoxorubicin. 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 includingdoxorubicin. 12 children receiving treatment includingdoxorubicin, and ten children receiving treatment excluding doxorubicin, died, with the remaining deaths from tumour recurrence. INTERPRETATION: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. FUNDING: See Acknowledgments for funders.
RCT Entities:
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. FINDINGS: 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. INTERPRETATION: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. FUNDING: See Acknowledgments for funders.
Authors: Marry M van den Heuvel-Eibrink; Janna A Hol; Kathy Pritchard-Jones; Harm van Tinteren; Rhoikos Furtwängler; Arnauld C Verschuur; Gordan M Vujanic; Ivo Leuschner; Jesper Brok; Christian Rübe; Anne M Smets; Geert O Janssens; Jan Godzinski; Gema L Ramírez-Villar; Beatriz de Camargo; Heidi Segers; Paola Collini; Manfred Gessler; Christophe Bergeron; Filippo Spreafico; Norbert Graf Journal: Nat Rev Urol Date: 2017-10-31 Impact factor: 14.432
Authors: Thomas J Jackson; Richard D Williams; Jesper Brok; Tanzina Chowdhury; Milind Ronghe; Mark Powis; Kathy Pritchard-Jones; Gordan M Vujanić Journal: Pediatr Blood Cancer Date: 2019-02-13 Impact factor: 3.167
Authors: Howard M Katzenstein; Max R Langham; Marcio H Malogolowkin; Mark D Krailo; Alexander J Towbin; Mary Beth McCarville; Milton J Finegold; Sarangarajan Ranganathan; Stephen Dunn; Eugene D McGahren; Gregory M Tiao; Allison F O'Neill; Muna Qayed; Wayne L Furman; Caihong Xia; Carlos Rodriguez-Galindo; Rebecka L Meyers Journal: Lancet Oncol Date: 2019-04-08 Impact factor: 41.316
Authors: Conrad V Fernandez; Elizabeth A Mullen; Yueh-Yun Chi; Peter F Ehrlich; Elizabeth J Perlman; John A Kalapurakal; Geetika Khanna; Arnold C Paulino; Thomas E Hamilton; Kenneth W Gow; Zelig Tochner; Fredric A Hoffer; Janice S Withycombe; Robert C Shamberger; Yeonil Kim; James I Geller; James R Anderson; Paul E Grundy; Jeffrey S Dome Journal: J Clin Oncol Date: 2017-12-06 Impact factor: 44.544