Get access

High dose melphalan in the treatment of advanced neuroblastoma: Results of a randomised trial (ENSG-1) by the European Neuroblastoma Study Group

Authors

  • Jon Pritchard FRCPE, FRCPCH,

    1. Department of Surgery, Institute of Child Health, London, United Kingdom/Department of Haematology and Oncology, Royal Hospital for Sick Children, Edinburgh, United Kingdom
    Search for more papers by this author
  • Simon J. Cotterill BA,

    Corresponding author
    1. Sir James Spence Institute of Child Health/School of Medical Education Development, University of Newcastle upon Tyne, United Kingdom
    • Senior Research Associate, School of Medical Educational Development, The Medical School, University of Newcastle upon Tyne, Newcastle NE1 4LP, UK.
    Search for more papers by this author
  • Shirley M. Germond,

    1. Department of Surgery, Institute of Child Health, London, United Kingdom/Department of Haematology and Oncology, Royal Hospital for Sick Children, Edinburgh, United Kingdom
    Search for more papers by this author
  • John Imeson PhD,

    1. United Kingdom Children's Cancer Study Group Data Centre, Leicester, United Kingdom
    Search for more papers by this author
  • Jan de Kraker MD, PhD,

    1. Academish Ziekenhuis, Amsterdam, The Netherlands
    Search for more papers by this author
  • David R. Jones PhD

    1. Department of Health Sciences, University of Leicester, Leicester, United Kingdom
    Search for more papers by this author

  • Members of the European Neuroblastoma Study Group participating in this study (ENSG1): Belgium: Dr. J. Ninane, Cliniques Universitaires St. Luc, Brussels; Dr. J. Otten, Academisch Ziekenhuis, Brussels; Eire: Dr. F. Breatnach, Our Lady's Hospital for Sick Children, Dublin 12; France: Dr. O. Hartmann, Dr. C. Bayle, Prof. J. Lemerle, Institut Gustave Roussy, Villejuif, Paris; Holland: Prof. P.A. Voute, Dr. J. de Kraker, Emma Kinderziekenhuis, Amsterdam; Italy: Prof. M.A. Castello, Dr. A. Clerico, 1a Clinica Paediatrica-Roma, University-Rome; Norway: Prof. S.P. Lie, Dr. I. Storm-Mathison, Pediatrisk Forskningsinstitutt, Rikshospitalet, Oslo 1; United Kingdom: Dr. I. Hann (now at the Hospital for Sick Children, London), Dr. B. Gibson, Royal Hospital for Sick Children, Glasgow; Dr. J. Pritchard (now at the Institute of Child Health, London & Royal Hospital for Sick Children, Edinburgh), Mrs. S. Germond, Dr. J.R. Pincott, Dr. D.W. Rogers, Hospitals for Sick Children, London; The late Prof. T. McElwain, Prof. A. Barrett (now at Department of Radiotherapy & Oncology, University of East Anglia); Dr. S. Mellor, Prof. C.R. Pinkerton, Royal Marsden Hospital, Sutton; Prof. A.W. Craft, Prof. A.D.J. Pearson, Royal Victoria Infirmary, Newcastle-upon-Tyne; Prof. J.S. Malpas, Dr. J. Kingston, St. Bartholemew's & Royal London Hospitals, London; Prof. J. Lilleyman (now at Royal London Hospital, London), Sheffield Children's Hospital, Sheffield; Prof. O.B. Eden (now at Royal Manchester Children's Hospital, Manchester), The Royal Sick Children's Hospital, Edinburgh; Prof. C. Bailey (now at NHS Regional Research and Development, Leeds), Dr. I. Lewis, Seacroft Hospital, Leeds; Dr. P. Morris-Jones, Dr. R. Campbell, Royal Manchester Children's Hospital, Manchester; Prof. D.R. Jones (now at Department of Health Sciences, University of Leicester), St. George's Hospital Medical School, London.

Abstract

Background

High dose myeloablative chemotherapy (“megatherapy”), with haematopoietic stem cell support, is now widely used to consolidate response to induction chemotherapy in patients with advanced neuroblastoma.

Procedure

In this study (European Neuroblastoma Study Group, ENSG1), the value of melphalan myeloablative “megatherapy” was evaluated in a randomised, multi-centre trial. Between 1982 and 1985, 167 children with stages IV and III neuroblastoma (123 stage IV > 1 year old at diagnosis and 44 stage III and stage IV from 6 to 12 months old at diagnosis) were treated with oncovin, cisplatin, epipodophyllotoxin, and cyclophosphamide (OPEC) induction chemotherapy every 3 weeks. After surgical excision of primary tumour, the 90 patients (69% of the total) who achieved complete response (CR) or good partial response (GPR) were eligible for randomisation either to high dose melphalan (180 mg per square meter) with autologous bone marrow support or to no further treatment.

Results

Sixty-five (72%) of eligible children were actually randomised and 21 of these patients were surviving at time of this analysis, with median follow-up from randomisation of 14.3 years. Five year event-free survival (EFS) was 38% (95% confidence interval (CI) 21–54%) in the melphalan-treated group and 27% (95% CI 12–42%) in the “no-melphalan” group. This difference was not statistically significant (P = 0.08, log rank test) but for the 48 randomised stage IV patients aged >1 year at diagnosis outcome was significantly better in the melphalan-treated group-5 year EFS 33% versus 17% (P = 0.01, log rank test).

Conclusions

In this trial, high dose melphalan improved the length of EFS and overall survival of children with stage IV neuroblastoma >1 year of age who achieved CR or GPR after OPEC induction therapy and surgery. Multi-agent myeloablative regimens are now widely used as consolidation therapy for children with stage IV disease and in those with other disease stages when the MYCN gene copy number in tumour cells is amplified. Because they are more toxic, complex, and costly these combination megatherapy regimens should be compared with single agent melphalan in randomised clinical trials. © 2004 Wiley-Liss, Inc.

Ancillary