Investigating the heterogeneity of alkylating agents' efficacy and toxicity between sexes: A systematic review and meta-analysis of randomized trials comparing cyclophosphamide and ifosfamide (MAIAGE study)

Research output: Contribution to journalArticle


  • Brice Fresneau
  • A Hackshaw
  • D S Hawkins
  • M Paulussen
  • J R Anderson
  • I Judson
  • S Litière
  • U Dirksen
  • I Lewis
  • H van den Berg
  • N Gaspar
  • H Gelderblom
  • J Whelan
  • A V Boddy
  • J P Pignon
  • F De Vathaire
  • M C Le Deley
  • G Le Teuff

Colleges, School and Institutes

External organisations

  • Department of Pediatric oncology, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
  • University College London
  • Division of Hematology/Oncology, Department of Pediatrics, Seattle Children's Hospital, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington.
  • Vestische Kinder-und Jugendklinik Datteln, Witten/Herdecke University, Datteln, Germany.
  • Merck Research Laboratories-Oncology, North Wales, Pennsylvania.
  • The Royal Marsden NHS Foundation Trust, London, United Kingdom.
  • Statistics Department, EORTC Headquarters, Brussels, Belgium.
  • Department of Pediatric Hematology and Oncology, University Hospital, Muenster, Germany.
  • Alder Hey Children's NHS Foundation Trust, Liverpool, United Kingdom.
  • Emma Children's Hospital/Academic Medical Center, Amsterdam, The Netherlands.
  • Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands.
  • Cancer Medicine and Consultant Medical Oncologist, The London Sarcoma Service, University College Hospital, London, United Kingdom.
  • Faculty of Pharmacy, University of Sydney, NSW 2006, Australia
  • Cancer Research UK, Cancer Trials Unit, University of Birmingham, Birmingham, United Kingdom.
  • Departments of Biostatistics and Epidemiology, Gustave-Roussy, Paris, France.
  • Radiation EpidemiologyGroup, INSERM, UMR1018, Villejuif, France.


BACKGROUND: A marginal interaction between sex and the type of alkylating agent was observed for event-free survival in the Euro-EWING99-R1 randomized controlled trial (RCT) comparing cyclophosphamide and ifosfamide in Ewing sarcoma. To further evaluate this interaction, we performed an individual patient data meta-analysis of RCTs assessing cyclophosphamide versus ifosfamide in any type of cancer.

METHODS: A literature search produced two more eligible RCTs (EICESS92 and IRS-IV). The endpoints were progression-free survival (PFS, main endpoint) and overall survival (OS). The hazard ratios (HRs) of the treatment-by-sex interaction and their 95% confidence interval (95% CI) were assessed using stratified multivariable Cox models. Heterogeneity of the interaction across age categories and trials was explored. We also assessed this interaction for severe acute toxicity using logistic models.

RESULTS: The meta-analysis comprised 1,528 pediatric and young adult sarcoma patients from three RCTs: Euro-EWING99-R1 (n = 856), EICESS92 (n = 155), and IRS-IV (n = 517). There were 224 PFS events in Euro-EWING99-R1 and 200 in the validation set (EICESS92 + IRS-IV), and 171 and 154 deaths in each dataset, respectively. The estimated treatment-by-sex interaction for PFS in Euro-EWING99-R1 (HR = 1.73, 95% CI = 1.00-3.00) was not replicated in the validation set (HR = 0.97, 95% CI = 0.55-1.72), without heterogeneity across trials (P = 0.62). In the pooled analysis, the treatment-by-sex interaction was not significant (HR = 1.31, 95% CI = 0.89-1.95, P = 0.17), without heterogeneity across age categories (P = 0.88) and trials (P = 0.36). Similar results were observed for OS. No significant treatment-by-sex interaction was observed for leucopenia/neutropenia (P = 0.45), infection (P = 0.64), or renal toxicity (P = 0.20).

CONCLUSION: Our meta-analysis did not confirm the hypothesis of a treatment-by-sex interaction on efficacy or toxicity outcomes.


Original languageEnglish
JournalPediatric Blood & Cancer
Early online date23 Jan 2017
Publication statusE-pub ahead of print - 23 Jan 2017


  • Sarcoma, alkylating agent, cyclophosphamide, ifosfamide, efficacy, acute toxicity, treatment-by sex interaction, systematic review, meta-analysis, individual patient data