title: 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).
abstract: 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).
  
  
  CONCLUSIONS
  Our meta-analysis did not confirm the hypothesis of a treatment-by-sex interaction on efficacy or toxicity outcomes.
authors.affiliation: Department of Pediatric oncology, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
authors.forename: Brice
authors.initials: B
authors.lastname: Fresneau
authors.affiliation: Cancer Research UK & UCL Cancer Trials Centre, University College London, London, United Kingdom.
authors.forename: A
authors.initials: A
authors.lastname: Hackshaw
authors.affiliation: Division of Hematology/Oncology, Department of Pediatrics, Seattle Children's Hospital, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington.
authors.forename: D S
authors.initials: DS
authors.lastname: Hawkins
authors.affiliation: Vestische Kinder-und Jugendklinik Datteln, Witten/Herdecke University, Datteln, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Paulussen
authors.affiliation: Merck Research Laboratories-Oncology, North Wales, Pennsylvania.
authors.forename: J R
authors.initials: JR
authors.lastname: Anderson
authors.affiliation: The Royal Marsden NHS Foundation Trust, London, United Kingdom.
authors.forename: I
authors.initials: I
authors.lastname: Judson
authors.affiliation: Statistics Department, EORTC Headquarters, Brussels, Belgium.
authors.forename: S
authors.initials: S
authors.lastname: Litière
authors.affiliation: Department of Pediatric Hematology and Oncology, University Hospital, Muenster, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Dirksen
authors.affiliation: Alder Hey Children's NHS Foundation Trust, Liverpool, United Kingdom.
authors.forename: I
authors.initials: I
authors.lastname: Lewis
authors.affiliation: Emma Children's Hospital/Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: van den Berg
authors.affiliation: Department of Pediatric oncology, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
authors.forename: N
authors.initials: N
authors.lastname: Gaspar
authors.affiliation: Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Gelderblom
authors.affiliation: Cancer Medicine and Consultant Medical Oncologist, The London Sarcoma Service, University College Hospital, London, United Kingdom.
authors.forename: J
authors.initials: J
authors.lastname: Whelan
authors.affiliation: Faculty of Pharmacy, University of Sydney, Sydney, Australia.
authors.forename: A V
authors.initials: AV
authors.lastname: Boddy
authors.affiliation: Cancer Research UK, Cancer Trials Unit, University of Birmingham, Birmingham, United Kingdom.
authors.forename: K
authors.initials: K
authors.lastname: Wheatley
authors.affiliation: Departments of Biostatistics and Epidemiology, Gustave-Roussy, Paris, France.|Paris-Saclay and Paris-SudUniversities, CESP, INSERM, Villejuif, France.|Gustave Roussy, Ligue Nationale Contre le Cancer Meta-analysis Platform, Villejuif, France.
authors.forename: J P
authors.initials: JP
authors.lastname: Pignon
authors.affiliation: Radiation EpidemiologyGroup, INSERM, UMR1018, Villejuif, France.
authors.forename: F
authors.initials: F
authors.lastname: De Vathaire
authors.affiliation: Departments of Biostatistics and Epidemiology, Gustave-Roussy, Paris, France.|Paris-Saclay and Paris-SudUniversities, CESP, INSERM, Villejuif, France.
authors.forename: M C
authors.initials: MC
authors.lastname: Le Deley
authors.affiliation: Departments of Biostatistics and Epidemiology, Gustave-Roussy, Paris, France.|Paris-Saclay and Paris-SudUniversities, CESP, INSERM, Villejuif, France.|Gustave Roussy, Ligue Nationale Contre le Cancer Meta-analysis Platform, Villejuif, France.
authors.forename: G
authors.initials: G
authors.lastname: Le Teuff
mesh_terms: D000477:Alkylating Agents / Q000009:adverse effects; D000970:Antineoplastic Agents / Q000009:adverse effects*; D003520:Cyclophosphamide / Q000009:adverse effects*; D005260:Female; D006801:Humans; D007069:Ifosfamide / Q000009:adverse effects*; D008297:Male; D016032:Randomized Controlled Trials as Topic; D012509:Sarcoma / Q000188:drug therapy*; D012727:Sex Characteristics
chemical_list: D000477:Alkylating Agents; D000970:Antineoplastic Agents; D003520:Cyclophosphamide; D007069:Ifosfamide
keywords: acute toxicity; alkylating agent; cyclophosphamide; efficacy; ifosfamide; individual patient data; meta-analysis; sarcoma; systematic review; treatment-by sex interaction