Impact of gender on efficacy and acute toxicity of alkylating agent -based chemotherapy in Ewing sarcoma: secondary analysis of the Euro-Ewing99-R1 trial
Language English Country Great Britain, England Media print-electronic
Document type Comparative Study, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't
Grant support
15958
Cancer Research UK - United Kingdom
CRUK/02/014
Cancer Research UK - United Kingdom
PubMed
26271204
DOI
10.1016/j.ejca.2015.06.123
PII: S0959-8049(15)00649-8
Knihovny.cz E-resources
- Keywords
- Alkylating agent, CYP2B6, CYP3A4, Constitutive androstane receptor, Efficacy, Ewing sarcomas, Gender, Interaction, Metabolism, Toxicity,
- MeSH
- Antineoplastic Agents, Alkylating administration & dosage adverse effects MeSH
- Time Factors MeSH
- Cyclophosphamide administration & dosage MeSH
- Health Status Disparities MeSH
- Doxorubicin administration & dosage MeSH
- Sarcoma, Ewing drug therapy pathology MeSH
- Ifosfamide administration & dosage MeSH
- Humans MeSH
- Adolescent MeSH
- Bone Neoplasms drug therapy pathology MeSH
- Drug Substitution MeSH
- Disease-Free Survival MeSH
- Disease Progression MeSH
- Proportional Hazards Models MeSH
- Antineoplastic Combined Chemotherapy Protocols administration & dosage adverse effects MeSH
- Risk Factors MeSH
- Sex Factors MeSH
- Vincristine administration & dosage MeSH
- Treatment Outcome MeSH
- Check Tag
- Humans MeSH
- Adolescent MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
- Research Support, Non-U.S. Gov't MeSH
- Randomized Controlled Trial MeSH
- Comparative Study MeSH
- Geographicals
- Europe MeSH
- Names of Substances
- Antineoplastic Agents, Alkylating MeSH
- Cyclophosphamide MeSH
- Doxorubicin MeSH
- Ifosfamide MeSH
- Vincristine MeSH
BACKGROUND: Based on the randomised Euro-EWING99-R1 trial, vincristine, adriamycin, cyclophosphamide (VAC) may be able to replace vincristine, adriamycin, ifosfamide (VAI) in the treatment of standard-risk Ewing sarcoma. However some heterogeneity of treatment effect by gender was observed. The current exploratory study aimed at investigating the influence of gender on treatment efficacy and acute toxicity. PATIENTS AND METHODS: Impact of gender on event-free survival (EFS), acute toxicity by course, switches between treatment arms and cumulative dose of alkylating agents was evaluated in multivariable models adjusted for age including terms to test for heterogeneity of treatment effect by gender. The analysis of the EFS was performed on the intention-to-treat population. RESULTS: EFS did not significantly differ between the 509 males and 347 females (p=0.33), but an interaction in terms of efficacy was suspected between treatment and gender (p=0.058): VAC was associated with poorer EFS than VAI in males, hazard ratio (HR) (VAC/VAI)=1.37 [95% confidence interval (CI), 0.98-1.90], contrasting with HR=0.81 [95%CI, 0.53-1.24] in females. Severe toxicity was more frequent in females, whatever the toxicity type. Thirty patients switched from VAI to VAC (9/251 males, 4%, and 21/174 females, 12%) mostly due to renal toxicity, and three from VAC to VAI (2/258 males, 0.8%, and 1/173 females, 0.6%). A reduction of alkylating agent cumulative dose >20% was more frequent in females (15% versus 9%, p=0.005), with no major difference between VAC and VAI (10% versus 13%, p=0.15). CONCLUSION: Differences of acute toxicity rate and cumulative doses of alkylating agents could not explain the marginal interaction observed in the Euro-EWING99-R1 trial data. Effects of gender-dependent polymorphism/activity of metabolic enzymes (e.g. known for CYP2B6) of ifosfamide versus cyclophosphamide should be explored. External data are required to further evaluate whether there is heterogeneity of alkylating agent effect by gender. TRIAL NUMBERS: NCT00987636 and EudraCT 2008-003658-13.
Cancer Research UK Cancer Trials Unit University of Birmingham Birmingham
Cliniques Universitaires Saint Luc Brussels Belgium
Department of Paediatric Hematology and Oncology University Hospital Muenster Germany
Emma Children's Hospital Academic Medical Center Amsterdam The Netherlands
Institut d'Hématologie et d'Oncologie Pédiatrie Lyon France
Institute Gustave Roussy Villejuif France
Institute Gustave Roussy Villejuif France; Paris Sud University Le Kremlin Bicêtre France
Leiden University Medical Center Leiden The Netherlands
Royal Manchester Children's Hospital Manchester United Kingdom
Skåne University Hospital Lund University Lund Sweden
St Anna Children's Hospital and Research Institute Vienna Austria
The Royal Marsden NHS Foundation Trust London United Kingdom
United Kingdom Sir James Spence Institute Newcastle upon Tyne United Kingdom
University Children's Hospital Basel Basel Switzerland
University College Hospital London United Kingdom
Vestische Kinder und Jugendklinik Datteln Witten Herdecke University Datteln Germany
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