Impact of gender on efficacy and acute toxicity of alkylating agent -based chemotherapy in Ewing sarcoma: secondary analysis of the Euro-Ewing99-R1 trial.
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.


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).


CONCLUSIONS
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.


BACKGROUND
NCT00987636 and EudraCT 2008-003658-13.
Emma Children's Hospital/Academic Medical Center, Amsterdam, The Netherlands.
Henk
H
van den Berg
Vestische Kinder-und Jugendklinik Datteln, Witten/Herdecke University, Datteln, Germany.
Michael
M
Paulussen
Institute Gustave Roussy, Villejuif, France.
Gwénaël
G
Le Teuff
The Royal Marsden NHS Foundation Trust, London, United Kingdom.
Ian
I
Judson
Leiden University Medical Center, Leiden, The Netherlands.
Hans
H
Gelderblom
Department of Paediatric Hematology and Oncology, University Hospital, Muenster, Germany.
Uta
U
Dirksen
Royal Manchester Children's Hospital, Manchester, United Kingdom.
Bernadette
B
Brennan
University College Hospital, London, United Kingdom.
Jeremy
J
Whelan
St. Anna Children's Hospital and Research Institute, Vienna, Austria.
Ruth Lydia
RL
Ladenstein
Institut d'Hématologie et d'Oncologie Pédiatrie, Lyon, France.
Perrine
P
Marec-Berard
Department of Paediatric Haematology and Oncology, Charles University, Motol Hospital, Prague, Czech Republic.
Jarmila
J
Kruseova
Skåne University Hospital, Lund University, Lund, Sweden.
Lars
L
Hjorth
University Children's Hospital Basel, Basel, Switzerland.
Thomas
T
Kühne
Cliniques Universitaires Saint Luc, Brussels, Belgium.
Benedicte
B
Brichard
Cancer Research UK, Cancer Trials Unit, University of Birmingham, Birmingham.
Keith
K
Wheatley
United Kingdom Sir James Spence Institute, Newcastle upon Tyne, United Kingdom.
Alan
A
Craft
Department of Paediatric Hematology and Oncology, University Hospital, Muenster, Germany.
Heribert
H
Juergens
Institute Gustave Roussy, Villejuif, France.
Nathalie
N
Gaspar
Institute Gustave Roussy, Villejuif, France; Paris-Sud University, Le Kremlin-Bicêtre, France.
Marie-Cécile
MC
Le Deley
D000293:Adolescent; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000473:pathology; D003520:Cyclophosphamide / Q000008:administration & dosage; D018450:Disease Progression; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage; D057915:Drug Substitution; D005060:Europe; D005260:Female; D054624:Health Status Disparities; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage; D008297:Male; D016016:Proportional Hazards Models; D012307:Risk Factors; D012512:Sarcoma, Ewing / Q000188:drug therapy* / Q000473:pathology; D012737:Sex Factors; D013997:Time Factors; D016896:Treatment Outcome; D014750:Vincristine / Q000008:administration & dosage
D018906:Antineoplastic Agents, Alkylating; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D007069:Ifosfamide
Alkylating agent; CYP2B6; CYP3A4; Constitutive androstane receptor; Efficacy; Ewing sarcomas; Gender; Interaction; Metabolism; Toxicity