TY - JOUR
T1 - Impact of gender on efficacy and acute toxicity of alkylating agent -based chemotherapy in Ewing sarcoma
T2 - secondary analysis of the Euro-Ewing99-R1 trial
AU - van den Berg, Henk
AU - Paulussen, Michael
AU - Le Teuff, Gwénaël
AU - Judson, Ian
AU - Gelderblom, Hans
AU - Dirksen, Uta
AU - Brennan, Bernadette
AU - Whelan, Jeremy
AU - Ladenstein, Ruth Lydia
AU - Marec-Berard, Perrine
AU - Kruseova, Jarmila
AU - Hjorth, Lars
AU - Kühne, Thomas
AU - Brichard, Benedicte
AU - Wheatley, Keith
AU - Craft, Alan
AU - Juergens, Heribert
AU - Gaspar, Nathalie
AU - Le Deley, Marie-Cécile
AU - Euro-EWING99 Group
N1 - Copyright © 2015 Elsevier Ltd. All rights reserved.
PY - 2015/11
Y1 - 2015/11
N2 - 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.
AB - 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.
KW - Ewing sarcomas
KW - Alkylating agent
KW - Gender
KW - Efficacy
KW - Toxicity
KW - Interaction
KW - Metabolism
KW - Constitutive androstane receptor
KW - CYP3A4
KW - CYP2B6
U2 - 10.1016/j.ejca.2015.06.123
DO - 10.1016/j.ejca.2015.06.123
M3 - Article
C2 - 26271204
SN - 0959-8049
VL - 51
SP - 2453
EP - 2464
JO - European Journal of Cancer
JF - European Journal of Cancer
IS - 16
ER -