Late toxicity comparison of alkylating-based maintenance regimen with cyclophosphamide (VAC) vs ifosfamide (VAI) in Ewing sarcoma survivors treated in the randomized clinical trial Euro-EWING99-R1 in France

Victoria Corvest (1) , Perrine Marec-Bérard (2, 3) , Cyril Lervat (4) , Hélène D. Pacquement (5) , Maud Toulmonde (6) , Jean Claude Gentet (7) , Valérie Laurence (5) , Morgane Cleirec (8) , Ludovic Mansuy (9) , Emmanuelle Bompas (10) , Marie Pierre Castex (11) , Sophie Taque (12) , Bruno Filhon (13) , Marie Dominique P. Tabone (14, 15) , Cécile Verité (16) , Natacha Entz-Werle (17) , Laure Saumet (18) , Grégory Guimard (19) , Morgane Pondrom (20) , Christine Chevreau (21, 22) , Jennifer Flandrin (23) , Lise Duranteau (23) , Christine Md Phd Rousset-Jablonski (24, 2) , Laurence Brugières (1) , Marta M. Jimenez (25) , Marie Cécile Cécile Le Deley (26, 4) , Nathalie Gaspar (1) , Brice C. Fresneau (26, 1)

1 IGR - Institut Gustave Roussy
2 Centre Léon Bérard [Lyon]
3 IHOPe - Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL]
4 UNICANCER/Lille - Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille]
5 Institut Curie [Paris]
6 Institut Bergonié [Bordeaux]
7 TIMONE - Hôpital de la Timone [CHU - APHM]
8 CHU Nantes - Centre Hospitalier Universitaire de Nantes
9 CHRU Nancy - Centre Hospitalier Régional Universitaire de Nancy
10 CRLCC René Gauducheau
11 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
12 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Ponchaillou]
13 CHU Rouen
14 CHU Trousseau [APHP]
15 SU - Sorbonne Université
16 Hôpital Pellegrin
17 CHU Strasbourg - Centre Hospitalier Universitaire [Strasbourg]
18 Hôpital Arnaud de Villeneuve [CHRU Montpellier]
19 Hôpital universitaire Robert Debré [Reims]
20 CHU Nice - Centre Hospitalier Universitaire de Nice
21 Institut Claudius Regaud
22 Pôle IUCT [CHU Toulouse]
23 Hôpital Bicêtre [AP-HP, Le Kremlin-Bicêtre]
24 RESHAPE - Inserm U1290 - UCBL1 - Research on Healthcare Performance
25 UNICANCER
26 CESP - Centre de recherche en épidémiologie et santé des populations

In Euro-EWING99-R1 randomized trial, cyclophosphamide was shown to be noninferior to ifosfamide in the consolidation of standard-risk Ewing sarcoma (SR-EWS) after a common induction with VIDE (vincristine-ifosfamide-doxorubicin-etoposide). We present the results of the late effects analysis of VAC (vincristine-dactinomycin-cyclophoshamide) vs VAI (vincristine-dactinomycin-ifosfamide) conducted in Euro-EWING99-R1 French cohort. Of 267 French randomized patients, 204 were alive and free-of-relapse at 5-years including 172 with available long-term follow-up data concerning cardiac, renal and/or gonadal functions (sex-ratio M/F = 1.3, median age at diagnosis = 14 years): 84 randomized in VAC (median cumulative doses: cyclophosphamide = 9.7 g/m2, ifosfamide = 59.4 g/m2) and 88 in VAI (ifosfamide = 97.1 g/m2). With a median follow-up of 10 years (range = 5-17), five late relapses and five second malignancies were recorded. The 10-year event-free survival among 5-year free-of-relapse survivors was similar between VAC and VAI (93% vs 95%, P =.63). We estimated the 10-year cumulative probabilities of cardiac and kidney toxicities at 4.4% (95% confidence interval [95% CI] = 1.1%-7.6%) and 34.8% (95% CI = 26.8%-42.0%), respectively. Cardiac toxicity cumulative probability was similar in both arms, whereas kidney toxicity was higher in VAI (at 10 years, 43.0% vs 25.7%, P =.02), resulting from significant difference in glomerular toxicity (31.1% vs 13.1%, P <.01). At 10 years, gonadal toxicity was observed in 27% and 28% of pubertal men and women, respectively, without significant difference between VAC and VAI. Kidney and gonadal toxicities represent major issues in Euro-EWING99-R1, with significantly higher risk of kidney toxicities with VAI, without significant gonadal toxicity reduction. These results support the need to limit cumulative doses of both alkylating agents and to use mixed regimen as in VIDE-VAC or VDC/IE (vincristine-doxorubicin-cyclophoshamide/ifosfamide-etoposide).

Mots clés: antineoplastic combined chemotherapy protocols/adverse effects; child; cyclophosphamide/adverse effects; Ewing/drug therapy; Ifosfamide/adverse effects

Domaines: Cancer

Victoria Corvest, Perrine Marec-Bérard, Cyril Lervat, Hélène D. Pacquement, Maud Toulmonde, et al.. Late toxicity comparison of alkylating-based maintenance regimen with cyclophosphamide (VAC) vs ifosfamide (VAI) in Ewing sarcoma survivors treated in the randomized clinical trial Euro-EWING99-R1 in France. International Journal of Cancer, 2023, 152 (8), pp.1659-1667. ⟨10.1002/ijc.34326⟩. ⟨hal-04122360⟩