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Master Thesis

Cyclophosphamide versus Ifosfamide dans le traitement de consolidation du sarcome d'Ewing de risque standard : étude comparative de la toxicité à long terme dans le cadre de l'essai randomisé Euro-EWING99-R1 en France

Abstract : In the randomized trial Euro-EWING99-R1, it was shown that cyclophosphamide and ifosfamide had a similar efficacy in consolidation treatment of standard risk Ewing’s tumors. Consequently, for future treatment strategy decisions, it is necessary to investigate the comparative long-term toxicity of each regimen. The objective of this study is to evaluate the long-term health status (especially cardiac, renal and gonadic toxicities) of patients included in Euro-EWING99-R1 and to compare it between cyclophosphamide and ifosfamide consolidation regimens. Of the 267 French patients randomized in Euro-EWING99-R1, 172 patients who survived at least 5 years after cancer diagnosis and who were prospectively investigated for late effects were included in this multicenter comparative study. Allocated treatment was either 7 VAC (vincristine, dactinomycin, and cyclophosphamide) courses (84 patients, median total cumulative cyclophosphamide dose 9.7 g/m2 and median total cumulative ifosfamide dose 59.4 g/m2) or 7 VAI (vincristine, dactinomycin, and ifosfamide) courses (88 patients, median total cumulative ifosfamide dose 97.1 g/m2). Data were collected retrospectively from the routine follow-up medical records. Cardiac evaluation consisted of echocardiography and history of cardiac failure treatment. Renal investigations included glomerular filtration rate, phosphate reabsorption rate, proteinuria, glycosuria, and history of renal dysfunction treatment. Gonadal evaluation was based on the use of hormone replacement or infertility therapy, hormonal measurements, sperm analysis results and ovarian echography findings. Combined toxicity outcomes were derived from these data. Median age at diagnosis was 14 years (range 1 to 43). After a median follow-up of 10 years, 7% of the 111 patients with long-term echocardiographic evaluation suffered from cardiac late effects, 62/172 patients (36%) suffered from renal late effects and 27% of intra- or post-pubertal men and women suffered from fertility impairment and ovarian toxicity. 10-year cumulative incidences of persistent cardiac and renal toxicities were 6.8% (95%CI 2.8-10.6) and 42.9% (95%CI 34.4-50.2), respectively. Patients experienced more frequent long-term renal toxicity in the VAI arm than in the VAC arm (46.6% vs 25.0%, p<0.01), mainly resulting from significantly diminished glomerular filtration rate in this group (88 vs 105 ml/min/1.73m2, p=0.02). 10-year cumulative incidence of persistent renal toxicity was greater in the VAI arm (52.7% vs 31.7%, p<0,01). There were no significant differences between allocation groups for all cardiac and gonadal outcomes. Treatment-related renal and gonadal late-occurring side effects represent a major issue in 5-year survivors of standard-risk Ewing sarcoma, with a significantly higher nephrotoxicity occurrence identified in the VAI arm without reduction in gonadal toxicity. This supports the need for lifelong regular follow-up of these patients and additional studies to better characterize very long-term outcomes. The role of ifosfamide could be reconsidered in standard-risk chemotherapy protocols.
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Master Thesis
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https://dumas.ccsd.cnrs.fr/dumas-02996329
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Submitted on : Monday, November 9, 2020 - 3:43:48 PM
Last modification on : Wednesday, February 17, 2021 - 3:19:24 AM

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Victoria Corvest. Cyclophosphamide versus Ifosfamide dans le traitement de consolidation du sarcome d'Ewing de risque standard : étude comparative de la toxicité à long terme dans le cadre de l'essai randomisé Euro-EWING99-R1 en France. Médecine humaine et pathologie. 2019. ⟨dumas-02996329⟩

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