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Addition of dose-intensified doxorubicin to standard chemotherapy for rhabdomyosarcoma (EpSSG RMS 2005): a multicentre, open-label, randomised controlled, phase 3 trial - 03/08/18

Doi : 10.1016/S1470-2045(18)30337-1 
Gianni Bisogno, MD a, , Meriel Jenney, MD b, Christophe Bergeron, MD c, Soledad Gallego Melcón, MD d, Andrea Ferrari, MD e, Odile Oberlin, MD f, Modesto Carli, ProfMD a, Michael Stevens, ProfMD g, Anna Kelsey, MD h, Angela De Paoli, MSc i, Mark N Gaze, MD j, Helene Martelli, ProfMD k, Christine Devalck, MD l, Johannes H Merks, MD m, Myriam Ben-Arush, ProfMD n, Heidi Glosli, MD o, Julia Chisholm, MD p, Daniel Orbach, MD q, Veronique Minard-Colin, MD f, Gian Luca De Salvo, MD i
for the

European paediatric Soft tissue sarcoma Study Group

Maja Cesen, Adriana Rose, Sima Ferman, Peter Mudry, Daniela Sejnova, Paola Dal Bianco, Ilaria Zanetti, Felix Niggli, Timothy Rogers, Giovanni Cecchetto, Federica De Corti, Florent Guerin, Sheila Terwisscha, Dominique Ranchere, Rita Alaggio, Janet Shipley, Angelo Rosolen, Henry Mandeville, Giovanni Scarzello, Valerie Bernier, Kieran McHugh

a Hematology Oncology Division, Department of Women’s and Children’s Health, University of Padova, Padova, Italy 
b Department of Paediatric Oncology, Children’s Hospital for Wales, Cardiff, UK 
c Institut d’Hématologie et d’Oncologie Pédiatrique, Centre Léon Bérard, Lyon, France 
d Servicio de Oncología y Hematología Pediatrica, Hospital Universitari Vall d’Hebron, Barcelona, Spain 
e Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy 
f Department of Pediatric and Adolescent Oncology, Gustave-Roussy, Villejuif, France 
g Department of Paediatric Oncology, Bristol Royal Hospital for Children, Bristol, UK 
h Department of Paediatric Histopathology, Royal Manchester Children’s Hospital, Manchester, UK 
i Clinical Trials and Biostatistics Unit, Istituto Oncologico Veneto IOV–IRCCS, Padova, Italy 
j Department of Oncology, University College London Hospitals NHS Foundation Trust, London, UK 
k Department of Paediatric Surgery, Hôpital Bicêtre-Hôpitaux Universitaires Paris Sud, Assistance Publique-Hôpitaux de Paris, Le Kremlin Bicêtre, Paris, France 
l Pediatric Hematology and Oncology, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles, Brussels, Belgium 
m Department of Pediatric Oncology Emma Children’s Hospital–Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands 
n The Joan and Sanford Weill Pediatric Hematology Oncology and Bone Marrow Transplantation Division, The Ruth Rappaport Children’s Hospital, Rambam Medical Center, Haifa, Israel 
o Department of Paediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway 
p Children and Young Peoples Unit, The Royal Marsden Hospital, Surrey, UK 
q SIREDO Oncology Center, Institut Curie, PSL University, Paris, France 

* Correspondence to: Dr Gianni Bisogno, Hematology Oncology Division, Department of Women’s and Children’s Health, University of Padova, Padova 35128, Italy Hematology Oncology Division Department of Women’s and Children’s Health University of Padova Padova 35128 Italy

Summary

Background

Rhabdomyosarcoma is an aggressive tumour that can develop in almost any part of the body. Doxorubicin is an effective drug against rhabdomyosarcoma, but its role in combination with an established multidrug regimen remains controversial. Therefore, we aimed to evaluate the possible benefit of early dose intensification with doxorubicin in patients with non-metastatic rhabdomyosarcoma.

Methods

We did a multicentre, open-label, randomised controlled, phase 3 trial involving 108 hospitals from 14 countries. We included patients older than 6 months but younger than 21 years with a pathologically proven diagnosis of rhabdomyosarcoma. We assigned each patient to a specific subgroup according to the EpSSG stratification system. Those with embryonal rhabdomyosarcoma incompletely resected and localised at unfavourable sites with or without nodal involvement, or those with alveolar rhabdomyosarcoma without nodal involvement were considered at high risk of relapse. These high-risk patients were randomly assigned (1:1) to receive either nine cycles of IVA (ifosfamide 3 g/m2 given as a 3-h intravenous infusion on days 1 and 2, vincristine 1·5 mg/m2 weekly during the first 7 weeks then only on day 1 of each cycle [given as a single intravenous injection], and dactinomycin 1·5 mg/m2 on day 1 given as a single intravenous injection) or four cycles of IVA with doxorubicin 30 mg/m2 given as a 4-h intravenous infusion on days 1 and 2 followed by five cycles of IVA. The interval between cycles was 3 weeks. Randomisation was done using a web-based system and was stratified (block sizes of four) by enrolling country and risk subgroup. Neither investigators nor patients were masked to treatment allocation. The primary endpoint was 3-year event-free survival assessed by the investigator at each centre in the intention-to-treat population. Patients who received at least one dose of study treatment were considered in the safety analysis. In agreement with the independent data monitoring committee, the study was closed to patient entry on Dec 16, 2013, after futility analysis. This trial is registered with EudraCT, number 2005-000217-35, and is currently in follow-up.

Findings

Between Oct 1, 2005, and Dec 16, 2013, 484 patients were randomly assigned to receive each chemotherapy regimen (242 in the IVA group and 242 in the IVA plus doxorubicin group). Median follow-up was 63·9 months (IQR 44·6–78·9). The 3-year event-free survival was 67·5% (95% CI 61·2–73·1) in the IVA plus doxorubicin group and 63·3% (56·8–69·0) in the IVA group (hazard ratio 0·87, 95% CI 0·65–1·16; p=0·33). Grade 3–4 leucopenia (232 [93%] of 249 patients in the IVA plus doxorubicin group vs 194 [85%] of 227 in the IVA group; p=0·0061), anaemia (195 [78%] vs 111 [49%]; p<0·0001), thrombocytopenia (168 [67%] vs 59 [26%]; p<0.0001), and gastrointestinal adverse events (78 [31%] vs 19 [8%]; p<0·0001) were significantly more common in the IVA plus doxorubicin group than in the IVA group. Grade 3–5 infections (198 [79%] vs 128 [56%]; p<0·0001) were also significantly more common in the IVA plus doxorubicin group than in the IVA group, in which one patient had grade 5 infection. Two treatment-related deaths were reported (one patient developed septic shock and one affected by Goldenhar syndrome developed intractable seizures) in the IVA plus doxorubicin group, both occurring after the first cycle of treatment, and none were reported in the IVA group.

Interpretations

The addition of dose-intensified doxorubicin to standard IVA chemotherapy did not show a significant improvement in the outcome of patients with high-risk non-metastatic rhabdomyosarcoma. Therefore, the IVA chemotherapy regimen should remain the standard of care for patients with localised rhabdomyosarcoma in Europe.

Funding

Fondazione Città della Speranza, Italy, and the Association Léon Berard Enfant Cancéreux, France.

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Vol 19 - N° 8

P. 1061-1071 - août 2018 Retour au numéro
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