Vinorelbine and continuous low-dose cyclophosphamide as maintenance chemotherapy in patients with high-risk rhabdomyosarcoma (RMS 2005): a multicentre, open-label, randomised, phase 3 trial
Language English Country England, Great Britain Media print-electronic
Document type Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't
Grant support
28028
Cancer Research UK - United Kingdom
5943
Cancer Research UK - United Kingdom
PubMed
31562043
DOI
10.1016/s1470-2045(19)30617-5
PII: S1470-2045(19)30617-5
Knihovny.cz E-resources
- MeSH
- Rhabdomyosarcoma, Alveolar drug therapy mortality pathology MeSH
- Time Factors MeSH
- Cyclophosphamide administration & dosage adverse effects MeSH
- Child MeSH
- Rhabdomyosarcoma, Embryonal drug therapy mortality pathology MeSH
- Risk Assessment MeSH
- Remission Induction MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Disease-Free Survival MeSH
- Disease Progression MeSH
- Antineoplastic Combined Chemotherapy Protocols administration & dosage adverse effects MeSH
- Risk Factors MeSH
- Maintenance Chemotherapy * adverse effects mortality MeSH
- Vinorelbine administration & dosage adverse effects MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase III MeSH
- Multicenter Study MeSH
- Research Support, Non-U.S. Gov't MeSH
- Randomized Controlled Trial MeSH
- Geographicals
- Argentina MeSH
- Brazil MeSH
- Europe MeSH
- Israel MeSH
- Names of Substances
- Cyclophosphamide MeSH
- Vinorelbine MeSH
BACKGROUND: For more than three decades, standard treatment for rhabdomyosarcoma in Europe has included 6 months of chemotherapy. The European paediatric Soft tissue sarcoma Study Group (EpSSG) aimed to investigate whether prolonging treatment with maintenance chemotherapy would improve survival in patients with high-risk rhabdomyosarcoma. METHODS: RMS 2005 was a multicentre, open-label, randomised, controlled, phase 3 trial done at 102 hospitals in 14 countries. We included patients aged 6 months to 21 years with rhabdomyosarcoma who were considered to be at high risk of relapse: those with non-metastatic incompletely resected embryonal rhabdomyosarcoma occurring at unfavourable sites with unfavourable age (≥10 years) or tumour size (>5 cm), or both; those with any non-metastatic rhabdomyosarcoma with nodal involvement; and those with non-metastatic alveolar rhabdomyosarcoma but without nodal involvement. Patients in remission after standard treatment (nine cycles of ifosfamide, vincristine, dactinomycin with or without doxorubicin, and surgery or radiotherapy, or both) were randomly assigned (1:1) to stop treatment or continue maintenance chemotherapy (six cycles of intravenous vinorelbine 25 mg/m2 on days 1, 8, and 15, and daily oral cyclophosphamide 25 mg/m2, on days 1-28). Randomisation was done by use of a web-based system and was stratified (block size of four) by enrolling country and risk subgroup. Neither investigators nor patients were masked to treatment allocation. The primary outcome was disease-free survival in the intention-to-treat population. Secondary outcomes were overall survival and toxicity. This trial is registered with EudraCT, number 2005-000217-35, and ClinicalTrials.gov, number NCT00339118, and follow-up is ongoing. FINDINGS: Between April 20, 2006, and Dec 21, 2016, 371 patients were enrolled and randomly assigned to the two groups: 186 to stop treatment and 185 to receive maintenance chemotherapy. Median follow-up was 60·3 months (IQR 32·4-89·4). In the intention-to-treat population, 5-year disease-free survival was 77·6% (95% CI 70·6-83·2) with maintenance chemotherapy versus 69·8% (62·2-76·2) without maintenance chemotherapy (hazard ratio [HR] 0·68 [95% CI 0·45-1·02]; p=0·061), and 5-year overall survival was 86·5% (95% CI 80·2-90·9) with maintenance chemotherapy versus 73·7% (65·8-80·1) without (HR 0·52 [95% CI 0·32-0·86]; p=0·0097). Toxicity was manageable in patients who received maintenance chemotherapy: 136 (75%) of 181 patients had grade 3-4 leucopenia, 148 (82%) had grade 3-4 neutropenia, 19 (10%) had anaemia, two (1%) had thrombocytopenia, and 56 (31%) had an infection. One (1%) patient had a grade 4 non-haematological toxicity (neurotoxicity). Two treatment-related serious adverse events occurred: one case of inappropriate antidiuretic hormone secretion and one of a severe steppage gait with limb pain, both of which resolved. INTERPRETATION: Adding maintenance chemotherapy seems to improve survival for patients with high-risk rhabdomyosarcoma. This approach will be the new standard of care for patients with high-risk rhabdomyosarcoma in future EpSSG trials. FUNDING: Fondazione Città della Speranza, Association Léon Berard Enfant Cancéreux, Clinical Research Hospital Program (French Ministry of Health), and Cancer Research UK.
Children and Young Peoples Unit Royal Marsden Hospital Sutton Surrey UK
Clinical Research Unit Istituto Oncologico Veneto IOV IRCCS Padova Italy
Department of Paediatric and Adolescent Oncology Gustave Roussy Villejuif France
Department of Paediatric Histopathology Royal Manchester Children's Hospital Manchester UK
Department of Paediatric Oncology Children's Hospital for Wales Heath Park Cardiff UK
Institut d'Hématologie et d'Oncologie Pédiatrique Centre Léon Bérard Lyon France
Instituto Nacional de Câncer Rio de Janeiro Brazil
Paediatric Oncology Unit Fondazione IRCCS Istituto Nazionale dei Tumori Milan Italy
Servicio de Oncología y Hematología Pediatrica Hospital Universitari Vall d'Hebron Barcelona Spain
SIREDO Oncology Center Institut Curie PSL University Paris France
References provided by Crossref.org
ClinicalTrials.gov
NCT00339118
