Soledad Gallego1, Ilaria Zanetti2, Daniel Orbach3, Dominique Ranchère4, Janet Shipley5, Angelica Zin6, Christophe Bergeron4, Gian Luca de Salvo7, Julia Chisholm8, Andrea Ferrari9, Meriel Jenney10, Henry C Mandeville8, Timothy Rogers11, Johannes H M Merks12, Peter Mudry13, Heidi Glosli14, Giuseppe Maria Milano15, Sima Ferman16, Gianni Bisogno2. 1. Pediatric Oncology and Hematology, Children's Hospital Vall d'Hebron, Barcelona, Spain. 2. Padova University Hospital, Padova, Italy. 3. Pediatric Oncology, SIREDO Oncology Center, Institute Curie, Paris Sciences and Letters University, Paris, France. 4. IHOPE/Center Leon Berard, Lyon, France. 5. Institute of Cancer Research, London, United Kingdom. 6. Pediatric Research Institute Citta della Speranza, Padova, Italy. 7. Clinical Trials and Biostatistics Unit, Veneto Oncologic Institute IOV-IRCCS, Padova, Italy. 8. The Royal Marsden National Health Service Foundation Trust, Sutton, United Kingdom. 9. National Tumor Institute, Milan, Italy. 10. Pediatric Oncology, Children Hospital for Wales Cardiff and Vale University Health Board, Cardiff, United Kingdom. 11. University Hospitals Bristol National Health Service Foundation Trust, Bristol, United Kingdom. 12. Pediatric Oncology, Emma Children's Hospital-Academic Medical Center, Amsterdam, The Netherlands. 13. Pediatric Oncology, University Children's Hospital Brno, Brno, Czech Republic. 14. Pediatric Oncology, Oslo University Hospital, Oslo, Norway. 15. Pediatric Oncology, Children's Hospital Bambino Gesu, IRCCS, Rome, Italy. 16. Pediatric Oncology, National Cancer Institute, Rio de Janeiro, RJ, Brazil.
Abstract
BACKGROUND: Alveolar rhabdomyosarcoma (aRMS) with lymph node involvement (N1 classification) accounts for up to 10% of all cases of RMS. The prognosis is poor, and is comparable to that of distant metastatic disease. In the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG) RMS2005 protocol, patients with a histologic diagnosis of aRMS/N1 received intensified chemotherapy with systematic locoregional treatment. METHODS: Patients with aRMS/N1 were enrolled prospectively after primary surgery/biopsy and fusion status was assessed in tumor samples. All patients received 9 cycles of induction chemotherapy and 6 months of maintenance therapy. Local treatment included radiotherapy to the primary site and lymph nodes with or without secondary surgical resection. RESULTS: A total of 103 patients were enrolled. The clinical characteristics of the patients were predominantly unfavorable: 90% had macroscopic residual disease after initial surgery/biopsy, 63% had locally invasive tumors, 77% had a tumor measuring >5 cm, and 81% had disease at unfavorable sites. Fusion genes involving forkhead box protein O1 (FOXO1) were detected in 56 of 84 patients. Events occurred in 52 patients: 43 developed disease recurrence, 7 had disease that was refractory to treatment, and 2 patients developed second neoplasms. On univariate analysis, unfavorable disease site, tumor invasiveness, Intergroup Rhabdomyosarcoma Study group III, and fusion-positive status correlated with worse prognosis. The 5-year event-free survival rate of patients with fusion-positive tumors was 43% compared with 74% in patients with fusion-negative tumors (P = .01). On multivariate analysis, fusion positivity and tumor invasiveness proved to be unfavorable prognostic markers. CONCLUSIONS: Fusion status and tumor invasiveness appear to have a strong impact on prognosis in patients with aRMS/N1. Fusion status will be used to stratify these patients in the next EpSSG RMS study, and treatment will be intensified in patients with fusion-positive tumors. Cancer 2018.
BACKGROUND:Alveolar rhabdomyosarcoma (aRMS) with lymph node involvement (N1 classification) accounts for up to 10% of all cases of RMS. The prognosis is poor, and is comparable to that of distant metastatic disease. In the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG) RMS2005 protocol, patients with a histologic diagnosis of aRMS/N1 received intensified chemotherapy with systematic locoregional treatment. METHODS:Patients with aRMS/N1 were enrolled prospectively after primary surgery/biopsy and fusion status was assessed in tumor samples. All patients received 9 cycles of induction chemotherapy and 6 months of maintenance therapy. Local treatment included radiotherapy to the primary site and lymph nodes with or without secondary surgical resection. RESULTS: A total of 103 patients were enrolled. The clinical characteristics of the patients were predominantly unfavorable: 90% had macroscopic residual disease after initial surgery/biopsy, 63% had locally invasive tumors, 77% had a tumor measuring >5 cm, and 81% had disease at unfavorable sites. Fusion genes involving forkhead box protein O1 (FOXO1) were detected in 56 of 84 patients. Events occurred in 52 patients: 43 developed disease recurrence, 7 had disease that was refractory to treatment, and 2 patients developed second neoplasms. On univariate analysis, unfavorable disease site, tumor invasiveness, Intergroup Rhabdomyosarcoma Study group III, and fusion-positive status correlated with worse prognosis. The 5-year event-free survival rate of patients with fusion-positive tumors was 43% compared with 74% in patients with fusion-negative tumors (P = .01). On multivariate analysis, fusion positivity and tumor invasiveness proved to be unfavorable prognostic markers. CONCLUSIONS: Fusion status and tumor invasiveness appear to have a strong impact on prognosis in patients with aRMS/N1. Fusion status will be used to stratify these patients in the next EpSSG RMS study, and treatment will be intensified in patients with fusion-positive tumors. Cancer 2018.
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