BACKGROUND: The authors report the prospective evaluation of reduced dose alkylator chemotherapy combined with radiotherapy for European Pediatric Soft Tissue Sarcoma Study Group (EpSSG) standard risk nonalveolar rhabdomyosarcoma (NA-RMS). PATIENTS AND METHODS: Localized node negative Intergroup Rhabdomyosarcoma Study (IRS) II/III NA-RMS at favorable sites (subgroup C), <25 years old, received five cycles of ifosfamide, vincristine, and dactinomycin (IVA) chemotherapy (30 g/m2 ifosfamide) and four cycles of vincristine and dactinomycin (if receiving radiotherapy), or nine cycles of IVA (54 g/m2 ifosfamide) ± radiotherapy. Delayed primary tumor excision was considered for IRS III tumors. The primary end points were event-free survival (EFS) and overall survival (OS). RESULTS: From October 2005 to December 2016, 359 evaluable patients were recruited: orbit, 164 (45.7%); head and neck nonparameningeal, 77 (21.4%); and genitourinary non-bladder/prostate, 118 (32.9%). EFS and OS were 77.4% (95% confidence interval [CI], 72.5-81.6) and 93.5% (95% CI, 90.1-95.8), respectively. Lower dose alkylator chemotherapy and radiotherapy achieved 5-year OS of 93.7% but the difference with higher dose alkylator chemotherapy +/- radiotherapy was not significant (p = 0.8003). Adjuvant radiotherapy improved EFS with 5-year estimates of 84.7% versus 65.2% for nonirradiated (p < .0001), but not OS (p = .9298). Omitting radiotherapy for orbital tumors reduced OS (5-year was 87.1% vs. 97.3% for irradiated, p = .0257). Following R0 resection (n = 60), radiotherapy did not significantly improve EFS or OS. CONCLUSIONS: Radiotherapy for local tumor control allows for reduction of cumulative dose of alkylators in EpSSG standard risk subgroup C RMS patients. The omission of radiotherapy did not affect OS in all patients except those with orbital RMS and was associated with inferior EFS.

Centre for Rare Disorders Division of Paediatric and Adolescent Medicine Oslo University Hospital Oslo Norway

Children's Hospital for Wales Heath Park Cardiff UK

Department of Paediatric Surgery Royal Manchester Children's Hospital Manchester UK

Department of Pediatric and Adolescent Oncology INSERM U1015 Gustave Roussy Université Paris Saclay Villejuif France

Department of Pediatric Oncology and Haematology Hospital Universitari Vall d'Hebron Barcelona Spain

Department of Radiotherapy Hospital Universitari Vall d'Hebron Barcelona Spain

Hematology Oncology Division Department of Women's and Children's Health University of Padova Padova Italy

Hôpital Universitaire des Enfants Reine Fabiola ULB Brussels Belgium

Paediatric Oncology Unit Fondazione IRCCS Istituto Nazionale Tumori Milano Italy

Pathology Unit Department of Laboratories Bambino Gesu Children's Hospital IRCCS Rome Italy

Pediatric Oncology Department National Cancer Institute Rio de Janeiro Brazil

Pediatric Oncology Department University Hospital Brno and Faculty of Medicine Masaryk University Brno Czech Republic

Princess Máxima Center for Pediatric Oncology Utrecht the Netherlands

Radiation Oncology Gustave Roussy Cancer Campus Villejuif France

Ruth Rappaport Children's Hospital Rambam Medical Center Joan and Sanford Weill Pediatric Hematology Oncology and Bone Marrow Transplantation Division Haifa Israel

SIREDO Oncology Center Institut Curie PSL University Paris France

The Royal Marsden Hospital and The Institute of Cancer Research Surrey UK

Zobrazit více v PubMed

Pastore G, Peris‐Bonet R, Carli M, Martínez‐García C, de Toledo JS, Steliarova‐Foucher E. Childhood soft tissue sarcomas incidence and survival in European children (1978‐1997): report from the Automated Childhood Cancer Information System project. Eur J Cancer. 2006;42(13):2136‐2149. doi:10.1016/j.ejca.2006.05.016

Stiller CA, Stevens MCG, Magnani C, Corazziari I. Survival of children with soft‐tissue sarcoma in Europe since 1978: results from the EUROCARE study. Eur J Cancer. 2001;37(6):767‐774. doi:10.1016/S0959‐8049(01)00007‐7

Skapek SX, Ferrari A, Gupta AA, et al. Rhabdomyosarcoma. Nat Rev Dis Primers. 2019;5(1):1. doi:10.1038/s41572‐018‐0051‐2

Cecchetto G, Bisogno G, De Corti F, et al. Biopsy or debulking surgery as initial surgery for locally advanced rhabdomyosarcomas in children? Cancer. 2007;110(11):2561‐2567. doi:10.1002/cncr.23079

Cecchetto G, Bisogno G, Treuner J, et al. Role of surgery for nonmetastatic abdominal rhabdomyosarcomas. Cancer. 2003;97(8):1974‐1980. doi:10.1002/cncr.11285

Oberlin O, Rey A, Sanchez de Toledo J, et al. Randomized comparison of intensified six‐drug versus standard three‐drug chemotherapy for high‐risk nonmetastatic rhabdomyosarcoma and other chemotherapy‐sensitive childhood soft tissue sarcomas: long‐term results from the International Society of Pediatric Oncology MMT95 study. J Clin Oncol. 2012;30(20):2457‐2465. doi:10.1200/JCO.2011.40.3287

Stevens MCG, Rey A, Bouvet N, et al. Treatment of nonmetastatic rhabdomyosarcoma in childhood and adolescence: third study of the International Society of Paediatric Oncology—SIOP Malignant Mesenchymal Tumor 89. J Clin Oncol. 2005;23(12):2618‐2628. doi:10.1200/JCO.2005.08.130

Koscielniak E, Jürgens H, Winkler K, et al. Treatment of soft tissue sarcoma in childhood and adolescence. A report of the German Cooperative Soft Tissue Sarcoma Study. Cancer. 1992;70(10):2557‐2567. doi:10.1002/1097‐0142(19921115)70:10<2557::aid‐cncr2820701027>3.0.co;2‐8

Rudzinski ER, Anderson JR, Hawkins DS, Skapek SX, Parham DM, Teot LA. The World Health Organization classification of skeletal muscle tumors in pediatric rhabdomyosarcoma: a report from the Children’s Oncology Group. Arch Pathol Lab Med. 2015;139(10):1281‐1287. doi:10.5858/arpa.2014‐0475‐OA

Oberlin O, Rey A, Anderson J, et al. Treatment of orbital rhabdomyosarcoma: survival and late effects of treatment ‐ results of an international workshop. J Clin Oncol. 2001;19(1):197‐204. doi:10.1200/JCO.2001.19.1.197

Oberlin O, Rey A, Sanchez De Toledo J, et al. Randomized comparison of intensified six‐drug versus standard three‐drug chemotherapy for high‐risk nonmetastatic rhabdomyosarcoma and other chemotherapy‐sensitive childhood soft tissue sarcomas: long‐term results from the International Society of Pediatric Oncology MMT95 study. J Clin Oncol. 2012;30(20):2457‐2465. doi:10.1200/JCO.2011.40.3287

Stevens MCG, Rey A, Bouvet N, et al. Treatment of nonmetastatic rhabdomyosarcoma in childhood and adolescence: third study of the International Society of Paediatric Oncology‐SIOP malignant mesenchymal tumor 89. J Clin Oncol. 2005;23(12):2618‐2628. doi:10.1200/JCO.2005.08.130

Minard‐Colin V, Walterhouse D, Bisogno G, et al. Localized vaginal/uterine rhabdomyosarcoma—results of a pooled analysis from four international cooperative groups. Pediatr Blood Cancer. 2018;65(9). doi:10.1002/pbc.27096

Cecchetto G, Carretto E, Bisogno G, et al. Complete second look operation and radiotherapy in locally advanced non‐alveolar rhabdomyosarcoma in children: a report from the AIEOP soft tissue sarcoma committee. Pediatr Blood Cancer. 2008;51(5):593‐597. doi:10.1002/PBC.21702

Bhakta N, Liu Q, Ness KK, et al. The cumulative burden of surviving childhood cancer: an initial report from the St Jude Lifetime Cohort Study (SJLIFE). Lancet. 2017;390(10112):2569‐2582. doi:10.1016/S0140‐6736(17)31610‐0

Sung L, Anderson JR, Donaldson SS, Spunt SL, Crist WM, Pappo AS. Late events occurring five years or more after successful therapy for childhood rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Children’s Oncology Group. Eur J Cancer. 2004;40(12):1878‐1885. doi:10.1016/j.ejca.2004.04.005

Bergeron C, Jenney M, de Corti F, et al. Embryonal rhabdomyosarcoma completely resected at diagnosis: the European Paediatric Soft Tissue Sarcoma Study Group RMS2005 experience. Eur J Cancer. 2021;146:21‐29. doi:10.1016/j.ejca.2020.12.025

Green DM, Liu W, Kutteh WH, et al. Cumulative alkylating agent exposure and semen parameters in adult survivors of childhood cancer: a report from the St Jude Lifetime Cohort Study. Lancet Oncol. 2014;15(11):1215‐1223. doi:10.1016/S1470‐2045(14)70408‐5

Hawkins DS, Chi YY, Anderson JR, et al. Addition of vincristine and irinotecan to vincristine, dactinomycin, and cyclophosphamide does not improve outcome for intermediate‐risk rhabdomyosarcoma: a report from the children’s oncology group. J Clin Oncol. 2018;36(27):2770‐2777. doi:10.1200/JCO.2018.77.9694

Spalding AC, Hawkins DS, Donaldson SS, et al. The effect of radiation timing on patients with high‐risk features of parameningeal rhabdomyosarcoma: an analysis of IRS‐IV and D9803. Int J Radiat Oncol Biol Phys. 2013;87(3):512‐516. doi:10.1016/j.ijrobp.2013.07.003

Hawkins DS, Bisogno G, Koscielniak E. Introducing INSTRuCT: an international effort to promote cooperation and data sharing. Pediatr Blood Cancer. 2020;70(3). doi:10.1002/pbc.28701

Orbach D, Mosseri V, Gallego S, et al. Nonparameningeal head and neck rhabdomyosarcoma in children and adolescents: lessons from the consecutive International Society of Pediatric Oncology Malignant Mesenchymal Tumor studies. Head Neck. 2017;39(1):24‐31. doi:10.1002/hed.24547

Réguerre Y, Martelli H, Rey A, et al. Local therapy is critical in localised pelvic rhabdomyosarcoma: experience of the International Society of Pediatric Oncology Malignant Mesenchymal Tumor (SIOP‐MMT) Committee. Eur J Cancer. 2012;48(13):2020‐2027. doi:10.1016/j.ejca.2011.11.011

Dehner CA, Rudzinski ER, Davis JL. Rhabdomyosarcoma: updates on classification and the necessity of molecular testing beyond immunohistochemistry. Hum Pathol. 2023;147:72‐81. doi:10.1016/j.humpath.2023.12.004

Lautz TB, Chi YY, Li M, et al. Benefit of delayed primary excision in rhabdomyosarcoma: a report from the Children’s Oncology Group. Cancer. 2021;127(2):275‐283. doi:10.1002/cncr.33275