Long-Term Clinical Outcome and Prognostic Factors of Children and Adolescents with Localized Rhabdomyosarcoma Treated on the CWS-2002P Protocol

Abstract

We report here the results of the prospective, non-randomized, historically controlled CWS-2002P study in patients ≤ 21 years with localized RMS developed with the aim to improve the long-term outcome by adapting the burden of therapy to risk profile and to investigate the feasibility and relation to the outcome of maintenance therapy (MT) in the high-risk groups. Patients were allocated into low-risk (LR), standard-risk (SR), high-risk (HR), and very high-risk (VHR) groups. Chemotherapy consisted of vincristine (VCR) and dactinomycin (ACTO-D) for all patients with the addition of ifosfamide (IFO) in the SR, HR, and VHR and doxorubicin (DOX) in the HR and VHR groups. Low-dose cyclophosphamide and vinblastine maintenance therapy (MT) over 6 months was recommended in the HR and VHR groups. A total of 444 patients have been included in this analysis. With a median follow-up of 9·6 years (IQR 7·6–10·9) for patients alive, the 5-year EFS and OS for the whole group was 73% (95% CI 69–77) and 80% (95% CI 76–84), respectively. The 5-year EFS by risk group was 100% in the LR, 79% (95% CI 72–84) in the SR, 69% (95% CI 63–75) in the HR, and 42% (95% CI 23–61) in the VHR (log-rank p = 0.000). The 5-year EFS was 77% (95% CI 70–84) for 155 patients in the HR group who received MT as compared to 63% (95% CI 50–76) for 49 patients who did not (log-rank p = 0.015). Neither the reduction in the IFO dose in the SR nor the increased dose intensity of DOX in HR groups influenced the outcome when compared to the previous CWS and other European studies. MT was feasible, seemed to have an impact on prognosis, and should be studied in a well-controlled prospective trial in this patient population. The weighting of risk factors used for therapy stratification needs to be reevaluated.

Second‐line treatment of pediatric patients with relapsed rhabdomyosarcoma adapted to initial risk stratification: Data of the European Soft Tissue Sarcoma Registry (SoTiSaR)

“…12 Resection margins were defined at the time of pathological assessment and led to postsurgical staging adapted from the International Rhabdomyosarcoma Study Group (IRS). 13 18 ), minor PR (PR <2/3, former "poor response," and "objective response" 18 ), PD or stable disease (SD, Table S2). For the purpose of this analysis, all PR were summarized to one group.…”

“…15 Maintenance CHT was not regularly indicated as patients were assigned to the CWS-2007 HR trial, which included the randomization of stop of treatment or continuation with oral treatment with idarubicin, trofosfamide, and etoposide (O-TIE) for 6 months 16 based on results of the HD CWS-96 and CWS-2002P studies. 16,18 Delayed resection was applied in all patients with IRS stage II/III. Radiotherapy (RT) was indicated according to the CWS guidance analogous to RMS 2005 8,9,19 (Table S3).…”

“…Maintenance therapy with O-TIE or cyclophosphamide/vinblastine was offered for patients who achieved complete or very good partial remission. 16,18 Local control with delayed resection and/or RT was aimed to achieve a second CR, preferably after response to second-line CHT analogous to the time point of the primary treatment. Mutilating surgery was performed as individual decision of the treating center.…”

Pediatric Patients with Stage IV Rhabdomyosarcoma Significantly Benefit from Long-Term Maintenance Therapy: Results of the CWS-IV 2002 and the CWS DOK IV 2004-Trials

“…STS has an incidence of 0.9 per 100,000 in children under the age of 15 years and consists in 70% of RMS [ 1 , 2 ]. Whereas more than 90% of patients with a localized low-risk RMS can be cured [ 3 , 4 , 5 ], metastatic, very high-risk RMS have a poor prognosis, with a 5-year overall survival (OS) rate of less than 30% [ 6 , 7 , 8 ]. For example, patients suffering from alveolar RMS or RMS with two or more nowadays called Oberlin risk factors, including age (≤1 year or ≥10 years), multiple metastatic sites (≥3), bone or bone marrow involvement, or unfavorable primary site, have a 3-year event-free survival (EFS) of 14% only [ 9 ].…”

“…The subsequent studies CWS-IV 2002 and CWS DOK IV 2004 on metastatic disease included long-term maintenance therapy (LTMT) up to 24 months at the end of intensive treatment for patients with metastatic disease with trofosfamide and etoposide alternating with trofosfamide and idarubicin (O-TIE) [ 15 ] or maintenance therapy using oral cyclophosphamide and intravenous vinblastine (CYC/VBL). CYC/VBL was first introduced in the CWS-2002P study for high-risk patients [ 4 ]. A similar maintenance chemotherapy with vinorelbine and low-dose cyclophosphamide for treatment of patients with nonmetastatic high-risk RMS was included after a pilot study [ 19 ] into the RMS 2005 trial of the European pediatric Soft tissue sarcoma Study Group (EpSSG) and seemed to improve the outcome of these patients [ 20 , 21 ].…”