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

Ewa Koscielniak,Bernd Blank,Irene Schmid,Bernarda Kazanowska,Rüdiger Wessalowski,Ruth Ladenstein,Monika Sparber-Sauer,Christian Vokuhl,Gustaf Ljungman,Jörg Fuchs,Thomas Klingebiel,Birgit Fröhlich,Felix Niggli,Monika Scheer,Rupert Handgretinger,Guido Seitz

doi:10.3390/cancers14040899

Abstract

Simple SummaryThe major challenge in pediatric oncology is the optimal adaptation of therapy burden to risk profile, aiming to achieve the best outcome with minimum toxicities. The CWS-2002P study in patients ≤ 21 years with localized rhabdomyosarcoma was developed with this goal by reducing or intensifying the chemotherapy depending on the risk group. An important additional aim was to investigate the use of low-dose maintenance chemotherapy. The risk stratification system was effective in predicting outcomes in the four risk groups with very good long-term results. Neither the reduction nor the intensification of chemotherapy influenced the outcome in comparison to previous studies showing that further de-escalation of chemotherapy should be investigated. The weighting of risk factors used for therapy stratification needs to be reevaluated. Maintenance therapy seemed to have an impact on prognosis.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.

Highlights

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in the first two decades of life
The study shows that a reduction in the IFO dose did not deteriorate the outcome, and an increase in the dose intensity of doxorubicin did not improve prognosis in comparison to the Cooperative Weichteilsarkom Studiengruppe (CWS)-91 and -96 and EpSSG RMS 2005 study
This is an important message in relation to the acute and long-term effects of therapy

Summary

Introduction

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in the first two decades of life. Survival has improved steadily over the last three decades for patients with localized disease and exceeds 70%. Many outcome-related factors such as histologic subtype, site, age, and size have been defined and included in risk-adapted stratification systems [2–4]. CWS studies, the concept of therapy intensification was followed, and all patients with. The risk grouping was optimized, adding additional outcome-related factors (Supplementary Table S1), and the therapy intensity and the cumulative doses were reduced for the groups with a low and standard risk of recurrence without deterioration of prognosis [8]. The tumor volume reduction after neoadjuvant chemotherapy, which has been shown to be related to prognosis, was included for the secondary risk stratification [6,7]

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Discussion

Conclusion