Treatment Of Localized Ewing's Sarcoma Research Articles

Current Status of Management and Outcome for Patients with Ewing Sarcoma.

Simple SummaryEwing sarcoma is a highly aggressive malignancy affecting primarily children and adolescents. It is the second most common bone sarcoma among children, affecting between 1 and 3 persons per million inhabitants. The tumor typically carries a pathognomonic chromosomal translocation resulting in a fusion transcript (EWSR1-FLI1), which plays an orchestral role in tumor development. While the fusion transcript has been known for decades, targeted treatment has been disappointing. However, new molecular techniques such as next-generation sequencing have significantly increased our understanding of this rare disease. Moreover, new closely related tumors with similar morphology but different characteristics have evolved. Treatment today consists of multiagent chemotherapy, radiation treatment, and surgery, all of which are associated with significant short- and long-term side effects. In this review article, we describe the currently existing diagnostic- and treatment-related challenges as well as the most important ongoing or recently conducted studies.Ewing sarcoma is the second most common bone sarcoma in children after osteosarcoma. It is a very aggressive malignancy for which systemic treatment has greatly improved outcome for patients with localized disease, who now see survival rates of over 70%. However, for the quarter of patients presenting with metastatic disease, survival is still dismal with less than 30% of patients surviving past 5 years. Patients with disease relapse, local or distant, face an even poorer prognosis with an event-free 5-year survival rate of only 10%. Unfortunately, Ewing sarcoma patients have not yet seen the benefit of recent years’ technical achievements such as next-generation sequencing, which have enabled researchers to study biological systems at a level never seen before. In spite of large multinational studies, treatment of Ewing sarcoma relies entirely on chemotherapeutic agents that have been largely unchanged for decades. As many promising modern therapies, including monoclonal antibodies, small molecules, and immunotherapy, have been disappointing to date, there is no clear candidate as to which drug should be investigated in the next large-scale clinical trial. However, the mechanisms driving tumor development in Ewing sarcoma are slowly unfolding. New entities of Ewing-like tumors, with fusion transcripts that are related to the oncogenic EWSR1-FLI1 fusion seen in the majority of Ewing tumors, are being mapped. These tumors, although sharing much of the same morphologic features as classic Ewing sarcoma, behave differently and may require a different treatment. There are also controversies regarding local treatment of Ewing sarcoma. The radiosensitive nature of the disease and the tendency for Ewing sarcoma to arise in the axial skeleton make local treatment very challenging. Surgical treatment and radiotherapy have their pros and cons, which may give rise to different treatment strategies in different centers around the world. This review article discusses some of these controversies and reproduces the highlights from recent publications with regard to diagnostics, systemic treatment, and surgical treatment of Ewing sarcoma.

Seeking international consensus on approaches to primary tumour treatment in Ewing sarcoma

BackgroundThe local treatment of Ewing sarcoma of bone involves surgery, radiotherapy or both. The selection of treatment depends on the anatomical extent of the tumour, the effectiveness of the proposed treatment, its morbidity, and the expectation of cure. However, not only are there variations in the approach to local treatment between individual patients, but also between treatment centres and countries. Our aim was to explore variation in practice and develop consensus statements about local treatment.MethodsA three stage modified Delphi technique was used with international collaborators. This involved an expert panel to identify areas of controversy, an online survey of international collaborators and a consensus meeting in London, UK in June 2017. In the consensus meeting, teams of clinicians discussed the local management of selected cases and their responses were collected with electronic voting.ResultsAreas of greater or less consensus were identified. The lack of evidence underpinning different approaches was noted and areas for collaborative research became apparent.ConclusionThis has demonstrated that there is an international consensus around many aspects of the local treatment of Ewing sarcoma of bone, including the use of specialist MultiDisciplinary Team (MDT) meetings with access to all appropriate treatments. However, considerable variation remains including the use of different staging investigations, decision making, definitions of response, and radiotherapy doses and timing. Further collaborative work should be undertaken to determine the impact of these variations in order to define best practice.

Relationship between treatment center case volume and survival for localized Ewing sarcoma: The role of radiotherapy timing.

In the treatment of localized Ewing sarcoma (EWS), delays in local therapy are known to adversely impact overall survival (OS). However, the role of treatment center volume in EWS outcomes, and the interaction between center volume and local therapy timing with definitive radiotherapy, remains unknown. Using the National Cancer Database, we demonstrate that treatment at the lowest EWS volume centers is associated with reduced OS, explained partly by higher rates of delayed local therapy. Treatment at the highest volume centers results in improved OS, but appears independent of radiotherapy timing. Future efforts to improve care for EWS patients across treatment centers are imperative.

Survival is influenced by approaches to local treatment of Ewing sarcoma within an international randomised controlled trial: analysis of EICESS-92

BackgroundTwo national clinical trial groups, United Kingdom Children’s Cancer and Leukaemia Group (CCLG) and the German Paediatric Oncology and Haematology Group (GPOH) together undertook a randomised trial, EICESS-92, which addressed chemotherapy options for Ewing’s sarcoma. We sought the causes of unexpected survival differences between the study groups.Methods647 patients were randomised. Cox regression analyses were used to compare event-free survival (EFS) and overall survival (OS) between the two study groups.Results5-year EFS rates were 43% (95% CI 36–50%) and 57% (95% CI 52–62) in the CCLG and GPOH patients, respectively; corresponding 5-year OS rates were 52% (95% CI 45–59%) and 66% (95% CI 61–71). CCLG patients were less likely to have both surgery and radiotherapy (18 vs. 59%), and more likely to have a single local therapy modality compared to the GPOH patients (72 vs. 35%). Forty-five percent of GPOH patients had pre-operative radiotherapy compared to 3% of CCLG patients. In the CCLG group local recurrence (either with or without metastases) was the first event in 22% of patients compared with 7% in the GPOH group. After allowing for the effects of age, metastases, primary site, histology and local treatment modality, the risk of an EFS event was 44% greater in the CCLG cohort (95% CI 10–89%, p = 0.009), and the risk of dying was 30% greater, but not statistically significant (95% CI 3–74%, p = 0.08).ConclusionsUnexpected differences in EFS and OS occurred between two patient cohorts recruited within an international randomised trial. Failure to select or deliver appropriate local treatment modalities for Ewing’s sarcoma may compromise chances of cure.Trial registration Supported by Deutsche Krebshilfe (Grants No. DKH M43/92/Jü2 and DKH 70-2551 Jü3), and European Union Biomedicine and Health Programme (Grants No. BMH1-CT92-1341 and BMH4-983956), and Cancer Research United Kingdom. Clinical trial information can be found for the following: NCT0000251