Ewing sarcoma : treatment, prognosis and late effects

Ewing sarcoma (ES) is a rare and aggressive childhood/adolescent malignancy which relies on a multidisciplinary treatment approach for cure. The overall survival rate for this young patient group has hardly improved over the last 30 years despite large multinational treatment trials. Thus, there are important research questions to be answered with regards to systemic treatment. However, this thesis is about local treatment. Local treatment is indisputably important for overall survival, yet we have not reached a consensus for which local treatment regime is best for the individual patient. Therefore, local treatment is always a matter of debate on multidisciplinary meetings in sarcoma centers around the world. In the national multidisciplinary sarcoma conferences hosted at the Karolinska University Hospital every fortnight, every ES case in the country is brought up for discussion and there is an unproportioned amount of time spent on each case compared to other sarcomas. Due to the rare nature of this disease, randomized trials on local treatment are unlikely to occur and local treatment relies on case series and studies hampered by low number of patients. This thesis aims to shed light on the following questions: (1) which is the optimal local treatment strategy for pelvic ES; (2) how are ES of the spine treated in Scandinavia and what is the neurologic and oncologic outcome; (3) what is the true risk for subsequent primary neoplasms (SPNs) among ES survivors and (4) what is the effect of local treatment on local failure, long term mortality and morbidity? Study 1 evaluates different local treatment options in treatment of pelvic ES and whether local control of sacral ES can be achieved with radiotherapy alone. Innominate bone ES were in most cases treated surgically and sacral bone tumors were largely treated with radiotherapy (RT) alone. We found that sacral site was an independently favorable site as regards disease- free survival compared with the innominate bones. Furthermore, good local control could be obtained with RT alone for tumors located in the sacrum. Study 2 investigated if the same good outcome found among ES of the sacrum could be seen among patients with ES of the mobile spine. Additionally, the neurologic deficits at time of diagnosis and at end of follow-up for ES of the mobile spine were examined in relation to local treatment. Only 24 patients with sufficient data were found eligible for the analysis. Neurologic deficits at presentation were common which often led to emergency decompression before having a histopathologic diagnosis. Emergency decompression was associated with a higher rate of local failure. Most patients recovered neurologically regardless of local treatment, perhaps because of prompt initiation of systemic treatment leading to tumor shrinkage and less pressure on the spinal cord. Disease-free survival was relatively favorable, but perhaps not as good as that of sacral ES. As was the case with sacral ES, the majority of patient were treated with RT exclusively which reflects the difficulties in performing “en bloc” surgery in this site. Local control was excellent for the few patients with tumors manageable by surgery. Study 3 investigated the risk for secondary malignancies among Ewing- and osteosarcoma (OS) survivors in a population-based nationwide cohort. ES survivors had double the risk of OS survivors, and a four times higher risk than the general population of acquiring an SPN. The excess risk was largely driven by breast cancer and female genital malignancies for ES as well as OS survivors, and not as much by secondary sarcoma as anticipated. Due to the high background breast cancer incidence in the general population, the excess breast cancer risk among ES survivors translates to 127 extra breast cancers per 10 000 person years. The excess cancer risk remained elevated with increasing follow-up and over calendar time. Study 4 evaluated the role of surgery and RT in relation to surgical margin and local control. Secondarily, the effect of local treatment on long-term mortality, occurrence of SPN and hospitalization was studied. Local treatment had a significant effect not only on local failure, but also on overall survival. Surgical treatment gave superior local control compared with definitive RT. The lowest local failure rate was achieved if surgery was performed with a wide surgical margin. Nonetheless, RT also played a significant role with regards to local control since marginally resected tumors treated with adjuvant RT achieved an equal local control rate to that of a wide margin. This is a key finding because accomplishing a wide surgical margin is rarely possible for tumors located in the pelvis or spine, sites which comprise a third of all ES. In conclusion, tumor site is an important prognostic factor in ES. Pelvic and spinal sites pose a specific challenge since surgery of the primary tumor is less often performed due to the morbidity associated with surgery in these sites. Hence, more patients will receive definitive RT. Definitive RT seems to achieve good local control for tumors of the sacrum. Nevertheless, the long-term results of definitive RT are unknown. For tumors located in sites other than the sacrum, surgery is superior to definitive RT in achieving local control and improving survival. Moreover, best local control is achieved when surgery is carried out with wide margins, in which case RT does not improve outcome. Importantly, radiotherapy improves local control for marginally resected tumors. The long-term excess risks for SPNs are mainly driven by breast cancer among females. Unfortunately, the risks remain high in recent treatment periods. Moreover, the excess risk persists with extended follow-up, indicating the need for lifelong surveillance and tailored follow-up. However, the outcome after local recurrence is dismal. The benefit of administering RT when indicated must therefore not be overshadowed by the risk for treatment related cancer

Current Status of Management and Outcome for Patients with Ewing Sarcoma

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

Ewing sarcoma of the mobile spine; predictive factors for survival, neurological function and local control. A Scandinavian sarcoma group study with a mean follow-up of 12 years

Object: Many patients with Ewing sarcoma (ES) of the mobile spine present with neurologic symptoms leading to emergency decompressive surgery. Only rarely is optimal treatment involving neo-adjuvant chemotherapy followed by en bloc excision possible. The purpose of this study was to study treatment, neurologic and oncologic outcome in patients with ES of the mobile spine. Methods: Twenty-four patients diagnosed between 1986 and 2012 were identified through the Scandinavian Sarcoma Group registry. Charts were reviewed in order to assess details in patient characteristics, neurologic status, treatment and outcome. Prognostic factors were analyzed with respect to local control, disease-free survival and overall survival. Results: Neurologic symptoms were frequently observed at presentation, being present in 19/23 patients with documented neurologic status. Most (13/19) patients had a complete neurologic recovery regardless of whether or not emergency decompressive surgery was performed. The majority (18/24) of patients were treated with definitive radiotherapy. However, only 9/17 received the recommended dose of ≥ 50.4 Gy. The disease-free and overall survival rates were 48% and 57% at 5 and 10 years, respectively. The local recurrence rates were 19% and 27% at 5 and 10 years, respectively. Only year of diagnosis, categorized into periods with significant changes in chemotherapy protocols, was a significant factor for local recurrence, but there was a trend (p = 0.06) for an increased risk of a local recurrence if emergency decompressive surgery was performed. Conclusion: Patients with ES of the mobile have a relatively favorable prognosis. Nonetheless, local recurrence rate is high for this group of patients for which local treatment mainly relies on definitive radiotherapy. Emergency decompressive surgery may increase the risk for local recurrence