Survival outcome among patients with Ewing’s sarcoma of bones and joints: a population-based cohort study

ABSTRACT BACKGROUND: The aim here was to elucidate the current survival condition of patients diagnosed with Ewing’s sarcoma of the bones and joints and determine independent risk factors associated with the prognosis. DESIGN AND SETTING: Retrospective cohort study based on the Surveillance, Epidemiology and End Results (SEER) database in the United States. METHODS: We identified 397 patients who were diagnosed with Ewing’s sarcoma of the bones and joints between January 2004 and December 2013. The multivariate Cox proportional hazards model was used to determine factors associated with the risk of death by adjusting for various factors. RESULTS: The one, two and five-year disease-specific survival rates were 89.08%, 78.08% and 62.47%, respectively. The factors related to death were age (≥ 18 years versus < 18 years; hazard ratio, HR = 1.77; 95% confidence interval, CI: 1.38-2.31); tumor site (extremity versus spine and pelvis; HR = 2.03; 95% CI: 1.31-2.62); tumor size (> 10 cm versus ≤ 10 cm; HR = 1.78; 95% CI: 1.34-2.56); and type of treatment (surgery alone versus radiotherapy with surgery; HR = 0.51; 95% CI: 0.38-0.89; or radiotherapy alone versus radiotherapy with surgery; HR = 1.61; 95% CI: 1.10-2.39; or no treatment versus radiotherapy with surgery; HR = 1.86; 95% CI: 1.23, 2.58). CONCLUSIONS: Patients with Ewing’s sarcoma showed poor survival in situations of age ≥ 18 years, tumor size > 10 cm, receiving radiotherapy alone and receiving no treatment. Patients undergoing surgery alone had better survival.


INTRODUCTION
Ewing's sarcoma is a rare cancer that accounts for less than 10% of all malignancies existing in the human body. It stems from primitive neuroepithelial cells, which are able to differentiate into various mesenchymal cells, and has a propensity to metastasize to distant sites at an early stage . This cancer typically occurs in adolescents and young adults, accompanied by a very poor prognosis. It is considered to be a high-grade malignancy, ranking second in the list of malignant bone tumors. [1][2][3][4][5][6][7] It is commonly considered to be an extremely aggressive osteolytic cancer that usually occurs in the bones of the limbs and pelvis and it can metastasize to distant locations such as bone marrow, the lungs and other soft tissues at an early stage. 1,3,7 In the United States, the overall incidence rate of Ewing's sarcoma is approximately 0.1 case per 100,000 individuals per year, and this rate had not undergone any obvious change over past 30 years. An estimated 90% of these patients are under 20 years old, and the death rate is approximately 0.05 cases per 100,000 individuals per year. Additionally, most cases of Ewing's sarcoma of the bones and joints are found in the limbs, pelvis or spine. 4,8 Nonetheless, there is a lack of survival studies on Ewing's sarcoma arising in the bones and joints and associated prognostic factors, based on up-to-date data on nationwide populations.

OBJECTIVE
The purpose of this study was to demonstrate the survival conditions of patients with Ewing's sarcoma of the bones and joints and determine independent risk factors associated with their prognosis. nancies at the time of diagnosis or whose diagnoses were not confirmed by means of histopathological evaluation were also excluded.

METHODS
Cases without complete information were excluded. The inclusion and exclusion procedure is showed in the flow chart of Figure 1.
Well-differentiated and moderately differentiated histological features were classified as low grade while poorly-differentiated and undifferentiated histological types were classified as high grade. Differences between groups were taken to be statistically significant when the P value was less than 0.05.

RESULTS
During the 10-year period, 397 patients diagnosed with Ewing's sarcoma of the bones and joints were included (249 males and 148 females). The overall one, two and five-year survival rates after diagnosis were 89.08%, 78.08% and 62.47%, respectively (Figure 2).
The five-year relative survival rates were 78.4%, 66.9%, 47.8% and 44.8% for patients receiving surgery, surgery with radiotherapy, radiotherapy alone and no therapy, respectively (Figure 3). Overall, patients with tumor size ≤ 10 cm had a higher five-year survival rate than did those with tumor size > 10 cm (70.8% versus 52.4%; P < 0.001) (Figure 4). The five-year survival rate were 68.7% and 50.2% for those < 18 and ≥ 18 years ( Figure 5). were associated with increased risk of mortality, while receiving surgery alone (HR = 0.51; 95% CI = 0.38-0.89) was an independent predictor for longer survival.

DISCUSSION
In our study, we found that the one, two and five-year DSS rates were 89.08%, 78.08% and 62.47%, respectively. These proportions were reported to be higher in a previous investigation. 10 This difference may reflect that the prognosis of Ewing's sarcoma originating bones and joints is much worse than that of Ewing It has been reported that the t(11;22) (q24;q12) translocation is found in 85% of cases of Ewing's sarcoma. 11,12 Yang et al. 13        In our study, most of the patients included were young, i.e. under 18 years of age, and the median age of our cohort was 17.8 years at the time of diagnosis. This was almost identical to the results reported previously in the worldwide literature, i.e. that most cases of Ewing's sarcoma not surprisingly emerged before the second decade of life, and that younger patients were likely to have a better prognosis. [15][16][17] Regarding the reasons for this phenomenon, Lee et al. 18 and Grevener et al. 16 found that fewer cases among adult patients were treated with chemotherapy. Moreover, elderly patients were more likely to have several comorbidities, including diabetes mellitus hypertension or secondary cancers, which made the situation much more complex.
Tumor size was considered to be a prognostic indicator in our study. We found that the mean size was 10.3 cm, which was almost consistent with the results declared in previous studies. We noticed that sizes larger than 10 cm were associated with a negative impact on DSS. However, there is no consensus regarding any critical cutoff size that might indicate a completely different prognosis for this disease. [19][20][21][22][23] In a study on 182 patients, Fizazi et al. 24 found that tumor size greater than 10 cm was an independent prognostic factor for survival. Canter 25 also recommended that patients with tumors larger than 10 cm should accept neoadjuvant chemotherapy and investigational therapies, because they were at a high risk of relapse and disease-specific death.
Even so, several studies have asserted that 8 cm might be a more appropriate boundary value. In a retrospective analysis on 220 patients at St. Jude Children's Research Hospital, Rodriguez-Galindo et al. 23 found that neoplasm size larger than 8 cm affected survival adversely.
In our analysis, tumors arising from the spine and pelvis were an independent factor for poorer survival. The proportion of the patients who accepted surgery was 56.0%, while 47.5% received radiotherapy. We found that surgery alone, radiotherapy alone, and no treatment were independent risk factors.
There are several explanations for this phenomenon. Oberlin et al. 26 asserted that it was recommendable that smaller and more peripheral tumors should be dealt with through surgical resection, while larger and more central unresectable entities should be managed with radiotherapy. On the other hand, Granowetter et al. 27 pointed out that radiotherapy was not appropriate for patients in whom there was no proof of microscopic remainders of malignant tissue after they underwent operations.
Normally, it is accepted that surgery will provide a decisive partial cure. Only when the neoplasm is unresectable or after palliative surgery should radiation therapy be considered. Such patients' prognoses have been found to be relatively much worse than those of patients who underwent surgery alone. 10,28 In a retrospective study on 512 cases, Bacci et al. 29 concluded that surgical resection is more ideal than radiation therapy for Our analysis was based on the data documented in the SEER database, which means that we need to acknowledge that there were some limitations relating to our study. Firstly, some variables including data on comorbidities, surgical margins, extent of surgical resection, tumor recrudescence and use of targeted therapy in managing this cancer were missing or not recorded in the database. Secondly, because of the principle of anonymity in the SEER Program, it was impossible for us to contact the patients in order to gain additional information. Thirdly, it also should not be ignored that because of the existence of confounders, the consequences deduced from a retrospective analysis would normally be of lower methodological grade than those from randomized controlled trials. Finally, we were unable to evaluate some specific molecular indicators, such as Ewing's Sarcoma-Friend leukemia integration 1 transcription factor (EWS-FLI1) and serum LDH, which help in making an early diagnosis and in judging the prognosis.
In spite of these limitations, use of the SEER Program database has significant advantages, in that it provides possibilities for conducting studies of this nature based on large populations suffering from rare types of cancer.

CONCLUSION
In conclusion, the contemporary five-year DSS rate of Ewing's sarcoma of the bones and joints was 62.47%. Age ≥ 18 years, tumors originating in the spine and pelvis, tumor size > 10 cm, receiving radiotherapy alone and no treatment were independent risk factors for poor DSS, while surgery alone was an