Abstract
Objective
The aim of this study was to compare the results of chemotherapy or combined chemotherapy-radiation therapy with surgical intervention following neodjuvant therapy in pelvic Ewing’s sarcoma patients.
Methods
The study population consisted of 39 patients with pelvic Ewing’s sarcoma treated in our clinic between 1994 and 2014. Of these patients, 28 patients (11 boys and 17 girls; mean age: 19.57±6.8 years) were treated with chemotherapy and radiation therapy and the remaining 11 patients (9 boys and 2 girls; mean age: 18.64±8.1 years) patients underwent surgical intervention after neo-adjuvant chemotherapy or chemotherapy plus radiation therapy. Internal hemipelvectomy was performed in 10 patients, and external hemipelvectomy was performed in one patient. Survival rates were compared between the surgical and non-surgical treatment groups. Predictive factors, such as treatment protocol (surgery, neoadjuvant chemotherapy, definitive radiotherapy), mass localisation, mass size, presence of metastasis at the time of diagnosis, and presence of late metastases were compared between the groups. The effects of each variable on survival were also examined.
Results
The overall 3- and 5-year survival rates of the 28 non-surgical patients were 41.4% and 26.1%, respectively, while those of the surgical patients were 53% and 35.4%, respectively (p=0.777). Large mass size, presence of metastasis at the time of diagnosis, and presence of late metastases were significantly associated with lower survival rates.
Conclusion
The survival rates of the patients who underwent surgery were higher than those of non-surgical patients, although the difference was not statistically significant. Definitive radiation and chemotherapy would be preferable in selected cases, such as patients with sacral localisation, without surgical intervention.
Level of Evidence
Level III, Therapeutic Study
Keywords: Ewing’s sarcoma, Pelvis, Surgery, Radiotherapy, Survival, Metastasis
Ewing’s sarcoma is a disease frequently seen in young individuals. It must be diagnosed at an early stage and treatment must be started early to improve survival. Neoadjuvant chemotherapy + surgery + adjuvant chemotherapy is the most widely accepted treatment protocol for Ewing’s sarcoma. The primary tumor localization is one of the most critical prognostic factors in Ewing’s sarcoma (1). Patients with pelvic masses had poorer prognosis and lower survival rates compared to those with other tumor localizations (2–4). Adjuvant therapy might be delayed due to high rates of post-operative infection and frequent skin problems in this area. The anatomical adjacency of pelvic tumors could make wide resection challenging and it, therefore, is not always easy to reach a tumor-free surgical margin, resulting in high local recurrence rates (5–10). Reconstruction after resection is also challenging (11, 12). Due to the challenges outlined above, survival rates for pelvic Ewing’s sarcoma are lower than for lesions localized to the extremities. Our treatment protocol for Ewing’s sarcoma consists of neoadjuvant chemotherapy + surgery + adjuvant chemotherapy +/− radiation therapy. In selected cases, neoadjuvant radiation is added to the treatment to reduce tumor size. Due to the high morbidity of surgical intervention in patients with sacral localization involving sacral nerve roots, we, however, also provide definitive radiation therapy as an option to patients. Here, we present the results of chemotherapy +/− radiation therapy with or without surgical intervention in pelvic Ewing’s sarcoma patients.
Materials and Methods
Hospital records of 49 patients diagnosed with pelvic Ewing’s sarcoma between 1994 and 2011 were reviewed retrospectively. Patients that were treated up to 2011 were included in the study to assess the 5-year survival data. Ten patients who were followed up in other centers were excluded from the study; therefore, including only 39 patients. None of the patients had previous interventions outside of our clinic. The patients were divided into two groups according to the treatment protocol: Group 1, neoadjuvant treatment followed by surgery and adjuvant therapy; and Group 2, chemotherapy with definitive radiotherapy. One patient in Group 1 underwent external hemipelvectomy. All the other patients underwent internal hemipelvectomy and reconstruction with extracorporeal irradiated autografts and modular hip prostheses. Table 1 lists the age, gender, mass localization, and initial symptoms of the patients. During treatment, the patients were administered radiotherapy according to the National Comprehensive Cancer Network (NCCN) protocol. This algorithm divides patients into two main groups, i.e., primary tumour and metastatic disease. Primary tumour treatment is reviewed under four headings: definitive radiotherapy, pre-operative radiotherapy, post-operative radiotherapy, and hemithorax irradiation. Preoperative radiotherapy is usually administered at a dose of 36–45 Gray (Gy) and the post-operative radiotherapy dose is 45 Gy. In metastatic disease, metastasectomy is followed by whole-lung irradiation. Definitive radiotherapy consists of 45 Gy to cover the original bony extent + 2 cm field (clinical target volume (CTV) + planning target volume (PTV)). This is followed by cone down procedure to deliver a total of 50.4–55.8 Gy.
Table 1.
Demographic data
| Group 1 (n=11) | Group 2 (n=28) | |
|---|---|---|
| Gender | 9 ♂/2♀ | 11♂/17♀ |
| Age | 18.64±8.1 | 19.57±6.8 |
| Localization | iliac, n=7; pubic ramus, n=2; sacrum n=1; proximal femur, n=1 | iliac, n=16; sacrum, n=7; acetabulum,; pubic ramus, n=2; proximal femur, n=1 |
| Initial symptom | pain, n=11 | pain, n=24; swelling, n=2; pain and swelling, n=1; constipation, n=1 |
Patients were administered chemotherapy according to the European Intergroup Cooperative Ewing’s Sarcoma Study-92 (EICESS-92) protocol. After four cycles of vincristine + dactinomycin [actinomycin D] + ifosfamide + doxorubicin (VAIA) treatment, local control status was assessed using magnetic resonance imaging (MRI) or computed tomography (CT) (13, 14). Surgical treatment was planned for selected cases while other patients received definitive radiotherapy. Both groups received adjuvant chemotherapy (VAIA for 10 more cycles). The treatment protocols (surgery, neoadjuvant chemotherapy, definitive radiotherapy), mass localization, mass size, the presence of metastasis at the time of diagnosis, and the presence of late metastases were investigated in both groups (Table 2). The effect of each variable on survival was also examined (Table 3). Statistical Package for Social Sciences software version 22.0 (IBM Corp.; Armonk, NY, USA) was used to analyze the data at a 95% confidence level. In all analyses, p<0.05 was indicated statistical significance. The Kaplan-Meier (product-limit method) analysis, log-rank (Mantel-Cox), and Breslow (Generalized Wilcoxon) methods were used to analyze the effects of the factors on mortality and lifespan. Written informed consent was obtained from patients and patients’ parents who participated in this study. Ege University Rectorship Clinical Research Ethics Committee approved the study protocol (Permission no: 51015598-050.06.04/179).
Table 2.
Quantitative data
| Group 1 | Group 2 | Total | p | |
|---|---|---|---|---|
| Number of patients | 11 (100%) | 28 (100%) | 39 | |
| Size ≥ 10 cm | 6 (54.5%) | 16 (57.1%) | 22 | 0.999 |
| Size <10 cm | 5 (45.5%) | 12 (42.9%) | 17 | |
| Presence of sacral involvement | 5 (45.5%) | 17 (40.5%) | 22 | 0.633 |
| Presence of metastasis at the time of diagnosis | 4 (36.4%) | 21 (50%) | 25 | |
| Presence of late metastasis | 2 (18.2%) | 4 (9.5%) | 6 |
p=0.999: Fisher’s Exact Test (Exact); p=0.633: Fisher–Freeman–Halton test (Monte Carlo)
Table 3.
Overall and disease-free survival rates according to predictive factors
| Overall Survival | Disease-Free Survival | |||||||
|---|---|---|---|---|---|---|---|---|
|
|
|
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| 3 Years | 5 Years | 3 Years | 5 Years | |||||
|
| ||||||||
| n | (%) | (%) | p | n | (%) | (%) | p | |
| All Patients | 39 | 43.7 | 31.2 | 14 | 29 | 29 | ||
| Surgical | 11 | 53.0 | 35.4 | 0.777 | 7 | 64.3 | 64.3 | 0.532 |
| Non-surgical | 28 | 41.4 | 26.1 | 7 | 71.4 | 71.4 | ||
| Sacral Involvement (+) | 22 | 51.6 | 34.4 | 7 | 31.2 | 31.2 | ||
| Surgical | 5 | 60.0 | 0.0 | 0.695 | 3 | 66.7 | (−) | 0.559 |
| Non-surgical | 17 | 50.7 | 31.7 | 4 | 75.0 | 75.0 | ||
| Sacral Involvement (−) | 17 | 34.3 | 27.5 | 7 | 25.7 | 25.7 | ||
| Surgical | 6 | 50.0 | 50.0 | 0.452 | 4 | 66.7 | (−) | 0.705 |
| Non-surgical | 11 | 27.3 | 18.2 | 3 | 66.7 | 66.7 | ||
| Size <10 cm | 17 | 62.7 | 48.8 | 9 | 42.9 | 42.9 | ||
| Surgical | 5 | 80.0 | 40.0 | 0.881 | 3 | 100.0 | 100.0 | 0.466 |
| Non-surgical | 12 | 58.3 | 41.7 | 6 | 66.7 | 66.7 | ||
| Size ≥10 cm | 22 | 29.1 | 17.5 | 5 | 17.0 | 17.0 | ||
| Surgical | 6 | 33.3 | 33.3 | 0.868 | 4 | 37.5 | (−) | 0.388 |
| Non-surgical | 16 | 27.5 | 13.8 | 1 | (−) | (−) | ||
| Metastasis at the time of diagnosis (+) | 25 | 29.6 | 8.4 | 0 | (−) | (−) | ||
| Surgical | 4 | 25.0 | 0.0 | 0.550 | 0 | (−) | (−) | (−) |
| Non-surgical | 21 | 30.5 | 10.2 | 0 | (−) | (−) | ||
| Metastasis at the time of diagnosis (−) | 14 | 68.8 | 68.8 | 14 | 66.5 | 66.5 | ||
| Surgical | 7 | 68.6 | 68.6 | 0.691 | 7 | 64.3 | 64.3 | 0.532 |
| Non-surgical | 7 | 71.4 | 71.4 | 7 | 71.4 | 71.4 | ||
| Late metastasis (+) | 6 | 16.7 | 0.0 | 0 | (−) | (−) | ||
| Surgical | 2 | 0.0 | 0.0 | 0.142 | 0 | (−) | (−) | (−) |
| Non-surgical | 4 | 25.0 | 0.0 | 0 | (−) | (−) | ||
| Late metastasis (−) | 33 | 48.7 | 37.5 | 14 | 34.2 | 34.2 | ||
| Surgical | 9 | 64.8 | 43.2 | 0.513 | 7 | 64.3 | 64.3 | 0.532 |
| Non-surgical | 24 | 43.9 | 30.7 | 7 | 71.4 | 71.4 | ||
Results
Thirty-nine patients with Ewing’s sarcoma showing pelvic involvement were followed up for an average of 37.95 months. Eleven of the patients (Group 1) were treated with surgery and adjuvant chemotherapy and radiotherapy, following neoadjuvant chemotherapy, while the remaining 28 patients (Group 2) were treated with chemotherapy and definitive radiotherapy. Of the 11 surgical patients, 10 underwent internal hemipelvectomy and one underwent external hemipelvectomy. Four had early infections and three patients had late infections. Implants were removed in five patients because of infection. Mass localizations were classified according to Enneking and Dunham’s system, and the results indicated that 22 (56.4%) patients had sacral involvement (Group 1: n=5; Group 2: n=17). Although the difference was not statistically significant, survival rates were higher in the surgical group. The other types were Type 1: n=2 patients; Type 2: n=3 patients; Type 3: n=1 patient, and Type 4: n=5 patients. The surgical margin was positive in one patient and negative in all other patients.
Of the 39 patients, 22 (56.4%) (Group 1: n=6; Group 2: n=16) had a mass size ≥10 cm, and 17 (43.6%) (Group 1: n=5; Group 2: n=12) had a mass size <10 cm. There was no significant difference regarding the size between the two groups (p=0.999).
Twenty-five (25) patients (64.1%) (Group 1: n=4; Group 2: n=21) had metastases at the time of diagnosis. These lesions were localized to the lungs in 21 of these patients. The difference between the groups was not statistically significant (p=0.550). Seven (7) patients from each group did not have metastasis at the time of diagnosis. Metastases were detected in two (2) (3rd and 6th months) of the seven (7) surgical patients without metastasis at the time of diagnosis, and in four (4) (5th, 9th, 12th, and 14th months) of the seven (7) non-surgical patients without metastasis at the time of diagnosis (Table 2). The average 3- and 5-year survival rates for all patients were 43.7% and 31.2%, respectively. Patients with metastasis at diagnosis were excluded from the disease-free survival rate analysis, and their 3-year disease-free survival rate was 29% (Table 2, 3).
In this study, the 5-year overall survival rate of patients with metastasis at the time of diagnosis was 8.4% (0% for surgical cases, and 10.2% for non-surgical cases). The overall 3- and 5-year survival rates of the surgical patients were 53% and 35.4%, respectively, and those of the non-surgical patients were 41.4% and 26.1%, respectively (p=0.777) (Figure 1–3). According to Enneking and Dunham’s classification system, there was no significant difference in the overall survival rates of 22 patients with sacral involvement and 17 patients without sacral involvement (p=0.714). In patients with or without sacral involvement, both overall and disease-free survival rates in the surgical group were better than those in the non-surgical group but the differences were not statistically significant (overall survival: p=0.695 for patients with sacral involvement, and p=0.452 for patients without sacral involvement; disease-free survival: p=0.559 for patients with sacral involvement, and p=0.705 for patients without sacral involvement). The overall survival rate of patients with tumors <10 cm was significantly higher than that of patients with tumors ≥10 cm (3-year overall survival rates were 62.7%/29.1%, and 5-year overall survival rates were 48.8%/17.5%, respectively) (p=0.018). The surgical group seemed to have better results than the non-surgical group regarding size vs. survival, but the differences were not significant (overall survival: p=0.881 for patients with tumors <10 cm, p=0.868 for patients with tumors ≥10 cm; disease-free survival: p=0.466 for patients with tumors <10 cm, and p=0.388 for patients with tumors ≥10 cm).
Figure 1.
Overall survival in pelvic Ewing’s sarcoma patients
Figure 2.
Disease-free survival in pelvic Ewing’s sarcoma patients
Figure 3.
Operation: overall survival relationship
The 5-year overall survival rates differed significantly between patients with and without metastases at diagnosis (8.4% and 68.8%, respectively; p=0.001) (Figure 4). The overall survival rates, however, did not differ statistically among patients with metastatic disease at the time of diagnosis (p=0.55). The 3-year overall survival rate was significantly lower in patients with late metastases than in patients without late metastases (16.7% and 48.7%, respectively; p=0.01). The pathology reports of 11 surgical patients indicated an average of 64.1% (20–100) tumor necrosis when evaluated for response to chemotherapy. Statistical analysis was not performed because the number of patients was not enough to compare survival with tumor necrosis. Local recurrence was detected in five (5) of the 39 patients (one in Group 1 and four in Group 2).
Figure 4.
Presence of metastasis at the time of diagnosis: overall survival relationship
Discussion
Several studies have reported the survival rates of Ewing’s sarcoma patients with different variables. In 2006, Yock et al. reported a 5-year disease-free survival rate of 49% (15). In 2015, Dramis et al. reported a 5-year overall survival of 40.7% in a cohort of 85 patients with non-metastatic Ewing’s sarcoma with pelvic involvement (16). In this study, the 3- and 5-year overall survival rates were 43.7% and 31.2%, respectively. Patients without metastasis at the time of diagnosis, however, had a similar 5-year survival rate (Group 1: 68.6%; Group 2: 71.4%). Complications are frequently seen in patients undergoing surgery due to pelvic Ewing’s sarcoma, specifically those with deep-seated masses (17). In this study, seven (7) out of 12 patients had infections, and implants were removed in five (5) patients. Despite the high complication rates, the overall survival rates of surgical patients were higher than those of non-surgical patients, although the difference was not statistically significant.
Many scholars have investigated survival rates in patients with pelvic Ewing’s sarcoma, and the effects of many factors on survival, including tumor size, the presence of metastasis at the time of diagnosis, and treatment modalities (18, 19).
In 2000, Hoffmann et al. studied a population of 241 pelvic Ewing’s sarcoma patients and reported that the initial tumor volume >100 mL negatively affected survival (p=0.006) (20). In contrast, in 2006, Yock et al. studied a population of 75 patients and reported no significant difference in survival rates between patients with tumors greater than or less than 8 cm (15). In the present study, patients with a tumor size <10 cm had better 3- and 5-year overall survival rates than those with tumors measuring >10 cm (p=0.018), and large tumor size negatively affected both overall and disease-free survival rates.
As with many tumors, the presence of metastasis at the time of diagnosis was reported to lead to poor prognosis in cases of Ewing’s sarcoma. The presence of metastasis at the time of diagnosis is the most significant negative predictive factor regarding survival (21). Based on 1989–2007 data from the California Cancer Registry Database, pelvic involvement increased the incidence rate of metastasis (p<0.0002) and was correlated with low survival rates (p<0.0001) (22). The present study obtained similar results. The presence of metastasis at the time of diagnosis was correlated with low survival rates (p=0.001). Of the 25 patients diagnosed with metastases at the time of diagnosis, 21 were treated with definitive radiotherapy and adjuvant chemotherapy. The overall survival rate of patients diagnosed with late metastasis was lower than that of patients without metastasis (p=0.014).
Local recurrence was detected in five (5) (n=1 in Group 1; n=4 in Group 2) of the 39 patients (12.8%). Sacral involvement was detected in four (4) of the patients with local recurrence. All these patients were in Group 2 and had lung metastases at the time of diagnosis, which made it impossible to analyze the effects of definitive radiotherapy versus surgery.
The effects of surgery on survival in the present study were different from the results reported in the literature. In 2016, Ahmed et al. reported that local control was still problematic, especially in patients treated with definitive radiotherapy (19). They suggested that surgical treatment of pelvic-located Ewing’s sarcoma positively affected survival, although the effect was not statistically significant (19). In 2007, Donati et al. studied 56 patients without metastasis at the time of diagnosis, and reported a significantly higher 5-year disease-free survival rate in patients treated with surgery +/− radiotherapy compared to patients given definitive radiotherapy (73.9% vs. 30.3%, respectively, p=0.036) (23). In a retrospective study of a cohort of 39 patients published in 2014, Raciborska et al. concluded that internal hemipelvectomy surgery positively affected survival despite the associated complications (24). Several other studies obtained similar results (16, 18, 25, 26).
Despite the positive effects of surgery indicated by these studies, in 2006, Yock et al. reported no differences in survival between surgery, radiotherapy, and a combination of both surgery and radiotherapy (15). They reported a 5-year disease-free survival rate of 49% in Ewing’s sarcoma patients with pelvic involvement. In 2015, Ng et al. studied 40 patients and found that the best results were obtained with the combined use of chemotherapy, radiation, and surgery (21).
In 2016, Akagündüz et al. reported that radiotherapy, either alone or adjuvant to surgery, provided local control in 80% of patients with non-extremity Ewing’s sarcomas and is critical in treatment (27). Of the patients included in their study and followed up for 49 months, 23 (52.3%) were found to have pelvic masses (27). In the present study, 3- and 5-year overall survival rates were higher in patients treated with surgery than in non-surgical patients, but the difference was not statistically significant (p=0.77) (Table 3).
In a 2016 study by the Scandinavian Sarcoma Group, Hesla et al. compared the survival rates of 88 patients with innominate bone involvement and 29 patients with sacral involvement (28). They administered definitive radiotherapy to 40% of the patients with innominate bone involvement and 79% of the patients with sacral involvement, and reported a higher 5-year disease-free survival rate in those with sacral involvement than innominate bone involvement (66% and 40%, respectively; p=0.02). Accordingly, they suggested that radiotherapy might be a more appropriate treatment option for sacral tumors.
Chemotherapy + surgery and neoadjuvant chemotherapy + surgery + radiotherapy are accepted treatment options for Ewing’s sarcoma. Our main treatment protocol consists of neoadjuvant chemotherapy and surgery. In certain cases, neoadjuvant radiotherapy is added to shrink the tumor. In cases with sacral involvement where surgery would cause significant morbidity, we also propose definitive radiotherapy as an option. Neither the tumor size nor the presence of metastasis at the time of diagnosis was considered other than morbidity, and both groups were found to be homogenous regarding tumor size and metastasis (Table 2). Patients treated with definitive radiotherapy are followed up similarly to those receiving surgery, and surgery is performed regardless of the loss of function in the event of a recurrence.
The preferred treatment for patients with Ewing’s sarcoma in an extremity is surgery. Radiotherapy, however, is also an effective treatment method for patients with pelvic involvement (19, 21, 22, 27). In this study, no significant difference was found between the survival of patients with sacral involvement and others (p=0.714). Furthermore, among patients with sacral involvement, there was no significant difference between the two groups regarding survival (overall survival, p=0.695; disease-free survival, p=0.559) (Table 3). Definitive radiation therapy, which avoids morbidity and has a lower complication rate, is, therefore, also considered as an effective option for the treatment of pelvic Ewing’s sarcoma.
Although this study was performed at a center that has dealt with orthopedic oncology for 40 years, the number of patients remained low due to the rarity of pelvic Ewing’s sarcoma, which prevented strong statistical results in certain analyses. Furthermore, the retrospective study design did not allow us to standardize the patient groups. Fortunately, however, the number of patients in both groups in our cohort was similar, which allowed statistical comparisons between the groups in most of the analyses (Table 2). Nevertheless, more studies with larger series are needed to provide more accurate information and obtain better interpretations.
The results of the present study suggest that definitive radiation therapy should be the preferred alternative to surgery in selected cases to avoid severe morbidity and high complication rates.
Footnotes
Ethics Committee Approval: Ethics committee approval was received for this study from the Clinical Research Ethics Committee of Rectorship of the Ege University (51015598-050.06.04/179).
Informed Consent: Written informed consent was obtained from patients and patients’ parents who participated in this study.
Author Contributions: Concept - İ.E.K., B.K.; Design - İ.E.K., B.K.; Supervision - D.S., C.D.B.; Resources - İ.E.K., B.K.; Materials - İ.E.K., C.D.B.; Data Collection and/or Processing - İ.E.K., C.D.B.; Analysis and/or Interpretation - İ.E.K., D.S.; Literature Search - İ.E.K., B.K.; Writing Manuscript - İ.E.K., D.S.; Critical Review - D.S., B.K.
Conflict of Interest: The authors have no conflicts of interest to declare.
Financial Disclosure: The authors declared that this study has received no financial support.
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