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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 11  |  Issue : 4  |  Page : 167-173

Management and outcome of extraosseous ewing's sarcoma family tumors treated at a tertiary care center in North East India: A retrospective analysis


1 Department of Radiation Oncology, Dr. B. Borooah Cancer Institute, Guwahati, Assam, India
2 Department of Cancer Registry and Biostatistics, Dr. B. Borooah Cancer Institute, Guwahati, Assam, India
3 Department of Medical Oncology, Dr. B. Borooah Cancer Institute, Guwahati, Assam, India

Date of Submission08-Aug-2020
Date of Acceptance21-Sep-2020
Date of Web Publication30-Dec-2020

Correspondence Address:
Dr. Faridha Jane R M Momin
Department of Radiation Oncology, Dr. B. Borooah Cancer Institute, Guwahati, Assam
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jrcr.jrcr_42_20

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  Abstract 


Introduction: Extraosseous Ewing's Sarcoma is rare, aggressive malignant soft-tissue tumors treated similar to Ewing's sarcoma of bone. This study evaluates the clinicopathological pattern, treatment and outcomes of localized extraosseous Ewing's sarcoma family tumors (ESFTs) treated with an uniform treatment regimen. Materials and Methods: This is a retrospective single institution study where we evaluated the hospital records of localized extraosseous ESFT treated between January 2011 and December 2018. Fifteen patients were found eligible for analysis. Patient demographics, management details, and outcomes were analyzed statistically. Time to event was measured from the date of diagnosis and survival curves were estimated by Kaplan–Meier method with Log-rank test for comparison. Results: The median follow-up of the cohort was 17 months (range: 3–81 months). The mean age of patients was 14.4 years and the average tumor size was 9.92 cm. Two-thirds of the patients received definitive radiotherapy as the local treatment with 93.3% patients receiving induction chemotherapy. The 5-year local control rate, progression-free survival, and overall survival (OS) were 80%, 53.3%, and 46.7%, respectively. On univariate analysis, tumor size <8 cm and good response to chemotherapy were associated with significantly improved OS (P = 0.049 and 0.04, respectively), while local control rates were better for patients receiving radiotherapy dose 54 Gray and above (P = 0.044). Conclusion: The optimum management of extraosseous ESFT consists of multimodality therapy with multidrug chemotherapy, surgery, and radiotherapy. Localized tumors of <8 cm size with favorable response to induction chemotherapy have the best prognosis.

Keywords: Ewing's sarcoma, extraosseous, management, primitive neuroectodermal tumor


How to cite this article:
Bhattacharyya M, Medhi PP, Kalita AK, M Momin FJ, Saikia S, Kalita M, Mishra R, Bora G, Bansal S. Management and outcome of extraosseous ewing's sarcoma family tumors treated at a tertiary care center in North East India: A retrospective analysis. J Radiat Cancer Res 2020;11:167-73

How to cite this URL:
Bhattacharyya M, Medhi PP, Kalita AK, M Momin FJ, Saikia S, Kalita M, Mishra R, Bora G, Bansal S. Management and outcome of extraosseous ewing's sarcoma family tumors treated at a tertiary care center in North East India: A retrospective analysis. J Radiat Cancer Res [serial online] 2020 [cited 2021 Apr 17];11:167-73. Available from: https://www.journalrcr.org/text.asp?2020/11/4/167/305724




  Introduction Top


Ewing's sarcoma family tumors (ESFTs) are highly malignant small round cell tumors arising from bone and soft tissues showing varying degrees of neuroectodermal differentiation, with a common genetic translocation-t (11;22) (q24;q12)[1] in 90% cases. The translocation results in the fusion of EWS and FLI1 genes generating chimeric fusion transcript EWS-FLI1 that is associated with tumorigenesis of this group of tumors.[2] Immunohistochemistry stains for diagnosing ESFTs are CD99 (MIC2), FLI1, and neuron-specific enolase (NSE).[3],[4]

ESFTs comprise of Ewing's sarcoma of bone, extraosseous Ewing's sarcoma, peripheral primitive neuroectodermal tumor (PNET) and Askin tumor of the chest wall. They occur mainly in children and young adults with a higher male preponderance and is more common in western population.[5],[6] It has a poor prognosis due to high chances of local recurrence and distant metastasis, especially in older population, larger tumor size and in those with metastatic disease at presentation.[7]

Extraosseous ESFTs are rare with various studies reporting its incidence to be 6%–47% of all ESFTs.[8],[9],[10],[11] Because of the low incidence, there are no randomized prospective trials evaluating this group of tumors and hence their treatment is similar to that of Ewing's sarcoma of bone. Multimodality management consists of high dose multiagent cytoreductive chemotherapy followed by surgery and/or radiotherapy as local treatment at 9–12 weeks with adjuvant chemotherapy till 48 weeks to eliminate micrometastasis.[12] The current Ewing's family tumour (EFT) treatment protocols have been able to improve the survival rates from 36% in 1980s to 56% in 1990s to over 70% in the 21st century[13],[14]

This retrospective study evaluates the clinicopathological features, management, and outcomes of localized extraosseous ESFTs treated with an uniform treatment regimen at a tertiary care cancer center in North East India over a period of 8 years.


  Materials and Methods Top


Between January 2011 to December 2018, patients of localized extraosseous Ewing's Sarcoma treated at our institute, were assessed for inclusion in this study. Data were obtained from patients' case files and Hospital-Based Cancer Registry records. The study was approved by the Institutional Ethics Committee. Requirement of patients' consent was waived owing to the retrospective nature of the study.

Patients diagnosed as localized extraosseous ESFT who received definitive treatment for their tumor were eligible for analysis in this study. The diagnosis of ESFT on histopathology was established by the presence of a small round cell tumor with no differentiating features on light microscopy and presence of cytoplasmic glycogen. Immunohistochemistry confirmation with positive CD99, FLI-1, and NSE was essential for final diagnosis of ESFT. Among them, those cases with no evidence of bone destruction on primary imaging (magnetic resonance imaging/computed tomography scan) and no evidence of increased tracer uptake in bone or periosteum adjacent to the tumor on static isotope bone scan images were considered to be extraosseous ESFT and eligible for inclusion in this study.[15] Investigation for translocation (EWS-FLI1) analysis was not considered mandatory.

Patients in whom there was confusion regarding the exact origin of the tumor, i.e., osseous versus extraosseous based on the above criteria, were excluded from analysis. Patients who were diagnosed with distant metastasis at presentation were also excluded from analysis as this cohort of patients have poorer prognosis and are often unable to complete multi-modality definitive treatment.[7] Furthermore, patients who declined or defaulted treatment, and those receiving palliative treatment were excluded.

All patients included were treated with an uniform multi-modality treatment strategy as per EFT protocol. Neoadjuvant chemotherapy included two courses of vincristine, ifosfamide, and etoposide (VIE) 3 weekly followed by two courses of vincristine, adriamycin, and cyclophosphamide (VAC) 2 weekly. Local therapy in the form of surgery or radiotherapy or both had to be offered between weeks 9 and 12 of treatment. Maintenance therapy after local treatment consisted of 3 weekly chemotherapy with 4 cycles VAC, 2 cycles VIE, and 6 cycles of VCD-actinomycin D replacing doxorubicin after a cumulative dose of 360 mg/m2. Vincristine was given weekly throughout the chemotherapy schedule and also along with radiotherapy.[12],[14]

Patient demographics and tumor characteristics of the cases eligible for inclusion were noted. Treatment details namely chemotherapy, surgery, and radiotherapy received by them were also evaluated. Response to neoadjuvant chemotherapy was assessed from the surgical specimen and/or imaging findings. The revised RECIST 1.1 criteria were employed for response evaluation to treatment and during follow-up.[16]

Tumors with complete or partial response or stable disease at the primary site after treatment completion were considered locally controlled. Clinical or radiographic increase in the size of primary or metastatic tumor or appearance of new metastatic lesion from the time of diagnosis and initial staging was classified as progression-free survival (PFS). Overall survival (OS) was defined as the time from diagnosis till death from any cause.

IBM SPSS Statistics for Windows, version 21 (IBM Corp., Armonk, N.Y., USA) software was used for statistical analysis. Chi-square test was used to evaluate treatment and prognostic factors for local control. Survival and local control rates were calculated using Kaplan–Meier estimation and Log-rank test was used for group comparisons. Statistical significance was defined as a P < 0.05.


  Results Top


Taking into consideration the above criteria, 15 patients were found eligible for retrospective review during the study. The median follow-up of entire cohort was 17 months (range 3–81 months). The various patient and tumor related variables of the study are shown in [Table 1].
Table 1: Patient demographics, tumor and treatment related characteristics

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Clinicopathological characteristics

The mean age of patients was 14.4 years (standard deviation [SD] = 9.956) and M: F ratio of 2:1. The median duration of symptoms among the patients was 6 months (range: 1–12 months). The mean tumor size was 9.92 cm (SD = 4.030). In 80% of patients, the tumor was centrally located. The locations of the tumor among the study cohort are shown in [Figure 1].
Figure 1: Location of extraskeletal Ewing's sarcoma in the 15 patients analyzed in the study

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Treatment characteristics

All 15 patients analyzed were planned with curative intent. Fourteen patients received neoadjuvant chemotherapy with 11 patients (78.6%) showing good response to it. Surgery as local treatment was used in 5 cases (33.3%). Among them, 2 patients had complete resection with clear margins (R0) while 2 had marginal/intralesional resection (R1) and in 1 case margins could not be commented on.

Radiotherapy was the definitive local therapy in 66.7% (10/15). All the cases that underwent surgery also received radiotherapy-1 preoperatively and 4 postoperatively. Radiotherapy dose of 54 Gy or above was used in 8 patients (53.3%) and 7 patients received <54 Gy (46.7%). Conformal radiotherapy techniques such as three-dimensional conformal radiotherapy/intensity modulated radiotherapy were used in 46.7% of the cases.

Local control, patterns of failure and survival

Local control rate was 80% [Figure 2] and PFS 53.3% [Figure 3]a at 5 years. Seven patients had disease progression or relapse in this study with none of them alive at the time of analysis of the results. The median time to failure among these patients was 4 months (range: 1–14 months) and their median survival was 11 months (range: 3–20 months). Distant metastasis to lung and/or bones was the most common type of failure (40%). Local failure was seen in 3 cases (20%) with 2 of them also having distant metastasis to lungs. The 5-year OS of the study subjects was 46.7% [Figure 3]b.
Figure 2: Kaplan–Meier curve showing local control rate among the study population

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Figure 3: Kaplan-Meier curve showing progression-free survival (a) and overall survival (b) rates among the study population

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Analysis of prognostic variables

The various prognostic indicators with relation to study parameters are shown in [Table 2]. Age (<18 years vs. 18 years and above), gender (male vs. female), tumor location (central vs. peripheral), and duration of symptoms (<6 months vs. >6 months) did not impact local control, PFS or OS in this study (all P values >0.05). Type of local treatment received (radiotherapy alone vs. surgery and RT combined) also did not have any difference in local control and survival in our patients.
Table 2: Univariate analysis of prognostic factors with relation to local control, progression-free survival and overall survival

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Patients with tumor size <8 cm had significantly improved PFS (83.3% vs. 33.3%, P = 0.047) and OS (83.3% vs. 18.5%, P = 0.049) although there was no significant difference in local control (P = 0.132). Response to neoadjuvant chemotherapy (complete or partial response) was also associated with significant improvement in OS (58.4% vs. 25%, P = 0.04) and a trend toward better local tumor control (90.9% vs. 50%, P = 0.052). The single most significant variable for better local control in our patients was the radiotherapy dose-100% for dose >/=54 Gray versus 57.1% for dose <54 Gray (P = 0.044).


  Discussion Top


Extraosseous Ewing's Sarcoma/PNET is a rare entity and there is paucity in literature which deals with managing this malignancy specifically. In one of the earliest published studies, Rud et al.[17] evaluated the management and outcome of 42 cases of extraosseous Ewing's Sarcoma (EES) over a period of 50 years (1935–1985). They found EES to be an aggressive disease with high chances of local and distant failures and emphasized the role of combination therapy to improve prognosis for patients of EES. However, most of the available literature on EES are retrospective single institution studies[18],[19],[20],[21],[22] and there are no randomized clinical trials till date. Therefore, the principles of management of EES have been extrapolated from the experience of treating Ewing's Sarcoma/PNET of bone.

Applebaum et al.[23] have analyzed the US Surveillance, Epidemiology, and End Results program database between 1973 and 2007 and reported the largest data on clinical features and outcome of EES, comparing the results with skeletal Ewing's sarcoma for the same time period. They have shown that EES developed at a higher mean age and had lower male preponderance than skeletal tumors. They were more likely to arise in axial locations, but less likely in the pelvis. The 5-year OS was superior for localized EES when compared to localized skeletal Ewing's sarcoma (69.7% vs. 62.6%, P = 0.02). Thus, although both skeletal and extraskeletal Ewing's sarcoma/PNET are included together in the ESFT group and are managed similarly, yet their outcomes may vary.

Ours is a retrospective observational study of localized extraosseous Ewing's sarcoma/PNET treated with an uniform treatment protocol at a regional cancer center from a resource constrained region of the globe. In our study, the mean age of the patients (14.4 years) was lower than that reported from studies outside India[18],[23] but was comparable to the findings of Biswas et al.[19] (15.1 years). The gender predilection (M: F = 2:1), average tumor size (9.92 cm) and tumor location (axial 80% >appendicular 20%) were comparable to the findings by other researchers.[18],[19],[20],[21],[22],[23] The most common locations of EES in our study were the head and neck region, pelvis, and extremities (3 cases/20% each). Some unusual locations included the brain, suprarenal, and vulva (1 case each) while the remaining cases occurred in the paravertebral and chest wall regions [Figure 1]. Different investigators have reported various regions as the most common sites in their findings - Extremities by Rud et al.[17] and Xie et al.,[18] Abdomen by Biswas et al.[19] and Trunk and Chest wall by El Weshi et al.[20] and Tural et al.[21] Thus, it is clear that EES can arise from soft tissue of any part of the body without any particular predilection Multimodality treatment approach with systemic combination chemotherapy (neoadjuvant and adjuvant) along with surgery and/or radiotherapy for local control is the standard of care for ESFT which was also utilized in our study population. All patients, except the one with EES in brain, received neoadjuvant chemotherapy (NACT) in this study. The response to NACT was 78.6% in our study, which was comparable to the results of Biswas et al.[19] (84%) and Venkitaraman et al.[22] (80%) while being significantly superior to that reported by El Weshi et al.[20] (40%) and Tural et al.[21] (62%) in adult extraskeletal ESFTs. Surgery and RT combination local therapy was used in one-third of our patients while definitive RT alone was used in the rest. Our surgical resection rate of 33.3% was lower than that reported in previously published studies (58%–81%).[17],[18],[19],[20],[21] The reason could be more number of large sized tumors located in surgically inaccessible locations or where preservation of functional ability of the affected organs could not be achieved with surgery (e.g., Nasopharynx, Abdomen, Paravertebral region, and Pelvis). It is to be noted that studies with the highest rates of surgical resection included a greater number of cases in the extremities than central locations[17],[18] whereas in our study only 20% (3 cases) had tumors located in extremities which might be the explanation to our low surgical resection rates.

The 5-year PFS was 53.3% and OS 46.7% in our study. On comparison with the subgroup of localized extraosseous ESFT in other published studies, our results were inferior to those reported by Biswas et al.,[19] El Weshi et al.[20] and Applebaum et al.[23] but superior in comparison to Xie et al.[18] and Venkitaraman et al.[22] It is to be noted that the studies[19],[20],[23] which showed better survival had a larger sample size of cases (range: 57–683 cases) and longer duration of follow-ups in comparison to our study and the other studies[18],[22] showing inferior survival, which shows that the difference could be because of the less number of patients analyzed for a shorter period of time.

Age of the patients did not impact survival outcomes in our study and although males had better local control (90% vs. 60%), PFS (60% vs. 40%), and OS (64% vs. 20%) than females, the difference was not statistically significant. Results of primary tumor control and survival were also better for centrally located tumors in our study (LC: 83.3% vs. 66.7%, OS: 53.3% vs. 33.3%) although not found to be statistically significant [Table 2]. This is in contrast to the outcomes of Biswas et al.[19] who found that primary tumors in abdomen, spine, and pelvis had significantly worse OS (P = 0.04).

Tumors <8 cm had significantly better PFS (83.3% vs. 33.3%, P = 0.04) and OS (83.3% vs. 18.5%, P = 0.04) in our study. In the study by Biswas et al.[19] also it was seen that EES with tumor size up to 8 cm had significantly better 5 year survival (91.7% vs. 46.4%, P = 0.02) and Tural et al.[21] found that such patients showed significantly improved 5-year event-free survival (80% vs. 38%, P = 0.005) as well as OS (hazard ratio: 0.03, P = 0.01). Another treatment variable that significantly impacted survival in our study was the response to neoadjuvant chemotherapy, with good responders showing better survival outcomes (5-year OS: 58.4% vs. 25%, P = 0.04). El Weshi et al.[20] and Tural et al.[21] have also shown that a good histologic response to induction chemotherapy in the resected specimens, characterized by >90% tumor necrosis rate or <10% viable tumor cells was associated with significantly improved 5-year EFS and OS (all P values <0.05). In our study, a good response to NACT was assessed for the resected tumors based on histologic findings and for the unresected tumors based on the decrease in tumor size on post-NACT imaging (complete/partial response based on? RECIST version 1.1)[16]

Our study results did not show any difference in outcomes for patients based on the type of local treatment delivered. Both subgroups receiving radical RT alone versus combined surgery and radiotherapy showed equivalent 5-year EFS (50% vs. 60%, P = 0.706) and OS (40% vs. 60%, P = 0.481). Biswas et al.[19] also found no difference in outcome based on local treatment type in their study, whereas El Weshi et al.[20] and Tural et al.[21] found that combined surgery and radiotherapy improved EFS and OS significantly. A wide negative margin of resection has also been shown as an important prognostic indicator by them, but such an analysis could not be performed in our study as only 5 patients underwent surgery. Patients receiving radiotherapy dose of 54 Gy and above had better local control of their tumors (100% vs. 57.1%, P = 0.044) in our study although it did not translate into improved survival [Table 2]. Dunst et al.[24] have shown that although surgery yields better local control than radiotherapy alone in ESFT, for patients at high risk of local failure (positive margins, poor histologic response to chemotherapy) combined local therapy seems justified for better prognosis, with definitive radiotherapy reserved for lesions that are not resectable with clear margins. In our study, 80% of the patients had lesions in central locations and not amenable to resection which justifies the use of radical radiotherapy alone in majority of our patients (66.7%) in accordance with the observations of Dunst et al.[24]

Our study is a retrospective single institution study that is reported from a region where the incidence of ESFTs is lower than the worldwide incidence.[25] As extraosseous ESFTs are even rarer, this is the reason for less number of cases included and analyzed in our study (n = 15) when compared to other studies.[17],[20],[21],[23] Furthermore, cases with widespread metastasis that did not receive radical treatment were omitted as we believe it would have impacted the survival analysis adversely of the already sparse study population. The presence of distant metastasis has already been proven as the most important prognostic factor impacting survival in EES in all the previously published reports[7],[17],[18],[19],[20],[21] and our aim in this study was to evaluate the other clinicopathological and treatment related prognostic factors that determined outcomes in localized EES. Nevertheless, our study adds value to the dearth of literature on extraosseous ESFT.


  Conclusion Top


Extraosseous ESFTs are rare but aggressive malignant tumors that are treated similar to osseous ESFT. The management consists of multimodality therapy with chemotherapy, surgery, and radiotherapy in combinations. Tumors that are localized, smaller in size (<8 cm) and show good response to induction chemotherapy often have favorable prognosis. Radiotherapy is an effective local control modality for extraosseous ESFT and dose above 54 Gray appears to improve local control.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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