Introduction

Ewing sarcoma (ES) is the second most common primary bone tumor. Approximately 70% are diagnosed in childhood, while the rest occur in adults.1 ES is considered part of the primitive neuroectodermal family of tumors harboring characteristic translocation between chromosomes 11 and 22. The gold standard for diagnosing ES is the demonstration of t (11; 22) by fluorescent in situ hybridization (FISH) or polymerase chain reaction (PCR). ES occurs in both osseous and extraosseous sites with poor survival outcomes in certain sites such as the pelvis. Currently, the standard practice is multimodality management, typically with induction chemotherapy, followed by definitive local therapy with surgery and/or radiotherapy.2345678 Historically, vincristine, doxorubicin, and cyclophosphamide (VDC) regimen was used. The introduction of ifosfamide and etoposide (IE) to the VDC regimen resulted in a significant improvement in the survival.4 Further studies showed that intensification with 2-weekly administration of VDC/IE regimen instead of conventional 3-weekly regimen has further improved survival in localized adult ES patients.6

Treatment for metastatic ES is mainly palliative in nature although a fraction of these patients may have a significantly long survival, especially those with limited metastasis in sites such as the lung. There are no specific management guidelines for adult ES. Treatment approaches for adults are based on pediatric protocols. Majority of these trials had incorporated only 9 to 15% of patients with age > 18 years.23456 Historically, adult ES has been considered to have a poor prognosis compared with children.2456 Data on adult ES from the Indian subcontinent are scant. Most of them are studies, case series, or case reports on pediatric ES. The objective of the current study is to analyze the demographic, clinicopathologic features, and survival of localized and metastatic adult ES treated with multimodality and multiagent chemotherapy.

Subjects and Methods

This is a retrospective, observational study. Data of patients aged more than 18 years with ES diagnosed between 2010 and 2017 were analyzed for demographic and clinicopathologic features and survival outcomes. The diagnosis of ES was confirmed by local part imaging with MRI, biopsy, and FISH for ES breakpoint region 1 (EWSR1). The staging evaluation included a bone marrow aspiration and biopsy, CT chest, and a bone scan.

Most of the patients with the localized disease received neoadjuvant chemotherapy (NACT), followed by definitive surgery and/or radiation and adjuvant chemotherapy (ACT) thereafter. The chemotherapy regimen VDC/IE was given for a duration of 1 year. Some patients had surgery or radiotherapy upfront, followed by ACT.

Patients with the metastatic disease received palliative chemotherapy with the VDC regimen. Palliative radiation was given to selected patients. Those patients with localized or metastatic disease who received treatment for at least one cycle of chemotherapy were analyzed for survival rates. Patients who lost to follow-up were censored. Overall survival (OS) was defined as the time from diagnosis to the time of death due to any cause or lost to follow-up.

Results

Survival

At a median follow-up of 40 months, the 3-year OS in patients with localized disease was 87.4%. At a median follow-up of 13 months, the median OS in patients with metastatic disease was 13 months with a 3-year survival of 26%. Kaplan–Meier survival curves are shown in Fig. 1.

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Fig. 1: Overall survival of localized and metastatic disease by Kaplan–Meier estimates.

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Discussion

This is perhaps the first study from the Indian subcontinent on adult ES using the VAD/IE chemotherapy protocol. Similar to acute lymphoblastic leukemia, the treatment protocols for the adult ES were inspired from pediatric ES studies. The inclusion of adults in pediatric trials was limited. Even though these landmark studies included patients aged > 18 years, they accounted for 9 to 15% only.23456

In the current study, the median age at the time of diagnosis was 24.5 years and males accounted for 60.3%. The largest series of ES was studied by Verma et al (n = 1870), who reported the median age as 29 years.9 Other studies by Ahmed et al, Pretz et al, and Verrill et al reported a median age of 27.5, 28, and 24 years, respectively.101112 In this study, there was a male predominance (60.3%), similar to that of the studies by Verma et al (60%), Ahmed et al (67.7%), and Verrill et al (62.7%). Pretz et al had a female predominance, accounting for 60%.

In this study, pain and swelling were the most common presenting complaints seen in 75.3% and 42.5% patients, respectively, which is similar to other studies. The extremity was the most common site in majority of studies except in the study by Verma et al where the axial skeleton was most commonly involved.

Preoperative chemotherapy was given to 60.5% of the patients and 37.2% of the patients had undergone upfront curative surgery, who were diagnosed with ES on pathological examination of the tumor. One patient received local radical radiotherapy as therapy. Most of the patients received preoperative chemotherapy, followed by local control with either surgery and/or radiotherapy. Our data reflected the real-world practice of localized ES patients.

For patients with localized disease who received multimodality therapy, the 3-year OS was 87.4%. According to the historical data, before the introduction of VDC/IE regimen, the 5-year OS was 20 to 60%. This increased to more than 80% with the adoption of the VDC/IE regimen. Ahmed et al studied this impact of the addition of therapy in their recent study, showing improvement of 5-year OS from 49% to 73%, done between 1977 to 1992 and 1993 to 2007, respectively.10 A similar study by Nasaka et al reported the impact of the chemotherapy regimen on ES.13 She reported increased OS with the VDC/IE regimen. A recent study on adult ES by Pretz et al showed a 5-year OS of 79%.

In this study, 28.8% of the patients were diagnosed with a metastatic disease, which is similar to the study reported by Verma et al (33%) and Verrill et al (28.8%). Pretz and Varma’s studies reported lung as the most common site of metastasis, as was found in this study. However, Verrill et al reported bone as the frequent metastatic site. All patients in this study were given VDC-based regimen and 23.5% required radiation for palliation of symptoms. For metastatic ES, the 3-year OS was 13%, while it was 10% and 0% in studies by Verma et al and Verrill et al, respectively.

Retrospective nature, limited sample size, and missing data in a few patients are the limitations of this study. However, these problems reflect the ground reality of real-world scenario while treating patients with adult ES.

Conclusions

With the introduction of VDC/IE regimen, survival has dramatically improved. Metastatic ES patients still have adverse outcomes, pressing the need for additional therapies in future. Adoption of dose-dense regimens in select patients may further increase the survival.