Prognostic factors and treatment outcomes of adult Ewing sarcoma from 20 years of experience in a specialized center

INTRODUCTION

Ewing sarcoma (ES) ranks as the second most prevalent primary bone tumor and predominantly affects children and young adults, particularly in their early adolescence.^[1,2] It is highly aggressive, with a mortality rate exceeding 90% without treatment due to the disease.^[3] However, multimodality approaches improved overall survival (OS) to 65–75% at 5 years.^[4] The standard treatment for ES includes a local locoregional control with surgery, radiation therapy (RT), or a combination of both with chemotherapy. The effectiveness of these treatments varies depending on the cancer stage, site, patient’s age, and overall health status. While effective for some, the current therapeutic approaches still leave a subset of patients with metastatic or recurrent disease facing unfavorable prognoses.^[3-5] Survival outcomes in ES also exhibit racial and sex-related variations, particularly in Western countries,^[6] and the available knowledge about ES is predominantly derived from the pediatric group. However, adults are usually treated with the same strategy.^[7-11] The prognosis of ES is influenced by several key factors, including younger age and smaller tumor size, which are associated with better outcomes, whereas metastatic disease at diagnosis, poor histologic response to pre-operative chemotherapy (<90% tumor necrosis), elevated lactate dehydrogenase (LDH) levels, inadequate surgical resection margins, and adverse molecular markers such as TP53 mutations or STAG2 loss indicate a higher risk of recurrence and worse survival.^[12-17]

A paucity of research focuses specifically on ES within the Arab region, highlighting the importance of expanding the understanding of this malignancy across diverse populations. King Faisal Specialist Hospital and Research Center (KFSH&RC) possesses specialized expertise in sarcoma care, incorporating combined clinics and a Sarcoma Tumor Board dedicated to providing comprehensive and multidisciplinary management for patients with this complex disease. This study is unique in that it represents the largest center treating sarcoma patients, providing novel insights into regional disease patterns, treatment outcomes, and prognostic factors associated with ES in the Arab region. The primary objective of the present study is to examine the clinical characteristics, treatment outcomes, and prognostic factors related to ES in Saudi patients.

MATERIALS AND METHODS

This is a retrospective study of consecutive patients diagnosed with ES at KFSH&RC between 1997 and 2016. Ethical approval was obtained (RAC 2161205) from the hospital research committee at KFSH&RC. The patients were identified by screening the tumor registry database of KFSH&RC. The clinical information collected from charts and electronic records was entered into the Sarcoma database using Research Electronic Data Capture (REDCap), an electronic data capture tool hosted at KFSHRC.^[18,19] The gathered data included age, sex, patient history, Eastern Cooperative Oncology Group performance status, histologic confirmation for ES, tumor primary site and size (largest dimension in cm), baseline laboratory findings, clinical stage, and site of metastasis. Additionally, information was collected on patients’ local therapy (surgery, radiation, or combined), type of chemotherapy (neoadjuvant, adjuvant, or systemic), including best response and time to progression.

The patients are stratified into ages 14–17, 18–26, and >26 years.^[14,20,21] Tumor-related factors, including tumor type, were classified as skeletal, (further divided into extremities and axial) or extra-skeletal. The tumor sites were grouped into extremities, pelvis, trunk, head, neck, and spinal. Tumor size is categorized into <8 cm, 8–12 cm, and >12 cm.^[12,14,22] Absolute neutrophil count (ANC), LDH, and alkaline phosphatase (ALP) are categorized as high if >3,000 cells/mm³, >430 U/L, and >190 IU/L, respectively.^{[10,15,22-27]} Chemotherapy response is evaluated based on Response Evaluation Criteria in Solid Tumors. Objective response rate (ORR) is the rate of patients achieving complete response (CR) and partial response (PR). Hematological toxicity was recorded using Common Terminology Criteria for Adverse Events (CTCAE) V4.0.^[28] Events-free survival (EFS) is the time from starting therapy (chemo, surgery, or RT) to the date of progression, toxicity, or death. OS is defined as the time from the start of therapy to the date of death.

RESULTS

Prognostic factors and survival outcomes

The median follow-up duration was 82 months (63.2– 100.7). The median event-free survival (EFS) for the localized disease was 31 months (95% CI: 19.4–42.5), the median OS was not reached, and the 5-year OS was 68% [Figure 1a and b]. The median EFS and OS for metastatic disease were 10 (95% CI: 6.9–13.0) and 28 (95% CI: 13.0–65.7) months, respectively [Figure 2a and b]. The patients who underwent surgery alone had better EFS (P < 0.01) and OS (P = 0.06) than radiation or combined therapy but did not reach statistical significance for OS [Figure 3a and b]. The variables associated with worse OS were poor performance status, metastatic stage, high ANC, LDH, and ALP [Figure 4a-e]. Cox regression analysis for variables associated with survival outcomes of ES in our cohort is presented in Table 2.

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Figure 1:

Kaplan–Meier curve of patients with non-metastatic Ewing sarcoma (a) event-free survival and (b) overall survival (n = 66).

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Figure 2:

Kaplan–Meier curve of patients with metastatic Ewing sarcoma (a) event-free survival and (b) overall survival (n = 39).

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Figure 3:

Kaplan–Meier curve of patients with Ewing sarcoma stratified by local treatment modalities (a) event-free survival and (b) overall survival. The presence of metastases at diagnosis remains a significant prognostic factor and poses challenges in treatment planning. In line with current treatment paradigms, most patients in our cohort received multimodal therapy with a curative intent, comprising chemotherapy and local therapy.

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Figure 4:

Kaplan–Meier curve of overall survival of patients with Ewing sarcoma stratified by (a) performance status and (b) stage, (c) pre-treatment absolute neutrophil count, (d) pre-treatment lactate dehydrogenase, and (e) pre-treatment alkaline phosphatase.

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Table 2: Cox regression analysis for variables associated with survival outcomes of Ewing sarcoma.

Variables	Events-free survival			Overall survival
	Hazard ratio	95% confidence interval	P-value	Hazard ratio	95% confidence interval	P-value
Age
14–17	1			1
18–26	1.03	0.61–1.73	0.9	1.29	0.66–2.52	0.62
> 26	0.89	0.43–1.87		0.86	0.31–2.40
Sex
Male	1			1
Female	1.04	0.63–1.71	0.86	0.83	0.42–1.63	0.59
Tumor size
< 8 cm	1			1
8–12 cm	0.88	0.41–1.89	0.54	1.35	0.50–3.63	0.62
>12 cm	1.27	0.66–2.43		1.56	0.63–3.89
Type
Skeletal	1			1
Extra-skeletal	1.08	0.63–1.84	0.76	1.08	0.54–2.17	0.82
ECOG PS
0/1	1			1
≥2	1.88	1.30–2.70	<0.001	1.97	1.23–3.16	0.005
M stage
Localized	1			1
Metastatic	2.20	1.36–3.56	0.001	2.44	1.31–4.53	0.005
Year of diagnosis
1997–2007	1			1
2008–2016	0.79	0.49–1.29	0.35	0.84	0.45–1.55	0.57
ANC
Low (≤3)	1			1
High (>3)	4.77	2.49–9.14	<0.001	3.34	1.49–7.49	0.002
ALP
Normal (≤190)	1			1
High (>190)	2.04	1.13–3.68	0.01	2.38	1.17–4.85	0.01
LDH
Normal (≤430)	1			1
Low (>430)	3.42	1.55–7.47	0.002	3.71	1.47–9.36	0.003

ANC: Absolute neutrophil counts [number in thousands], ALP: Alkaline phosphatase, ECOG PS: Eastern Cooperative Oncology Group Performance Status, LDH: Lactate dehydrogenase

DISCUSSION

ES, a rare and aggressive malignancy primarily affecting adolescents and young adults, presents significant challenges in management and prognosis. Our study observed a cohort of 105 patients with a median age of 20 years and predominantly comprised young males. Painful swelling was the most common clinical presentation, occurring in nearly half of the patients, followed by pain at the tumor site and painless swelling. This spectrum of presentations underscores the importance of maintaining a high index of suspicion for ES, especially in young individuals presenting with musculoskeletal symptoms. Typically, patients experience pain and swelling, with a history of trauma often occurring around the time of diagnosis. It is common for symptoms to persist for more than 6 months before the patient seeks medical attention.^[29] The distribution of primary tumor sites in our cohort reflected previous reports, with extremities and the pelvic region being the most affected locations. Notably, a considerable proportion of patients presented with metastatic disease, 37.1%, compared to 20–25 worldwide.^[23,24] The pattern of metastatic sites with the lung as the most common site is consistent with the previous reports.^[4,30,31]

The VAIA for 14 cycles was the most frequently used chemotherapy regimen in localized and metastatic settings in the study period in our institution.^[7,32] With a median follow-up duration of 82 months, the observed median EFS and OS rates provide valuable insights into the long-term prognosis of this disease. Furthermore, our analysis of survival outcomes according to treatment modalities provides valuable insights into the potential impact of local therapy on disease control and patient survival. VAIA chemotherapy protocol is quite a toxic regimen; however, showing comparable outcomes to the reported outcomes in clinical trials, and the toxicity was managed as per CTCAE recommendations. However, since 2020, our institution has adopted the VAC/IE regimen (Vincristine, Actinomycin-D/Adriamycin, Cyclophosphamide/Ifosfamide, Etoposide) for ES, replacing as per standard guidelines.^[33]

The majority of our patients with localized diseases (92%) underwent local control with either surgery, RT, or a combination of both. Consistent with previous reports, our findings showed significant differences in OS based on the type of local control; however, surgeries were associated with higher EFS.^[31,34,35] However, relapse remains a major challenge, necessitating salvage therapies and highlighting the need for continued research into novel treatment strategies. Distant recurrence was the predominant pattern, occurring in 69% of relapsed cases, consistent with previously reported literature. The VIP protocol was the most common salvage or second-line chemotherapy; however, disease progression remained high despite systemic and local therapy.^[5] Although a considerable proportion of patients with metastatic disease achieved objective responses to chemotherapy, the prognosis remained guarded, with a substantial number experiencing disease progression.

The 5-year EFS and OS for localized disease in the current study were 40.4% and 68%, respectively, which are comparable to reported EFS (43–57%) and OS (52–73%) in Western countries.^[9,27,32,36] In addition, the median OS of 28 months in this study for metastatic group is consistent with the median OS reported in Western populations, which ranges from 18 to 29 months.^[37-41]

In this cohort, the variables correlated with deteriorated OS in patients with ES included suboptimal performance status; metastatic at presentation; and elevated ANC, LDH, and ALP levels. Consistent with prior scholarly findings, the presence of metastases at the time of diagnosis markedly deteriorates prognostic outcomes.^[21,42] The correlation between serum ALP concentrations and ES remains sparse. Nevertheless, it has been established that heightened ALP values serve as a prognostic indicator in osteosarcoma, particularly in relation to metastatic development and treatment efficacy.^[43] Given that ALP plays a key role in bone metabolism and remodeling, its elevation in ES may reflect high tumor burden, osteolytic activity, or increased bone turnover, especially in cases with skeletal involvement. Further investigations into the biological significance of ALP in ES could refine risk stratification and prognostic assessments, allowing for more tailored therapeutic strategies. LDH has emerged as a critical prognostic biomarker in ES, with high LDH levels significantly correlating with worse survival outcomes.^[13] LDH is a key enzyme in anerobic glycolysis, and its elevation suggests increased metabolic activity, tumor hypoxia, and resistance to apoptosis – hallmarks of aggressive tumor behavior. High LDH levels may indicate a shift toward a glycolytic phenotype (Warburg effect), contributing to tumor progression and therapy resistance. These findings underscore the importance of LDH monitoring in clinical settings, not only as a prognostic marker but also as a potential target for metabolic interventions.^{[13,14,44,45]} In addition to ALP and LDH, the systemic inflammation indicators like ANC have garnered increasing recognition for its prognostic relevance in various malignancies, including ES. An elevated ANC generally signifies an inflammatory state, which has been linked to tumor progression and poorer outcomes. High neutrophil levels can create a pro-tumor microenvironment: Neutrophils release pro-angiogenic factors that facilitate angiogenesis and secrete mediators that suppress anti-tumor immune responses.^[46] When ANC is considered together with lymphocyte and platelet counts – yielding ratios such as the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) – it serves as an even more informative marker of systemic inflammation and immune imbalance. A high NLR or PLR (driven by increased neutrophils and/or decreased lymphocytes) is associated with an impaired immune surveillance and worse prognosis in many malignancies, highlighting the interplay between the immune system and tumor biology in ES.^[26,47] Moreover, exploring immune-related biomarkers presents a promising avenue for enhancing prognostic assessments in ES. Recent studies have indicated that the tumor microenvironment, characterized by varying levels of immune cell infiltration, plays a crucial role in disease progression and treatment response.^[48] For instance, the expression of ANXA1 has been correlated with metastasis and OS, suggesting its potential as an independent prognostic biomarker.^[48] In addition, incorporating inflammatory markers such as C-reactive protein into routine evaluations could provide further insights into patient prognosis, especially given their established associations with adverse outcomes in other malignancies.^[49] As we navigate the complexities of ES management, integrating these novel biomarkers into clinical practice may refine our understanding of tumor biology and guide personalized therapeutic strategies to improve long-term survival rates among affected patients.

Emerging therapies in ES focus on immunotherapy and targeted treatments to improve outcomes, particularly in relapsed or metastatic disease. Checkpoint inhibitors (e.g., pembrolizumab) have shown limited efficacy as monotherapy due to ES’s immunologically cold nature, but combination approaches are being explored.^[50,51] CAR T-cell therapy, targeting B7-H3, GD2, ROR1, and CD99, has demonstrated pre-clinical success and is now in early-phase trials.^[52,53] Monoclonal antibodies, such as IGF-1R inhibitors (ganitumab and cixutumumab), initially showed promise but failed to significantly improve survival.^[54] Epigenetic therapies, including LSD1 inhibitors (seclidemstat) and HDAC inhibitors, are being tested to disrupt key regulatory pathways associated with EWS-FLI1, the fusion oncoprotein driving ES.^[55] Trabectedin, in combination with irinotecan, has shown promising activity in relapsed ES by exploiting DNA damage and transcriptional disruption, leading to ongoing Phase II trials evaluating its efficacy. In addition, its immunomodulatory effects on the tumor microenvironment make it a potential candidate for combination with checkpoint inhibitors and other immunotherapies.^[56] Future strategies involve combining immunotherapy, molecularly targeted agents, and chemotherapy to enhance treatment efficacy. These advancements hold promise for improving prognosis in high-risk patients, addressing therapy resistance, and personalizing treatment approaches for better long-term outcomes in ES.

The key strength of this study is its long-term follow-up of a well-characterized cohort, providing valuable real-world insights into survival outcomes and prognostic factors in ES in Saudi Arabia. However, as a single-institution, retrospective study, it is subject to selection bias and may limit generalizability. In addition, the exclusion of cases with missing biomarker data, while necessary for analysis, could introduce bias and reduce statistical power. While potential prognostic biomarkers were identified, validation in larger, multi-institutional prospective studies is essential to confirm their clinical significance.

CONCLUSION

This study demonstrates promising response rates in patients with localized disease, underscoring the efficacy of current treatment approaches. However, challenges persist, particularly in the management of metastatic disease and the prevention of disease relapse. Identifying prognostic factors associated with worse outcomes highlights the importance of risk stratification in treatment decision-making. Collaborative research endeavors to elucidate novel therapeutic targets and refine treatment strategies are crucial to addressing the challenges in managing this aggressive malignancy and ultimately improving patient outcomes.