STRATEGIES OF THE MANAGEMENT OF PULMONARY METASTASES IN CHILDREN WITH EWING SARCOMA- SINGLE INSTITUTION EXPERIENCE OF 137 PATIENTS

STRATEGIES OF THE MANAGEMENT OF PULMONARY METASTASES IN CHILDREN WITH EWING SARCOMA- SINGLE INSTITUTION EXPERIENCE OF 137 PATIENTS | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 13 June 2025 V1 Latest version Share on STRATEGIES OF THE MANAGEMENT OF PULMONARY METASTASES IN CHILDREN WITH EWING SARCOMA- SINGLE INSTITUTION EXPERIENCE OF 137 PATIENTS Authors : Krzysztof Bronowicki [email protected] , Justyna Antoniuk-Majchrzak , Iwona Malesza , Tomasz Walenta , Agnieszka Szymborska , and Anna Raciborska Authors Info & Affiliations https://doi.org/10.22541/au.174982169.94946404/v1 Published Surgical Oncology Version of record Peer review timeline 233 views 127 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract The treatment of Ewing’s sarcoma in children remains difficult and unpredictable. Especially in the group with lung metastases (PM), the role of metastectomy has not been still clearly defined. The study aimed to define the best management strategies in children with PM. Clinical factors (age, localization, response to chemotherapy (CHT) of the primary tumor (PT), R0 and R1 primary resections, metastectomy, the use of radiotherapy (RT), autologous hematopoietic stem cell transplantation (aHSCT) were analyzed in the group of 137 patients (pts) with PM (85-isolated, 52-lungs and extrapulmonary (ExPM)) treated during the period 1998-2024. The mean f-up was 103.8 months (8.19 years). Descriptive statistics were used to summarize the characteristics of a data set. Survival curves were obtained by using the Kaplan-Meier method. Log-rank test was used to identify the prognostic significance of clinical factors. Pts with isolated PM (85 pts) had better OS than pts with PM and ExPM (p=0.000003). The good histological response of the PT (<10% viable tumor cells) to CHT was only the EFS-predictive factor in this group (p = 0.002). Pts with isolated PM and good histological response treated or not with metastectomy had better EFS than pts with poor response to CHT (p = 0.001). Pts treated with thoracotomy had significantly better OS (p = 0.001) than pts treated with RT of metastases. Good response to CHT of the PT had the same impact on OS (p = 0.001) in this group. A similar trend was observed in the groups with good response to CHT treated with thoracotomy and RT of metastases vs RT only (OS – p = 0.02). Pts with poor response to CHT and isolated PM treated with RT without thoracotomy had the worst prognosis (p = 0.02). In the group of 52 pts with PM and ExPM RT of PM and extrapulmonary metastases (p = 0.04) was EFS-predictive factors. Conclusions Metastectomy of isolated PM may improve the results of patients with good histological response to CHT of the PT. Patients with simultaneous pulmonary and ExPM achieve worse treatment results. The use of RT on PM and extrapulmonary metastatic lesions seems to improve outcomes. Introduction Ewing sarcoma (ES) was first reported by James Ewing in 1921, as a primary, separate, malignant tumor with no osteogenic properties [1]. ES is now considered a highly malignant sarcoma of bone or soft tissue and belongs to the group of small round blue cell neoplasms of neuroectodermal origin [2]. ES is the second after osteosarcoma most common type of primary bone malignancy in children and young adults. Event-free survival (EFS) rates raised to greater than 70% for localized disease [3, 4]. Metastatic disease at presentation is the most significant predictor of survival. 25% of patients with ES present with metastatic disease at diagnosis. The most common sides are lungs and bones (10%: lung; 10%: bones/ bone marrow; 5%: combinations or others). The 5-year EFS in those patients is approximately 30%, however, patients with isolated pulmonary metastasis are associated with long-term survival rates about of 45–50%. Multiple bone metastases confer a poorer outcome than isolated lung metastases [5-9,14,15,36,37]. For patients with lung metastases, whether isolated or in combination with metastases to other organs, the key issue remains selecting the optimal therapeutic strategy. Various treatment methods are proposed, including chemotherapy (CHT), radiotherapy (RT), whole lung irradiation, autologous hematopoietic stem cell transplantation (aHSCT), and resection of lung metastases. CHT and RT play a crucial role in such cases [16,17,13]. However, the place of metastectomy in the treatment of patients with lung metastases is still discussed [10,11,12,13]. In this study, pediatric patients with Ewing sarcoma and metastases to the lungs and other organs were analyzed. The aim of the study was to compare the clinical characteristics and treatment outcomes of patients with isolated lung metastases and those with metastases to the lungs and other organs, as well as to evaluate the impact of metastectomy on EFS and overall survival (OS). Special attention was paid to prognostic factors such as treatment response, the use of RT, and the thoracotomy of metastases. Material and methods The study included a group of 137 patients with lung metastases (PM) and/or without extrapulmonary metastases (ExPM) treated during the period 1998-2024 at the Institute of Mother and Child in Warsaw. The principles of the Euro-EWING regimen were applied to all patients. All patients underwent standard tumor imaging. Histological confirmation of ES at the time of diagnosis was required [16, 17, 35]. Local control was performed after neoadjuvant CHT and included surgery, RT, or both. Good histological response was classified as ≥90% necrosis in the primary tumor (PT), and poor histology response as <90% necrosis. Patients with unresectable disease, microscopic residual after surgery, or poor histological response received 45.0-54.0 Gy. For patients with complete tumor resection, with good response to CHT (≥ 90% necrosis), small tumor volume, and absence of metastasis RT were not recommended (except axial location). Patients with complete response of all pulmonary nodules in CT after CHT did have additional lung RT treatment. RT was not used in patients without radiological confirmation of PM. Patients with residual disease in the lung nodules underwent lung surgery. Moreover, RT (15 Gy for patients < 14 years of age and 18 Gy for patients ≥ 14 years) was recommended for patients with active disease on pathology after thoracotomy, and in cases not undergoing lung surgery. For the patients with metastatic disease or poor histology, a consolidation with high-dose therapy and aHSCT was recommended. Clinical factors (age, localization of the tumor - axial, limb, soft tissue), response to CHT of the PT, R0 and R1 primary resections, metastectomy - lungs, the use of RT, and aHSCT were retrospectively analyzed. Descriptive statistics were used to summarize the characteristics of a data set. Continuous characteristics (age) were compared between groups using the Mann–Whitney U test, while categorical ones (localization, outcome, death, surgery PT, radicalness, surgery – metastatic tumor, aHSCT, RT, type of treatment) were compared using Fisher’s exact test or Chi-squared test. OS was defined as the time from the date of initial diagnosis to the date of death or last follow-up. EFS was defined as the time from the date of initial diagnosis to the date of recurrence or last follow-up. Survival curves were obtained by using the Kaplan-Meier method. Log-rank test was used to identify the prognostic significance of clinical factors. A p-value of <0.05 was considered statistically significant. All statistical analyses were conducted using R version 4.3.0 (R Core Team, 2023) in R Studio version 2023.3.1.446 (RStudio Team, 2022). Approval for this retrospective study was obtained from all the relevant institutions in compliance with the international regulations for the protection of human research subjects. Results The age of all 137 patients ranged from 2 to 22 years. The group with isolated PM had 85 patients (45 female, 40 male). Median age was 12.3 years (mean 12.26 ± 4.06). The group of patients with ES with PM and ExPM included 52 patients (20 female, 32 male). The median age was 13.2 years (mean 12.88 ± 3.95). All patients with isolated PM and PM and ExPM were divided into two subgroups: <10 years and ≥10 years. In the isolated PM group and in the PM and ExPM group, there were no significant differences in EFS (p=0.4078) or OS (p=0.6095) between the age subgroups (EFS (p=0.4078) or OS (p=0.6095) and EFS (p = 0.2839) and OS (p = 0.9507) respectively) . In the group with <10 years old patients no significant difference was observed in EFS (p = 0.6887) between the patients with isolated PM and the patients with PM and ExPM. However, patients with isolated PM had better OS (p = 0.0548) ( Figure 1C ). Better, statistically significant EFS (p = 0.0083) and OS (p = 0.00041) results were achieved by patients with isolated PM in the age group ≥10 years of age ( Figure 1A and 1B ). Figure 1. Kaplan-Meier curves for overall survival (OS) and event-free survival (EFS) in patients with isolated pulmonary metastases (PM) and those with PM and extrapulmonary metastases (ExPM). Panels A and B show OS and EFS for patients aged 10 years or older, respectively. Panel C depicts OS for patients younger than 10 years. Patients’ age and certain treatment-related characteristics, such as PT surgery, metastatic tumor surgery, and treatment type ( Table 1 and Table 2 ), showed statistically significant differences between groups with isolated PM and those with PM and ExPM. TABLE 1. Baseline characteristics of patients with isolated pulmonary metastases (PM) and PM with extrapulmonary metastases (ExPM). Gender (N, (%)) Female Male 45 (52.94%) 40 (47.06%) 20 (38.45%) 32 (61.54%) 0.1414 a Age (median years (Q1-Q3)) 12.3 (9.3 – 15.3) 13.1 (10.6 – 15.9) 0.0207 b Localization (N, (%)) Upper limb Axial Lower limb 5 (5.88%) 42 (49.41%) 36 (42.35%) 7 (13.46%) 28 (53.85%) 16 (30.75%) 0.1881 c Outcome (N, (%)) Recurrence/Progression Non- recurrence 44 (51,76%) 41 (48.24%) 29 (55.77%) 23 (44.23%) 0.7799 a Death (N, (%)) Yes No 34 (40.00%) 51 (60.00%) 28 (53.83%) 24 (46.15%) 0.1606 a a Chi-squared test, b Mann-Whitney U test, c Fisher’s exact test TABLE 2. Treatment characteristics of patients with isolated pulmonary metastases (PM) and PM with extrapulmonary metastases (ExPM). Surgery – PT * (N, (%)) Yes No 69 (81.18%) 16 (18.82%) 29 (55.77%) 23 (44.23%) 0.0027 a Radicalness (N, (%)) R0 R1 57 (82.61%) 12 (17.39%) 22 (75.87%) 6 (21.43%) 0.7738 c Surgery - metastatic tumor (N, (%)) Yes No 39 (45.88%) 46 (54.12%) 9 (17.31%) 43 (82.69%) 0.0013 a aHSCT ** (N, (%)) Yes No 24 (28.23%) 61 (71.76%) 16 (30.77%) 36 (69.23%) 0.9021 a RT *** (N, (%)) Yes No 54 (63.53%) 31 (36.47%) 31 (59.62%) 21 (40.38%) 0.7820 a Type of treatment (N, (%)) 1 2 3 4 23 (27.06%) 11 (12.94%) 14 (16.47%) 37 (43.53%) 4 (7.69%) 16 (30.77%) 5 (9.62%) 2 (51.92%) 0.000005 c a Chi-squared test, b Mann-Whitney U test, c Fisher’s exact test; PT * - primary tumor, aHSTCT ** - autologous hematopoietic stem cell transplantation, RT *** - radiotherapy, Type of treatment: 1 – thoracotomy, 2 – radiotherapy, 3 thoracotomy + radiotherapy, 4 – only chemotherapy In univariate analysis response to treatment was the only prognostic factor in EFS in patients with isolated PM (p = 0.002) ( Table 3 ). TABLE 3. Univariate analysis of prognostic factors for event-free survival (EFS) in patients with isolated pulmonary metastases (PM). Tumor localization Axial Upper limb Lower limb Soft tissue 42 5 36 2 30 34 58 23 0.9 Radicalness R0 R1 56 11 58 19 0.1 Gender Female Male 45 40 29 38 0.8 Response to treatment Good Poor 46 21 NA 25 0.002 aHSCT Yes No 24 61 58 30 0.3 Univariate analysis of prognostic factors for EFS in patients with PM and ExPM showed tumor localization as prognostic factor ( Table 4 ). TABLE 4. Univariate analysis of prognostic factors for event-free survival (EFS) in patients with pulmonary metastases (PM) and extrapulmonary metastases (ExPM). Tumor localization Axial Upper limb Lower limb Soft tissue 28 7 16 1 18 15 25 NA 0.01 Radicalness R0 R1 22 5 25 16 0.8 Gender Female Male 20 32 NA 16 0.004 Response to treatment Good Poor 19 8 26 24 0.3 aHSCT Yes No 16 36 25 18 0.3 In univariate analysis patients with isolated PM (85 patients) had better OS than patients with PM and ExPM (p = 0.000003) ( Figure 3 ). The good histological response of the PT (<10% viable tumor cells) to CHT was only the EFS-predictive factor in this group (p = 0.002) ( Table 3 ). Patients with isolated PM and good histological response treated or not with metastectomy had better EFS than patients with poor response to CHT (p = 0.001) ( Table 5 ). Patients treated with thoracotomy had significantly better OS (p = 0.001) than patients treated with RT of metastases ( Figure 2 ). Good response to CHT of the PT had the same impact on OS (p = 0.002) in this group ( Table 5 ). A similar trend was observed in the groups with good response to CHT treated with thoracotomy and RT of metastases vs RT only (OS - p = 0.02) ( Table 5 ). Patients with poor response to CHT and isolated PM treated with RT without thoracotomy had the worst prognosis (p = 0.02) ( Table 5 ). In the group of 52 patients with PM and ExPM the localization of the PT appears to have a significant impact on survival (p = 0.01). In this group, only RT of metastases (p = 0.04) was EFS-predictive factors ( Table 5 ). Fourteen patients with isolated PM were treated with thoracotomy and RT. Similarly, five patients with PM and ExPM were treated in the same way. No statistically significant differences were observed between patients treated with thoracotomy and RT and those treated with other methods. The aHSCT was performed in 24 patients with isolated PM and in 16 patients with PM and ExPM. No statistically significant differences were observed between patients treated with aHSCT and those who were not. PM * Yes No 21 125 0.000008 No Yes 7 38 PM and ExPM ** Yes No 3 NA No Yes 7 20 * PM – lung metastates, ** PM and ExPM – lung metastates and metastates to other locations Figure 2. Kaplan-Meier survival curves for overall survival (OS) in patients with isolated pulmonary metastases (PM) treated with thoracotomy (red line) and radiotherapy (RT) of metastases (blue line). Patients treated with thoracotomy showed significantly better OS compared to those treated with RT (p=0.001). TABLE 5. Univariate analysis of prognostic factors for overall survival (OS) and event-free survival (EFS) in patients with isolated pulmonary metastases (PM) and those with PM and extrapulmonary metastases (ExPM). Character PM * PM and ExPM ** 85 52 111 66 0.000003 32 21 0.1 Age = 10 years 31 106 94 100 0.5 29 28 0.8 Isolated Response to CHT *** Good Poor 46 20 122 78 0.3 NA 25 0.002 Metastasectomy and response to CHT *** Yes + Good response Yes + Poor response No + Good response No + Poor response 22 9 24 11 125 78 108 27 0.3 NA 25 NA 30 0.001 Metastasectomy vs RT **** of metastates Metastasectomy RT 23 10 119 38 0.001 30 NA 0.4 Metastasectomy + Good response RT + Good response 15 4 125 40 0.001 NA NA 0.2 Metastasectomy + RT + Good response RT + Good response Metastasectomy + RT + Poor response RT + Poor response 7 4 3 3 123 40 78 27 0.02 20 NA 19 6 0.2 Other Gender Female Male 20 32 66 49 0.9 16 NA 0.004 RT of metastates Yes No 21 31 49 66 0.3 38 18 0.04 * PM – lung metastates, ** PM and ExPM – lung metastates and metastates to other locations, CHT *** - chemotherapy, RT **** - radiotherapy Figure 3. Kaplan-Meier survival curves for overall survival (OS) in patients with isolated pulmonary metastases (PM, red line) and PM with extrapulmonary metastases (ExPM, green line). Patients with isolated PM showed significantly better OS compared to patients with PM and ExPM (p=0.000003). Discussion This study focused on the treatment outcomes of pediatric patients with ES who presented with PM, both isolated and in combination with ExPM. The results emphasize key aspects of treatment and prognosis for these patients, particularly in the context of the role of thoracotomy and multimodal therapy in improving survival outcomes. Patients’ age and certain treatment-related characteristics, such as PT surgery, metastatic tumor surgery, and treatment type, showed statistically significant differences between groups with isolated PM and those with PM and ExPM. Differences in group sizes may affect the statistical power of the tests, so the results should be interpreted within this context. The imbalance in group sizes (85 vs. 52 patients) might have influenced the statistical results, particularly regarding subtle differences between the groups. However, this study focuses on a rare disease, making it challenging to assemble larger and more balanced groups. Despite these limitations, the analysis of the available data provides valuable insights and highlights the need for further research, even though recruiting larger patient groups for this condition may be difficult. The data obtained in this study, consistent with previous reports, suggest that thoracotomy plays a significant role in improving survival in patients with isolated PM. Surgical removal of isolated PM was associated with higher OS (median 111 months vs 66 in patients with PM and PM and ExPM; p=0.000003). Numerous earlier studies have shown that metastectomy can improve outcomes in patients with isolated PM, often achieving better survival rates than CHT or RT alone [10,11,12,18,19]. Authors with different opinions remain in the minority [20]. In contrast, the role of thoracotomy in patients with multi-organ (PM and ExPM) metastases remains controversial. The results obtained in this study indicate that although thoracotomy may offer some benefits for these patients, the overall prognosis remains poor. Survival rates for patients with PM and ExPM were significantly lower than for those with PM only. Consistent with the literature, these studies show that patients with widespread disease have a poor prognosis, even with aggressive surgical interventions [3,6,7,8,10.11.12.18.19]. CHT, which is the backbone of ES treatment, plays a critical role in reducing tumor size and controlling the spread of metastases. In this study, good histological response to CHT of the PT was identified as a prognostic factor. Patients with good histological response had significantly better survival rates, which highlights the importance of systemic control in achieving long-term remission. This confirms the concept that an effective systemic response is crucial for the success of local interventions, such as thoracotomy [3,6,7,8,21,22,23,24]. Many authors recommend whole lung irradiation in all patients with pulmonary metastases of ES [13,16,17,25-32,34]. In this study patients treated with thoracotomy had significantly better OS (p=0.001) than patients treated with RT of metastases. Good response to CHT of the PT had the same impact on OS (p=0.001) in this group. A similar trend was observed in the groups with good response to CHT treated with thoracotomy and RT of metastases vs RT only (OS-p=0.02). This confirms our previous observations regarding the crucial role of thoracotomy in isolated PM. In the group of 52 patients with PM and ExPM the localization of the PT appears to have a significant impact on survival (p = 0.01), the observed difference in survival based on gender (p = 0.004) is less likely to reflect a true biological effect. There is no evidence in the literature to suggest that gender significantly influences survival in this context. It is plausible that the observed difference results from the disparity in group sizes (20 females vs. 32 males), which may have affected the statistical outcome. In this group, only RT of metastases had a positive impact on EFS (median 38 vs 18 months in patients without RT, p = 0.04) was EFS-predictive factors. These data confirm that the use of RT on metastatic lesions can improve the final outcomes. In addition to surgery and CHT, the use of RT and whole lung irradiation remain key elements of a multimodal approach in the treatment of patients with pulmonary metastases in ES [16,17,33]. In conclusion, this study highlights the importance of individualized treatment strategies in pediatric patients with ES and pulmonary metastases. While thoracotomy remains a valuable tool in improving outcomes for patients with isolated PM and good histological response of the PT, its role in patients with multi-organ metastases is less clear. Multimodal therapy, including CHT, RT, aHSCT, and surgery, should be tailored to the extent of the disease and the patient’s response to treatment. Although the use of RT on metastatic lesions seems to support treatment, further research is needed to better understand the long-term outcomes and explore new therapeutic options for patients with more extensive metastatic disease. Conflict of Interest statement We, the authors, declare that we have no financial or personal relationships with other people or organizations that could inappropriately influence or bias our work. No conflicts of interest to declare. References 1. Ewing J. 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Lung Metastasis Probability in Ewing Sarcoma: a nomogram basedon the SEER databas. Curr Oncol. 2020 Dex 5;28(1):69-77, doi: 10.3390/curroncol28010009 Information & Authors Information Version history V1 Version 1 13 June 2025 Peer review timeline Published Surgical Oncology Version of Record 1 Feb 2026 Published Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords ewing's sarcoma pediatric oncology surgery Authors Affiliations Krzysztof Bronowicki [email protected] Instytut Matki i Dziecka View all articles by this author Justyna Antoniuk-Majchrzak Instytut Matki i Dziecka View all articles by this author Iwona Malesza Instytut Matki i Dziecka View all articles by this author Tomasz Walenta Instytut Matki i Dziecka View all articles by this author Agnieszka Szymborska Instytut Matki i Dziecka View all articles by this author Anna Raciborska Instytut Matki i Dziecka View all articles by this author Metrics & Citations Metrics Article Usage 233 views 127 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Krzysztof Bronowicki, Justyna Antoniuk-Majchrzak, Iwona Malesza, et al. STRATEGIES OF THE MANAGEMENT OF PULMONARY METASTASES IN CHILDREN WITH EWING SARCOMA- SINGLE INSTITUTION EXPERIENCE OF 137 PATIENTS. Authorea . 13 June 2025. 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