
==== Front
Medicine (Baltimore)
Medicine (Baltimore)
MD
Medicine
0025-7974
1536-5964
Lippincott Williams & Wilkins Hagerstown, MD

39252261
MD-D-24-05475
00048
10.1097/MD.0000000000039546
3
5700
Research Article
Observational Study
Lung and bone metastases patterns in Ewing sarcoma: Chemotherapy improves overall survival
https://orcid.org/0000-0002-0710-078X
Liu Binbin MM a*
Tang Liyuan MM tang1987_0605@126.com
b
a Department of Orthopedics, Cangzhou Central Hospital, Cangzhou, Hebei, P.R. China
b Drug Clinical Trial Institution, Cangzhou Central Hospital, Cangzhou, Hebei, P.R. China.
* Correspondence: Binbin Liu, Department of Orthopedics, Cangzhou Central Hospital, No. Cangzhou 061000, Hebei, P.R. China (e-mail: liubinbinliu@163.com).
06 9 2024
06 9 2024
103 36 e3954619 5 2024
09 8 2024
13 8 2024
Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal.

Ewing sarcoma (ES) is a small round cell malignancy, mainly in the bone tissue, followed by the soft tissue. Lung metastases (LM) and bone metastases (BM) are the most common types of metastases. From 2010 to 2018, the Surveillance, Epidemiology, and End Results database diagnosed 242 cases of ES with LM, 186 cases of ES with BM, and 74 cases of ES with LM and BM. Univariate and multivariate logistic regression analyses were used to determine the risk factors for LM and/or BM, and Kaplan–Meier curves and Cox regression analysis were used to determine the prognostic factors for LM and/or BM. Tumor size ≥50 mm, N1 stage, BM, liver metastases, and surgical treatment were significantly correlated with LM; tumor size >100 mm, brain metastases, LM, surgical treatment, and chemotherapy were significantly correlated with BM; female, N1 stage, brain metastases, liver metastases, and surgical treatment were significantly correlated with LM and BM. Older age, BM, higher T stage, no surgical treatment, and no chemotherapy were harmful to the survival of ES patients with LM; older age, female, LM, and no chemotherapy were harmful to the survival of ES patients with BM; older age and no chemotherapy were harmful to the survival of ES patients with LM and BM. Larger tumor size, N1 stages, and organ metastases were significantly associated with ES patients with LM and/or BM. Chemotherapy is effective in improving the survival.

bone metastases
Ewing sarcomas
lung metastases
risk factors
survival factors
OPEN-ACCESSTRUE
==== Body
pmc1. Introduction

Ewing sarcoma (ES) is a small round cell malignancy, mainly in the bone tissue, and tends to occur in children and adolescents.[1] Lung metastases (LM) and bone metastases (BM) are the most common types of metastases.[2,3] Approximately one-third of ES patients relapse after initial remission, and one-quarter have metastases at presentation.[4] ES can occur in all parts of the body, including bones, lungs, peripheral and central nervous systems, and kidneys.[5] Qi et al have shown that total tumor resection improves 2-year survival and prolongs median survival in patients with ES, but the tumor remains despite total resection and may relapse and metastasis.[6,7] Recent studies have found that combination therapy, such as surgery, radiotherapy, and chemotherapy can improve the prognosis of patients with ES.[8] After the 60s of the 20th century, chemotherapy as a postoperative adjuvant therapy method significantly improved the overall survival rate of ES, so that some scholars proposed the concept of multidisciplinary comprehensive treatment.[9] This study aimed to explore the factors influencing LM and BM patterns in ES and the treatment options that are more suitable for ES.

The Surveillance, Epidemiology, and End Results (SEER) database provides prevalence, risk, and prognostic data collected from 18 established cancer registries in the United States.[10] It was only after 2010 that data on malignant metastases were added to the SEER database. Tumor data were obtained from the open website (https://seer.cancer.gov/data/access.html), free SEER*Stat was downloaded, and the corresponding tumor was selected to download the data for analysis.[11–13] We downloaded and installed the free SEER*Stat 8.4.0 software from the open website (https://seer.cancer.gov/data/access.html), selected ES and its metastasis data, downloaded and analyzed it.[14–16] There has never been any research on LM and BM patterns in ES, and this study hopes to provide a reference for orthopedic or oncologists to develop treatment options.

2. Material and methods

2.1. Study population

Data were collected from the SEER database. This review reviewed patients with ES from 2010 to 2018, and the histological type of ES was limited to 9260/3 according to the International Classification of Diseases for Oncology-3 (ICD-O-3).[17] The trial data inclusion criteria were as follows: (1) patients with ES found in the SEER database from January 1, 2010 to December 31, 2018; and (2) ES as the primary disease of the patient.[2,18] From January 1, 2010, to December 31, 2018, 1289 ES patients were enrolled; 242 cases of lung metastases were diagnosed with ES with LM, 186 cases of BM were diagnosed with ES with BM, 74 cases of LM and BM were diagnosed with ES with LM and BM.

2.2. Statistical analysis

The demographic and clinical features of ES patients were divided into: age (≤24, 25–59 years, and ≥60 years); sex (female and male); race (White, Black, American Indian/Alaska Native, Asian or Pacific Islander, and unknown); tumor size (<50, 50–100, >100 mm, and unknown); tumor differentiation grade(I, II, III, IV, and unknown); T stage (T0–T3, and unknown); N stage (N0, N1, and unknown); M stage (M0, M1, and unknown); and absence or presence of lung, bone, brain, liver, surgery, radiation, and chemotherapy. The prevalence of ES was analyzed using Pearson chi-square test. Univariate logistic regression analysis identified risk factors for ES, and statistically significant risk factors were screened for multivariate analysis (P < .05). The Kaplan–Meier (K–M) curve and log-rank test were used to analyze the survival status of ES patients. Statistically significant factors were screened using multivariate Cox proportional hazards regression analysis (P < .05). The Social Science Statistics Package (SPSS) (version 25.0; IBM, Armonk, NY) was used to analyze all data, and GraphPad Prism 9 was used to create all survival graphs (GraphPad, Inc., San Diego, CA).

3. Results

3.1. Prevalence of ES

A total of 1289 ES patients were included in this study. There were 242 ES patients with LM, and the incidence of lung metastasis was 18.77%. The prevalence rates of ES patients with LM at ≤24, 25–59 and ≥60 years of age were 19.44%, 17.98%, and 14.86%, respectively. The prevalence rates of ES patients with LM in male and female were 20.66% and 16.34%, respectively. The prevalence rates of ES patients with LM in White, Black, American Indian/Alaska Native, and Asian or Pacific Islander populations were 18.27%, 27.27%, 5.88%, and 20.75%, respectively. The LM rate of female patients was significantly higher than that of male patients (χ2 = 3.881a, P = .049), and there were no significant differences in the prevalence of the LM among different ages and ethnic groups. There were 186 ES patients with BM, and the incidence of BM was 14.43%. The prevalence rates of ES patients with BM at ≤24, 25–59 and ≥60 years of age were 14.32%, 14.89%, and 13.51%, respectively. The prevalence rates of ES patients with BM in male and female were 16.53% and 11.72%, respectively. The prevalence rates of ES patients with BM in White, Black, American Indian/Alaska Native, and Asian or Pacific Islander populations were 14.00%, 16.36%, 17.65%, and 17.92%, respectively. The BM rate of female patients was significantly higher than that of male patients (χ2 = 5.932a, P = .015), and there were no significant differences in the prevalence of the BM among different ages and ethnic groups. There were 74 ES patients with LM and BM, and the incidence of lung and bone metastasis was 5.74%. The prevalence rates of ES patients with LM and BM at ≤24, 25–59 and ≥60 years of age were 6.17%, 5.06%, and 4.05%, respectively. The prevalence rates of ES patients with LM and BM in male and female were 7.71% and 3.20%, respectively. The prevalence rates of ES patients with LM and BM in White, Black, American Indian/Alaska Native, and Asian or Pacific Islander populations were 5.55%, 10.91%, 5.88%, and 4.72%, respectively. The LM and BM rate of female patients was significantly higher than that of male patients (χ2 = 11.953a, P = .001), and there were no significant differences in the prevalence of the LM and BM among different ages and ethnic groups. The clinical data for all demographics are shown in Table 1.

Table 1 Baseline of the demographic and related clinical characteristics among Ewing sarcoma patients with and without lung and/or bone metastases.

Subject characteristics	No. of Ewing sarcoma patients	P-value	No. of Ewing sarcoma patients	P-value	No. of Ewing sarcoma patients	P-value	
With LM (n, %)	Without LM(n, %)	With BM (n, %)	Without BM(n, %)	With LM and BM(n, %)	Without LM and BM(n, %)	
  n	242 (18.77)	1047 (81.23)		186 (14.43)	1103 (85.57)		74 (5.74)	1215 (94.26)		
Age, in years										
 24≤	167 (19.44)	692 (80.56)	.565	123 (14.32)	736 (85.68)	.942	53 (6.17)	806 (93.83)	.610	
 25–59	64 (17.98)	292 (82.02)	53 (14.89)	303 (85.11)	18 (5.06)	338 (94.94)	
 ≥60	11 (14.86)	63 (85.14)	10 (13.51)	64 (86.49)	3 (4.05)	71 (95.95)	
Sex										
 Male	150 (20.66)	576 (79.34)	.049*	120 (16.53)	606 (83.47)	.015*	56 (7.71)	670 (92.29)	.001*	
  Female	92 (16.34)	471 (83.66)	66 (11.72)	497 (88.28)	18 (3.20)	545 (96.80)	
Race										
 White	201 (18.27)	899 (81.73)	.246	154 (14.00)	946 (86.00)	.777	61 (5.55)	1039 (94.45)	.521	
 Black	15 (27.27)	40 (72.73)	9 (16.36)	46 (83.64)	6 (10.91)	49 (89.09)	
 AI	1 (5.88)	16 (94.12)	3 (17.65)	14 (82.35)	1 (5.88)	16 (94.12)	
 API	22 (20.75)	84 (79.25)	19 (17.92)	87 (82.08)	5 (4.72)	101 (95.28)	
 Unknown	3 (27.27)	8 (72.73)	1 (9.09)	10 (90.91)	1 (9.09)	10 (90.91)	
Tumor size(mm)										
 <50	15 (6.52)	215 (93.48)	<.001*	13 (5.65)	217 (94.35)	.005*	4 (1.74)	226 (98.26)	<.001*	
  50–100	80 (16.36)	409 (83.64)	60 (12.27)	429 (87.73)	20 (4.09)	469 (95.91)	
 >100	98 (29.25)	237 (70.75)	64 (19.10)	271 (80.90)	28 (8.36)	307 (91.64)	
 Unknown	49 (20.85)	186 (79.15)	49 (20.85)	186 (79.15)	22 (9.36)	213 (90.64)	
T stage										
 T0	2 (33.33)	4 (66.67)	<.001*	1 (16.67)	5 (83.33)	<.001*	0 (0.00)	6 (100.00)	<.001*	
 T1	33 (8.87)	339 (91.13)	23 (6.18)	349 (93.82)	6 (1.61)	366 (98.39)	
 T2	107 (23.57)	347 (76.43)	74 (16.30)	380 (83.70)	27 (5.95)	427 (94.05)	
 T3	19 (44.19)	24 (55.81)	25 (58.14)	18 (41.86)	14 (32.56)	29 (67.44)	
 Unknown	81 (19.57)	333 (80.43)	63 (15.22)	351 (84.78)	27 (6.52)	387 (93.48)	
N stage										
 N0	142 (15.90)	751 (84.10)	<.001*	122 (13.66)	771 (86.34)	<.001*	45 (5.04)	848 (94.96)	<.001*	
 N1	44 (50.57)	43 (49.43)	24 (27.59)	63 (72.41)	16 (18.39)	71 (81.61)	
 Unknown	56 (18.12)	253 (81.88)	40 (12.94)	269 (87.06)	13 (4.21)	296 (95.79)	
M stage										
 M0	0 (0.00)	709 (100.00)	<.001*	0 (0.00)	709 (100.00)	<.001*	0 (0.00)	709 (100.00)	<.001*	
 M1	207 (60.17)	137 (39.83)	164 (47.67)	180 (52.33)	69 (20.06)	275 (79.94)	
 Unknown	35 (14.83)	201 (85.17)	22 (9.32)	214 (90.68)	5 (2.12)	231 (97.88)	
Grade										
 Grade I	0 (0.00)	0 (0.00)	.524	0 (0.00)	0 (0.00)	.163	0 (0.00)	0 (0.00)	.285	
 Grade II	0 (0.00)	9 (100.00)	0 (0.96)	9 (100.00)	0 (0.00)	9 (100.00)	
 Grade III	19 (17.92)	87 (82.08)	9 (8.49)	97 (91.51)	2 (1.89)	104 (98.11)	
 Grade IV	38 (19.69)	155 (80.31)	31 (16.06)	162 (83.94)	12 (6.22)	181 (93.78)	
 Unknown	185 (18.86)	796 (81.14)	146 (14.88)	835 (85.12)	60 (6.12)	921 (93.88)	
Bone or/and Lung metastases										
 None	168 (15.23)	935 (84.77)	<.001*	112 (10.70)	935 (89.30)	<.001*	0 (0.00)	1215 (100.00)	NA	
 Yes	74 (39.78)	112 (60.22)	74 (30.58)	168 (69.42)	74 (100.00)	0 (0.00)	
 Unknown	0 (0.00)	0 (0.00)	0 (0.00)	0 (0.00)	0 (0.00)	0 (0.00)	
Brain metastases										
 None	237 (18.57)	1039 (81.43)	.068	177 (13.87)	1099 (86.13)	<.001*	70 (5.49)	1206 (94.51)	<.001*	
 Yes	5 (38.46)	8 (61.54)	9 (69.23)	4 (30.77)	4 (30.77)	9 (69.23)	
 Unknown	0 (0.00)	0 (00.00)	0 (0.00)	0 (00.00)	0 (0.00)	0 (00.00)	
Liver metastases										
 None	227 (18.03)	1032 (81.97)	.001*	173 (13.74)	1086 (86.26)	<.001*	64 (5.08)	1195 (94.92)	<.001*	
 Yes	14 (51.85)	13 (48.15)	11 (40.74)	16 (59.26)	9 (33.33)	18 (66.67)	
 Unknown	1 (33.33)	2 (66.67)	2 (66.67)	1 (33.33)	1 (33.33)	2 (66.67)	
Surg										
 None	152 (29.86)	357 (70.14)	<.001*	147 (28.88)	362 (71.12)	<.001*	59 (11.59)	450 (88.41)	<.001*	
 Yes	89 (11.56)	681 (88.44)	38 (4.94)	732 (95.06)	14 (1.82)	756 (98.18)	
 Unknown	1 (10.00)	9 (90.00)	1 (10.00)	9 (90.00)	1 (10.00)	9 (90.00)	
Radiation										
None/Unknown	96 (14.35)	573 (85.65)	<.001*	65 (9.72)	604 (90.28)	<.001*	28 (4.19)	641 (95.81)	.013*	
 Yes	146 (23.55)	474 (76.45)	121 (19.52)	499 (80.48)	46 (7.42)	574 (92.58)	
Chemotherapy										
No/Unknown	17 (18.89)	73 (81.11)	.977	6 (6.67)	84 (93.33)	.030*	3 (3.33)	87 (96.67)	.309	
 Yes	225 (18.77)	974 (81.23)	180 (15.01)	1019 (84.99)	71 (5.92)	1128 (94.08)	
 Unknown	2	1 (50.00)	NA	NA	NA	
AI = American Indian/Alaska Native, API = Asian or Pacific Islander, BM = bone metastases, LM = lung metastases, NA = not available, Surg = surgical treatments of primary site.

* Statistically significant.

3.2. Risk factors for developing ES

Univariate logistic regression analysis showed that various factors, such as a larger tumor size, were significantly correlated with the LM. These items were: female (odds ratio [OR] = 0.75, 95% confidence interval [CI]: 0.56–1.00, P = .049); tumor size: 50 to 100 mm (OR = 2.80, 95% CI: 1.58–4.99, P < .001), >100 mm (OR = 5.93, 95% CI: 3.34–10.52, P < .001); N1 stage (OR = 5.41, 95% CI: 3.43–8.55, P < .001); bone metastases (OR = 3.68, 95% CI: 2.63–5.15, P < .001); liver metastases (OR = 4.90, 95% CI: 2.27–10.56, P < .001); surgical treatment (OR = 0.31, 95% CI: 0.23–0.41, P < .001); and radiation (OR = 1.84, 95% CI: 1.38–2.44, P < .001) were significantly correlated with the LM. Multivariate logistic regression analysis showed that various factors, such as a larger tumor size, were significantly correlated with the LM. These items were as follows: tumor size: 50 to 100 mm (OR = 2.37, 95% CI: 1.31–4.32, P = .005), >100 mm (OR = 4.06, 95% CI: 2.23–7.41, P < .001); N1 stage (OR = 3.92, 95% CI: 2.39–6.41, P < .001); bone metastases (OR = 2.12, 95% CI: 1.46–3.09, P < .001); liver metastases (OR = 2.50, 95% CI: 1.08–5.77, P = .032); and surgical treatment (OR = 0.47, 95% CI: 0.34–0.66, P < .001) were significantly correlated with the LM. The risk factors for the LM are listed in Table 2.

Table 2 Multivariable logistic regression analysis of characteristics of Ewing sarcoma patients with lung and/or bone metastases.

Subject characteristics	Ewing sarcoma patients with lung metastases	Ewing sarcoma patients with bone metastases	Ewing sarcoma patients with lung and bone metastases	
OR (95% CI)	P-value	OR (95% CI)	P-value	OR (95% CI)	P-value	
Sex							
  Male	1 (Reference)	1.00	1 (Reference)	1.00	1 (Reference)	1.00	
 Female	0.93 (0.68–1.26)	.622	0.78 (0.54–1.11)	.165	0.47 (0.26–0.84)	.010*	
Tumor size (mm)							
  <50	1 (Reference)	1.00	1 (Reference)	1.00	1 (Reference)	1.00	
 50–100	2.37 (1.31–4.32)	.005*	1.77 (0.91–3.43)	.092	2.04 (0.65–6.34)	.220	
  >100	4.06 (2.23–7.41)	<.001*	2.15 (1.10–4.22)	.026*	2.94 (0.96–8.96)	.059	
 Unknown	NA	NA	NA	NA	NA	NA	
N stage							
 N0	1 (Reference)	1.00	1 (Reference)	1.00	1 (Reference)	1.00	
 N1	3.92 (2.39–6.41)	<.001*	1.35 (0.75–2.41)	.319	3.03 (1.54–5.98)	.001*	
 Unknown	NA	NA	NA	NA	NA	NA	
Bone or/and Lung metastases							
  None	1 (Reference)	1.00	1 (Reference)	1.00	NA	NA	
  Yes	2.12 (1.46–3.09)	<.001*	2.13 (1.45–3.13)	<.001*	NA	NA	
 Unknown	NA	NA	NA	NA	NA	NA	
Brain metastases							
  None	NA	NA	1 (Reference)	1.00	1 (Reference)	1.00	
  Yes	NA	NA	7.20 (1.79–28.90)	.005*	4.42 (1.05–18.62)	.043*	
 Unknown	NA	NA	NA	NA	NA	NA	
Liver metastases							
  None	1 (Reference)	1.00	1 (Reference)	1.00	1 (Reference)	1.00	
  Yes	2.50 (1.08–5.77)	.032*	1.94 (0.78–4.84)	.157	4.21 (1.64–10.81)	.003*	
 Unknown	NA	NA	NA	NA	NA	NA	
Surg							
  None	1 (Reference)	1.00	1 (Reference)	1.00	1 (Reference)	1.00	
  Yes	0.47 (0.34–0.66)	<.001*	0.17 (0.11–0.25)	<.001*	0.20 (0.11–0.38)	<.001*	
 Unknown	NA	NA	NA	NA	NA	NA	
Radiation							
 None/Unknown	1 (Reference)	1.00	1 (Reference)	1.00	1 (Reference)	1.00	
  Yes	1.33 (0.97–1.83)	.079	1.25 (0.86–1.82)	.239	1.16 (0.68–1.99)	.589	
Chemotherapy							
  No/Unknown	NA	NA	1 (Reference)	1.00	NA	NA	
 Yes	NA	NA	3.27 (1.30–8.23)	.012*	NA	NA	
 Unknown	2	1 (50.00)	NA	NA	N	
AI = American Indian/Alaska Native, API = Asian or Pacific Islander, NA = not available, Surg = surgical treatments of primary site.

* Statistically significant.

Univariate logistic regression analysis showed that various factors, such as a larger tumor size, were significantly correlated with the BM. These items were: female (OR = 0.67, 95% CI: 0.49–0.93, P = .015); tumor size: 50 to 100 mm (OR = 2.34, 95% CI: 1.25–4.35, P = .007), >100 mm (OR = 3.94, 95% CI: 2.12–7.35, P < .001); N1 stage (OR = 2.41, 95% CI: 1.45–4.00, P = .001); brain metastases (OR = 13.97, 95% CI: 4.26–45.85, P < .001); lung metastases (OR = 3.68, 95% CI: 2.63–5.15, P < .001); liver metastases (OR = 4.32, 95% CI: 1.97–9.46, P < .001); surgical treatment (OR = 0.13, 95% CI: 0.09–0.19, P < .001); and radiation (OR = 2.25, 95% CI: 1.63–3.12, P < .001) were significantly correlated with the BM. Multivariate logistic regression analysis showed that various factors, such as a larger tumor size, were significantly correlated with the BM. These items were as follows: tumor size: >100 mm (OR = 2.15, 95% CI: 1.10–4.22, P = .026); brain metastases (OR = 7.20, 95% CI: 1.79–28.90, P = .005); lung metastases (OR = 2.13, 95% CI: 1.45–3.13, P < .001); chemotherapy (OR = 3.27, 95% CI: 1.30–8.23, P = .012); and surgical treatment (OR = 0.17, 95% CI: 0.11–0.25, P < .001) were significantly correlated with the BM. The risk factors for the BM are listed in Table 2.

Univariate logistic regression analysis showed that various factors were significantly correlated with the LM and BM. These items were: female (OR = 0.40, 95% CI: 0.23–0.68, P = .001); tumor size: >100 mm (OR = 5.15, 95% CI: 1.78–14.90, P = .002); N1 stage (OR = 4.25, 95% CI: 2.29–7.89, P < .001); brain metastases (OR = 7.66, 95% CI: 2.30–25.48, P = .001); liver metastases (OR = 9.34, 95% CI: 4.04–21.60, P < .001); surgical treatment (OR = 0.14, 95% CI: 0.08–0.26, P < .001); and radiation (OR = 1.84, 95% CI: 1.13–2.97, P = .014) were significantly correlated with the LM and BM. Multivariate logistic regression analysis showed that various factors, such as a larger tumor size, were significantly correlated with the LM and BM. These items were as follows: tumor size: female (OR = 0.47, 95% CI: 0.26–0.84, P = .010); N1 stage (OR = 3.03, 95% CI: 1.54–5.98, P = .001); brain metastases (OR = 4.42, 95% CI: 1.05–18.62, P = .s043); liver metastases (OR = 4.21, 95% CI: 1.64–10.81, P = .003); and surgical treatment (OR = 0.20, 95% CI: 0.11–0.38, P < .001) were significantly correlated with the LM and BM. The risk factors for the LM and BM are listed in Table 2.

3.3. Prognostic factors for ES

Overall survival time of the K–M analysis was shown in Figure 1A. Forty-eight point seven six percent of ES patients with LM died. K–M analysis of overall survival showed that ES patients with LM aged 25 to 59 years old, ≥60 years old (Fig 1B, P < .001); tumor size: 50 to 100 mm, >100 mm (P < .001); bone metastases (Fig 1C, P < .001), brain metastases (P = .047), liver metastases (P = .001), and higher T stage (Fig 1D, P < .001) were less than their counterparts, and the patients who underwent surgical treatment at the primary site (Fig 1E, P < .001), radiation (P = .011), and chemotherapy (Fig 1F, P < .001) were higher than their counterparts. Multivariate Cox regression analysis showed that ES patients with LM aged 25 to 59 (hazard ratio, [HR] = 1.69, 95% CI: 1.08–2.67, P = .023), higher T stage (T1 stage: HR = 0.11, 95% CI: 0.02–0.59, P = .011; T2 stage: HR = 0.05, 95% CI: 0.01–0.29, P = .001; T3 stage: HR = 0.12, 95% CI: 0.02–0.77, P = .026), BM (HR = 2.31, 95% CI: 1.49–3.56, P < .001) were harmful for survival. Patients treated with chemotherapy (HR = 0.12, 95% CI: 0.06–0.25, P < .001) and surgical treatment at the primary site (HR = 0.61, 95% CI: 0.38–0.98, P = .042) had better survival rates than those who did not receive treatment.

Figure 1. Kaplan–Meier analysis was performed on Ewing sarcoma patients with lung and/or bone metastases: (A) overall, Ewing sarcoma patients with lung metastases: (B) age, (C) bone metastases, (D) T stage, (E) surgical treatments of the primary site, and (F) chemotherapy, Ewing sarcoma patients with bone metastases: (G) age, (H) sex, (I) lung metastases, (J) chemotherapy, Ewing sarcoma patients with lung and bone metastases: (K) age, (L) chemotherapy. BM = bone metastases, LM = lung metastases, ES = Ewing sarcoma, Surg = surgical treatments of the primary site.

52.03% of ES patients with BM died. K–M analysis of overall survival showed that ES patients with BM aged 25 to 59 years old, ≥60 years old (Fig 1G, P < .001); female (Fig 1H, P = .034); and lung metastases (Fig 1I, P = .011) were less than their counterparts, and the patients who underwent radiation (P = .001) and chemotherapy (Fig 1J, P = .002) were higher than their counterparts. Multivariate Cox regression analysis showed that ES patients with BM aged 25 to 59 years old (HR = 2.09, 95% CI: 1.34–3.27, P = .001), ≥60 years old (HR = 4.61, 95% CI: 2.13–10.01, P < .001), female (HR = 7.12, 95% CI: 1.16–2.56, P = .007), and LM (HR = 2.08, 95% CI: 1.41–3.07, P < .001) were harmful for survival. Patients treated with chemotherapy (HR = 0.23, 95% CI: 0.09–0.63, P = .004) had better survival rates than those who did not receive chemotherapy.

68.92% of ES patients with LM and BM died. K–M analysis of overall survival showed that ES patients with LM and BM aged 25 to 59 years old, ≥60 years old (Fig 1K, P < .001); and female (P = .019) were less than their counterparts, and the patients who underwent radiation (P = .012) and chemotherapy (Fig 1L, P < .001) were higher than their counterparts. Multivariate Cox regression analysis showed that ES patients with LM and BM aged ≥60 years old (HR = 6.21, 95% CI: 1.30–29.69, P = .022) was harmful for survival. Patients treated with chemotherapy (HR = 0.08, 95% CI: 0.02–0.42, P = .003) had better survival rates than those who did not receive chemotherapy. The survival time and prognostic factors of ES are shown in Table 3.

Table 3 Multivariate Cox regression analysis of prognostic factors in Ewing sarcoma patients with lung and/or bone metastases.

Subject characteristics	No. of Ewing sarcoma patients with lung or/and bone metastases	Median survival mouth	HR (95% CI)	P-value	
Overall	Deceased (n, %)	
Ewing sarcoma patients with lung metastases	242	118 (48.76)				
Age, in years						
 24≤	167	70 (41.92)	42.00 (32.92–51.08)	1 (Reference)	1.00	
 25–59	64	40 (62.50)	16.00 (8.90–23.10)	1.69 (1.08–2.67)	.023*	
 ≥60	11	8 (72.73)	11.00 (0.44–21.56)	1.56 (0.60–4.05)	.366	
Tumor size(mm)						
 <50	15	8 (53.33)	24.00 (14.30–33.70)	1 (Reference)	1.00	
 50–100	80	29 (36.25)	NA	0.71 (0.27–1.86)	.482	
 >100	98	45 (45.92)	31.00 (19.74–42.26)	1.57 (0.56–4.39)	.394	
 Unknown	49	36 (73.47)	NA	NA	NA	
T stage						
 T0	2	2 (100.00)	4 (NA -NA)	1 (Reference)	1.00	
 T1	33	14 (42.42)	39.00 (23.24–54.76)	0.11 (0.02–0.59)	.011*	
 T2	107	47 (43.93)	46.00 (22.23–69.78)	0.05 (0.01–0.29)	.001*	
 T3	19	15 (78.95)	16.00 (9.18–22.83)	0.12 (0.02–0.77)	.026*	
 Unknown	81	40 (49.38)	NA	NA	NA	
Bone metastases						
 None	168	67 (39.88)	46.00 (29.89–62.12)	1 (Reference)	1.00	
 Yes	74	51 (68.92)	19.00 (13.76–24.24)	2.31 (1.49–3.56)	<.001*	
 Unknown	0	0 (00.00)	NA	NA	NA	
Brain metastases						
 None	237	114 (48.10)	36.00 (28.90–43.10)	1 (Reference)	1.00	
 Yes	5	4 (80.00)	17.00 (12.32–21.68)	2.63 (0.77–9.00)	.124	
 Unknown	0	0 (00.00)	NA	NA	NA	
Liver metastases						
 None	227	106 (46.70)	36.00 (28.43–43.57)	1 (Reference)	1.00	
 Yes	14	11 (78.57)	9.00 (0.00–20.86)	1.95 (0.99–3.84)	.053	
 Unknown	1	1 (100.00)	NA	NA	NA	
Surg						
 None	152	90 (59.21)	23.00 (15.18–30.82)	1 (Reference)	1.00	
 Yes	89	27 (30.34)	NA	0.61 (0.38–0.98)	.042*	
 Unknown	1	1 (100.00)	NA	NA	NA	
 Radiation						
None/Unknown	96	54 (56.25)	23.00 (12.85–33.15)	1 (Reference)	1.00	
 Yes	146	64 (43.84)	42.00 (30.31–53.69)	0.72 (0.47–1.11)	.135	
Chemotherapy						
 No/Unknown	17	15 (88.24)	2.00 (0.00–5.23)	1 (Reference)	1.00	
 Yes	225	103 (45.78)	39.00 (31.29–46.71)	0.12 (0.06–0.25)	<.001*	
Ewing sarcoma patients with bone metastases	186	110 (59.14)				
Age, in years						
 24≤	123	64 (52.03)	30.00 (20.35–39.66)	1 (Reference)	1.00	
 25–59	53	38 (71.70)	13.00 (8.96–17.04)	2.09 (1.34–3.27)	.001*	
 ≥60	10	8 (80.00)	10.00 (4.16–15.84)	4.61 (2.13–10.01)	<.001*	
Sex						
 Male	120	66 (55.00)	29.00 (22.50–35.50)	1 (Reference)	1.00	
 Female	66	44 (66.67)	15.00 (7.99–22.01)	1.72 (1.16–2.56)	.007*	
Lung metastases						
 None	112	59 (52.68)	29.00 (17.02–40.98)	1 (Reference)	1.00	
 Yes	74	51 (68.92)	19.00 (13.76–24.24)	2.08 (1.41–3.07)	<.001*	
 Unknown	0	0 (00.00)	NA	NA	NA	
 Radiation						
 None/Unknown	65	45 (69.23)	12.00 (8.36–15.64)	1 (Reference)	1.00	
 Yes	121	65 (53.72)	28.00 (19.81–36.19)	0.66 (0.43–1.02)	.059	
Chemotherapy						
 No/Unknown	6	5 (83.33)	1.00 (NA -NA)	1 (Reference)	1.00	
 Yes	180	105 (58.33)	23.00 (17.43–28.57)	0.23 (0.09–0.63)	.004*	
Ewing sarcoma patients with lung and bone metastases	74	51 (68.92)				
Age, in years						
 24≤	53	33 (62.26)	22.00 (15.48–28.52)	1 (Reference)	1.00	
 25–59	18	15 (83.33)	10.00 (7.93–12.07)	1.74 (0.85–3.55)	.128	
 ≥60	3	3 (100.00)	1.00 (NA -NA)	6.21 (1.30–29.69)	.022*	
Sex						
 Male	56	36 (64.29)	23.00 (13.50–32.51)	1 (Reference)	1.00	
 Female	18	15 (83.33)	14.00 (7.99–20.01)	1.52 (0.76–3.03)	.236	
Radiation						
 None/Unknown	28	21 (75.00)	12.00 (6.24–17.76)	1 (Reference)	1.00	
 Yes	46	30 (65.22)	22.00 (15.18–28.82)	0.61 (0.32–1.16)	.131	
Chemotherapy						
 No/Unknown	3	3 (100.00)	1.00 (NA -NA)	1 (Reference)	1.00	
 Yes	71	48 (67.61)	19.00 (13.27–24.73)	0.08 (0.02–0.42)	.003*	
*Statistically significant.

4 . Discussion

ES is a highly aggressive tumor that can occur in people of all ages, but is predominantly seen in children and adolescents.[19] The peak age at onset in this study was 0 to 24 years (81%). In this present study, the male-to-female ratio was 1.49:1.[20] LM and BM are the most common types of metastases. ES is a tumor sensitive to radiotherapy and chemotherapy, and most patients have metastases at the time of diagnosis. The survival rate of patients with surgical resection alone or radiotherapy alone is <10%.[13,21] In 1974, Rosen et al first reported that 20 cases of ES improved the 5-year survival rate to 75% after radiotherapy and chemotherapy.[22] In addition to systemic chemotherapy, surgical resection combined with radiotherapy may improve patient survival.[23] This study found that surgery was not a protective factor against ES with LM and BM. Older age and no chemotherapy were harmful to the survival of ES patients with LM and/or BM.

Unfortunately, the SEER database does not provide detailed information about surgery and chemotherapy, including operation time, chemotherapy drug selection, dosage, and administration time.[24] I believe that more researchers will use the SEER database as a reference after completing the information.

5. Conclusion

Larger tumor size, N1 stages and organ metastases were significantly associated with ES patients with LM and/or BM. Chemotherapy is effective in improving the survival.

Acknowledgments

The authors are grateful to all the participating patients.

Author contributions

Conceptualization: Binbin Liu.

Data curation: Binbin Liu.

Formal analysis: Binbin Liu.

Funding acquisition: Liyuan Tang.

Investigation: Binbin Liu.

Methodology: Binbin Liu.

Project administration: Binbin Liu.

Resources: Liyuan Tang.

Software: Binbin Liu.

Supervision: Binbin Liu.

Validation: Binbin Liu.

Visualization: Binbin Liu.

Writing – original draft: Binbin Liu.

Writing – review & editing: Binbin Liu.

Abbreviations:

BM bone metastases

CI confidence interval

ES Ewing sarcoma

HR hazard ratio

K–M Kaplan–Meier

LM lung metastases

OR odds ratio

SEER the Surveillance, Epidemiology and End Results

All submitted images are created by the author, confirming that the images are original, not duplicated, and have never been published before.

The study was approved by the Ethics Committee of Cangzhou Central Hospital. This study was a retrospective study through the SEER database, all data were completely anonymized. The study is based on Helsinki Declaration and subsequent amendments.

The authors have no funding and conflicts of interest to disclose.

The datasets generated during and/or analyzed during the current study are publicly available.

How to cite this article: Liu B, Tang L. Lung and bone metastases patterns in Ewing sarcoma: Chemotherapy improves overall survival. Medicine 2024;103:36(e39546).
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