All-site radiotherapy for metastatic Ewing's sarcoma: a short-term analysis of feasibility, response, and safety

All-site radiotherapy for metastatic Ewing's sarcoma: a short-term analysis of feasibility, response, and safety | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article All-site radiotherapy for metastatic Ewing's sarcoma: a short-term analysis of feasibility, response, and safety YuanYou Yang, Lu Xie, Xin Sun, Jie Xu, Gang Ren This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8350070/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 27 Apr, 2026 Read the published version in Clinical & Experimental Metastasis → Version 1 posted 7 You are reading this latest preprint version Abstract Background Metastatic Ewing sarcoma (EWS) has a poor prognosis. While metastasis-directed therapy (MDT) benefits oligometastatic disease, the role of comprehensive radiotherapy targeting all metastatic sites in widespread disease remains underexplored. This study aimed to provide a preliminary assessment of the short-term efficacy and safety of all-site radiotherapy in metastatic EWS. Methods This retrospective analysis included 21 consecutive metastatic EWS patients treated with helical tomotherapy (Aug 2024–Jun 2025). All known metastatic lesions and the primary tumor (if unresected) received radiotherapy. Prescription doses were 45–55 Gy in 20 fractions for most sites; lung/pleural metastases received adapted regimens (12–45 Gy). Systemic therapy regimens varied (chemotherapy, tyrosine kinase inhibitors [TKIs], immune checkpoint inhibitors [ICIs], or combinations). Primary endpoints were local objective response rate (ORR, RECIST 1.1) and acute toxicity (CTCAE 5.0). Secondary/exploratory endpoints included progression-free survival (PFS), overall survival (OS). Results Median follow-up was 6 months (range 2–11). Among 77 target lesions, the objective response rate (ORR, complete response [CR] + partial response [PR]) was 61.0% (47/77), including a CR rate of 48.1% (37/77). The disease control rate (DCR, CR + PR + stable disease [SD]) was 97.4%. A striking finding was the significantly higher complete response rate in soft tissue lesions compared to bone metastases (78.3% vs 3.2%, p < 0.001). The median PFS was 6.0 months (95% CI: 2.30–9.70), and the median OS was 8.0 months (95% CI: 6.69–9.31). Multivariate analysis identified "Combination Systemic Therapy" as associated with improved PFS (HR 3.94, 95%CI 1.32–11.78; p = 0.014), with chemotherapy-based regimens showing the best median PFS (8.5 months). An exploratory analysis suggested shorter PFS in patients receiving TKI-containing regimens (4.0 vs 8.5 months, p = 0.048); however, this finding is likely confounded by selection bias, as TKIs were often used in more heavily pretreated patients. Acute toxicity was manageable: grade 3 thrombocytopenia (19.0%, n = 4) and one case (4.7%) of grade 3 pneumonitis resolved with steroids. Conclusion All-site radiotherapy achieved promising short-term local control with manageable toxicity in metastatic EWS. These short-term data demonstrate the feasibility of this approach and highlight a marked differential response by lesion site, warranting further biological investigation. Systemic therapy, particularly chemotherapy, was associated with improved PFS in this cohort. The high rate of systemic progression observed shortly after treatment underscores that improving long-term outcomes will require integration with more effective systemic therapies. Our findings provide a rationale and specific hypotheses for future prospective trials. Ewing’s sarcoma Metastatic disease All-site radiotherapy Figures Figure 1 Figure 2 Figure 3 INTRODUCTION Ewing sarcoma (EWS), the second most common malignant pediatric bone tumor (~ 1.5 per million incidence), primarily affects adolescents but also occurs in adults. It is highly sensitive to both chemotherapy and radiotherapy; standard treatment includes surgery, radiotherapy, and multi-agent chemotherapy [ 1 – 3 ]. The presence of metastatic disease is the most important prognostic factor, and even localized disease carries a high metastatic risk without systemic therapy. Metastatic patients require multiagent chemotherapy and may benefit from targeted agents [ 4 ]. While metastasis-directed therapy (MDT) improves survival in oligometastatic adults [ 5 – 6 ], the role of radiotherapy in widespread disease remains less clear. In contrast to MDT, which selectively targets a limited number of metastases, all-site radiotherapy aims to irradiate all known metastatic lesions. This strategy aims to reduce the systemic tumor burden and potentially improve survival in widespread metastatic disease—an unmet need in pediatric/adolescent EWS, where the timing and extent of MDT remain debated [ 7 ]. Current NCCN guidelines still recommend aggressive surgery or radiotherapy for metastases if tolerated [ 8 ]. Therefore, this study aimed to retrospectively analyze the short-term outcomes and feasibility of 21 metastatic Ewing sarcoma patients treated with all-site radiotherapy using helical tomotherapy. We sought to assess the short-term local efficacy, safety, and radiographic response patterns of this approach, thereby providing preliminary clinical data and generating hypotheses for this aggressive local strategy in the setting of widespread metastases. METHODS Patient Selection Patients with metastatic EWS who underwent helical tomotherapy (HT) at our center from August 2024 to June 2025 were enrolled. Inclusion criteria: patients with pathologically confirmed EWS; Patients diagnosed with metastatic EWS (including pulmonary and extrapulmonary metastases); Karnofsky Performance Status (KPS) ≥ 70; The metastatic and/or primary lesions could not be resected or refused surgical resection. Exclusion criteria: Patients who had previously received radiotherapy for the target lesion; Moderate-severe pulmonary dysfunction; Complicated with pulmonary or other site infection; Severe liver and kidney dysfunction may potentially affect the tolerance of radiotherapy; Other contraindications to radiotherapy included inability to cooperate with radiotherapy and pregnancy. This study was conducted in accordance with the ethical principles of the World Medical Association Declaration of Helsinki. The study protocol was approved by our Institutional Review Board (Approval No.: IRB-AF-37-03-2). Written informed consent was obtained from all individual participants (or their parents/legal guardians in the case of minors [under the age of 16]) prior to treatment. Radiation Treatment Simulation and immobilization: The patients were fixed with negative pressure vacuum pad and thermoplastic film, Patient respiratory motion management was performed when target lesions were located in the chest or abdomen, using an abdominal compression plate (Shenzhen Tengfei Yu Company) to limit respiratory movement and train patients to breathe quietly. Iodine contrast-enhanced CT scans (3 mm slice thickness) were performed using a Philips spiral CT. Delineation of the target volume: The gross tumor volume (GTV) was defined as all imaging-visible tumor, with each distinct lesion contoured as a separate GTV; isolated lymph nodes were considered a single GTV, and clustered or fused nodes or metastases were contoured as one combined GTV. The clinical target volume (CTV) was generated by expanding the GTV by 5–10 mm, and the planning target volume (PTV) was created with an additional 5 mm margin. For lymph node involvement, the CTV encompassed the respective nodal basin, while for lung metastases the CTV included the whole lung, and for pleural metastases it covered the involved hemithorax or bilateral pleura. Except in cases of lung metastases—where CT alone offers sufficient sensitivity—all other targets were co-registered with MRI or PET-CT to improve delineation accuracy. Prescribed dose and Dose Constraints for Organs at Risk (OARs): Five patients with lung metastases (with or without pleural metastasis) received whole lung irradiation (WLI) at 12–15 Gy in 10 fractions was selected based on COG and NCCN guidelines recommendations for balancing local control and pulmonary toxicity in metastatic EWS, and the GTV of lung metastases was sequentially boosted to 27–45 Gy in 15fractions. Two patients with bilateral pleural metastases (without lung metastasis) received whole pleural irradiation with a dose of 18 Gy in 12 fractions, and the GTV of pleural metastases was sequentially boosted to 45 Gy in 25 fractions. One patient with unilateral pleural metastasis (without lung metastasis) received hemi thoracic irradiation at the same dose as the whole pleural irradiation. For all other metastatic lesions, the PTV dose was 45 Gy in 20 fractions and the GTV dose was boosted to 55 Gy in 20 fractions simultaneously. For dose constraints on organs at risk (OAR), we refer to Timmerman's requirements for hypofractionated and conventionally fractionated dose constraints [ 9 ]. Patients receiving WLI or hemi-pleural/whole-pleural irradiation were referred to the EAWS1221 protocol for WLI and stereotactic body radiation therapy (SBRT) with 5 fractions after WLI. Management during radiotherapy and follow-up after treatment: Megavoltage computed tomography (MV-CT) was used for image guidance in each treatment for all patients. Toxicities were monitored and managed symptomatically. Blood tests every 3 days and triggered granulocyte colony-stimulating factor, thrombopoietin or erythropoietin injections if WBC < 3.0×10⁹/L, platelet < 75×10⁹/L, or hemoglobin < 9.5 g/L. Post-radiation, for patients who received whole-lung, half-pleural, and whole-pleural irradiation, weekly follow-ups included symptom checks (cough, fever, wheezing) for early pneumonitis detection. Imaging occurred every 2 months or immediately if pneumonitis was suspected. For patients receiving radiotherapy at other sites, blood routine and blood biochemical tests were reviewed weekly, and imaging examinations were performed every 2 months and at any time if urgently necessary. Methods of efficacy assessment: Efficacy assessment was performed according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 [ 10 ]: Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Toxicity was assessed according to RTOG or CTCAE 5.0 criteria. Statistics Analysis Continuous data are presented as mean ± standard error or median (range), as appropriate. An independent samples t-test was used to compare the maximum diameters between bone and soft tissue lesions. The relationship between tumor diameter and CR rate was analyzed by Pearson correlation analysis. In the survival time analysis, the end of radiotherapy was set as the starting point. PFS was calculated until disease progression (target-lesion progression or progression elsewhere) or death. OS was calculated until the last follow-up or the time of death. Kaplan-Meier method was used for survival analysis. Survival curves were compared with log-rank test. Prognostic factors for PFS and OS were first analyzed using univariate log-rank tests. Cox proportional hazards regression was used to analyze the influencing factors. A two-sided p-value of < 0.05 was considered statistically significant. Statistical analyses were performed with SPSS 26. Given the limited sample size (n = 21), the statistical power for subgroup analyses was constrained, and the results of the multivariate Cox regression should be interpreted with caution due to the risk of overfitting. Therefore, the results of these analyses, particularly those involving systemic therapy subgroups, should be interpreted as exploratory and hypothesis-generating. RESULTS Patient Baseline Characteristics This study included 21 consecutive patients with metastatic Ewing sarcoma. Key demographic and disease characteristics are summarized in Table 1 . In brief, the cohort was predominantly male with a median age of 23 years. Patients presented with heterogeneous treatment histories, as nearly half had metastatic disease at initial diagnosis, and the majority had undergone surgical resection of the primary tumor prior to enrollment. All patients received multi-agent systemic therapy per institutional protocols. Detailed parameters of radiotherapy targets and specific concurrent systemic therapies are provided in Table 2 . In summary, a total of 77 metastatic lesions were irradiated, and the median maximum diameter was comparable between bone and soft tissue lesions (p = 0.175). The median follow-up duration from the completion of radiotherapy was 6 months (range, 2–11). Table 1 Patient Demographics and Baseline Clinical Characteristics (N = 21) Category Characteristic Value / Count (%) or Median (Range) Demographics Sex Male 16 (76.2%) Female 5 (23.8%) Age (years) 23 (10–40) Karnofsky Performance Status (KPS) ≤70 10 (47.6%) ≥80 11 (52.4%) Disease Characteristics Stage at Initial Diagnosis M0 12 (57.1%) M1 9 (42.9%) Primary Tumor Location Iliac bone 5 (23.8%) Femur 3 (14.2%) Chest wall soft tissue 3 (14.2%) Clavicle 2 (9.5%) Other† 8 (38.1%) Lymph Node Metastasis at Baseline 7 (33.3%) Treatment History Primary Tumor Treatment Surgery 16 (76.2%) Systemic Therapy & Follow-up Definitive CCRT 5 (23.8%) First-line Regimen VDC/IE Second-line Regimens CTop or Iri ± TKI ± ICI Follow-up (months) 6 (2–11) Note: CCRT, Concurrent Chemoradiotherapy; VDC/IE, vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide; CTop, Cyclophosphamide and Topotecan; Iri, Irinotecan; TKI, Tyrosine kinase inhibitors; ICI, Immune checkpoint inhibitors. Table 2 Radiotherapy and Concurrent Treatment Details Category Characteristic Value / Count (%) or Median (Range) Radiotherapy Parameters Number of Target Lesions Per Patient 3 (1–9) Total GTV Volume (cc) 173.8 (0.53–1349.81) Total CTV Volume (cc) 1020.8 (29.6–3769.2) Total PTV Volume (cc) 1355.6 (70.8–4868.4) Maximum Diameter per Lesion (cm) 2.6 (0.6–17.3) Concurrent Systemic Therapy Combination Therapy with RT None 2 (9.5%) Chemotherapy alone 9 (42.8%) TKI alone 4 (19.1%) Chemotherapy + TKI 3 (14.3%) ICI + TKI 3 (14.3%) Treatment Course Radiotherapy Interruption 4 (19.1%) Note: GTV, Gross Tumor Volume; CTV, Clinical Target Volume; PTV, Planning Target Volume; TKI, Tyrosine kinase inhibitors (anlotinib, n = 6; apatinib, n = 3); ICI, Immune checkpoint inhibitors (Sintilimab); RT, Radiotherapy. arget Volume; TKI, Tyrosine kinase inhibitor; RT, Radiotherapy. Target-lesion response at the last follow-up: Local efficacy for all target lesions and key subgroups is detailed in Table 3 . In summary, a high disease control rate (DCR) of 97.4% was achieved across all lesions, with a key finding being the significantly higher complete response (CR) rate in soft tissue lesions compared to bone lesions (p < 0.001). The high efficacy of radiotherapy was further demonstrated in the subgroup of five patients receiving whole-lung irradiation (WLI), who exhibited a high objective response rate (ORR) and a 100% DCR (Table 3 ). Pearson correlation analysis showed that there was no significant correlation between the maximum tumor diameter and CR (correlation coefficient: -0.177, p = 0.123). Both instances of PD occurred in the same patient, who was found to have target lesions progression at the time of review 11 months after completion of radiotherapy. Representative imaging of treatment response is provided in Figs. 1 and 2 . Figure 1 illustrates a case of mixed response, with progressive disease (PD) in bone metastases alongside partial response (PR) in the primary tumor at 11 months post-radiotherapy. Figure 2 demonstrates achieving complete response (CR) and partial response (PR) in two other patients at the 3-month follow-up. Table 3 Local efficacy, acute toxicity, and tumor progression status Items Local efficacy(N/%) Lesion Category CR PR SD PD ORR DCR All Target Lesions 37 (48.1) 10 (12.9) 28 (36.4) 2 (2.6) 47 (61.0) 75 (97.4) Bone Lesions 1 (3.2) 5 (16.1) 23 (74.2) 2 (6.5) 6 (19.4) 29 (93.5) Soft Tissue Lesions 36 (78.3) 5 (10.9) 5 (10.9) 0 (0) 41 (89.1) 46 (100) WLI Subgroup Lesions 12 (63.2) 3 (15.8) 4 (21.1) 0 (0) 15 (78.9) 19 (100) Acute Toxicity (Number, %) Toxicity Type G1 G2 G3 G4 Nausea 1 (4.7) 1 (4.7) 0 0 Anorexia 5 (23.8) 4 (19.1) 0 0 Fatigue 1 (4.7) 0 0 0 Diarrhea 0 0 1 (4.7) 0 Radiation Pneumonitis 0 0 1 (4.7) 0 White Blood Cells 4 (19.1) 2 (9.5) 2 (9.5) 2 (9.5) Platelets 1 (4.7) 3 (14.2) 4 (19.1) 0 Neutrophils 2 (9.5) 1 (4.7) 2 (9.5) 1 (4.7) Hemoglobin 5 (23.8) 5 (23.8) 2 (9.5) 0 Tumor Progression Status Progression Pattern Number of Patients (%) Time after Radiotherapy Completion RLN Only 1 (4.7%) 4 months Distant Only 3 (14.3%) 2, 2, 11 months Both RLN and Distant (Synchronous) 5 (23.8%) 1.5, 2, 2, 4, 9 months Note: CR, Complete Response; PR, Partial Response; SD, Stable Disease; PD, Progressive Disease; ORR, Objective Response Rate (CR + PR); DCR, Disease Control Rate (CR + PR + SD); WLI, Whole-Lung Irradiation; RLN, Regional Lymph Node. Tumor progression status at last follow-up: At the last follow-up, disease progression occurred in 9 patients (42.8%). The most common pattern of failure was simultaneous regional and distant progression, which was observed in 5 of these patients (23.8% of the entire cohort). The detailed sites and timing of progression for each case are summarized in Table 3 . Survival Outcomes: We set the start time of calculating Progression-Free Survival (PFS) and Overall Survival (OS) to the end time of radiotherapy to observe the disease progression and survival after radiotherapy, so as to better understand the role of radiotherapy in survival. At the last follow-up, 16 patients survived and 5 patients died of extensive metastasis; among the deceased, 1 patient died of bleeding secondary to thrombocytopenia caused by extensive bone marrow metastasis. The other patient had a complete response but died from unexplained bleeding. PFS and OS : The results of the survival analysis are detailed in Table 4 . For the entire cohort, the median progression-free survival (PFS) was 6.0 months (95% CI: 2.30–9.70), and the median overall survival (OS) was 8.0 months (95% CI: 6.69–9.31). Univariate analysis identified several variables, including younger age (≤ 23 years) and smaller radiotherapy target volumes (PTV ≤ 1355.6 cc), that were associated with a numerically longer median PFS, although these trends did not reach statistical significance. In the multivariate Cox regression model, the administration of combination systemic therapy around the time of radiotherapy emerged as the only factor significantly associated with improved PFS (HR 3.94, 95%CI 1.32–11.78; p = 0.014). Supporting this finding, an exploratory analysis revealed that patients receiving chemotherapy-based regimens had the most favorable PFS outcomes. Conversely, patients treated with TKI-containing regimens had a significantly shorter median PFS compared to those who were not (4.0 vs. 8.5 months, p = 0.048; Fig. 3 ). No factors were independently prognostic for OS in multivariate analysis. Table 4 Survival Analysis of Patient, Treatment, and Tumor Characteristics Variable Category Median PFS (months) P Value (PFS) Median OS (months) P Value (OS) All Patients 6.0 8.0 Univariate Analysis Age ≤ 23 years 8.5 0.082 8.5 0.218 > 23 years 4.0 6.0 KPS ≥ 80 8.5 0.196 8.5 0.551 1355.6 cc 5.0 8.5 Systemic Therapy Chemotherapy-based 8.5 0.192 8.5 0.157 TKI-based 4.0 7.0 Other / None 6.0 6.0 RT Interruption No 8.0 0.879 8.0 0.270 Yes 3.5 3.5 Multivariate Analysis for PFS Hazard Ratio (95% CI) P Value Combination Systemic Therapy (Yes vs. No) 3.94 (1.32–11.78) 0.014 Exploratory Analysis for PFS Median PFS (months) P Value TKI-containing vs. Non-TKI regimens TKI-containing 4.0 0.048 Non-TKI 8.5 Note: CI, confidence interval; PFS, progression-free survival; OS, overall survival; KPS, Karnofsky Performance Status; PTV, Planning Target Volume; TKI, Tyrosine kinase inhibitor; RT, Radiotherapy. Acute toxicity: Acute toxicities observed during treatment are summarized in Table 3 . Manageable hematological toxicity was the most common adverse event, with four patients (19.0%) experiencing grade 3 thrombocytopenia requiring brief treatment interruption. Significant decreases in white blood cells, platelets, and neutrophils were observed after radiotherapy (all p < 0.05). One patient (4.7%) in the whole-lung irradiation group developed grade 3 radiation pneumonitis, which resolved with corticosteroid treatment. DISCUSSION EWS exhibits marked radiosensitivity. Given the limited data on all-site radiotherapy in widely metastatic EWS, this retrospective analysis provides a detailed assessment of its short-term feasibility. We demonstrated that comprehensive radiotherapy targeting all known metastatic sites achieves exceptional short-term local control (97.4% DCR) with a manageable toxicity profile. Beyond feasibility, a key and unexpected finding was the profound difference in complete response rates between soft tissue and bone metastases. This, along with the association between systemic therapy type and short-term PFS, forms the core contribution of this preliminary report. Our high local control rate aligns with prior studies utilizing radiotherapy for EWS metastases. Talleur et al. [ 11 ] reported outstanding local control (10-year cumulative failure rate 4.4% ± 3.1%) in 45 EWS patients (including 19 metastatic) treated with conventionally fractionated radiotherapy (median follow-up 54.5 months). Casey et al. [ 12 ] achieved cumulative local failure rates of 6.6% at 1 year and 9% at 3 years using SBRT for 49 bone metastases (22 EWS patients). Grewal et al. [ 13 ], in a cohort of 27 metastatic ES patients, observed a non-significant trend favoring metastasis-directed therapy (MDT), suggesting a 76% lower recurrence risk (OR 0.24; P = 0.38) compared to no MDT. Our short-term results, with a 2.6% local failure rate (affecting only two bone lesions), further substantiate the potent local efficacy of radiotherapy against EWS metastases, even when employing moderately hypofractionated regimens like those used here (45–55 Gy in 20 fractions). Notably, the CR rate of our bone lesions was significantly lower than that of soft tissue lesions (3.2% vs 78.3%, p < 0.001). This striking disparity, rarely highlighted in prior literature, suggests a fundamental biological difference in radiosensitivity or post-radiation tissue repair between metastatic sites. Potential explanations include the hypoxic microenvironment of bone metastases, differences in immune cell infiltration, or altered DNA damage repair capacity. This observation has direct clinical implications: it argues against a “one-size-fits-all” radiation prescription for all metastatic sites and strongly suggests that bone metastases may require combinatorial strategies to enhance response. Future studies should investigate dose escalation specifically to bone lesions, the use of bone-targeted radiosensitizers (e.g., radiopharmaceuticals, bisphosphonates), or novel systemic agents with enhanced bone penetration. Functional imaging (e.g., DCE-MRI, PET) in this context could shed light on the differential perfusion and metabolic response. Crucially, aggressive local control of all metastatic sites may translate into tangible survival benefits, as evidenced by previous studies. Haeusler et al. [ 14 ] demonstrated in the EURO-EWING 99 cohort that patients receiving local therapy to both the primary tumor and all metastases had significantly superior 3-year event-free survival compared to those with incomplete or no local therapy (39% vs. 17% vs. 14%, P < .001). This is further supported by Bronk et al. [ 15 ], who reported impressive 4-year outcomes (LC: 83%, PFS: 71%, OS: 86%) in pediatric metastatic Ewing sarcoma patients treated with comprehensive proton therapy, achieving survival rates approaching those of their localized disease cohort. Similarly, Ahmed et al. [ 16 ] specifically found that adults receiving radiotherapy to all metastases had significantly improved 4-year overall and event-free survival compared to those who did not (OS: 33% vs. 0%; EFS: 11% vs. 0%), and combining radiotherapy with VDC/IE chemotherapy further enhanced survival. In line with these findings, our study provides early, real-world evidence supporting the clinical feasibility of this approach. We observed a median PFS of 6.0 months and OS of 8.0 months, and our multivariate analysis reinforced the critical importance of effective systemic therapy, identifying its combination with radiotherapy as a significant factor for improved PFS (p = 0.014), with chemotherapy-based regimens yielding the numerically best median PFS of 8.5 months. These findings collectively underscore the promise of comprehensive MDT and provide a rationale for future prospective trials to validate its efficacy and optimize the integration with systemic agents. Our study adds to the growing body of evidence supporting the role of whole-lung irradiation (WLI) in the management of metastatic Ewing sarcoma. In our small cohort of five patients receiving WLI (with or without pleural involvement) for a total of 19 lesions, we observed a high objective response rate (ORR) of 78.9% and a 100% disease control rate (DCR), underscoring the potent radiosensitivity of pulmonary Ewing sarcoma metastases. This aligns with the established efficacy of WLI in both primary and relapsed settings. In patients with isolated lung metastases at diagnosis, the addition of WLI to chemotherapy has been associated with 5-year overall survival (OS) rates of approximately 50–70% [ 17 – 19 ]. Notably, the Italian Sarcoma Group study reported a 5-year pulmonary relapse-free survival (PRFS) of 70.5% and a 5-year OS of 69.8% in patients treated with WLI following high-dose busulfan/melphalan, highlighting its potential for durable disease control [ 17 ]. Similarly, in the specific context of pulmonary relapse—a scenario with historically poor outcomes—WLI has demonstrated a significant improvement in 3-year progression-free survival (36% vs 14%) and overall survival (47% vs 33%) compared to no WLI [ 19 ]. Our findings, though preliminary due to the sample size, contribute to this consensus by confirming excellent short-term local control with the WLI + boost regimen. Regarding safety, our observation of manageable toxicity (one case of grade 3 pneumonitis) is consistent with modern series. While WLI is generally well-tolerated, its combination with specific chemotherapies, particularly busulfan, warrants careful timing and dose consideration to mitigate pulmonary toxicity [ 17 ]. Promisingly, advanced techniques like intensity-modulated radiotherapy (IMRT) and proton therapy (PWLI) are now being employed to significantly reduce radiation dose to critical organs such as the heart, breasts, and thyroid, thereby potentially further improving the long-term therapeutic index of WLI [ 20 ]. In an exploratory analysis, we observed an association between TKI use (anlotinib or apatinib) and shorter PFS compared to no TKI use (4.0 vs. 8.5 months, p = 0.048). Several TKIs have demonstrated clinical activity in refractory EWS [ 21 ]; for instance, studies have reported promising response rates and PFS with anlotinib and apatinib in this setting [ 22 – 24 ]. Given this established efficacy, our finding most likely reflects significant confounding rather than a true detrimental effect of TKIs. As a salvage therapy in our cohort, TKIs were often used in more heavily pre-treated patients with inherently poorer prognosis. Therefore, this association should be interpreted with extreme caution and serves primarily as a hypothesis-generating observation regarding patient selection in real-world practice. It underscores the current lack of standardized protocols for integrating novel agents like TKIs with aggressive local therapies and the need for prospective studies to define their optimal sequencing. Importantly, despite achieving 97.4% local control within irradiated fields, 42.9% of patients experienced regional or distant progression at a median follow-up of only 6 months. This rapid out-of-field failure starkly illustrates the systemic nature of widespread metastatic EWS and the inherent limitation of any local therapy alone. These data powerfully reinforce our central conclusion: the high short-term local control achieved with all-site radiotherapy is clinically meaningful but insufficient for long-term disease control. Therefore, the primary therapeutic challenge remains the concomitant micrometastatic disease. This observation provides a compelling rationale for urgently integrating this aggressive local approach with more effective systemic therapies. Promising strategies under active investigation, which could logically build upon the local control we observed, include combining radiotherapy with immunotherapy to potentially induce abscopal effects [ 25 ], leveraging radiosensitizers like PARP inhibitors [ 26 ], and exploring novel cellular therapies [ 27 ]. Acute toxicities in our study were manageable, primarily manifesting as hematologic suppression, with 4 patients (19%) requiring temporary radiotherapy interruption due to thrombocytopenia. Considering our moderately hypofractionated regimen (Equivalent Dose in 2 Gy fractions [EQD₂] GTV ~ 58.44 Gy, PTV ~ 45.94 Gy for α/β = 10 [ 28 ]) was slightly higher than conventional NCCN-recommended EQD₂ levels (GTV ~ 54.87 Gy, PTV ~ 44.25 Gy [ 8 ]) and accounting for concurrent systemic therapy, no compensatory dose was delivered for treatment interruptions. One of the five patients who received whole-lung irradiation had grade 3 radiation pneumonitis. In this patient, the lung dosimetric parameters were safe (Mean dose [Dmean] 14.27Gy, Volume of lung receiving 20 Gy or more [V20] 3.9%), but the primary contributing factor was the concurrent treatment with sindilizumab during whole-lung irradiation. Bi et al. [ 29 – 30 ] demonstrated that thoracic radiotherapy with concurrent or sequential immunotherapy significantly increased the risk of radiation pneumonitis. For targeted therapy, the impact of anlotinib on RP remains unclear because of inconsistent study results [ 31 – 32 ]. Key limitations of our study must be acknowledged. First, the short median follow-up (6 months) precludes any assessment of long-term survival, late toxicity, or durable local control. This directly informs our interpretation of the progression-free and overall survival data as preliminary, short-term outcomes, and positions the study primarily as an analysis of feasibility, early response, and safety. Second, the retrospective, single-center design carries inherent risks of selection bias and limits data standardization. Third, significant heterogeneity existed in patients’ prior treatment histories, which confounds the interpretation of subgroup analyses and may contribute to the selection bias noted for agents like TKIs. Fourth, the small sample size (n = 21) severely limits the statistical power for subgroup analyses and multivariate modeling, increasing the risk of overfitting and Type II errors. Fifth, the heterogeneity in systemic therapies received concurrently or around the time of radiotherapy confounds the precise interpretation of their specific impact on outcomes. Given these constraints, all subgroup findings, including the striking differential response between bone and soft tissue lesions and the association between systemic therapy type and PFS, must be viewed as exploratory and hypothesis-generating, requiring validation in larger, prospective cohorts. We acknowledge that the small sample size and short follow-up period of our study limit the generalizability and strength of our conclusions. Nonetheless, this report provides one of the few detailed series on the application of comprehensive all-site radiotherapy in widely metastatic Ewing sarcoma. It offers valuable initial data on the high short-term local control achievable with this approach and generates important hypotheses regarding the interplay between radiotherapy and systemic therapies that warrant future investigation in larger, prospective cohorts. Conclusion In conclusion, this short-term analysis demonstrates that comprehensive all-site radiotherapy is a feasible and safe local strategy for metastatic Ewing sarcoma, providing high rates of initial local control. The integration of systemic therapy was crucial. The dramatic difference in response between bone and soft tissue metastases is a novel finding that merits further biological and clinical investigation. While the observed association with TKI use requires validation, the rapid systemic progression seen underscores the imperative to combine this aggressive local approach with next-generation systemic therapies. Future research should focus on prospectively testing all-site radiotherapy in combination with novel agents and on developing strategies to overcome the radioresistance suggested in bone metastases. Abbreviations EWS Ewing sarcoma MDT metastasis-directed therapy TKIs tyrosine kinase inhibitors ICIs immune checkpoint inhibitors ORR objective response rate RECIST Response Evaluation Criteria in Solid Tumors CR complete response PR partial response DCR disease control rate SD stable disease PD progressive disease PFS progression-free survival OS overall survival HT helical tomotherapy KPS Karnofsky Performance Status GTV gross tumor volume CTV clinical target volume PTV planning target volume WLI whole lung irradiation OARs organs at risk SBRT stereotactic body radiation therapy MV-CT Megavoltage computed tomography WBC white blood cells EQD₂ Equivalent Dose in 2 Gy fractions Dmean Mean dose V20 Volume of lung receiving 20 Gy or more RP radiation pneumonitis. Declarations Acknowledgments ： The authors have nothing to report. Financial Support ： None. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Data Sharing Statement The individual participant data that underlie the results reported in this article are not publicly available due to patient privacy concerns. However, deidentified summary data (e.g., aggregated statistical results) that support the findings of this study are available from the corresponding author upon reasonable request, subject to review and approval of a proposal. Ethics approval and consent to participate This study was conducted in accordance with the ethical principles of the World Medical Association Declaration of Helsinki. The study protocol was approved by the Institutional Review Board of Peking University Shougang Hospital (Approval No.: IRB-AF-37-03-2). Written informed consent was obtained from all individual participants (or their parents/legal guardians in the case of minors [under the age of 16]) prior to treatment. Consent for publication Written informed consent was obtained from all individual participants (or their parents/legal guardians for those under 16) for the publication of their personal or clinical details and any identifying images included in this study. Availability of data and materials The datasets generated and/or analyzed during the current study are not publicly available due to patient privacy and confidentiality considerations but are available from the corresponding author upon reasonable request and with permission from the Peking University Shougang Hospital Ethics Committee. Competing interests The authors declare that they have no competing interests as defined by the journal, or other interests that might be perceived to influence the results and/or discussion reported in this paper. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Authors' contributions YuanYou Yang: Conceptualization, Methodology, Investigation, Formal Analysis, Writing - Original Draft; Lu Xie, Xin Sun, Jie Xu: Methodology, Investigation; Gang Ren: Conceptualization, Supervision, Writing - Review & Editing. Acknowledgements None. References Grünewald TGP, Cidre-Aranaz F, Surdez D, Tomazou EM, de Álava E, Kovar H et al (2018) Ewing sarcoma. Nat Rev Dis Primers 4(1):5. 10.1038/S41572-018-0003-X Pappo AS (2018) Uta Dirksen. Rhabdomyosarcoma, Ewing sarcoma, and other round cell sarcomas. J Clin Oncol 36(2):168–179. 10.1200/jco.2017.74.7402 Gunderson LL, Tepper JE (eds) (2016) Clinical radiation oncology. Fourth Edition. Elsevier Health. Philadelphia, PA, pp.1412–1420 Karimi AM, Campbell SR, Parsai S, Angelov L, Scott J, Qi P et al (2020) Aggressive Local control with multisite stereotactic body radiation in metastatic Ewing Sarcoma: a literature review and case report. Anticancer Res 40(2):951–955. 10.21873/anticanres.14028 Palma DA, Olson R, Harrow S, Gaede S, Louie AV, Haasbeek C et al (2019) Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): A randomised, phase 2,open-label trial. Lancet 393:2051–2058 Gomez DR, Tang C, Zhang JJ, Blumenschein GR Jr, Hernandez M, Lee JJ et al (2019) Local consolidative therapy vs.maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer: Long-term results of a multi-institutional, phase II, randomized study. J Clin Oncol 37:1558–1565 Casey DL, Murphy ES, Shen CJ, Milgrom SA, Larrier NA, Bradley JA et al (2025) Metastatic-Site Radiation Therapy for Ewing Sarcoma and Rhabdomyosarcoma: Consensus Guidelines From the National Pediatric Cancer Foundation. Pract Radiat Oncol 15(2):180–186. 10.1016/j.prro.2024.10.004 NCCN clinical practice guidelines in oncology – Bone Cancer (2025) .https://www.nccn.org/professionals/physician_gls/pdf/bone.pdf Timmerman R (2022) A Story of Hypofractionation and the Table on the Wall. Int J Radiat Oncol Biol Phys 112(1):4–21. 10.1016/j.ijrobp.2021.09.027 Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45(2):228–247. 10.1016/j.ejca.2008.10.026 Talleur AC, Navid F, Spunt SL, McCarville MB, Wu J, Mao SH et al (2016) Limited Margin Radiation Therapy for Children and Young Adults With Ewing Sarcoma Achieves High Rates of Local Tumor Control. Int J Radiat Oncol Biol Phys 96(1):119–126. 10.1016/j.ijrobp.2016.04.001 Casey DL, Wexler LH, Meyers PA, Magnan H, Chou AJ, Wolden SL (2015) Radiation for bone metastases in Ewing sarcoma and rhabdomyosarcoma. Pediatr Blood Cancer 62(3):445–449. 10.1002/pbc.25294 Grewal AS, Li YM, Grewal SK, Bagatell R, Balamuth N, Womer R et al (2020) Role of Metastatic Site Irradiation in Pediatric Patients With Metastatic Ewing Sarcoma. J Pediatr Hematol Oncol 42(5):e305–e309. 10.1097/MPH.0000000000001752 Haeusler J, Ranft A, Boelling T, Gosheger G, Braun-Munzinger G, Vieth V et al (2010) The value of local treatment in patients with primary, disseminated, multifocal Ewing sarcoma (PDMES). Cancer 116(2):443–450. 10.1002/cncr.24740 Bronk JK, McAleer MF, McGovern SL, Lassen-Ramshad Y, Safwat A, Daw NC et al (2024) Comprehensive radiotherapy for pediatric Ewing Sarcoma: Outcomes of a prospective proton study. Radiother Oncol 195:110270. 10.1016/j.radonc.2024.110270 Ahmed SK, Robinson, Okuno SSH, Rose PS, Laack NNI (2014) Adult Ewing sarcoma: survival and local control outcomes in 36 patients with metastatic disease. Am J Clin Oncol 37(5):423–429. 10.1097/COC.0b013e31827de65e Abate ME, Cammelli S, Ronchi L, Diletto B, Gandola L, Paioli A et al (2021) Whole Lung Irradiation after High-Dose Busulfan/Melphalan in Ewing Sarcoma with Lung Metastases: An Italian Sarcoma Group and Associazione Italiana Ematologia Oncologia Pediatrica Joint Study. Cancers (Basel) 13(11):2789. 10.3390/cancers13112789 Elghazawy H, Nasr A, Zaky I, Zamzam M, Elgammal A, Farid N et al (2020) Whole lung irradiation for completely responding pulmonary metastases in pediatric Ewing sarcoma. Future Oncol 16(15):1043–1051. 10.2217/fon-2020-0066 Scobioala S, Ranft A, Wolters H, Jabar S, Paulussen M, Timmermann B et al (2018) Impact of Whole Lung Irradiation on Survival Outcome in Patients With Lung Relapsed Ewing Sarcoma. Int J Radiat Oncol Biol Phys 102(3):584–592. 10.1016/j.ijrobp.2018.06.032 Cunningham DA, Breen WG, Johnson JE, Mullikin TC, Bradley TB, Sorenson KL et al (2023) Proton Whole-Lung Irradiation: Initial Report of Outcomes. Int J Radiat Oncol Biol Phys 115(4):866–872. 10.1016/j.ijrobp.2022.10.001 Fleuren EDG, Vlenterie M, van der Graaf WTA (2023) Recent advances on anti-angiogenic multi-receptor tyrosine kinase inhibitors in osteosarcoma and Ewing sarcoma. Front Oncol. ;13:1013359. 10.3389/fonc.2023.1013359 . eCollection 2023 Xu J, Xie L, Sun X, Liu KS, Tang XD, Yan TQ et al (2021) Anlotinib, Vincristine, and Irinotecan for Advanced Ewing Sarcoma After Failure of Standard Multimodal Therapy: A Two-Cohort, Phase Ib/II Trial. Oncologist 26(7):e1256–e1262. 10.1002/onco.13726 Liu ZY, Gao ST, Zhu LY, Wang JQ, Zhang P, Li P et al (2021) Efficacy and safety of anlotinib in patients with unresectable or metastatic bone sarcoma: A retrospective multiple institution study. Cancer Med 10(21):7593–7600. 10.1002/cam4.4286 Wang YT, Min L, Zhou Y, Luo Y, Duan H, Tu CQ (2018) The efficacy and safety of apatinib in Ewing's sarcoma: a retrospective analysis in one institution. Cancer Manag Res. ;10:6835–6842. doi: 10.2147/CMAR.S181087. eCollection 2018 Callaghan CM, Seyedin SN, Mohiuddin IH, Hawkes KL, Petronek MS, Anderson CM et al (2020) The Effect of Concurrent Stereotactic Body Radiation and Anti-PD-1 Therapy for Recurrent Metastatic Sarcoma. Radiat Res 194(2):124–132. 10.1667/RADE-20-00017 Xie J, Mellado-Lagarde MM, Blankenship K, Ganguly D, Twarog NR, Bianski B et al (2025) The Combination of PARP and Topoisomerase 1 Inhibitors Improves Radiation Therapy for Ewing Sarcoma. Cancer Sci 116(6):1703–1714. 10.1111/cas.70042 Lam PY, Omer N, Wong JKM, Tu C, Alim L, Rossi GR et al (2025) Enhancement of anti-sarcoma immunity by NK cells engineered with mRNA for expression of a EphA2-targeted CAR. Clin Transl Med 15(1):e70140. 10.1002/ctm2.70140 Hall EJ (1994) Molecular biology in radiation therapy: the potential impact of recombinant technology on clinical practice. Int J Radiat Oncol Biol Phys 30(5):1019–1028. 10.1016/0360-3016(94)90305-0 Bi JP, Qian J, Yang DQ, Sun L, Lin SY, Li Y et al (2022) Dosimetric Risk Factors for Acute Radiation Pneumonitis in Patients With Prior Receipt of Immune Checkpoint Inhibitors. Front Immunol 12:828858 Bi JP, Meng R, Yang DQ, Li Y, Cai J, Zhang L et al (2024) Dosimetric predictors of radiation pneumonitis in patients with prior immunotherapy exposure: A multi-institutional analysis. Radiother Oncol 190:110040 Kroeze SGC, Fritz C, Basler L, Gkika E, Brunner TB, Grosu AL et al (2019) Combination of stereotactic radiotherapy and targeted therapy: patterns-of-care survey in German-speaking countries. Strahlenther Onkol 195(3):199–206. 10.1007/s00066-018-01422-5 Martínez E, Martínez M, Rico M, Hernández B, Casas F, Viñolas N et al (2016) Feasibility, tolerability, and efficacy of the concurrent addition of erlotinib to thoracic radiotherapy in locally advanced unresectable non-small-cell lung cancer: a Phase II trial. Onco Targets Ther. ;9:1057-66. 10.2147/OTT.S89755 . eCollection 2016 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 27 Apr, 2026 Read the published version in Clinical & Experimental Metastasis → Version 1 posted Editorial decision: Revision requested 07 Mar, 2026 Reviews received at journal 26 Feb, 2026 Reviewers agreed at journal 26 Feb, 2026 Reviewers invited by journal 05 Feb, 2026 Editor assigned by journal 12 Dec, 2025 Submission checks completed at journal 12 Dec, 2025 First submitted to journal 12 Dec, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8350070","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":586600657,"identity":"947e0bc6-5dee-4492-b3d8-b64d16fc8801","order_by":0,"name":"YuanYou Yang","email":"","orcid":"","institution":"Peking University Shougang Hospital","correspondingAuthor":false,"prefix":"","firstName":"YuanYou","middleName":"","lastName":"Yang","suffix":""},{"id":586600658,"identity":"47c1f073-d082-4773-94bb-b2b6fc414d01","order_by":1,"name":"Lu Xie","email":"","orcid":"","institution":"Peking University People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Lu","middleName":"","lastName":"Xie","suffix":""},{"id":586600659,"identity":"6bd7740d-5d3a-411b-bc9e-d08401ede555","order_by":2,"name":"Xin Sun","email":"","orcid":"","institution":"Peking University People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xin","middleName":"","lastName":"Sun","suffix":""},{"id":586600660,"identity":"baa43a85-5c75-45d2-8115-6b94179f2f8f","order_by":3,"name":"Jie Xu","email":"","orcid":"","institution":"Peking University People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jie","middleName":"","lastName":"Xu","suffix":""},{"id":586600661,"identity":"883132ed-20f1-4386-ad3e-3b8dcc9ef8ff","order_by":4,"name":"Gang Ren","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAwElEQVRIiWNgGAWjYFAC5gMGH378k2Njbz9ArBa2hMKZPQeM+XjOJBCrhUfhMwfbgcR5Eg4GxGngn5HDuJmB5056mwRDAsOPim2EtUjcyD1sXGDxLLdNuvEAY8+Z24S1GEjkpRnP4GHObZM5kMDM2EaUlhzz3zxszOlsEgkGRGsxMOZhO5xAvBaJM88SDGf2pBm2AQP5IFF+4W9PBkWljbx8e/vBBz8qiNDCIJCAYB8gQj3IGiLVjYJRMApGwQgGADX2Pf6ChGcTAAAAAElFTkSuQmCC","orcid":"","institution":"Peking University Shougang Hospital","correspondingAuthor":true,"prefix":"","firstName":"Gang","middleName":"","lastName":"Ren","suffix":""}],"badges":[],"createdAt":"2025-12-13 04:38:36","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8350070/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8350070/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10585-026-10406-0","type":"published","date":"2026-04-27T15:57:22+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":102376240,"identity":"cd517c3c-e884-4c9d-ac73-b102e93b43d1","added_by":"auto","created_at":"2026-02-11 05:26:45","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":65237,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMixed response to all-site radiotherapy in a patient with metastatic Ewing sarcoma.\u003c/strong\u003e\u003cbr\u003e\n \u003cstrong\u003e(A)\u003c/strong\u003e Baseline imaging showing the primary tumor (arrowhead) and a bone metastasis (arrow).\u003cbr\u003e\n \u003cstrong\u003e(B)\u003c/strong\u003e Follow-up imaging at 11 months post-radiotherapy demonstrates a partial response (PR) in the primary tumor (arrowhead shows shrinkage and reduced enhancement) alongside progressive disease (PD) in the bone metastasis (arrow shows increased size and lytic destruction). This case illustrates the differential response observed between soft tissue (primary site) and bone metastases.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8350070/v1/e0084c5972c911d677fefdbc.jpg"},{"id":102376236,"identity":"5d1cee97-0d3d-439a-a6cb-1fc4f4c1cdc5","added_by":"auto","created_at":"2026-02-11 05:26:42","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":74956,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eExamples of favorable response to all-site radiotherapy in metastatic Ewing sarcoma at 3-month follow-up.\u003c/strong\u003e\u003cbr\u003e\n \u003cstrong\u003e(A)\u003c/strong\u003e Complete response (CR) in a soft tissue metastasis (arrow) following radiotherapy, with complete resolution of the previously visible lesion.\u003cbr\u003e\n \u003cstrong\u003e(B)\u003c/strong\u003e Partial response (PR) in another patient, showing significant shrinkage (\u0026gt;30% reduction in diameter) of a metastatic lesion (arrow). These images represent the high objective response rate achieved with comprehensive radiotherapy.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8350070/v1/a2b736303ce6f43014203a4b.jpg"},{"id":102376264,"identity":"c4fdf961-28dd-4d53-82a7-02c2571e733e","added_by":"auto","created_at":"2026-02-11 05:26:46","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":26085,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan-Meier curve comparing progression-free survival (PFS) based on systemic therapy regimen.\u003c/strong\u003e\u003cbr\u003e\nPatients receiving tyrosine kinase inhibitor (TKI)-containing regimens (e.g., anlotinib or apatinib) had a significantly shorter median PFS (4.0 months) compared to those not receiving TKIs (8.5 months) (log-rank p=0.048). This exploratory analysis likely reflects selection bias, as TKIs were more frequently used in heavily pretreated patients with poorer prognosis, rather than a causative effect of TKIs.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-8350070/v1/d446df938ed2ac6faac8288e.png"},{"id":108438051,"identity":"d6920f6d-7e1d-484d-846a-d9a0e1b44771","added_by":"auto","created_at":"2026-05-04 16:06:04","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":607732,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8350070/v1/b6b71da0-af64-43ba-bdf1-24b6fc80e8fa.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"All-site radiotherapy for metastatic Ewing's sarcoma: a short-term analysis of feasibility, response, and safety","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eEwing sarcoma (EWS), the second most common malignant pediatric bone tumor (~\u0026thinsp;1.5 per million incidence), primarily affects adolescents but also occurs in adults. It is highly sensitive to both chemotherapy and radiotherapy; standard treatment includes surgery, radiotherapy, and multi-agent chemotherapy [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The presence of metastatic disease is the most important prognostic factor, and even localized disease carries a high metastatic risk without systemic therapy. Metastatic patients require multiagent chemotherapy and may benefit from targeted agents [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. While metastasis-directed therapy (MDT) improves survival in oligometastatic adults [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], the role of radiotherapy in widespread disease remains less clear. In contrast to MDT, which selectively targets a limited number of metastases, all-site radiotherapy aims to irradiate all known metastatic lesions. This strategy aims to reduce the systemic tumor burden and potentially improve survival in widespread metastatic disease\u0026mdash;an unmet need in pediatric/adolescent EWS, where the timing and extent of MDT remain debated [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Current NCCN guidelines still recommend aggressive surgery or radiotherapy for metastases if tolerated [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Therefore, this study aimed to retrospectively analyze the short-term outcomes and feasibility of 21 metastatic Ewing sarcoma patients treated with all-site radiotherapy using helical tomotherapy. We sought to assess the short-term local efficacy, safety, and radiographic response patterns of this approach, thereby providing preliminary clinical data and generating hypotheses for this aggressive local strategy in the setting of widespread metastases.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatient Selection\u003c/h2\u003e \u003cp\u003ePatients with metastatic EWS who underwent helical tomotherapy (HT) at our center from August 2024 to June 2025 were enrolled. Inclusion criteria: patients with pathologically confirmed EWS; Patients diagnosed with metastatic EWS (including pulmonary and extrapulmonary metastases); Karnofsky Performance Status (KPS)\u0026thinsp;\u0026ge;\u0026thinsp;70; The metastatic and/or primary lesions could not be resected or refused surgical resection. Exclusion criteria: Patients who had previously received radiotherapy for the target lesion; Moderate-severe pulmonary dysfunction; Complicated with pulmonary or other site infection; Severe liver and kidney dysfunction may potentially affect the tolerance of radiotherapy; Other contraindications to radiotherapy included inability to cooperate with radiotherapy and pregnancy. This study was conducted in accordance with the ethical principles of the World Medical Association Declaration of Helsinki. The study protocol was approved by our Institutional Review Board (Approval No.: IRB-AF-37-03-2). Written informed consent was obtained from all individual participants (or their parents/legal guardians in the case of minors [under the age of 16]) prior to treatment.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eRadiation Treatment\u003c/h3\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eSimulation and immobilization:\u003c/h2\u003e \u003cp\u003eThe patients were fixed with negative pressure vacuum pad and thermoplastic film, Patient respiratory motion management was performed when target lesions were located in the chest or abdomen, using an abdominal compression plate (Shenzhen Tengfei Yu Company) to limit respiratory movement and train patients to breathe quietly. Iodine contrast-enhanced CT scans (3 mm slice thickness) were performed using a Philips spiral CT.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eDelineation of the target volume:\u003c/h3\u003e\n\u003cp\u003eThe gross tumor volume (GTV) was defined as all imaging-visible tumor, with each distinct lesion contoured as a separate GTV; isolated lymph nodes were considered a single GTV, and clustered or fused nodes or metastases were contoured as one combined GTV. The clinical target volume (CTV) was generated by expanding the GTV by 5\u0026ndash;10 mm, and the planning target volume (PTV) was created with an additional 5 mm margin. For lymph node involvement, the CTV encompassed the respective nodal basin, while for lung metastases the CTV included the whole lung, and for pleural metastases it covered the involved hemithorax or bilateral pleura. Except in cases of lung metastases\u0026mdash;where CT alone offers sufficient sensitivity\u0026mdash;all other targets were co-registered with MRI or PET-CT to improve delineation accuracy.\u003c/p\u003e\n\u003ch3\u003ePrescribed dose and Dose Constraints for Organs at Risk (OARs):\u003c/h3\u003e\n\u003cp\u003e Five patients with lung metastases (with or without pleural metastasis) received whole lung irradiation (WLI) at 12\u0026ndash;15 Gy in 10 fractions was selected based on COG and NCCN guidelines recommendations for balancing local control and pulmonary toxicity in metastatic EWS, and the GTV of lung metastases was sequentially boosted to 27\u0026ndash;45 Gy in 15fractions. Two patients with bilateral pleural metastases (without lung metastasis) received whole pleural irradiation with a dose of 18 Gy in 12 fractions, and the GTV of pleural metastases was sequentially boosted to 45 Gy in 25 fractions. One patient with unilateral pleural metastasis (without lung metastasis) received hemi thoracic irradiation at the same dose as the whole pleural irradiation. For all other metastatic lesions, the PTV dose was 45 Gy in 20 fractions and the GTV dose was boosted to 55 Gy in 20 fractions simultaneously. For dose constraints on organs at risk (OAR), we refer to Timmerman's requirements for hypofractionated and conventionally fractionated dose constraints [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Patients receiving WLI or hemi-pleural/whole-pleural irradiation were referred to the EAWS1221 protocol for WLI and stereotactic body radiation therapy (SBRT) with 5 fractions after WLI.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eManagement during radiotherapy and follow-up after treatment:\u003c/h2\u003e \u003cp\u003eMegavoltage computed tomography (MV-CT) was used for image guidance in each treatment for all patients. Toxicities were monitored and managed symptomatically. Blood tests every 3 days and triggered granulocyte colony-stimulating factor, thrombopoietin or erythropoietin injections if WBC\u0026thinsp;\u0026lt;\u0026thinsp;3.0\u0026times;10⁹/L, platelet\u0026thinsp;\u0026lt;\u0026thinsp;75\u0026times;10⁹/L, or hemoglobin\u0026thinsp;\u0026lt;\u0026thinsp;9.5 g/L. Post-radiation, for patients who received whole-lung, half-pleural, and whole-pleural irradiation, weekly follow-ups included symptom checks (cough, fever, wheezing) for early pneumonitis detection. Imaging occurred every 2 months or immediately if pneumonitis was suspected. For patients receiving radiotherapy at other sites, blood routine and blood biochemical tests were reviewed weekly, and imaging examinations were performed every 2 months and at any time if urgently necessary.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eMethods of efficacy assessment:\u003c/h3\u003e\n\u003cp\u003eEfficacy assessment was performed according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]: Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \u0026lt;\u0026thinsp;10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Toxicity was assessed according to RTOG or CTCAE 5.0 criteria.\u003c/p\u003e\n\u003ch3\u003eStatistics Analysis\u003c/h3\u003e\n\u003cp\u003eContinuous data are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard error or median (range), as appropriate. An independent samples t-test was used to compare the maximum diameters between bone and soft tissue lesions. The relationship between tumor diameter and CR rate was analyzed by Pearson correlation analysis. In the survival time analysis, the end of radiotherapy was set as the starting point. PFS was calculated until disease progression (target-lesion progression or progression elsewhere) or death. OS was calculated until the last follow-up or the time of death. Kaplan-Meier method was used for survival analysis. Survival curves were compared with log-rank test. Prognostic factors for PFS and OS were first analyzed using univariate log-rank tests. Cox proportional hazards regression was used to analyze the influencing factors. A two-sided p-value of \u0026lt;\u0026thinsp;0.05 was considered statistically significant. Statistical analyses were performed with SPSS 26. Given the limited sample size (n\u0026thinsp;=\u0026thinsp;21), the statistical power for subgroup analyses was constrained, and the results of the multivariate Cox regression should be interpreted with caution due to the risk of overfitting. Therefore, the results of these analyses, particularly those involving systemic therapy subgroups, should be interpreted as exploratory and hypothesis-generating.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003ePatient Baseline Characteristics\u003c/h2\u003e \u003cp\u003eThis study included 21 consecutive patients with metastatic Ewing sarcoma. Key demographic and disease characteristics are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e1\u003c/span\u003e. In brief, the cohort was predominantly male with a median age of 23 years. Patients presented with heterogeneous treatment histories, as nearly half had metastatic disease at initial diagnosis, and the majority had undergone surgical resection of the primary tumor prior to enrollment. All patients received multi-agent systemic therapy per institutional protocols. Detailed parameters of radiotherapy targets and specific concurrent systemic therapies are provided in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e2\u003c/span\u003e. In summary, a total of 77 metastatic lesions were irradiated, and the median maximum diameter was comparable between bone and soft tissue lesions (p\u0026thinsp;=\u0026thinsp;0.175). The median follow-up duration from the completion of radiotherapy was 6 months (range, 2\u0026ndash;11).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient Demographics and Baseline Clinical Characteristics (N\u0026thinsp;=\u0026thinsp;21)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCategory\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eValue / Count (%) or Median (Range)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eDemographics\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 (76.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (23.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23 (10\u0026ndash;40)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eKarnofsky Performance Status (KPS)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026le;70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (47.6%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (52.4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisease Characteristics\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eStage at Initial Diagnosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (57.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (42.9%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePrimary Tumor Location\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIliac bone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (23.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFemur\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (14.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eChest wall soft tissue\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (14.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eClavicle\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (9.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOther\u0026dagger;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (38.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLymph Node Metastasis at Baseline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (33.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eTreatment History\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePrimary Tumor Treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSurgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 (76.2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eSystemic Therapy \u0026amp; Follow-up\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDefinitive CCRT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (23.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFirst-line Regimen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eVDC/IE\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSecond-line Regimens\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCTop or Iri\u0026thinsp;\u0026plusmn;\u0026thinsp;TKI\u0026thinsp;\u0026plusmn;\u0026thinsp;ICI\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFollow-up (months)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (2\u0026ndash;11)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eNote: CCRT, Concurrent Chemoradiotherapy; VDC/IE, vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide; CTop, Cyclophosphamide and Topotecan; Iri, Irinotecan; TKI, Tyrosine kinase inhibitors; ICI, Immune checkpoint inhibitors.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eRadiotherapy and Concurrent Treatment Details\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCategory\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eValue / Count (%) or Median (Range)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRadiotherapy Parameters\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNumber of Target Lesions Per Patient\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (1\u0026ndash;9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal GTV Volume (cc)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e173.8 (0.53\u0026ndash;1349.81)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal CTV Volume (cc)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1020.8 (29.6\u0026ndash;3769.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal PTV Volume (cc)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1355.6 (70.8\u0026ndash;4868.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMaximum Diameter per Lesion (cm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.6 (0.6\u0026ndash;17.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConcurrent Systemic Therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCombination Therapy with RT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (9.5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eChemotherapy alone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (42.8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTKI alone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (19.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eChemotherapy\u0026thinsp;+\u0026thinsp;TKI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (14.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eICI\u0026thinsp;+\u0026thinsp;TKI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (14.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreatment Course\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRadiotherapy Interruption\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (19.1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eNote: GTV, Gross Tumor Volume; CTV, Clinical Target Volume; PTV, Planning Target Volume; TKI, Tyrosine kinase inhibitors (anlotinib, n\u0026thinsp;=\u0026thinsp;6; apatinib, n\u0026thinsp;=\u0026thinsp;3); ICI, Immune checkpoint inhibitors (Sintilimab); RT, Radiotherapy.\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003earget Volume; TKI, Tyrosine kinase inhibitor; RT, Radiotherapy.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eTarget-lesion response at the last follow-up:\u003c/h2\u003e \u003cp\u003eLocal efficacy for all target lesions and key subgroups is detailed in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. In summary, a high disease control rate (DCR) of 97.4% was achieved across all lesions, with a key finding being the significantly higher complete response (CR) rate in soft tissue lesions compared to bone lesions (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The high efficacy of radiotherapy was further demonstrated in the subgroup of five patients receiving whole-lung irradiation (WLI), who exhibited a high objective response rate (ORR) and a 100% DCR (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Pearson correlation analysis showed that there was no significant correlation between the maximum tumor diameter and CR (correlation coefficient: -0.177, p\u0026thinsp;=\u0026thinsp;0.123). Both instances of PD occurred in the same patient, who was found to have target lesions progression at the time of review 11 months after completion of radiotherapy. Representative imaging of treatment response is provided in Figs.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e illustrates a case of mixed response, with progressive disease (PD) in bone metastases alongside partial response (PR) in the primary tumor at 11 months post-radiotherapy. Figure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e demonstrates achieving complete response (CR) and partial response (PR) in two other patients at the 3-month follow-up.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eLocal efficacy, acute toxicity, and tumor progression status\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eItems\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e \u003cp\u003eLocal efficacy(N/%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLesion Category\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eORR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eDCR\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAll Target Lesions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37 (48.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (12.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e28 (36.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 (2.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e47 (61.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e75 (97.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBone Lesions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (3.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (16.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e23 (74.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 (6.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6 (19.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e29 (93.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSoft Tissue Lesions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36 (78.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (10.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (10.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e41 (89.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e46 (100)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWLI Subgroup Lesions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (63.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (15.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (21.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0 (0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e15 (78.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e19 (100)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e \u003cp\u003eAcute Toxicity (Number, %)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eToxicity Type\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eG1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eG2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eG3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eG4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNausea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (4.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (4.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnorexia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (23.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (19.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFatigue\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (4.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiarrhea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (4.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRadiation Pneumonitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (4.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWhite Blood Cells\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (19.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (9.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (9.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 (9.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlatelets\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (4.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (14.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (19.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeutrophils\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (9.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (4.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (9.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (4.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHemoglobin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (23.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (23.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (9.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e \u003cp\u003eTumor Progression Status\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProgression Pattern\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eNumber of Patients (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003eTime after Radiotherapy Completion\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRLN Only\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003e1 (4.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003e4 months\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDistant Only\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003e3 (14.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003e2, 2, 11 months\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBoth RLN and Distant (Synchronous)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003e5 (23.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003e1.5, 2, 2, 4, 9 months\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eNote: CR, Complete Response; PR, Partial Response; SD, Stable Disease; PD, Progressive Disease; ORR, Objective Response Rate (CR\u0026thinsp;+\u0026thinsp;PR); DCR, Disease Control Rate (CR\u0026thinsp;+\u0026thinsp;PR\u0026thinsp;+\u0026thinsp;SD); WLI, Whole-Lung Irradiation; RLN, Regional Lymph Node.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eTumor progression status at last follow-up:\u003c/h2\u003e \u003cp\u003eAt the last follow-up, disease progression occurred in 9 patients (42.8%). The most common pattern of failure was simultaneous regional and distant progression, which was observed in 5 of these patients (23.8% of the entire cohort). The detailed sites and timing of progression for each case are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eSurvival Outcomes:\u003c/h2\u003e \u003cp\u003eWe set the start time of calculating Progression-Free Survival (PFS) and Overall Survival (OS) to the end time of radiotherapy to observe the disease progression and survival after radiotherapy, so as to better understand the role of radiotherapy in survival. At the last follow-up, 16 patients survived and 5 patients died of extensive metastasis; among the deceased, 1 patient died of bleeding secondary to thrombocytopenia caused by extensive bone marrow metastasis. The other patient had a complete response but died from unexplained bleeding.\u003c/p\u003e \u003cp\u003e \u003cb\u003ePFS and OS\u003c/b\u003e: The results of the survival analysis are detailed in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. For the entire cohort, the median progression-free survival (PFS) was 6.0 months (95% CI: 2.30\u0026ndash;9.70), and the median overall survival (OS) was 8.0 months (95% CI: 6.69\u0026ndash;9.31). Univariate analysis identified several variables, including younger age (\u0026le;\u0026thinsp;23 years) and smaller radiotherapy target volumes (PTV\u0026thinsp;\u0026le;\u0026thinsp;1355.6 cc), that were associated with a numerically longer median PFS, although these trends did not reach statistical significance. In the multivariate Cox regression model, the administration of combination systemic therapy around the time of radiotherapy emerged as the only factor significantly associated with improved PFS (HR 3.94, 95%CI 1.32\u0026ndash;11.78; p\u0026thinsp;=\u0026thinsp;0.014). Supporting this finding, an exploratory analysis revealed that patients receiving chemotherapy-based regimens had the most favorable PFS outcomes. Conversely, patients treated with TKI-containing regimens had a significantly shorter median PFS compared to those who were not (4.0 vs. 8.5 months, p\u0026thinsp;=\u0026thinsp;0.048; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). No factors were independently prognostic for OS in multivariate analysis.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSurvival Analysis of Patient, Treatment, and Tumor Characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCategory\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMedian PFS (months)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP Value (PFS)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMedian OS (months)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eP Value\u003c/p\u003e \u003cp\u003e(OS)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAll Patients\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnivariate Analysis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026le;\u0026thinsp;23 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.082\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.218\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;23 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKPS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.196\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.551\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePTV Volume\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026le;\u0026thinsp;1355.6 cc\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.082\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.807\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;1355.6 cc\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSystemic Therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eChemotherapy-based\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.192\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.157\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTKI-based\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOther / None\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRT Interruption\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.879\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.270\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMultivariate Analysis for PFS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHazard Ratio (95% CI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP Value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCombination Systemic Therapy (Yes vs. No)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.94 (1.32\u0026ndash;11.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExploratory Analysis for PFS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMedian PFS (months)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP Value\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTKI-containing vs. Non-TKI regimens\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTKI-containing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.048\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNon-TKI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eNote: CI, confidence interval; PFS, progression-free survival; OS, overall survival; KPS, Karnofsky Performance Status; PTV, Planning Target Volume; TKI, Tyrosine kinase inhibitor; RT, Radiotherapy.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eAcute toxicity:\u003c/h2\u003e \u003cp\u003eAcute toxicities observed during treatment are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. Manageable hematological toxicity was the most common adverse event, with four patients (19.0%) experiencing grade 3 thrombocytopenia requiring brief treatment interruption. Significant decreases in white blood cells, platelets, and neutrophils were observed after radiotherapy (all p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). One patient (4.7%) in the whole-lung irradiation group developed grade 3 radiation pneumonitis, which resolved with corticosteroid treatment.\u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eEWS exhibits marked radiosensitivity. Given the limited data on all-site radiotherapy in widely metastatic EWS, this retrospective analysis provides a detailed assessment of its short-term feasibility. We demonstrated that comprehensive radiotherapy targeting all known metastatic sites achieves exceptional short-term local control (97.4% DCR) with a manageable toxicity profile. Beyond feasibility, a key and unexpected finding was the profound difference in complete response rates between soft tissue and bone metastases. This, along with the association between systemic therapy type and short-term PFS, forms the core contribution of this preliminary report.\u003c/p\u003e \u003cp\u003eOur high local control rate aligns with prior studies utilizing radiotherapy for EWS metastases. Talleur et al. [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] reported outstanding local control (10-year cumulative failure rate 4.4% \u0026plusmn; 3.1%) in 45 EWS patients (including 19 metastatic) treated with conventionally fractionated radiotherapy (median follow-up 54.5 months). Casey et al. [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] achieved cumulative local failure rates of 6.6% at 1 year and 9% at 3 years using SBRT for 49 bone metastases (22 EWS patients). Grewal et al. [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], in a cohort of 27 metastatic ES patients, observed a non-significant trend favoring metastasis-directed therapy (MDT), suggesting a 76% lower recurrence risk (OR 0.24; P\u0026thinsp;=\u0026thinsp;0.38) compared to no MDT. Our short-term results, with a 2.6% local failure rate (affecting only two bone lesions), further substantiate the potent local efficacy of radiotherapy against EWS metastases, even when employing moderately hypofractionated regimens like those used here (45\u0026ndash;55 Gy in 20 fractions). Notably, the CR rate of our bone lesions was significantly lower than that of soft tissue lesions (3.2% vs 78.3%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). This striking disparity, rarely highlighted in prior literature, suggests a fundamental biological difference in radiosensitivity or post-radiation tissue repair between metastatic sites. Potential explanations include the hypoxic microenvironment of bone metastases, differences in immune cell infiltration, or altered DNA damage repair capacity. This observation has direct clinical implications: it argues against a \u0026ldquo;one-size-fits-all\u0026rdquo; radiation prescription for all metastatic sites and strongly suggests that bone metastases may require combinatorial strategies to enhance response. Future studies should investigate dose escalation specifically to bone lesions, the use of bone-targeted radiosensitizers (e.g., radiopharmaceuticals, bisphosphonates), or novel systemic agents with enhanced bone penetration. Functional imaging (e.g., DCE-MRI, PET) in this context could shed light on the differential perfusion and metabolic response.\u003c/p\u003e \u003cp\u003eCrucially, aggressive local control of all metastatic sites may translate into tangible survival benefits, as evidenced by previous studies. Haeusler et al. [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] demonstrated in the EURO-EWING 99 cohort that patients receiving local therapy to both the primary tumor and all metastases had significantly superior 3-year event-free survival compared to those with incomplete or no local therapy (39% vs. 17% vs. 14%, P\u0026thinsp;\u0026lt;\u0026thinsp;.001). This is further supported by Bronk et al. [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], who reported impressive 4-year outcomes (LC: 83%, PFS: 71%, OS: 86%) in pediatric metastatic Ewing sarcoma patients treated with comprehensive proton therapy, achieving survival rates approaching those of their localized disease cohort. Similarly, Ahmed et al. [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] specifically found that adults receiving radiotherapy to all metastases had significantly improved 4-year overall and event-free survival compared to those who did not (OS: 33% vs. 0%; EFS: 11% vs. 0%), and combining radiotherapy with VDC/IE chemotherapy further enhanced survival. In line with these findings, our study provides early, real-world evidence supporting the clinical feasibility of this approach. We observed a median PFS of 6.0 months and OS of 8.0 months, and our multivariate analysis reinforced the critical importance of effective systemic therapy, identifying its combination with radiotherapy as a significant factor for improved PFS (p\u0026thinsp;=\u0026thinsp;0.014), with chemotherapy-based regimens yielding the numerically best median PFS of 8.5 months. These findings collectively underscore the promise of comprehensive MDT and provide a rationale for future prospective trials to validate its efficacy and optimize the integration with systemic agents.\u003c/p\u003e \u003cp\u003eOur study adds to the growing body of evidence supporting the role of whole-lung irradiation (WLI) in the management of metastatic Ewing sarcoma. In our small cohort of five patients receiving WLI (with or without pleural involvement) for a total of 19 lesions, we observed a high objective response rate (ORR) of 78.9% and a 100% disease control rate (DCR), underscoring the potent radiosensitivity of pulmonary Ewing sarcoma metastases. This aligns with the established efficacy of WLI in both primary and relapsed settings. In patients with isolated lung metastases at diagnosis, the addition of WLI to chemotherapy has been associated with 5-year overall survival (OS) rates of approximately 50\u0026ndash;70% [\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Notably, the Italian Sarcoma Group study reported a 5-year pulmonary relapse-free survival (PRFS) of 70.5% and a 5-year OS of 69.8% in patients treated with WLI following high-dose busulfan/melphalan, highlighting its potential for durable disease control [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Similarly, in the specific context of pulmonary relapse\u0026mdash;a scenario with historically poor outcomes\u0026mdash;WLI has demonstrated a significant improvement in 3-year progression-free survival (36% vs 14%) and overall survival (47% vs 33%) compared to no WLI [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Our findings, though preliminary due to the sample size, contribute to this consensus by confirming excellent short-term local control with the WLI\u0026thinsp;+\u0026thinsp;boost regimen. Regarding safety, our observation of manageable toxicity (one case of grade 3 pneumonitis) is consistent with modern series. While WLI is generally well-tolerated, its combination with specific chemotherapies, particularly busulfan, warrants careful timing and dose consideration to mitigate pulmonary toxicity [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Promisingly, advanced techniques like intensity-modulated radiotherapy (IMRT) and proton therapy (PWLI) are now being employed to significantly reduce radiation dose to critical organs such as the heart, breasts, and thyroid, thereby potentially further improving the long-term therapeutic index of WLI [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn an exploratory analysis, we observed an association between TKI use (anlotinib or apatinib) and shorter PFS compared to no TKI use (4.0 vs. 8.5 months, p\u0026thinsp;=\u0026thinsp;0.048). Several TKIs have demonstrated clinical activity in refractory EWS [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]; for instance, studies have reported promising response rates and PFS with anlotinib and apatinib in this setting [\u003cspan additionalcitationids=\"CR23\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Given this established efficacy, our finding most likely reflects significant confounding rather than a true detrimental effect of TKIs. As a salvage therapy in our cohort, TKIs were often used in more heavily pre-treated patients with inherently poorer prognosis. Therefore, this association should be interpreted with extreme caution and serves primarily as a hypothesis-generating observation regarding patient selection in real-world practice. It underscores the current lack of standardized protocols for integrating novel agents like TKIs with aggressive local therapies and the need for prospective studies to define their optimal sequencing.\u003c/p\u003e \u003cp\u003eImportantly, despite achieving 97.4% local control within irradiated fields, 42.9% of patients experienced regional or distant progression at a median follow-up of only 6 months. This rapid out-of-field failure starkly illustrates the systemic nature of widespread metastatic EWS and the inherent limitation of any local therapy alone. These data powerfully reinforce our central conclusion: the high short-term local control achieved with all-site radiotherapy is clinically meaningful but insufficient for long-term disease control. Therefore, the primary therapeutic challenge remains the concomitant micrometastatic disease. This observation provides a compelling rationale for urgently integrating this aggressive local approach with more effective systemic therapies. Promising strategies under active investigation, which could logically build upon the local control we observed, include combining radiotherapy with immunotherapy to potentially induce abscopal effects [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], leveraging radiosensitizers like PARP inhibitors [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e], and exploring novel cellular therapies [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAcute toxicities in our study were manageable, primarily manifesting as hematologic suppression, with 4 patients (19%) requiring temporary radiotherapy interruption due to thrombocytopenia. Considering our moderately hypofractionated regimen (Equivalent Dose in 2 Gy fractions [EQD₂] GTV\u0026thinsp;~\u0026thinsp;58.44 Gy, PTV\u0026thinsp;~\u0026thinsp;45.94 Gy for α/β\u0026thinsp;=\u0026thinsp;10 [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]) was slightly higher than conventional NCCN-recommended EQD₂ levels (GTV\u0026thinsp;~\u0026thinsp;54.87 Gy, PTV\u0026thinsp;~\u0026thinsp;44.25 Gy [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]) and accounting for concurrent systemic therapy, no compensatory dose was delivered for treatment interruptions. One of the five patients who received whole-lung irradiation had grade 3 radiation pneumonitis. In this patient, the lung dosimetric parameters were safe (Mean dose [Dmean] 14.27Gy, Volume of lung receiving 20 Gy or more [V20] 3.9%), but the primary contributing factor was the concurrent treatment with sindilizumab during whole-lung irradiation. Bi et al. [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e] demonstrated that thoracic radiotherapy with concurrent or sequential immunotherapy significantly increased the risk of radiation pneumonitis. For targeted therapy, the impact of anlotinib on RP remains unclear because of inconsistent study results [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eKey limitations of our study must be acknowledged. First, the short median follow-up (6 months) precludes any assessment of long-term survival, late toxicity, or durable local control. This directly informs our interpretation of the progression-free and overall survival data as preliminary, short-term outcomes, and positions the study primarily as an analysis of feasibility, early response, and safety. Second, the retrospective, single-center design carries inherent risks of selection bias and limits data standardization. Third, significant heterogeneity existed in patients\u0026rsquo; prior treatment histories, which confounds the interpretation of subgroup analyses and may contribute to the selection bias noted for agents like TKIs. Fourth, the small sample size (n\u0026thinsp;=\u0026thinsp;21) severely limits the statistical power for subgroup analyses and multivariate modeling, increasing the risk of overfitting and Type II errors. Fifth, the heterogeneity in systemic therapies received concurrently or around the time of radiotherapy confounds the precise interpretation of their specific impact on outcomes. Given these constraints, all subgroup findings, including the striking differential response between bone and soft tissue lesions and the association between systemic therapy type and PFS, must be viewed as exploratory and hypothesis-generating, requiring validation in larger, prospective cohorts.\u003c/p\u003e \u003cp\u003eWe acknowledge that the small sample size and short follow-up period of our study limit the generalizability and strength of our conclusions. Nonetheless, this report provides one of the few detailed series on the application of comprehensive all-site radiotherapy in widely metastatic Ewing sarcoma. It offers valuable initial data on the high short-term local control achievable with this approach and generates important hypotheses regarding the interplay between radiotherapy and systemic therapies that warrant future investigation in larger, prospective cohorts.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, this short-term analysis demonstrates that comprehensive all-site radiotherapy is a feasible and safe local strategy for metastatic Ewing sarcoma, providing high rates of initial local control. The integration of systemic therapy was crucial. The dramatic difference in response between bone and soft tissue metastases is a novel finding that merits further biological and clinical investigation. While the observed association with TKI use requires validation, the rapid systemic progression seen underscores the imperative to combine this aggressive local approach with next-generation systemic therapies. Future research should focus on prospectively testing all-site radiotherapy in combination with novel agents and on developing strategies to overcome the radioresistance suggested in bone metastases.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eEWS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEwing sarcoma\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMDT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emetastasis-directed therapy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTKIs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003etyrosine kinase inhibitors\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eICIs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eimmune checkpoint inhibitors\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eORR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eobjective response rate\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRECIST\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eResponse Evaluation Criteria in Solid Tumors\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ecomplete response\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epartial response\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDCR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003edisease control rate\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003estable disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eprogressive disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePFS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eprogression-free survival\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eOS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eoverall survival\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ehelical tomotherapy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eKPS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eKarnofsky Performance Status\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGTV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003egross tumor volume\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCTV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eclinical target volume\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePTV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eplanning target volume\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eWLI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ewhole lung irradiation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eOARs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eorgans at risk\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSBRT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003estereotactic body radiation therapy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMV-CT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMegavoltage computed tomography\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eWBC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ewhite blood cells\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eEQD₂\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEquivalent Dose in 2 Gy fractions\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDmean\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMean dose\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eV20\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eVolume of lung receiving 20 Gy or more\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eradiation pneumonitis.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003cstrong\u003e：\u003c/strong\u003eThe authors have nothing to report.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFinancial Support\u003c/strong\u003e\u003cstrong\u003e：\u003c/strong\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of Competing Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Sharing Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe individual participant data that underlie the results reported in this article are not publicly available due to patient privacy concerns. However, deidentified summary data (e.g., aggregated statistical results) that support the findings of this study are available from the corresponding author upon reasonable request, subject to review and approval of a proposal.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was conducted in accordance with the ethical principles of the World Medical Association Declaration of Helsinki. The study protocol was approved by the Institutional Review Board of Peking University Shougang Hospital (Approval No.: IRB-AF-37-03-2). Written informed consent was obtained from all individual participants (or their parents/legal guardians in the case of minors [under the age of 16]) prior to treatment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from all individual participants (or their parents/legal guardians for those under 16) for the publication of their personal or clinical details and any identifying images included in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analyzed during the current study are not publicly available due to patient privacy and confidentiality considerations but are available from the corresponding author upon reasonable request and with permission from the Peking University Shougang Hospital Ethics Committee.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests as defined by the journal, or other interests that might be perceived to influence the results and/or discussion reported in this paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYuanYou Yang: Conceptualization, Methodology, Investigation, Formal Analysis, Writing - Original Draft; Lu Xie, Xin Sun, Jie Xu: Methodology, Investigation; Gang Ren: Conceptualization, Supervision, Writing - Review \u0026amp; Editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGr\u0026uuml;newald TGP, Cidre-Aranaz F, Surdez D, Tomazou EM, de \u0026Aacute;lava E, Kovar H et al (2018) Ewing sarcoma. Nat Rev Dis Primers 4(1):5. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/S41572-018-0003-X\u003c/span\u003e\u003cspan address=\"10.1038/S41572-018-0003-X\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePappo AS (2018) Uta Dirksen. Rhabdomyosarcoma, Ewing sarcoma, and other round cell sarcomas. J Clin Oncol 36(2):168\u0026ndash;179. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1200/jco.2017.74.7402\u003c/span\u003e\u003cspan address=\"10.1200/jco.2017.74.7402\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGunderson LL, Tepper JE (eds) (2016) Clinical radiation oncology. Fourth Edition. Elsevier Health. Philadelphia, PA, pp.1412\u0026ndash;1420\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKarimi AM, Campbell SR, Parsai S, Angelov L, Scott J, Qi P et al (2020) Aggressive Local control with multisite stereotactic body radiation in metastatic Ewing Sarcoma: a literature review and case report. Anticancer Res 40(2):951\u0026ndash;955. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.21873/anticanres.14028\u003c/span\u003e\u003cspan address=\"10.21873/anticanres.14028\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePalma DA, Olson R, Harrow S, Gaede S, Louie AV, Haasbeek C et al (2019) Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): A randomised, phase 2,open-label trial. Lancet 393:2051\u0026ndash;2058\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGomez DR, Tang C, Zhang JJ, Blumenschein GR Jr, Hernandez M, Lee JJ et al (2019) Local consolidative therapy vs.maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer: Long-term results of a multi-institutional, phase II, randomized study. J Clin Oncol 37:1558\u0026ndash;1565\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCasey DL, Murphy ES, Shen CJ, Milgrom SA, Larrier NA, Bradley JA et al (2025) Metastatic-Site Radiation Therapy for Ewing Sarcoma and Rhabdomyosarcoma: Consensus Guidelines From the National Pediatric Cancer Foundation. Pract Radiat Oncol 15(2):180\u0026ndash;186. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.prro.2024.10.004\u003c/span\u003e\u003cspan address=\"10.1016/j.prro.2024.10.004\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNCCN clinical practice guidelines in oncology \u0026ndash; Bone Cancer (2025) \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e.https://www.nccn.org/professionals/physician_gls/pdf/bone.pdf\u003c/span\u003e\u003cspan address=\"http://.https://www.nccn.org/professionals/physician_gls/pdf/bone.pdf\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTimmerman R (2022) A Story of Hypofractionation and the Table on the Wall. Int J Radiat Oncol Biol Phys 112(1):4\u0026ndash;21. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.ijrobp.2021.09.027\u003c/span\u003e\u003cspan address=\"10.1016/j.ijrobp.2021.09.027\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45(2):228\u0026ndash;247. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.ejca.2008.10.026\u003c/span\u003e\u003cspan address=\"10.1016/j.ejca.2008.10.026\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTalleur AC, Navid F, Spunt SL, McCarville MB, Wu J, Mao SH et al (2016) Limited Margin Radiation Therapy for Children and Young Adults With Ewing Sarcoma Achieves High Rates of Local Tumor Control. Int J Radiat Oncol Biol Phys 96(1):119\u0026ndash;126. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.ijrobp.2016.04.001\u003c/span\u003e\u003cspan address=\"10.1016/j.ijrobp.2016.04.001\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCasey DL, Wexler LH, Meyers PA, Magnan H, Chou AJ, Wolden SL (2015) Radiation for bone metastases in Ewing sarcoma and rhabdomyosarcoma. Pediatr Blood Cancer 62(3):445\u0026ndash;449. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/pbc.25294\u003c/span\u003e\u003cspan address=\"10.1002/pbc.25294\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGrewal AS, Li YM, Grewal SK, Bagatell R, Balamuth N, Womer R et al (2020) Role of Metastatic Site Irradiation in Pediatric Patients With Metastatic Ewing Sarcoma. J Pediatr Hematol Oncol 42(5):e305\u0026ndash;e309. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/MPH.0000000000001752\u003c/span\u003e\u003cspan address=\"10.1097/MPH.0000000000001752\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHaeusler J, Ranft A, Boelling T, Gosheger G, Braun-Munzinger G, Vieth V et al (2010) The value of local treatment in patients with primary, disseminated, multifocal Ewing sarcoma (PDMES). Cancer 116(2):443\u0026ndash;450. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/cncr.24740\u003c/span\u003e\u003cspan address=\"10.1002/cncr.24740\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBronk JK, McAleer MF, McGovern SL, Lassen-Ramshad Y, Safwat A, Daw NC et al (2024) Comprehensive radiotherapy for pediatric Ewing Sarcoma: Outcomes of a prospective proton study. Radiother Oncol 195:110270. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.radonc.2024.110270\u003c/span\u003e\u003cspan address=\"10.1016/j.radonc.2024.110270\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAhmed SK, Robinson, Okuno SSH, Rose PS, Laack NNI (2014) Adult Ewing sarcoma: survival and local control outcomes in 36 patients with metastatic disease. Am J Clin Oncol 37(5):423\u0026ndash;429. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/COC.0b013e31827de65e\u003c/span\u003e\u003cspan address=\"10.1097/COC.0b013e31827de65e\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAbate ME, Cammelli S, Ronchi L, Diletto B, Gandola L, Paioli A et al (2021) Whole Lung Irradiation after High-Dose Busulfan/Melphalan in Ewing Sarcoma with Lung Metastases: An Italian Sarcoma Group and Associazione Italiana Ematologia Oncologia Pediatrica Joint Study. Cancers (Basel) 13(11):2789. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/cancers13112789\u003c/span\u003e\u003cspan address=\"10.3390/cancers13112789\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eElghazawy H, Nasr A, Zaky I, Zamzam M, Elgammal A, Farid N et al (2020) Whole lung irradiation for completely responding pulmonary metastases in pediatric Ewing sarcoma. Future Oncol 16(15):1043\u0026ndash;1051. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.2217/fon-2020-0066\u003c/span\u003e\u003cspan address=\"10.2217/fon-2020-0066\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eScobioala S, Ranft A, Wolters H, Jabar S, Paulussen M, Timmermann B et al (2018) Impact of Whole Lung Irradiation on Survival Outcome in Patients With Lung Relapsed Ewing Sarcoma. Int J Radiat Oncol Biol Phys 102(3):584\u0026ndash;592. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.ijrobp.2018.06.032\u003c/span\u003e\u003cspan address=\"10.1016/j.ijrobp.2018.06.032\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCunningham DA, Breen WG, Johnson JE, Mullikin TC, Bradley TB, Sorenson KL et al (2023) Proton Whole-Lung Irradiation: Initial Report of Outcomes. Int J Radiat Oncol Biol Phys 115(4):866\u0026ndash;872. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.ijrobp.2022.10.001\u003c/span\u003e\u003cspan address=\"10.1016/j.ijrobp.2022.10.001\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFleuren EDG, Vlenterie M, van der Graaf WTA (2023) Recent advances on anti-angiogenic multi-receptor tyrosine kinase inhibitors in osteosarcoma and Ewing sarcoma. Front Oncol. ;13:1013359. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fonc.2023.1013359\u003c/span\u003e\u003cspan address=\"10.3389/fonc.2023.1013359\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. eCollection 2023\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXu J, Xie L, Sun X, Liu KS, Tang XD, Yan TQ et al (2021) Anlotinib, Vincristine, and Irinotecan for Advanced Ewing Sarcoma After Failure of Standard Multimodal Therapy: A Two-Cohort, Phase Ib/II Trial. Oncologist 26(7):e1256\u0026ndash;e1262. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/onco.13726\u003c/span\u003e\u003cspan address=\"10.1002/onco.13726\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu ZY, Gao ST, Zhu LY, Wang JQ, Zhang P, Li P et al (2021) Efficacy and safety of anlotinib in patients with unresectable or metastatic bone sarcoma: A retrospective multiple institution study. Cancer Med 10(21):7593\u0026ndash;7600. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/cam4.4286\u003c/span\u003e\u003cspan address=\"10.1002/cam4.4286\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang YT, Min L, Zhou Y, Luo Y, Duan H, Tu CQ (2018) The efficacy and safety of apatinib in Ewing's sarcoma: a retrospective analysis in one institution. Cancer Manag Res. ;10:6835\u0026ndash;6842. doi: 10.2147/CMAR.S181087. eCollection 2018\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCallaghan CM, Seyedin SN, Mohiuddin IH, Hawkes KL, Petronek MS, Anderson CM et al (2020) The Effect of Concurrent Stereotactic Body Radiation and Anti-PD-1 Therapy for Recurrent Metastatic Sarcoma. Radiat Res 194(2):124\u0026ndash;132. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1667/RADE-20-00017\u003c/span\u003e\u003cspan address=\"10.1667/RADE-20-00017\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXie J, Mellado-Lagarde MM, Blankenship K, Ganguly D, Twarog NR, Bianski B et al (2025) The Combination of PARP and Topoisomerase 1 Inhibitors Improves Radiation Therapy for Ewing Sarcoma. Cancer Sci 116(6):1703\u0026ndash;1714. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/cas.70042\u003c/span\u003e\u003cspan address=\"10.1111/cas.70042\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLam PY, Omer N, Wong JKM, Tu C, Alim L, Rossi GR et al (2025) Enhancement of anti-sarcoma immunity by NK cells engineered with mRNA for expression of a EphA2-targeted CAR. Clin Transl Med 15(1):e70140. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/ctm2.70140\u003c/span\u003e\u003cspan address=\"10.1002/ctm2.70140\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHall EJ (1994) Molecular biology in radiation therapy: the potential impact of recombinant technology on clinical practice. Int J Radiat Oncol Biol Phys 30(5):1019\u0026ndash;1028. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/0360-3016(94)90305-0\u003c/span\u003e\u003cspan address=\"10.1016/0360-3016(94)90305-0\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBi JP, Qian J, Yang DQ, Sun L, Lin SY, Li Y et al (2022) Dosimetric Risk Factors for Acute Radiation Pneumonitis in Patients With Prior Receipt of Immune Checkpoint Inhibitors. Front Immunol 12:828858\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBi JP, Meng R, Yang DQ, Li Y, Cai J, Zhang L et al (2024) Dosimetric predictors of radiation pneumonitis in patients with prior immunotherapy exposure: A multi-institutional analysis. Radiother Oncol 190:110040\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKroeze SGC, Fritz C, Basler L, Gkika E, Brunner TB, Grosu AL et al (2019) Combination of stereotactic radiotherapy and targeted therapy: patterns-of-care survey in German-speaking countries. Strahlenther Onkol 195(3):199\u0026ndash;206. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00066-018-01422-5\u003c/span\u003e\u003cspan address=\"10.1007/s00066-018-01422-5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMart\u0026iacute;nez E, Mart\u0026iacute;nez M, Rico M, Hern\u0026aacute;ndez B, Casas F, Vi\u0026ntilde;olas N et al (2016) Feasibility, tolerability, and efficacy of the concurrent addition of erlotinib to thoracic radiotherapy in locally advanced unresectable non-small-cell lung cancer: a Phase II trial. Onco Targets Ther. ;9:1057-66. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.2147/OTT.S89755\u003c/span\u003e\u003cspan address=\"10.2147/OTT.S89755\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. eCollection 2016\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"clinical-and-experimental-metastasis","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"clin","sideBox":"Learn more about [Clinical \u0026 Experimental Metastasis](http://link.springer.com/journal/10585)","snPcode":"10585","submissionUrl":"https://submission.nature.com/new-submission/10585/3","title":"Clinical \u0026 Experimental Metastasis","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Ewing’s sarcoma, Metastatic disease, All-site radiotherapy","lastPublishedDoi":"10.21203/rs.3.rs-8350070/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8350070/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eMetastatic Ewing sarcoma (EWS) has a poor prognosis. While metastasis-directed therapy (MDT) benefits oligometastatic disease, the role of comprehensive radiotherapy targeting all metastatic sites in widespread disease remains underexplored. This study aimed to provide a preliminary assessment of the short-term efficacy and safety of all-site radiotherapy in metastatic EWS.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis retrospective analysis included 21 consecutive metastatic EWS patients treated with helical tomotherapy (Aug 2024\u0026ndash;Jun 2025). All known metastatic lesions and the primary tumor (if unresected) received radiotherapy. Prescription doses were 45\u0026ndash;55 Gy in 20 fractions for most sites; lung/pleural metastases received adapted regimens (12\u0026ndash;45 Gy). Systemic therapy regimens varied (chemotherapy, tyrosine kinase inhibitors [TKIs], immune checkpoint inhibitors [ICIs], or combinations). Primary endpoints were local objective response rate (ORR, RECIST 1.1) and acute toxicity (CTCAE 5.0). Secondary/exploratory endpoints included progression-free survival (PFS), overall survival (OS).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eMedian follow-up was 6 months (range 2\u0026ndash;11). Among 77 target lesions, the objective response rate (ORR, complete response [CR]\u0026thinsp;+\u0026thinsp;partial response [PR]) was 61.0% (47/77), including a CR rate of 48.1% (37/77). The disease control rate (DCR, CR\u0026thinsp;+\u0026thinsp;PR\u0026thinsp;+\u0026thinsp;stable disease [SD]) was 97.4%. A striking finding was the significantly higher complete response rate in soft tissue lesions compared to bone metastases (78.3% vs 3.2%, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The median PFS was 6.0 months (95% CI: 2.30\u0026ndash;9.70), and the median OS was 8.0 months (95% CI: 6.69\u0026ndash;9.31). Multivariate analysis identified \"Combination Systemic Therapy\" as associated with improved PFS (HR 3.94, 95%CI 1.32\u0026ndash;11.78; p\u0026thinsp;=\u0026thinsp;0.014), with chemotherapy-based regimens showing the best median PFS (8.5 months). An exploratory analysis suggested shorter PFS in patients receiving TKI-containing regimens (4.0 vs 8.5 months, p\u0026thinsp;=\u0026thinsp;0.048); however, this finding is likely confounded by selection bias, as TKIs were often used in more heavily pretreated patients. Acute toxicity was manageable: grade 3 thrombocytopenia (19.0%, n\u0026thinsp;=\u0026thinsp;4) and one case (4.7%) of grade 3 pneumonitis resolved with steroids.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eAll-site radiotherapy achieved promising short-term local control with manageable toxicity in metastatic EWS. These short-term data demonstrate the feasibility of this approach and highlight a marked differential response by lesion site, warranting further biological investigation. Systemic therapy, particularly chemotherapy, was associated with improved PFS in this cohort. The high rate of systemic progression observed shortly after treatment underscores that improving long-term outcomes will require integration with more effective systemic therapies. Our findings provide a rationale and specific hypotheses for future prospective trials.\u003c/p\u003e","manuscriptTitle":"All-site radiotherapy for metastatic Ewing's sarcoma: a short-term analysis of feasibility, response, and safety","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-11 05:26:33","doi":"10.21203/rs.3.rs-8350070/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-03-07T15:45:20+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-26T09:14:00+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"26121520233158570159691664557583550598","date":"2026-02-26T07:50:12+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-05T21:59:22+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-12-13T04:55:27+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-12-13T04:54:22+00:00","index":"","fulltext":""},{"type":"submitted","content":"Clinical \u0026 Experimental Metastasis","date":"2025-12-13T04:34:44+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"clinical-and-experimental-metastasis","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"clin","sideBox":"Learn more about [Clinical \u0026 Experimental Metastasis](http://link.springer.com/journal/10585)","snPcode":"10585","submissionUrl":"https://submission.nature.com/new-submission/10585/3","title":"Clinical \u0026 Experimental Metastasis","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"8604371d-82ab-4e0f-965a-f61a816ec1ba","owner":[],"postedDate":"February 11th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-05-04T16:05:59+00:00","versionOfRecord":{"articleIdentity":"rs-8350070","link":"https://doi.org/10.1007/s10585-026-10406-0","journal":{"identity":"clinical-and-experimental-metastasis","isVorOnly":false,"title":"Clinical \u0026 Experimental Metastasis"},"publishedOn":"2026-04-27 15:57:22","publishedOnDateReadable":"April 27th, 2026"},"versionCreatedAt":"2026-02-11 05:26:33","video":"","vorDoi":"10.1007/s10585-026-10406-0","vorDoiUrl":"https://doi.org/10.1007/s10585-026-10406-0","workflowStages":[]},"version":"v1","identity":"rs-8350070","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8350070","identity":"rs-8350070","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}