Clinical Outcomes and Toxicity After Extracranial Stereotactic Body Radiotherapy for Pediatric Malignancies in a Two Center Retrospective Study

Clinical Outcomes and Toxicity After Extracranial Stereotactic Body Radiotherapy for Pediatric Malignancies in a Two Center Retrospective Study | 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 Clinical Outcomes and Toxicity After Extracranial Stereotactic Body Radiotherapy for Pediatric Malignancies in a Two Center Retrospective Study Senay Mutaf Gecgel, Zeynep Gural, Ayca Irıbas Celık, Erkın AKyuz, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9001868/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Stereotactic body radiotherapy (SBRT) in pediatric malignancies offers precise, high-dose radiation delivery to tumors while minimizing exposure to surrounding healthy tissues—an important consideration in preventing adverse effects on growth and development. The use of SBRT in pediatric oncology has been increasing; however, clinical data and outcome reports remain limited. This study aimed to evaluate local control (LC), progression-free survival (PFS), overall survival (OS), and toxicity rates following SBRT in pediatric patients with extracranial metastases. Materials/Methods Between 2012 and 2024, 21 pediatric patients treated in our department for extracranial lesions of malignant tumors using linear accelerator–based, CT-guided SBRT were retrospectively analyzed. LC and OS were assessed using the Kaplan–Meier method. Results All patients received definitive SBRT for oligometastatic disease. At diagnosis, 13 patients (61.9%) presented with metastatic disease. The median follow-up time was 10 months (range, 4–157), and the median age was 13 years (range, 4–17). Ewing sarcoma was the most common histologic subtype (52.4%). A total of 37 extracranial lesions were irradiated; 21 (56.7%) were bone metastases. SBRT was delivered to four sites in one patient and to three simultaneous sites in five patients.The median number of fractions was 5 (range, 3–5), with a median dose per fraction of 5 Gy (range, 5–9 Gy). Median BED₁₀and EQD₂were 37.5 Gy (31.25–72) and 31.2 Gy (31.2–60), respectively. The median PTV volume was 68 cm³ (range, 2.1–541 cm³). Median PFS was 8 ± 1.29 months (95% CI: 5.4–10.5), and median OS was 12 ± 3.07 months (95% CI: 5.98–18).Local recurrence occurred in 10 patients (47.6%), of whom 6 (60%) had in-field recurrences. Among these, 3 of 6 patients had osteosarcoma histology. One- and two-year LC rates were 25% and 18%, respectively, while OS rates were 49% and 30%. There was a statistically significant difference in both PFS and OS among histologic subtypes (p = 0.03 and p = 0.004, respectively). No ≥Grade 3 acute or late toxicity was observed. Conclusion SBRT was well tolerated in pediatric patients, with minimal toxicity. However, longer follow-up is required to assess late effects. The preference for more moderate fractionation schemes due to large tumor volumes and younger age groups may also be related to higher rates of in-field recurrence in histologies that are more resistant to radiotherapy. Further studies are warranted to establish the optimal SBRT dose and fractionation parameters for pediatric malignancies. Pediatric malignancy stereotactic body radiotherapy extracranial metastases oligometastatic disease local control toxicity INTRODUCTION Radiotherapy is an indispensable component of both curative and palliative treatment approaches in childhood malignancies. However, to minimize the potential adverse effects of radiotherapy on growth and development in pediatric patients, modern high-precision radiotherapy techniques have gained increasing importance. One such technique is stereotactic body radiotherapy (SBRT), a noninvasive treatment modality that allows the delivery of high doses of radiation to the targeted tumor volume with millimetric accuracy, typically in 1–5 fractions. With the use of advanced imaging technologies and modern radiotherapy planning systems, SBRT enables the administration of highly conformal and ablative radiation doses to the tumor while minimizing exposure of surrounding healthy tissues. The ablation-like effect of SBRT as an alternative to surgery, together with its potential immunological mechanisms and noninvasive nature, represents major advantages of this technique. High local control rates observed in adult patients, survival benefits in oligometastatic disease, and effective symptom palliation have led to the widespread clinical aplication of SBRT. In contrast, SBRT is not routinely incorporated into treatment protocols for pediatric malignancies, and the available evidence is largely limited to case series and retrospective studies. In childhood cancers, SBRT is primarily used for extracranial metastases—particularly bone metastases—for palliative purposes and to achieve long-term disease control in oligometastatic settings. Additionally, SBRT is employed for re-irradiation of residual or recurrent lesions, extracranial soft tissue tumors, and spinal or paraspinal lesions to provide palliation and local disease control. In this study, we evaluated local control (LC), progression-free survival (PFS), overall survival (OS), and toxicity outcomes in pediatric patients who received SBRT for extracranial lesions at two institutions. MATERIALS AND METHODS Between 2012 and 2024, the databases of MAA Acıbadem University Atakent Hospital and Istanbul University Faculty of Medicine, Çapa Hospital were retrospectively reviewed to identify pediatric patients who received SBRT for metastatic disease. Inclusion Criteria Age < 18 years and treatment delivered to an extracranial site SBRT delivered in a maximum of five fractions using linear accelerator–based systems A minimum follow-up duration of three months During follow-up, progression sites were evaluated using CT, PET-CT, or MRI in cases of symptom development or suspected disease progression. Medical records were reviewed to collect data on treatment response, acute and late toxicities, last follow-up date, and current disease status. Tumor response was assessed based on follow-up imaging studies. Collected patient data included age, sex, ECOG performance status, primary tumor histology, date of diagnosis, presence of multiple metastases, metastasis-directed surgery, local or distant progression after SBRT, last follow-up date, and current survival status. All patients were treated with SBRT using CT-based linear accelerator systems with daily cone-beam CT–guided image-guided radiotherapy (IGRT). Treatment-related data, including number of fractions, dose per fraction, and total prescribed dose, were recorded. Statistical Analysis PFS and OS were calculated using the Kaplan–Meier method. OS was defined as the interval from the first SBRT session to death from any cause or to the last follow-up date for surviving patients. LC was characterized by the absence of lesion size progression, no significant increase in contrast enhancement, and no notable increase in surrounding edema on follow-up imaging of the area treated with SBRT. Prognostic analyses according to tumor type and dosimetric factors were performed using the log-rank test. A p-value < 0.05 was considered statistically significant. All statistical analyses were performed using SPSS v23 (IBM, Armonk, NY, USA). RESULTS Patient Demographics and Treatment Characteristics A total of 21 pediatric patients treated with definitive SBRT for oligometastatic or oligoprogresive disease at two centers were included. Of these patients, 23.8% (n = 5) were female and 76.2% (n = 16) were male. The median age was 13 years (range: 4–17 years). Histopathological evaluation revealed Ewing sarcoma as the most common subtype, accounting for 52.4% (n = 11) of cases. Other histologies included osteosarcoma (28.6%, n = 6), rhabdomyosarcoma (RMS) (14.3%, n = 3), and paraganglioma (4.7%, n = 1). At diagnosis, 13 patients (61.9%) presented with metastatic disease. A total of 37 extracranial lesions were treated with SBRT. One patient received SBRT to four distinct sites, while five patients received SBRT simultaneously to three different sites. The most frequently irradiated sites were bone metastases (59.3%), followed by organ/soft tissue and lymph node metastases. The median planning target volume (PTV) was 68 cm³ (range: 2.1–541 cm³). The median follow-up duration from the first SBRT session was 10 months (range: 4–157 months). Patient demographics and treatment characteristics details are summarized in Table 1 . Table 1 Patient Demographics and Treatment Characteristics (n = 21) Characteristic Value Number of patients 21 Age, median (range), years 13 (4–17) Sex Male, n (%) 16 (76.2%) Female, n (%) 5 (23.8%) Histopathology • Ewing sarcoma, n (%) 11 (52.4%) • Osteosarcoma, n (%) 6 (28.6%) • Rhabdomyosarcoma, n (%) 3 (14.3%) • Paraganglioma, n (%) 1 (4.7%) Metastatic disease at diagnosis, n (%) 13 (61.9%) Total extracranial lesions treated with SBRT, n 37 Distribution of irradiated lesions: • Bone metastases, n (%) 22 (59.3%) • Organ / soft tissue metastases, n (%) 12 (32.4%) • Lymph node metastases, n (%) 3 (8.1%) PTV volume, median (range), cm³ 68 (2.1–541) Follow-up duration, median (range), months 10 (4–157) Local Control and Survival Outcomes Tumor response was primarily assessed using post-SBRT PET-CT or CT imaging. During follow-up, local recurrence occurred in 10 patients (47.6%), of whom 6 (60%) experienced in-field recurrence. Among patients with in-field recurrence, histologies included osteosarcoma (n = 3), rhabdomyosarcoma (n = 1), Ewing sarcoma (n = 1), and paraganglioma (n = 1). One- and two-year LC rates were 25% and 18%, respectively. Median PFS was 8 ± 1.29 months (95% confidence interval [CI]: 5.4–10.5), while median OS was 12 ± 3.07 months (95% CI: 5.98–18). One- and two-year OS rates were 49% and 30%, respectively. According to histological subgroup analysis, median OS was 62 months for patients with Ewing sarcoma, 9 months for those with rhabdomyosarcoma, and 6 months for those with osteosarcoma. A statistically significant difference in OS was observed among histological subtypes, primarily driven by patients with osteosarcoma (p = 0.004). A statistically significant difference in PFS was also observed among histological subtypes (p = 0.03). Median PFS was 19 months in patients with Ewing sarcoma, 4 months in those with rhabdomyosarcoma, and 2 months in patients with osteosarcoma and paraganglioma. Dosimetric Outcomes The median total prescribed dose was 25 Gy (range: 25–40 Gy). The median biologically effective dose (BED₁₀) was 37.5 Gy (range: 31.25–72 Gy), and the median equivalent dose in 2-Gy fractions (EQD2) was 31.2 Gy (r Table 2 Dose and Fractionation Characteristics Parameter Value Prescribed total dose, median (range), Gy 25 (25–40) BED₁₀, median (range), Gy 37.5 (31.25–72) EQD2, median (range), Gy 31.2 (31.2–60) Ten patients received BED ≥ 40 Gy, while eleven received BED < 40 Gy. Median LC duration was 8 months in the BED ≥ 40 Gy group and 6 months in the BED < 40 Gy group, with no statistically significant difference between the groups (p = 0.18). When analyzed according to PTV volume, 9 patients had PTV ≥ 100 cm³ and 12 had PTV < 100 cm³. Median PFS was 4 months in patients with PTV < 100 cm³ and 9 months in those with PTV ≥ 100 cm³; however, this difference did not reach statistical significance (p = 0.07). In contrast, median OS was significantly longer in patients with PTV < 100 cm³ (26 months) compared to those with PTV ≥ 100 cm³ (9 months) (p = 0.017). Toxicity No grade ≥ 3 acute or late toxicities were observed. No acute toxicity greater than grade 2 was recorded. One patient developed late-onset lymphedema. DISCUSSION This two-center retrospective study is among the limited number of investigations evaluating the efficacy and safety of SBRT in pediatric patients. The primary finding of our study is that SBRT can be safely administered in appropriately selected pediatric patients without increasing acute toxicity, while achieving acceptable local control rates. SBRT has become a widely used treatment modality in adult oncology, particularly for early-stage non-small cell lung cancer, prostate cancer, and limited metastatic disease [ 1 , 2 ]. Numerous retrospective and prospective studies have demonstrated high local control rates and low acute and late toxicity in adult populations [ 3 ]. In contrast, the literature on pediatric SBRT remains limited [ 4 ], primarily due to the rarity of pediatric cancers, small patient numbers, long life expectancy, and concerns regarding late toxicity and adverse effects on growth and development [ 5 ]. In this context, our real-world data from two centers represent a meaningful contribution to the pediatric SBRT literature. One of the most robust studies in pediatric SBRT is a systematic review comprising nine studies and a total of 42 pediatric/adolescent and young adult patients, which reported one- and two-year local control rates of 83.5% and 74.0%, respectively. In the same review, higher BED₁₀ values were associated with significantly improved two-year local control rates, particularly in sarcoma-dominant cohorts [ 6 ]. In our study, no correlation was identified between BED value and LC. In a multicenter SBRT cohort conducted by Tinkle et al., including 55 patients and 107 extracranial lesions, the one-year cumulative local failure rate was 25.2% (95% CI: 17.2–36.1), corresponding to an approximate one-year local control rate of 75% [ 7 ]. The local control rates observed in our study were lower than those reported in some series, which may be attributed to differences in patient populations and prescribed radiation doses. Regarding OS outcomes, a two-center study published in 2024 including 48 patients under 30 years of age reported one-year OS rates of 70–85% and two-year OS rates of 40–60% [ 8 ]. In a multicenter prospective phase II study by Elledge et al. involving 14 patients, the one-year OS rate was 84% (95% CI: 49–96) [ 9 ]. In a major review of pediatric SBRT, the OS rate was reported as 75.4% (95% CI: 54.5–96.3) [ 6 ]. In contrast, our one- and two-year OS rates were 49% and 30%, respectively. One of the main reasons for the relatively lower local control and OS rates observed in our cohort is the radiation dose delivered. Brown et al. reported a median prescribed dose of 40 Gy in five fractions in patients with metastatic and recurrent Ewing sarcoma and osteosarcoma [ 10 ]. Parsai et al. reported a median dose of 30 Gy in five fractions in patients with recurrent and/or metastatic sarcomas [ 11 ]. In the study by Tinkle et al., doses ranged from 12 to 45 Gy, with a median of 35 Gy in five fractions [ 7 ]. In our cohort, the median total dose was 25 Gy in five fractions. This conservative dose approach was driven by the high proportion of patients under 10 years of age, large PTV volumes treated with SBRT, and concerns regarding late toxicities associated with higher doses, including growth and developmental abnormalities, organ dysfunction, and secondary malignancy risk. Additionally, proximity to critical organs and cumulative dose constraints from prior treatments limited dose escalation in some cases. This conservative approach may have contributed to lower local control and survival outcomes. Analysis of PFS data demonstrated that although SBRT improves local control, it has limited impact on systemic disease progression. In a broader cohort of patients under 30 years of age, the one-year PFS rate was reported as 22%, while high local control rates suggested that progression was largely driven by out-of-field disease [ 7 ]. Similarly, the low PFS rates observed in our study support the notion that PFS is primarily constrained by tumor biology and systemic dissemination. The identification of histological subtype as a significant prognostic factor for both PFS and OS highlights the critical role of tumor biology in determining SBRT outcomes. Although osteosarcoma accounted for 28.6% of our patient population, it represented 50% of in-field recurrences, suggesting a higher risk of local failure in this subgroup. The in-field local recurrence rate was 50% (3/6) in osteosarcoma patients compared to 20% (3/15) in non-osteosarcoma histologies. Although statistical significance was not reached due to the limited sample size, this finding is clinically meaningful. The radioresistant nature of osteosarcoma has been well characterized [ 12 ], with contributing radiobiological factors including a low α/β ratio, pronounced tumor hypoxia, a heterogeneous microenvironment, and enhanced DNA repair capacity [ 13 , 14 ]. These features may limit local control even with high-dose-per-fraction approaches such as SBRT. Based on these findings, SBRT in pediatric patients should be regarded primarily as a modality for achieving local disease control, symptom palliation, and integration with systemic therapies rather than a curative approach. Appropriate patient selection, particularly in oligometastatic or oligoprogressive disease, may enhance the clinical benefit of SBRT. The main limitations of this study include its retrospective design, limited sample size, and histological heterogeneity. In addition, the relatively short follow-up duration limits the assessment of long-term local control and late toxicity outcomes. Nevertheless, the real-world data obtained from two centers represent a major strength of our study, demonstrating the feasibility of SBRT in routine pediatric oncology practice. Particularly in carefully selected patients with oligometastatic or oligoprogressive disease, SBRT has reflected the potential to achieve meaningful local disease control with minimal toxicity. The observed survival outcomes appear to be largely influenced by tumor biology and conservative dose selection driven by concerns regarding late toxicity. All these findings emphasize the importance of individualized treatment schemes and multidisciplinary treatment decision-making in pediatric SBRT practice. Larger-scale, prospective, and histology-specific studies are needed to determine optimal patient selection and dose–fractionation strategies for pediatric SBRT. Declarations ETHICS STATEMENT This study was approved by the local institutional ethics committees. Due to the retrospective nature of the study, informed consent was waived. All procedures performed in this study involving human participants were conducted in accordance with the ethical standards of the institutional research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Clinical trial number: Not applicable. Competing Interests The authors declare no competing interests. Funding This study received no external funding. Data Availability The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request. All figures include descriptive captions to ensure accessibility. References Timmerman R, Paulus R, Galvin J, Michalski J, Straube W, Bradley J, et al. Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA. 2010;303(11):1070–6. 10.1001/jama.2010.261 . Milano MT, Zhang H, Metcalfe SK, Muhs AG, Okunieff P. Oligometastatic breast cancer treated with curative-intent stereotactic body radiation therapy. Breast Cancer Res Treat. 2009;115(3):601–8. 10.1007/s10549-008-0157-4 . Tree AC, Khoo VS, Eeles RA, Ahmed M, Dearnaley DP, Hawkins MA, et al. Stereotactic body radiotherapy for oligometastases. Lancet Oncol. 2013;14(1):e28–37. 10.1016/S1470-2045(12)70510-7 . Tsang DS, Murphy E, Salerno KE, Parkes J, Hiniker SM, Braunstein S. Stereotactic radiation therapy in children and young adults: can we apply adult treatment paradigms? Int J Radiat Oncol Biol Phys. 2025;123(1):43–53. 10.1016/j.ijrobp.2025.05.011 . Palmer JD, Tsang DS, Tinkle CL, Olch AJ, Kremer LCM, Ronckers CM, et al. Late effects of radiation therapy in pediatric patients and survivorship. Pediatr Blood Cancer. 2021;68(Suppl 2):e28349. 10.1002/pbc.28349 . Singh R, Valluri A, Didwania P, Lehrer EJ, Baliga S, Hiniker S, et al. Efficacy and safety of stereotactic body radiation therapy for pediatric malignancies: the LITE-SABR systematic review and meta-analysis. Adv Radiat Oncol. 2023;8(2):101123. 10.1016/j.adro.2022.101123 . Tinkle CL, Singh C, Lloyd S, Guo Y, Li Y, Pappo AS, et al. Stereotactic body radiation therapy for metastatic and recurrent solid tumors in children and young adults. Int J Radiat Oncol Biol Phys. 2021;109(5):1396–405. 10.1016/j.ijrobp.2020.11.030 . Upadhyay R, Klamer B, Matsui J, Chakravarthy VB, Scharschmidt T, Yeager N, et al. Disease control and toxicity outcomes after stereotactic ablative radiation therapy for recurrent and/or metastatic cancers in young-adult and pediatric patients. Cancers (Basel). 2024;16(11):2090. 10.3390/cancers16112090 . Elledge CR, Krasin MJ, Ladra MM, Alcorn SR, Han P, Gibbs IC, et al. A multi-institutional phase 2 trial of stereotactic body radiotherapy in the treatment of bone metastases in pediatric and young adult patients with sarcoma. Cancer. 2021;127(5):739–47. 10.1002/cncr.33306 . Brown LC, Lester RA, Grams MP, Haddock MG, Olivier KR, Arndt CA, et al. Stereotactic body radiotherapy for metastatic and recurrent Ewing sarcoma and osteosarcoma. Sarcoma. 2014;2014:418270. 10.1155/2014/418270 . Parsai S, Sedor G, Smile TD, Scott J, Ochocki A, Vassil N, et al. Multiple site SBRT in pediatric, adolescent, and young adult patients with recurrent and/or metastatic sarcoma. Am J Clin Oncol. 2021;44(3):126–30. 10.1097/COC.0000000000000794 . Suit HD. The role for radiation therapy in the management of patients with sarcoma of soft tissue in 1988. Cancer Treat Res. 1989;44:65–74. 10.1007/978-1-4613-1757-9_5 . DeLaney TF, Park L, Goldberg SI, Hug EB, Liebsch NJ, Munzenrider JE, et al. Radiotherapy for local control of osteosarcoma. Int J Radiat Oncol Biol Phys. 2005;61(2):492–8. 10.1016/j.ijrobp.2004.06.018 . Locquet MA, Brahmi M, Blay JY, Dutour A. Radiotherapy in bone sarcoma: the quest for better treatment option. BMC Cancer. 2023;23(1):742. 10.1186/s12885-023-11232-3 . Additional Declarations No competing interests reported. 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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-9001868","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":612139099,"identity":"628b6619-3fff-4daf-a02b-955d2b053002","order_by":0,"name":"Senay Mutaf Gecgel","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAz0lEQVRIiWNgGAWjYDAD9vYGIGlgQbQGAwaeMwdAtAQpWm4kgBhEaJGf3WPAdLPtjzyP5POrG34USDDwt3cn4Df+zhkD5tw2A8Me6Zyymz1Ah0mcObsBvxaJHLAWxv3SOWk3eIBaDCRy8WuRnwHRYt8jeSbt5h9itDDcgGhJ7JFgP3abKFsMbqQVHM45Z5zcw5PDdlvGQIKHoF/kZyRvfJxTJmfbw3782c03f2zk+Nt7CTiMgcPgAITBYwAmCSgHAfYH6IxRMApGwSgYBagAABJCRDQAvfxiAAAAAElFTkSuQmCC","orcid":"","institution":"Acıbadem MAA University School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Senay","middleName":"Mutaf","lastName":"Gecgel","suffix":""},{"id":612139100,"identity":"ac72a2b1-9b10-4703-9dd0-b11d3bd79e5f","order_by":1,"name":"Zeynep Gural","email":"","orcid":"","institution":", Acıbadem MAA University School of Medicine Atakent Hospital","correspondingAuthor":false,"prefix":"","firstName":"Zeynep","middleName":"","lastName":"Gural","suffix":""},{"id":612139101,"identity":"98ebf693-dbb5-4d9f-9fd8-811190783b73","order_by":2,"name":"Ayca Irıbas Celık","email":"","orcid":"","institution":"İstanbul University Faculty of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Ayca","middleName":"Irıbas","lastName":"Celık","suffix":""},{"id":612139102,"identity":"c45752c0-dbfd-4c0e-a06b-fb29aa99ac65","order_by":3,"name":"Erkın AKyuz","email":"","orcid":"","institution":"İstanbul University Faculty of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Erkın","middleName":"","lastName":"AKyuz","suffix":""},{"id":612139103,"identity":"f510365e-6b92-4357-a811-2d0074e0b3c1","order_by":4,"name":"Serap Yucel","email":"","orcid":"","institution":", Acıbadem MAA University School of Medicine Atakent Hospital","correspondingAuthor":false,"prefix":"","firstName":"Serap","middleName":"","lastName":"Yucel","suffix":""},{"id":612139104,"identity":"3f99eb37-f268-418a-862a-e5f52acce472","order_by":5,"name":"Fulya Agaoglu","email":"","orcid":"","institution":", Acıbadem MAA University School of Medicine Atakent Hospital","correspondingAuthor":false,"prefix":"","firstName":"Fulya","middleName":"","lastName":"Agaoglu","suffix":""}],"badges":[],"createdAt":"2026-03-01 13:53:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9001868/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9001868/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":108083687,"identity":"c46cbd0f-2a48-453a-936b-748c8c2fd46b","added_by":"auto","created_at":"2026-04-29 08:11:59","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":186325,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9001868/v1/46247328-c9d5-4771-9dfd-20ddc00b61c1.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eClinical Outcomes and Toxicity After Extracranial Stereotactic Body Radiotherapy for Pediatric Malignancies in a Two Center Retrospective Study\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eRadiotherapy is an indispensable component of both curative and palliative treatment approaches in childhood malignancies. However, to minimize the potential adverse effects of radiotherapy on growth and development in pediatric patients, modern high-precision radiotherapy techniques have gained increasing importance.\u003c/p\u003e \u003cp\u003eOne such technique is stereotactic body radiotherapy (SBRT), a noninvasive treatment modality that allows the delivery of high doses of radiation to the targeted tumor volume with millimetric accuracy, typically in 1\u0026ndash;5 fractions. With the use of advanced imaging technologies and modern radiotherapy planning systems, SBRT enables the administration of highly conformal and ablative radiation doses to the tumor while minimizing exposure of surrounding healthy tissues.\u003c/p\u003e \u003cp\u003eThe ablation-like effect of SBRT as an alternative to surgery, together with its potential immunological mechanisms and noninvasive nature, represents major advantages of this technique. High local control rates observed in adult patients, survival benefits in oligometastatic disease, and effective symptom palliation have led to the widespread clinical aplication of SBRT.\u003c/p\u003e \u003cp\u003eIn contrast, SBRT is not routinely incorporated into treatment protocols for pediatric malignancies, and the available evidence is largely limited to case series and retrospective studies. In childhood cancers, SBRT is primarily used for extracranial metastases\u0026mdash;particularly bone metastases\u0026mdash;for palliative purposes and to achieve long-term disease control in oligometastatic settings. Additionally, SBRT is employed for re-irradiation of residual or recurrent lesions, extracranial soft tissue tumors, and spinal or paraspinal lesions to provide palliation and local disease control.\u003c/p\u003e \u003cp\u003eIn this study, we evaluated local control (LC), progression-free survival (PFS), overall survival (OS), and toxicity outcomes in pediatric patients who received SBRT for extracranial lesions at two institutions.\u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cp\u003eBetween 2012 and 2024, the databases of MAA Acıbadem University Atakent Hospital and Istanbul University Faculty of Medicine, \u0026Ccedil;apa Hospital were retrospectively reviewed to identify pediatric patients who received SBRT for metastatic disease.\u003c/p\u003e \u003cp\u003e \u003cb\u003eInclusion Criteria\u003c/b\u003e \u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eAge\u0026thinsp;\u0026lt;\u0026thinsp;18 years and treatment delivered to an extracranial site\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eSBRT delivered in a maximum of five fractions using linear accelerator\u0026ndash;based systems\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eA minimum follow-up duration of three months\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003eDuring follow-up, progression sites were evaluated using CT, PET-CT, or MRI in cases of symptom development or suspected disease progression. Medical records were reviewed to collect data on treatment response, acute and late toxicities, last follow-up date, and current disease status. Tumor response was assessed based on follow-up imaging studies.\u003c/p\u003e \u003cp\u003eCollected patient data included age, sex, ECOG performance status, primary tumor histology, date of diagnosis, presence of multiple metastases, metastasis-directed surgery, local or distant progression after SBRT, last follow-up date, and current survival status.\u003c/p\u003e \u003cp\u003eAll patients were treated with SBRT using CT-based linear accelerator systems with daily cone-beam CT\u0026ndash;guided image-guided radiotherapy (IGRT). Treatment-related data, including number of fractions, dose per fraction, and total prescribed dose, were recorded.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003ePFS and OS were calculated using the Kaplan\u0026ndash;Meier method. OS was defined as the interval from the first SBRT session to death from any cause or to the last follow-up date for surviving patients. LC was characterized by the absence of lesion size progression, no significant increase in contrast enhancement, and no notable increase in surrounding edema on follow-up imaging of the area treated with SBRT. Prognostic analyses according to tumor type and dosimetric factors were performed using the log-rank test. A p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. All statistical analyses were performed using SPSS v23 (IBM, Armonk, NY, USA).\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003ePatient Demographics and Treatment Characteristics\u003c/h2\u003e \u003cp\u003eA total of 21 pediatric patients treated with definitive SBRT for oligometastatic or oligoprogresive disease at two centers were included. Of these patients, 23.8% (n\u0026thinsp;=\u0026thinsp;5) were female and 76.2% (n\u0026thinsp;=\u0026thinsp;16) were male. The median age was 13 years (range: 4\u0026ndash;17 years).\u003c/p\u003e \u003cp\u003eHistopathological evaluation revealed Ewing sarcoma as the most common subtype, accounting for 52.4% (n\u0026thinsp;=\u0026thinsp;11) of cases. Other histologies included osteosarcoma (28.6%, n\u0026thinsp;=\u0026thinsp;6), rhabdomyosarcoma (RMS) (14.3%, n\u0026thinsp;=\u0026thinsp;3), and paraganglioma (4.7%, n\u0026thinsp;=\u0026thinsp;1). At diagnosis, 13 patients (61.9%) presented with metastatic disease.\u003c/p\u003e \u003cp\u003eA total of 37 extracranial lesions were treated with SBRT. One patient received SBRT to four distinct sites, while five patients received SBRT simultaneously to three different sites. The most frequently irradiated sites were bone metastases (59.3%), followed by organ/soft tissue and lymph node metastases.\u003c/p\u003e \u003cp\u003eThe median planning target volume (PTV) was 68 cm\u0026sup3; (range: 2.1\u0026ndash;541 cm\u0026sup3;). The median follow-up duration from the first SBRT session was 10 months (range: 4\u0026ndash;157 months). Patient demographics and treatment characteristics details are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\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 Treatment Characteristics (n\u0026thinsp;=\u0026thinsp;21)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"1\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e \u003ccolgroup cols=\"2\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eValue\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of patients\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, median (range), years\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (4\u0026ndash;17)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale, n (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (76.2%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale, n (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (23.8%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistopathology\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026bull; Ewing sarcoma, n (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (52.4%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026bull; Osteosarcoma, n (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (28.6%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026bull; Rhabdomyosarcoma, n (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (14.3%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026bull; Paraganglioma, n (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (4.7%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMetastatic disease at diagnosis, n (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (61.9%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal extracranial lesions treated with SBRT, n\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDistribution of irradiated lesions:\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026bull; Bone metastases, n (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (59.3%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026bull; Organ / soft tissue metastases, n (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (32.4%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026bull; Lymph node metastases, n (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (8.1%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePTV volume, median (range), cm\u0026sup3;\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e68 (2.1\u0026ndash;541)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFollow-up duration, median (range), months\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (4\u0026ndash;157)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eLocal Control and Survival Outcomes\u003c/h3\u003e\n\u003cp\u003eTumor response was primarily assessed using post-SBRT PET-CT or CT imaging. During follow-up, local recurrence occurred in 10 patients (47.6%), of whom 6 (60%) experienced in-field recurrence. Among patients with in-field recurrence, histologies included osteosarcoma (n\u0026thinsp;=\u0026thinsp;3), rhabdomyosarcoma (n\u0026thinsp;=\u0026thinsp;1), Ewing sarcoma (n\u0026thinsp;=\u0026thinsp;1), and paraganglioma (n\u0026thinsp;=\u0026thinsp;1).\u003c/p\u003e \u003cp\u003eOne- and two-year LC rates were 25% and 18%, respectively. Median PFS was 8\u0026thinsp;\u0026plusmn;\u0026thinsp;1.29 months (95% confidence interval [CI]: 5.4\u0026ndash;10.5), while median OS was 12\u0026thinsp;\u0026plusmn;\u0026thinsp;3.07 months (95% CI: 5.98\u0026ndash;18). One- and two-year OS rates were 49% and 30%, respectively.\u003c/p\u003e \u003cp\u003eAccording to histological subgroup analysis, median OS was 62 months for patients with Ewing sarcoma, 9 months for those with rhabdomyosarcoma, and 6 months for those with osteosarcoma. A statistically significant difference in OS was observed among histological subtypes, primarily driven by patients with osteosarcoma (p\u0026thinsp;=\u0026thinsp;0.004).\u003c/p\u003e \u003cp\u003eA statistically significant difference in PFS was also observed among histological subtypes (p\u0026thinsp;=\u0026thinsp;0.03). Median PFS was 19 months in patients with Ewing sarcoma, 4 months in those with rhabdomyosarcoma, and 2 months in patients with osteosarcoma and paraganglioma.\u003c/p\u003e\n\u003ch3\u003eDosimetric Outcomes\u003c/h3\u003e\n\u003cp\u003eThe median total prescribed dose was 25 Gy (range: 25\u0026ndash;40 Gy). The median biologically effective dose (BED₁₀) was 37.5 Gy (range: 31.25\u0026ndash;72 Gy), and the median equivalent dose in 2-Gy fractions (EQD2) was 31.2 Gy (r\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\u003eDose and Fractionation Characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameter\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eValue\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrescribed total dose, median (range), Gy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25 (25\u0026ndash;40)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBED₁₀, median (range), Gy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37.5 (31.25\u0026ndash;72)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEQD2, median (range), Gy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31.2 (31.2\u0026ndash;60)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTen patients received BED\u0026thinsp;\u0026ge;\u0026thinsp;40 Gy, while eleven received BED\u0026thinsp;\u0026lt;\u0026thinsp;40 Gy. Median LC duration was 8 months in the BED\u0026thinsp;\u0026ge;\u0026thinsp;40 Gy group and 6 months in the BED\u0026thinsp;\u0026lt;\u0026thinsp;40 Gy group, with no statistically significant difference between the groups (p\u0026thinsp;=\u0026thinsp;0.18).\u003c/p\u003e \u003cp\u003eWhen analyzed according to PTV volume, 9 patients had PTV\u0026thinsp;\u0026ge;\u0026thinsp;100 cm\u0026sup3; and 12 had PTV\u0026thinsp;\u0026lt;\u0026thinsp;100 cm\u0026sup3;. Median PFS was 4 months in patients with PTV\u0026thinsp;\u0026lt;\u0026thinsp;100 cm\u0026sup3; and 9 months in those with PTV\u0026thinsp;\u0026ge;\u0026thinsp;100 cm\u0026sup3;; however, this difference did not reach statistical significance (p\u0026thinsp;=\u0026thinsp;0.07). In contrast, median OS was significantly longer in patients with PTV\u0026thinsp;\u0026lt;\u0026thinsp;100 cm\u0026sup3; (26 months) compared to those with PTV\u0026thinsp;\u0026ge;\u0026thinsp;100 cm\u0026sup3; (9 months) (p\u0026thinsp;=\u0026thinsp;0.017).\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eToxicity\u003c/h2\u003e \u003cp\u003eNo grade\u0026thinsp;\u0026ge;\u0026thinsp;3 acute or late toxicities were observed. No acute toxicity greater than grade 2 was recorded. One patient developed late-onset lymphedema.\u003c/p\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis two-center retrospective study is among the limited number of investigations evaluating the efficacy and safety of SBRT in pediatric patients. The primary finding of our study is that SBRT can be safely administered in appropriately selected pediatric patients without increasing acute toxicity, while achieving acceptable local control rates.\u003c/p\u003e \u003cp\u003eSBRT has become a widely used treatment modality in adult oncology, particularly for early-stage non-small cell lung cancer, prostate cancer, and limited metastatic disease [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Numerous retrospective and prospective studies have demonstrated high local control rates and low acute and late toxicity in adult populations [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In contrast, the literature on pediatric SBRT remains limited [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], primarily due to the rarity of pediatric cancers, small patient numbers, long life expectancy, and concerns regarding late toxicity and adverse effects on growth and development [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In this context, our real-world data from two centers represent a meaningful contribution to the pediatric SBRT literature.\u003c/p\u003e \u003cp\u003eOne of the most robust studies in pediatric SBRT is a systematic review comprising nine studies and a total of 42 pediatric/adolescent and young adult patients, which reported one- and two-year local control rates of 83.5% and 74.0%, respectively. In the same review, higher BED₁₀ values were associated with significantly improved two-year local control rates, particularly in sarcoma-dominant cohorts [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. In our study, no correlation was identified between BED value and LC. In a multicenter SBRT cohort conducted by Tinkle et al., including 55 patients and 107 extracranial lesions, the one-year cumulative local failure rate was 25.2% (95% CI: 17.2\u0026ndash;36.1), corresponding to an approximate one-year local control rate of 75% [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The local control rates observed in our study were lower than those reported in some series, which may be attributed to differences in patient populations and prescribed radiation doses.\u003c/p\u003e \u003cp\u003eRegarding OS outcomes, a two-center study published in 2024 including 48 patients under 30 years of age reported one-year OS rates of 70\u0026ndash;85% and two-year OS rates of 40\u0026ndash;60% [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. In a multicenter prospective phase II study by Elledge et al. involving 14 patients, the one-year OS rate was 84% (95% CI: 49\u0026ndash;96) [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. In a major review of pediatric SBRT, the OS rate was reported as 75.4% (95% CI: 54.5\u0026ndash;96.3) [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. In contrast, our one- and two-year OS rates were 49% and 30%, respectively.\u003c/p\u003e \u003cp\u003eOne of the main reasons for the relatively lower local control and OS rates observed in our cohort is the radiation dose delivered. Brown et al. reported a median prescribed dose of 40 Gy in five fractions in patients with metastatic and recurrent Ewing sarcoma and osteosarcoma [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Parsai et al. reported a median dose of 30 Gy in five fractions in patients with recurrent and/or metastatic sarcomas [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In the study by Tinkle et al., doses ranged from 12 to 45 Gy, with a median of 35 Gy in five fractions [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. In our cohort, the median total dose was 25 Gy in five fractions. This conservative dose approach was driven by the high proportion of patients under 10 years of age, large PTV volumes treated with SBRT, and concerns regarding late toxicities associated with higher doses, including growth and developmental abnormalities, organ dysfunction, and secondary malignancy risk. Additionally, proximity to critical organs and cumulative dose constraints from prior treatments limited dose escalation in some cases. This conservative approach may have contributed to lower local control and survival outcomes.\u003c/p\u003e \u003cp\u003eAnalysis of PFS data demonstrated that although SBRT improves local control, it has limited impact on systemic disease progression. In a broader cohort of patients under 30 years of age, the one-year PFS rate was reported as 22%, while high local control rates suggested that progression was largely driven by out-of-field disease [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Similarly, the low PFS rates observed in our study support the notion that PFS is primarily constrained by tumor biology and systemic dissemination.\u003c/p\u003e \u003cp\u003eThe identification of histological subtype as a significant prognostic factor for both PFS and OS highlights the critical role of tumor biology in determining SBRT outcomes. Although osteosarcoma accounted for 28.6% of our patient population, it represented 50% of in-field recurrences, suggesting a higher risk of local failure in this subgroup. The in-field local recurrence rate was 50% (3/6) in osteosarcoma patients compared to 20% (3/15) in non-osteosarcoma histologies. Although statistical significance was not reached due to the limited sample size, this finding is clinically meaningful. The radioresistant nature of osteosarcoma has been well characterized [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], with contributing radiobiological factors including a low α/β ratio, pronounced tumor hypoxia, a heterogeneous microenvironment, and enhanced DNA repair capacity [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. These features may limit local control even with high-dose-per-fraction approaches such as SBRT.\u003c/p\u003e \u003cp\u003eBased on these findings, SBRT in pediatric patients should be regarded primarily as a modality for achieving local disease control, symptom palliation, and integration with systemic therapies rather than a curative approach. Appropriate patient selection, particularly in oligometastatic or oligoprogressive disease, may enhance the clinical benefit of SBRT.\u003c/p\u003e \u003cp\u003eThe main limitations of this study include its retrospective design, limited sample size, and histological heterogeneity. In addition, the relatively short follow-up duration limits the assessment of long-term local control and late toxicity outcomes. Nevertheless, the real-world data obtained from two centers represent a major strength of our study, demonstrating the feasibility of SBRT in routine pediatric oncology practice. Particularly in carefully selected patients with oligometastatic or oligoprogressive disease, SBRT has reflected the potential to achieve meaningful local disease control with minimal toxicity. The observed survival outcomes appear to be largely influenced by tumor biology and conservative dose selection driven by concerns regarding late toxicity. All these findings emphasize the importance of individualized treatment schemes and multidisciplinary treatment decision-making in pediatric SBRT practice. Larger-scale, prospective, and histology-specific studies are needed to determine optimal patient selection and dose\u0026ndash;fractionation strategies for pediatric SBRT.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eETHICS STATEMENT\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the local institutional ethics committees. Due to the retrospective nature of the study, informed consent was waived. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll procedures performed in this study involving human participants were conducted in accordance with the ethical standards of the institutional research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.\u003c/p\u003e\n\u003cp\u003eClinical trial number: Not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study received no external funding.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003eAll figures include descriptive captions to ensure accessibility.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eTimmerman R, Paulus R, Galvin J, Michalski J, Straube W, Bradley J, et al. 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BMC Cancer. 2023;23(1):742. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s12885-023-11232-3\u003c/span\u003e\u003cspan address=\"10.1186/s12885-023-11232-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Pediatric malignancy, stereotactic body radiotherapy, extracranial metastases, oligometastatic disease, local control, toxicity","lastPublishedDoi":"10.21203/rs.3.rs-9001868/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9001868/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStereotactic body radiotherapy (SBRT) in pediatric malignancies offers precise, high-dose radiation delivery to tumors while minimizing exposure to surrounding healthy tissues—an important consideration in preventing adverse effects on growth and development. The use of SBRT in pediatric oncology has been increasing; however, clinical data and outcome reports remain limited. This study aimed to evaluate local control (LC), progression-free survival (PFS), overall survival (OS), and toxicity rates following SBRT in pediatric patients with extracranial metastases.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMaterials/Methods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBetween 2012 and 2024, 21 pediatric patients treated in our department for extracranial lesions of malignant tumors using linear accelerator–based, CT-guided SBRT were retrospectively analyzed. LC and OS were assessed using the Kaplan–Meier method.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll patients received definitive SBRT for oligometastatic disease. At diagnosis, 13 patients (61.9%) presented with metastatic disease. The median follow-up time was 10 months (range, 4–157), and the median age was 13 years (range, 4–17). Ewing sarcoma was the most common histologic subtype (52.4%).\u003c/p\u003e\n\u003cp\u003eA total of 37 extracranial lesions were irradiated; 21 (56.7%) were bone metastases. SBRT was delivered to four sites in one patient and to three simultaneous sites in five patients.The median number of fractions was 5 (range, 3–5), with a median dose per fraction of 5 Gy (range, 5–9 Gy). Median BED₁₀and EQD₂were 37.5 Gy (31.25–72) and 31.2 Gy (31.2–60), respectively. The median PTV volume was 68 cm³ (range, 2.1–541 cm³). Median PFS was 8 ± 1.29 months (95% CI: 5.4–10.5), and median OS was 12 ± 3.07 months (95% CI: 5.98–18).Local recurrence occurred in 10 patients (47.6%), of whom 6 (60%) had in-field recurrences. Among these, 3 of 6 patients had osteosarcoma histology. One- and two-year LC rates were 25% and 18%, respectively, while OS rates were 49% and 30%. There was a statistically significant difference in both PFS and OS among histologic subtypes (p = 0.03 and p = 0.004, respectively). No ≥Grade 3 acute or late toxicity was observed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSBRT was well tolerated in pediatric patients, with minimal toxicity. However, longer follow-up is required to assess late effects. The preference for more moderate fractionation schemes due to large tumor volumes and younger age groups may also be related to higher rates of in-field recurrence in histologies that are more resistant to radiotherapy. Further studies are warranted to establish the optimal SBRT dose and fractionation parameters for pediatric malignancies.\u003c/p\u003e","manuscriptTitle":"Clinical Outcomes and Toxicity After Extracranial Stereotactic Body Radiotherapy for Pediatric Malignancies in a Two Center Retrospective Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-27 07:06:34","doi":"10.21203/rs.3.rs-9001868/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"af503f2f-d308-46e8-8727-116e56ff2886","owner":[],"postedDate":"March 27th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-04-29T08:11:09+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-27 07:06:34","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9001868","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9001868","identity":"rs-9001868","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}