Systematic review and meta-analysis of photon radiotherapy versus proton beam therapy for pediatric Ewing sarcoma: TRP-Ewing sarcoma 2024

Systematic review and meta-analysis of photon radiotherapy versus proton beam therapy for pediatric Ewing sarcoma: TRP-Ewing sarcoma 2024 | 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 Systematic review and meta-analysis of photon radiotherapy versus proton beam therapy for pediatric Ewing sarcoma: TRP-Ewing sarcoma 2024 Kumie Nagatomo, Masashi Mizumoto, Hiroko Fukushima, Sho Hosaka, and 12 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7654899/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: Advances in multimodal treatment strategies and chemotherapy have led to improved outcomes for patients with Ewing sarcoma (EWS). Proton beam therapy (PBT) has increasingly been utilized in pediatric oncology to minimize late toxicities associated with conventional treatments; however, studies specifically addressing the use of PBT in EWS remain limited. Methods: We conducted a meta-analysis to compare the efficacy of photon radiotherapy (RT) and PBT in the treatment of pediatric EWS. We analyzed English-language articles published between 1990 and 2022 that included at least 10 patients and described RT treatment protocols. The primary endpoints were overall survival (OS) and local control (LC). Results: A total of 38 studies from 36 articles (8 reporting PBT and 30 reporting photon RT) were included in the meta-analysis. PBT showed better 5-year OS and 4- and 3-year LC rates compared to photon RT. In analyses restricted to studies published since 2015, only the 5-year OS remained significantly different. No associations were found between OS or LC and variables such as age, sex ratio, or the rate of concurrent chemotherapy or surgery. Discussion: The observed differences across the entire study period may be attributed to improvements in treatment protocols, including interval-compressed chemotherapy, and recent advancements in supportive care and radiation technology, which could have influenced outcomes. Conclusion: PBT appears to be non-inferior to photon RT in the treatment of pediatric EWS. Further studies are needed to assess long-term outcomes and the potential treatment-related toxicities of PBT. Ewing sarcoma radiotherapy modality proton beam therapy meta-analysis Figures Figure 1 Figure 2 Figure 3 Introduction Ewing sarcoma (EWS) is a common solid malignancy in children, adolescents and young adults, with onset typically occurring during the teenage years [1,2]. It primarily affects bone or soft tissue and can arise in various locations, including the extremities, pelvis, spine, and trunk. Approximately 25% of cases present with metastatic disease at the time of diagnosis [1,3]. Multimodal treatment is standard for EWS, involving induction chemotherapy followed by local treatment with surgery and/or radiotherapy (RT), along with postoperative chemotherapy. While several chemotherapy regimens are available, the EuroEwing 2012 trial demonstrated that interval-compressed VDC-IE therapy, administered every two weeks, offered superior outcomes compared to the traditional European protocol [4]. As a result, interval-compressed VDC-IE has become the global standard of care. In the Children’s Oncology Group report, event-free survival for patients with localized disease exceeds 75% [5], although the prognosis for patients with metastatic or relapsed disease remains poor [6-8]. Multiple studies are in progress on the role of high-dose chemotherapy with autologous stem cell transplantation and molecular-targeted therapies in refractory or relapsed cases [6,9,10]. In contrast, strategies for local control continue to be a topic of discussion, given the diverse sites of tumor presentation. Surgery, or a combination of surgery and RT, is generally preferred over definitive RT alone, provided the tumor is resectable [11,12]. This is particularly true for pelvic tumors, where total surgical resection is often challenging due to anatomical constraints and the need to preserve tissue function. In such cases, RT plays a critical role in management [13]. The use of proton beam therapy (PBT) for pediatric cancers has been increasingly reported in recent years. Proton beams generate Bragg peaks at specific depths depending on their energy, which limits radiation exposure to tissues beyond the target area. This property enables PBT to reduce irradiation of surrounding normal tissues. Consequently, PBT has been shown to minimize both acute and late adverse effects, such as secondary neoplasms, making it an increasingly preferred option for children and young patients. Previous meta-analyses comparing PBT and conventional photon RT across various pediatric malignancies have generally found no significant differences in clinical outcomes between the two modalities [14-17]. While reports on the use of PBT for EWS are gradually increasing, its comparative efficacy to photon RT remains unclear. Therefore, we performed a meta-analysis of existing studies to assess whether there are differences in local control (LC) and overall survival (OS) between photon RT and PBT in pediatric EWS. Methods Selection criteria for meta-analysis The review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [18]. Only articles published in English were included. Two independent reviewers screened all extracted articles. The inclusion criteria were as follows: (1) clinically diagnosed Ewing sarcoma, (2) treatment with RT (photon RT or PBT), (3) availability of data on OS or LC rate with RT, and (4) inclusion of at least 10 cases. A PubMed search was conducted using the terms “Ewing” AND (“radiotherapy” OR “proton”) AND (“children” OR “pediatrics”) for publications from 1990 to 2022, yielding 913 articles. Of these, 183 articles that described the treatment outcome of RT for EWS were selected based on their title or abstract. 108 articles were identified that reported OS, progression-free survival (PFS) or LC rate either in the abstract or full text. Finally, 38 results from 36 articles (8 PBT, 30 photon RT) were included after excluding studies with significant biases in patient characteristics or overlapping publication periods from the same center [2,12,13,19-52]. If different modalities were discussed within a single article, they were treated as separate results. The included articles are listed in Supplementary Table 1. Figure 1 illustrates the summarization of the manuscript selection process. Data extracted from the selected studies included: authors, year of publication, country, study design, number of patients, number of deaths, all recurrences, local recurrences, follow-up period, 1- to 5-year OS and LC rates, age, male-to-female ratio, rates of concurrent chemotherapy and surgery, and treatment modality (photon RT vs. PBT). If the 1- to 5-year OS and LC rates were not directly reported, these rates were estimated from the figures. Within the limits specified in the manuscript, the irradiation method of photon RT was either Three-Dimensional Conformal Radiation Therapy (3D-CRT) or Intensity Modulated Radiation Therapy (IMRT). Statistical analysis Random-effects meta-analyses were conducted to assess the 1- to 5-year OS and LC rates for both photon RT and PBT, and forest plots were generated. In cases where studies had missing accuracy data, these values were imputed based on the survival probability, the number of cases, the risk set size at each year, and the mean dropout rate [53]. Heterogeneity in each meta-analysis was evaluated by I-square statistics. To compare the treatment modalities, random-effects meta-regression was performed with modality as the explanatory variable. All analyses were conducted using R (R Core Team, Vienna, Austria) and its accompanying meta package [54]. Differences in radiation dose by modality were assessed using the Mann-Whitney U test in SPSS Statistics version 28.0 (IBM Corporation, Tokyo, Japan). Abbreviation CI Confidence interval EWS Ewing sarcoma LC Local control OS Overall survival PBT Proton beam therapy RCT Randomized controlled trial RT Radiotherapy TRP Tsukuba review project Results Figures 2 and 3 display the forest plots for each modality regarding the 1- to 5-year OS and LC rates, respectively. A meta-analysis of the 38 results from 36 articles (8 for PBT and 28 for photon RT) showed the following 1- to 5-year OS rates (95% confidence interval (CI)) for PBT vs. photon RT, respectively: at 1-year OS, 94.3% (89.0%-97.1%) vs. 87.6% (83.7%-90.7%) (p=0.5480); at 2-years OS, 87.3% (80.7%-91.8%) vs. 75.8% (69.9%-80.7%) (p=0.3834); at 3-years OS, 82.0% (72.3%-88.6%) vs. 70.2% (64.2%-75.4%) (p=0.2456); at 4-years OS, 78.2% (68.1%-85.4%) vs. 64.8% (59.0%-70.0%) (p=0.3543); and at 5-years OS,76.3% (65.8%-83.9%) vs. 61.2% (57.0%-65.1%) (p=0.0008<0.05). Result of meta-analysis of the 1- to 5-year LC rates (95% CI) for PBT vs. photon RT, respectively, were as follows: at 1-year LC, 98.1% (93.6%-99.4%) vs. 93.2% (90.8%-95.0%) (p=0.2063); at 2-years LC, 91.7% (80.5%-96.6%) vs. 86.6% (83.6%-89.0%) (p=0.1042); at 3-years LC, 89.0% (79.6%-94.2%) vs. 83.6% (80.3%-86.4%) (p=0.0151); at 4-years LC, 88.2% (75.8%-94.5%) vs. 82.0% (78.2%-85.1%) (p=0.0363); and at 5-years LC, 83.1% (68.7%-91.3%) vs. 79.7% (75.4%-83.4%) (p=0.4745). Meta-regression analysis was conducted using modality (photon RT vs. PBT), age, male-to-female ratio, concurrent chemotherapy rate, and concurrent surgery rate as risk factors. The median age was 13.3 years (range 9.8-23) in the photon RT group and 10.0 years (range 5.9-16) in PBT group. The respective percentages (median) for each factor (photon RT vs. PBT) were: male-to-female ratio, 46.2%-69.8% (55.9%) vs. 47.1%-63.8% (50.3%); concurrent chemotherapy, 88.4%-100% (100%) vs. 100% (100%); and concurrent surgery, 0%-100% (50.2%) vs. 24.0%-100% (94.1%), respectively. The total doses for photon RT ranged from 44.7 to 56.1 Gy (median 52.2 Gy), and for PBT, it ranged from 50.4 to 59.4 GyE (median 54.9 GyE) with no significant difference between the two modalities (p=0.079), and thus, these were excluded from further analysis. The meta-regression analysis identified a significant better OS associated with a higher male rate at 1-,4-and 5-year OS, and with concurrent surgery at 4-, 5-year OS. No significant risk factors for LC were identified (Table 1). Furthermore, the analysis showed that PBT was significantly associated with better 5-year OS and 3-, 4-year LC rates. We considered that advancements in chemotherapy regimens and radiological techniques might influence the outcomes, so we performed a re-analysis limiting the studies to those published in 2015 or later (Supplementary Figures 1, 2) [12,13,30-52]. A meta-analysis of the 27 results from 25 articles (7 for PBT and 20 for photon RT) revealed a significant difference between PBT and photon RT only in the 5-year OS rate (95% CI); with PBT showing 78.1% (65.6%-86.5%) compared to 65.2% (60.9%-69.2%) for photon RT (p=0.0034<0.05). No significant differences were observed for other OS or LC rates. The meta-regression analysis identified a significant association between treatment modality of RT and improved 5-year OS in favor of PBT (Supplementary Table 2). Discussion We conducted a meta-analysis comparing the treatment outcomes of photon RT and PBT in pediatric EWS. Significant differences were observed only in the 5-year OS rate, with no clear distinction in OS and LC rates at other time points. For studies published from 2015 onwards, the 5-year EFS rates were 65% for photon RT and 78% for PBT, while the 5-year LC rates were around 80% for both modalities. Although the analysis included reports with metastases or various primary tumor sites, it is evident that better outcomes have been achieved in recent years. Inadequate local treatment, such as intralesional resection, increases the risk of local extension and recurrence [19], with poor prognosis after recurrence, as demonstrated by a 6-month EFS of only 12.7% [8]. When planning local therapy, the feasibility of complete resection and the response to induction chemotherapy are crucial factors. Achieving complete resection should be the goal whenever possible; otherwise, effective RT should be used in cases where complete resection is unachievable. PBT is increasingly replacing photon RT in the treatment of pediatric solid tumors. However, conducting RCTs to compare PBT with photon RT remains challenging, making the results of this study particularly significant. In the context of RT for EWS, particularly with PBT, the treatment strategy has not yet been clearly defined, and several aspects remain open for discussion. The first point for discussion regarding RT is the timing of its administration. RT has traditionally been delivered either as definitive RT without surgery or as postoperative RT. However, preoperative RT is increasingly becoming the method of choice. European studies have shown that the local failure rate in patients treated with preoperative RT, particularly those with large tumors or poor clinical responses to induction chemotherapy, was 5.3% [55]. This outcome was non-inferior to the local recurrence rate observed in low-risk patients treated with surgery alone. In the AEWS1031 trial, 7.4% of participants who underwent combined modality local therapy received preoperative RT with a dose of 36 Gy to the tumor and a 1 cm margin [56]. The 3-year cumulative incidence of local failure in patients receiving preoperative RT was 12.5%, and R0 resection rates improved with lower doses and smaller target volumes, alongside better pathological responses. A single-center study in the UK reported that using PBT as preoperative RT for pelvic localized EWS also improved local recurrence-free survival compared to postoperative RT [48]. Furthermore, in the same study, complications related to RT, such as wound issues or infections, did not differ significantly between modalities. Based on these findings, preoperative RT could be considered in cases where marginal resection is expected. PBT may be particularly advantageous in preoperative settings, as it limits normal tissue toxicity and reduces the delay in post-irradiation recovery before surgery. Secondly, the optimal irradiation dose for EWS has not yet been established. While the standard definitive RT dose for EWS is typically between 50-60 Gy, studies have reported that using higher doses, such as 60 Gy or more, can enhance the therapeutic efficacy of RT. In a retrospective study, Kacar et al. found that a median dose of 64.8 Gy resulted in a 5-year local failure rate of 6.6% for tumors larger than 8 cm [58]. Laskar et al. conducted a randomized controlled trial (RCT) comparing 55.8 Gy and 70.2 Gy doses in nonmetastatic unresectable EWS/primitive neuroectodermal tumors. The study reported a statistically significant improvement in the high-dose group, with a 5-year LC rate of 76.4% [52]. Although acute skin toxicity was more common in the high-dose group, late toxic effects did not differ between the two groups. These findings suggest that high-dose RT is feasible with acceptable levels of toxicity and functional outcomes. A third point of debate is whether the use of PBT in EWS increases side effects, a concern that remains insufficiently addressed in the literature. Lex et al. reported that, in primary pelvic cases, no significant association between RT type and toxicity, such as radiation dermatitis or avascular necrosis, was observed [58]. Rhabdomyosarcoma is one of the tumors treated with a combination of chemotherapy and RT, like EWS. Suzuki et al. conducted a single-center, retrospective analysis of side effects associated with chemotherapy with or without PBT for rhabdomyosarcoma [59]. They found that when PBT was combined with chemotherapy, the duration of opioid use for managing dermatitis or mucositis was longer than when chemotherapy alone was administered. However, PBT was not associated with the duration of fever or the highest C-reactive protein levels. Notably, grade 4 or higher nonhematological toxicities were not observed. Based on these findings, the authors concluded that PBT is feasible for children when appropriate supportive care is provided. Furthermore, secondary malignancy is a significant late complication following RT. In EWS, the 30-year cumulative incidence of secondary malignancies has been reported to be 10.1% [60]. Among the PBT studies included in this analysis, only Rombi et al. reported that 4 out of 30 patients developed secondary malignancies: 3 cases of acute myeloid leukemia (AML) and 1 case of myelodysplastic syndrome (MDS) [26]. In this study, the development of secondary hematological malignancies was attributed to chemotherapy, particularly alkylating agents. However, the development of solid tumors was not reported in any of the PBT studies included in this analysis. Most of the articles collected in this study had relatively short follow-up periods, with the median follow-up for PBT studies being 46.2 months (range: 27.5-54.6 months), and all studies reported follow-up of less than 5 years. Given the short follow-up duration, it is not possible to draw conclusions regarding the development of solid secondary malignancies associated with RT. This study has several limitations. First, the number of included studies was relatively small (36 studies). Furthermore, many of these reports involved a limited number of patients, primarily due to the rarity of the disease. Second, only one of the studies included in this analysis was a prospective RCT, while the remaining studies were retrospective in nature. Third, four of the eight studies involving PBT were conducted at the same institution, which may introduce sample bias. In conclusion, our analysis suggests that there is no significant difference between photon RT and PBT in the treatment of EWS. Among local therapies, PBT is likely to become an increasingly important modality as further data on RT are gathered. Reports on long-term outcomes and treatment-related toxicity are urgently needed. Declarations Acknowledgement: We would like to thank all the children with Ewing sarcoma, their family members, and the collaborating medical staff. We would also like to thank Thomas Mayers (Medical English Communications Center, University of Tsukuba) for English language editing. Declarations Conflict of interest statement : The authors have no conflicts of interest to declare. Ethical approval: Not required. Funding sources : This work was supported by institutional funds only. Author contributions: Conception/design: MM, YO, SH. Collection and/or assembly of data: HF, MM, SH, KN, YL, YO, HH, TI, TS, MI, RS, HT, SS. Data analysis and interpretation: MM, KM. Manuscript writing: KN, HF. MM and HS supervised the management of the research and the overall structure of the manuscript. All authors made substantial contributions to the study concept or the data analysis or interpretation; drafted the manuscript or revised it critically for important intellectual content; approved the final version of the manuscript to be published; and agreed to be accountable for all aspects of the work. Data availability s tatement: All data generated or analyzed during this study are included in this article. Further enquiries can be directed to the corresponding author. References Esiashvili N, Goodman M, Marcus RB Jr (2008) Changes in incidence and survival of Ewing sarcoma patients over the past 3 decades: Surveillance Epidemiology and End Results data. J Pediatr Hematol Oncol 30:425-430. https://doi.org/10.1097/MPH.0b013e31816e22f3 Nakata K, Ito Y, Magadi W, et al (2018) Childhood cancer incidence and survival in Japan and England: A population-based study (1993-2010) Cancer Sci 109:422-434. https://doi.org/ 10.1111/cas.13457 Shi J, Yang J, Ma X, et al (2020) Risk factors for metastasis and poor prognosis of Ewing sarcoma: a population based study. J Orthop Surg Res 15:88. https://doi.org/10.1186/s13018-020-01607-8 Brennan B, Kirton L, Berard PM, et al (2022) Comparison of two chemotherapy regimens in patients with newly diagnosed Ewing sarcoma (EE2012): an open-label, randomised, phase 3 trial. Lancet 400:1513-1521. https://doi.org/10.1016/S0140-6736(22)01790-1 Leavey PJ, Laack NN, Krailo MD, et al (2021) Phase III Trial Adding Vincristine-Topotecan-Cyclophosphamide to the Initial Treatment of Patients with Nonmetastatic Ewing Sarcoma: A Children's Oncology Group Report. J Clin Oncol 39:4029-4038. https://doi.org/10,1200/JCO.21.00358 Ladenstein R, Pötschger U, Le Deley MC, et al (2010) Primary disseminated multifocal Ewing sarcoma: results of the Euro-EWING 99 trial. J Clin Oncol 28:3284-3291. https://doi.org/10.1200/JCO.2009.22.9864 Leavey PJ, Mascarenhas L, Marina N, et al (2008) Prognostic factors for patients with Ewing sarcoma (EWS) at first recurrence following multi-modality therapy: A report from the Children's Oncology Group. Pediatr Blood Cancer 51:334-338. https://doi.org/10.1200/pbc.21618 Collier AB 3 rd , Krailo MD, Dang HM, et al (2021) Outcome of patients with relapsed or progressive Ewing sarcoma enrolled on cooperative group phase 2 clinical trials: A report from the Children's Oncology Group. Pediatr Blood Cancer 68: e29333. https://doi.org/10.1002/pbc.29333 DuBois SG, Krailo MD, Glade-Bender J, et al (2023) Randomized Phase III Trial of Ganitumab With Interval-Compressed Chemotherapy for Patients With Newly Diagnosed Metastatic Ewing Sarcoma: A Report From the Children's Oncology Group. J Clin Oncol 41:2098-2107. https://doi.org/10.1200/JCO.22.01815 Reed DR, Grohar P, Rubin E, et al (2023) Children's Oncology Group's 2023 blueprint for research: Bone tumors. Pediatr Blood Cancer 70: e30583. https://doi.org/10.1002/pbc.30583 Heesen P, Rnft A, Bhadri V, et al (2023) Association between local treatment modalities and event-free survival, overall survival, and local recurrence in patients with localised Ewing Sarcoma. Report from the Ewing 2008 trial. Eur J Cancer 192:113260. https://doi.org/10.1016/j.ejca.2023.113260 Ahmed SK, Randall RL, DuBois SG, et al (2017) Identification of Patients With Localized Ewing Sarcoma at Higher Risk for Local Failure: A Report From the Children's Oncology Group. Int J Radiat Oncol Biol Phys 99:1286-1294. https://doi.org/10.1016/j.ijrobp.2017.08.020 Andreou D, Ranft A, Gosheger G, et al (2020) Which Factors Are Associated with Local Control and Survival of Patients with Localized Pelvic Ewing's Sarcoma? A Retrospective Analysis of Data from the Euro-EWING99 Trial. Clin Orthop Relat Res 478:290-302. https://doi.org/10.1097/CORR.0000000000000962 Nakamura M, Mizumoto M, Saito T, et al (2024) A systematic review and meta-analysis of radiotherapy and particle beam therapy for skull base chondrosarcoma: TRP-chondrosarcoma 2024. Front Oncol 14:1380716. https://doi.org/10.3389/fonc.2024.1380716 Saito T, Mizumoto M, Oshiro Y, et al (2024) Systematic Review and Meta-Analysis of Particle Beam Therapy versus Photon Radiotherapy for Skull Base Chordoma: TRP-Chordoma 2024. Cancers (Basel) 16:2569. https://doi.org/10.3390/cancers16142569 Mizumoto M, Hosaka S, Nakai K, et al (2024) Systematic review and meta-analysis of photon radiotherapy versus proton beam therapy for pediatric intracranial ependymoma: TRP-ependymoma 2024. Heliyon 10: e40372. https://doi.org/10.1016/j.heliyon.2024.e40372 Fukushima H, Mizumoto M, Hosaka S, et al (2025) Systematic review and meta-analysis of photon radiotherapy versus proton beam therapy for pediatric rhabdomyosarcoma: TRP-rhabdomyosarcoma 2024. Int J Clin Oncol 2025 Jun 10. Online ahead of print. https://doi.org/10.1007/s10147-025-02794-2 Moher D, Liberati A, Tetzlaff J, et al (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6: e1000097. https://doi.org/10.1371/journal.pmed.1000097 Schuck A, Ahrens S, Schorlemer I, et al (2005) Radiotherapy in Ewing tumors of the vertebrae: treatment results and local relapse analysis of the CESS 81/86 and EICESS 92 trials. Int J Radiat Oncol Biol Phys 63:1562-1567. https://doi.org/10.1016/j.ijrobp.2005.05.036 Yock TI, Krailo M, Fryer CJ, et al (2006) Local control in pelvic Ewing sarcoma: analysis from INT-0091--a report from the Children's Oncology Group. J Clin Oncol 24:3838-3843. https://doi.org/10.1200/JCO.2006.05.9188. Rodríguez-Galindo C, Nabid F, Liu T, et al (2008) Prognostic factors for local and distant control in Ewing sarcoma family of tumors. Ann Oncol 19:814-820. https://doi.org/10.1093/annonc/mdm521 Intelicato DJ, Keole SR, Shahlaee AH, et al (2008) Definitive radiotherapy for ewing tumors of extremities and pelvis: long-term disease control, limb function, and treatment toxicity. Int J Radiat Oncol Biol Phys 72:871-877. https://doi.org/10.1016/j.ijrobp.2008.02.023 Intelicato DJ, Keole SR, Shahlaee AH, et al (2010) Spinal and paraspinal Ewing tumors. Int J Radiat Oncol Biol Phys 76:1463-1471. https://doi.org/10.1016/j.ijrobp.2009.03.042 Sari N, Toğral G, Cetindağ MF et al (2010) Treatment results of the Ewing sarcoma of bone and prognostic factors. Pediatr Blood Cancer 54:19-24 https://doi.org/10.1002/pbc.22278 Intelicato DJ, Keole SR, Lagmay JP, et al (2011) Chest wall Ewing sarcoma family of tumors: long-term outcomes. Int J Radiat Oncol Biol Phys 81:158-166. https://doi.org/10.1016/j.ijrobp.2010.04.066 Lopez JL, Cabrera P, Ordoñez R, et al (2011) Role of radiation therapy in the multidisciplinary management of Ewing's Sarcoma of bone in pediatric patients: An effective treatment for local control. Rep Pract Oncol Radiother 16:103-109. https://doi.org/10.1016/j.rpor.2011.01.006 Rombi B, DeLaney TF, MacDonald SM, et al (2012) Proton radiotherapy for pediatric Ewing's sarcoma: initial clinical outcomes. Int J Radiat Oncol Biol Phys 82:1142-1148. https://doi.org/10.1016/j.ijrobp.2011.03.038 Vogin G, Helfre S, Glorion C, et al (2013) Local control and sequelae in localised Ewing tumours of the spine: a French retrospective study. Eur J Cancer 49:1314-1323. https://doi.org/10.1016/j.ejca.2012.12.005 Raciborska A, Bliska K, Drabki K, et al (2014) Validation of a multi-modal treatment protocol for Ewing sarcoma--a report from the polish pediatric oncology group. Pediatr Blood Cancer 61:2170-2174. https://doi.org/10.1002/pbc.25167 DuBois SG, Krailo MD, Gebhardt MC, et al (2015) Comparative evaluation of local control strategies in localized Ewing sarcoma of bone: a report from the Children's Oncology Group. Cancer 121:467-475. https://doi.org/10.1002/cncr.29065 Choi Y, Lin DH, Lee SH, et al (2015) Role of Radiotherapy in the Multimodal Treatment of Ewing Sarcoma Family Tumors. Cancer Res Treat 47:904-912. https://doi.org/10.4143/crt.2014.158 Bedetti B, Wiebe K, Ranft A, et al (2015) Local control in Ewing sarcoma of the chest wall: results of the EURO-EWING 99 trial. Ann Surg Oncol 22:2853-2859. https://doi.org/10.1245/s10434-015-4630-0 Ning MS, Perkins SM, Borinstein SC, et al (2016) Role of radiation in the treatment of non-metastatic osseous Ewing sarcoma. J Med Imaging Radiat Oncol 60:119-128. https://doi.org/10.1111/1754-9485.12389 Grevener K, Haveman LM, Ranft A, et al (2016) Management and Outcome of Ewing Sarcoma of the Head and Neck. Pediatr Blood Cancer 63:604-610. https://doi.org/10.1002/pbc.25830 Daw NC, Laack NN, Mcllvaine EJ, et al (2016) Local Control Modality and Outcome for Ewing Sarcoma of the Femur: A Report From the Children's Oncology Group. Ann Surg Oncol 23:3541-3547. https://doi.org/10.1245/s10434-016-5269-1 Talleur AC, Navid F, Spunt SL, 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 96:119-126. https://doi.org/10.1016/j.ijrobp.2016.04.001 Hamilton SN, Carlson R, Hasan H, et al (2017) Long-term Outcomes and Complications in Pediatric Ewing Sarcoma. Am J Clin Oncol 40:423-428. https://doi.org/10.1097/COC.0000000000000176 Wan W, Lou Y, Hu Z, et al (2017) Factors affecting survival outcomes of patients with non-metastatic Ewing's sarcoma family tumors in the spine: a retrospective analysis of 63 patients in a single center. J Neurooncol 131:313-320. https://doi.org/10.1007/s11060-016-2295-6 Ahmed SK, Robinson SI, Arndt CAS, et al (2017) Pelvis Ewing sarcoma: Local control and survival in the modern era. Pediatr Blood Cancer 64. https://doi.org/10.1002/pbc.26504 Weber DC, Murray FR, Correia D, et al (2017) Pencil beam scanned protons for the treatment of patients with Ewing sarcoma. Pediatr Blood Cancer 64. https://doi.org/10.1002/pbc.26688 Ash S, Yaniv I, Toledano H, et al (2019) Improved Outcome in Local Ewing Sarcoma With an Intensified Pilot Treatment Protocol SCMCIE 94. J Pediatr Hematol Oncol 41:105-111. https://doi.org/10.1097/MPH.0000000000001384 Martin E, Radomski S, Harley EH (2019) Pediatric Ewing sarcoma of the head and neck: A retrospective survival analysis. Int J Pediatr Otorhinolaryngol 117:138-142. https://doi.org/10.1016/j.ijporl.2018.11.026 Seitz G, Urla C, Sparber-Sauer M, et al (2019) Treatment and outcome of patients with thoracic tumors of the Ewing sarcoma family: A report from the Cooperative Weichteilsarkom Studiengruppe CWS-81, -86, -91, -96, and -2002P trials. Pediatr Blood Cancer 66: e27884. https://doi.org/10.1002/pbc.27884 Kharod SM, Indelicato DJ, Rotondo RL, et al (2020) Outcomes following proton therapy for Ewing sarcoma of the cranium and skull base. Pediatr Blood Cancer 67: e28080. https://doi.org/10.1002/pbc.28080 Torabi SJ, Izreig S, Kasle DA, et al (2020) Clinical characteristics and treatment-associated survival of head and neck Ewing sarcoma. Laryngoscope 130:2385-2392. https://doi.org/10.1002/lary.28412 Uezono H, Indelicato DJ, Rotondo RL, et al (2020) Treatment Outcomes After Proton Therapy for Ewing Sarcoma of the Pelvis. Int J Radiat Oncol Biol Phys 107:974-981. https://doi.org/10.1016/j.ijrobp.2020.04.043 Guder WK, Hardes J, Nottrott M, et al (2020) Pelvic Ewing sarcoma: a retrospective outcome analysis of 104 patients who underwent pelvic tumor resection at a single supra-regional center. J Orthop Surg Res 15:534. https://doi.org/10.1186/s13018-020-02028-3 Lex JR, Kurisunkal V, Kaneuchi Y, et al (2021) Pelvic Ewing sarcoma: Should all patients receive pre-operative radiotherapy, or should it be delivered selectively? Eur J Surg Oncol 47:2618-2626. https://doi.org/0.1016/j.ejso.2021.05.027 Indelicato DJ, Vega RBM, Viviers E, et al (2022) Modern Therapy for Spinal and Paraspinal Ewing Sarcoma: An Update of the University of Florida Experience. Int J Radiat Oncol Biol Phys 113:161-165. https://doi.org/10.1016/j.ijrobp.2022.01.007 Indelicato DJ, Vega RBM, Viviers E, et al (2022) Modern Therapy for Chest Wall Ewing Sarcoma: An Update of the University of Florida Experience. Int J Radiat Oncol Biol Phys 113:345-354. https://doi.org/10.1016/j.ijrobp.2022.02.011 Worawongsakul R, Steinmeier T, Lin YL, et al (2022) Proton Therapy for Primary Bone Malignancy of the Pelvic and Lumbar Region - Data From the Prospective Registries ProReg and KiProReg. Front Oncol 12:805051. https://doi.org/10.3389/fonc.2022.805051 Laskar S, Sinha S, Chatterjee A, et al (2022) Radiation Therapy Dose Escalation in Unresectable Ewing Sarcoma: Final Results of a Phase 3 Randomized Controlled Trial. Int J Radiat Oncol Biol Phys 113:996-1002. https://doi.org/10.1016/j.ijrobp.2022.04.024 Maruo K, Yamaguchi Y, Ishii R, et al Simple imputation method for meta-analysis of survival rates when precision information is missing. Research Synthesis Methods https://doi.org/10.1017/rsm.2025.10024 ,in press. Balduzzi S, Rücker G, Schwarzer G (2019) How to perform a meta-analysis with R: a practical tutorial. Evid Based Ment Health. 22:153-160. https://doi.org/10.1136/ebmental-2019-300117 Schuck A, Ahrens S, Pauluseen M, et al (2003) Local therapy in localized Ewing tumors: results of 1058 patients treated in the CESS 81, CESS 86, and EICESS 92 trials. Int J Radiat Oncol Biol Phys 55:168-177. https://doi.org/10.1016/s0360-3016(02)03797-5 Indelicato DJ, Callan AK, Ahmed SK, et al (2025) Preoperative Radiotherapy in Patients With Localized Ewing Sarcoma Enrolled on AESFT1031: A Report From the Children's Oncology Group. Pediatr Blood Cancer 2025 May 25: e31820. Online ahead of print. https://doi.org/10.1002/pbc.31820 Eaton BR, Claude L, Indelicato DJ, et al (2021) Ewing sarcoma. Pediatr Blood Cancer 68: e28355. https://doi.org/10.1002/pbc.28355 Kacar M, Nagel MB, Liang J, et al (2024) Radiation therapy dose escalation achieves high rates of local control with tolerable toxicity profile in pediatric and young adult patients with Ewing sarcoma. Cancer 130:1836-1843. https://doi.org/10.1002/cncr.35196 Suzuki R, Fukushima H, Okuwaki H, et al (2021) Proton beam therapy with concurrent chemotherapy is feasible in children with newly diagnosed rhabdomyosarcoma. Rep Pract Oncol Radiother 26:616-625. https://doi.org/10.5603/RPOR.a2021.0082 Friedman DL, Whitton J, Leisenring W, et al (2010) Subsequent neoplasms in 5-year survivors of childhood cancer: the Childhood Cancer Survivor Study. J Natl Cancer Inst 102(14):1083-1095. https://doi.org/10.1093/jnci/djq238 Supplementary Files SIfig1.tiff Supplementary Figure 1. Forest plots of overall survival of studies since 2015 Forest plots of 1- to 5-year overall survival for each radiotherapy modality. SIfig2.tiff Supplementary Figure 2. Forest plots of local control of studies since 2015 Forest plots of 1- to 5-year local control for each radiotherapy modality. metaEWSSITable.xlsx Cite Share Download PDF Status: Posted Version 1 posted 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-7654899","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":519816133,"identity":"6463e971-e190-4dbd-8748-b66b5838a98f","order_by":0,"name":"Kumie Nagatomo","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0002-7286-054X","institution":"Tsukuba Daigaku","correspondingAuthor":true,"prefix":"","firstName":"Kumie","middleName":"","lastName":"Nagatomo","suffix":""},{"id":519816135,"identity":"43cb2488-959f-4e61-aa65-2526eca4eb8f","order_by":1,"name":"Masashi Mizumoto","email":"","orcid":"","institution":"Tsukuba Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Masashi","middleName":"","lastName":"Mizumoto","suffix":""},{"id":519816137,"identity":"1ff10f14-073a-49d9-9393-0dc946d5c45e","order_by":2,"name":"Hiroko Fukushima","email":"","orcid":"","institution":"Tsukuba Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Hiroko","middleName":"","lastName":"Fukushima","suffix":""},{"id":519816139,"identity":"ddbe3e35-58b6-4083-8056-3532838f8a15","order_by":3,"name":"Sho Hosaka","email":"","orcid":"","institution":"Tsukuba Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Sho","middleName":"","lastName":"Hosaka","suffix":""},{"id":519816140,"identity":"283c940d-ccc1-4de0-99be-b5ec873f272f","order_by":4,"name":"Yinuo Li","email":"","orcid":"","institution":"Tsukuba Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Yinuo","middleName":"","lastName":"Li","suffix":""},{"id":519816141,"identity":"da9fa2e7-09d2-4eef-9795-54f713365e1e","order_by":5,"name":"Kazushi Maruo","email":"","orcid":"","institution":"Tsukuba Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Kazushi","middleName":"","lastName":"Maruo","suffix":""},{"id":519816145,"identity":"b58a0f94-8c24-43bb-93f5-d8a2ff801f35","order_by":6,"name":"Yoshiko Oshiro","email":"","orcid":"","institution":"Tsukuba Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Yoshiko","middleName":"","lastName":"Oshiro","suffix":""},{"id":519816146,"identity":"ad17c5ee-7e74-4139-bbc3-09f2a66d6396","order_by":7,"name":"Hazuki Nitta","email":"","orcid":"","institution":"Tsukuba Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Hazuki","middleName":"","lastName":"Nitta","suffix":""},{"id":519816147,"identity":"5f49d165-08e9-41e8-8286-3e42aa503911","order_by":8,"name":"Takashi Iizumi","email":"","orcid":"","institution":"Tsukuba Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Takashi","middleName":"","lastName":"Iizumi","suffix":""},{"id":519816148,"identity":"b42ce8c2-cf0f-4683-83ab-8fc6589bfaac","order_by":9,"name":"Takashi Saito","email":"","orcid":"","institution":"Tsukuba Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Takashi","middleName":"","lastName":"Saito","suffix":""},{"id":519816149,"identity":"72f5343a-7726-40d9-b821-73b044a3ee9f","order_by":10,"name":"Masako Inaba","email":"","orcid":"","institution":"Tsukuba Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Masako","middleName":"","lastName":"Inaba","suffix":""},{"id":519816151,"identity":"e40946e7-b838-4029-87da-cf730e14c867","order_by":11,"name":"Ryoko Suzuki","email":"","orcid":"","institution":"Tsukuba Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Ryoko","middleName":"","lastName":"Suzuki","suffix":""},{"id":519816152,"identity":"475499a6-9563-4f01-830f-169c19cf4fc4","order_by":12,"name":"Kei Nakai","email":"","orcid":"","institution":"Tsukuba Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Kei","middleName":"","lastName":"Nakai","suffix":""},{"id":519816153,"identity":"165b9d0f-1196-471b-ac05-333901f82379","order_by":13,"name":"Shosei Shimizu","email":"","orcid":"","institution":"Tsukuba Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Shosei","middleName":"","lastName":"Shimizu","suffix":""},{"id":519816154,"identity":"a73d42da-e3ae-4d20-973c-d4c6e5b9757e","order_by":14,"name":"Hidetoshi Takada","email":"","orcid":"","institution":"Tsukuba Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Hidetoshi","middleName":"","lastName":"Takada","suffix":""},{"id":519816155,"identity":"45704989-e6f3-45b0-8773-f2f78cf9c20d","order_by":15,"name":"Hideyuki Sakurai","email":"","orcid":"","institution":"Tsukuba Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Hideyuki","middleName":"","lastName":"Sakurai","suffix":""}],"badges":[],"createdAt":"2025-09-19 06:00:02","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7654899/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7654899/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":93009162,"identity":"0c4003e1-8fcd-4915-af25-01bef4d6b02a","added_by":"auto","created_at":"2025-10-08 07:07:48","extension":"tiff","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":123062,"visible":true,"origin":"","legend":"","description":"","filename":"figure1.tiff","url":"https://assets-eu.researchsquare.com/files/rs-7654899/v1/1c4c9db4d8cfd0b0776a2223.tiff"},{"id":93009178,"identity":"2189c566-8353-4e0f-948a-100e0c20b545","added_by":"auto","created_at":"2025-10-08 07:07:50","extension":"tiff","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":39814914,"visible":true,"origin":"","legend":"","description":"","filename":"figure2.tiff","url":"https://assets-eu.researchsquare.com/files/rs-7654899/v1/402c066b4737c091244850d0.tiff"},{"id":93009164,"identity":"b0cd56ca-6eaa-4c52-8e1f-d7217e445fce","added_by":"auto","created_at":"2025-10-08 07:07:48","extension":"xlsx","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":15518,"visible":true,"origin":"","legend":"","description":"","filename":"metaEWSTable.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7654899/v1/acb47d1f151769f14f624939.xlsx"},{"id":93009176,"identity":"237439c3-bc67-418e-b70e-e212d3cd5b29","added_by":"auto","created_at":"2025-10-08 07:07:49","extension":"tiff","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":4504304,"visible":true,"origin":"","legend":"","description":"","filename":"figure3.tiff","url":"https://assets-eu.researchsquare.com/files/rs-7654899/v1/7ed600911c10977c35c0023f.tiff"},{"id":93009160,"identity":"9d00152a-d1e0-4b05-8475-668ffaeea789","added_by":"auto","created_at":"2025-10-08 07:07:48","extension":"xml","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":15950,"visible":true,"origin":"","legend":"","description":"","filename":"ijcoIJCOD2501147.xml","url":"https://assets-eu.researchsquare.com/files/rs-7654899/v1/35f6619f19838ff696973fd7.xml"},{"id":93010981,"identity":"e70c006a-6855-4b2b-baae-c41c8b68ddc7","added_by":"auto","created_at":"2025-10-08 07:15:49","extension":"xml","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":1187,"visible":true,"origin":"","legend":"","description":"","filename":"IJCOD250114714621.go.xml","url":"https://assets-eu.researchsquare.com/files/rs-7654899/v1/0ff08a9da0d75c4c986a6796.xml"},{"id":93009170,"identity":"4e25cd63-d1eb-455d-8dc5-cfe7b3729312","added_by":"auto","created_at":"2025-10-08 07:07:49","extension":"xml","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":877,"visible":true,"origin":"","legend":"","description":"","filename":"IJCOD2501147Import.xml","url":"https://assets-eu.researchsquare.com/files/rs-7654899/v1/081d8a312b7e4f900d43e900.xml"},{"id":93009169,"identity":"7a6f8c90-0080-4274-a7fe-50bca3ad2050","added_by":"auto","created_at":"2025-10-08 07:07:49","extension":"tiff","order_by":11,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":123062,"visible":true,"origin":"","legend":"","description":"","filename":"figure1.tiff","url":"https://assets-eu.researchsquare.com/files/rs-7654899/v1/3066071ac139116e338d48e0.tiff"},{"id":93009177,"identity":"c717fef1-162b-4c45-a0bc-5fd7007de085","added_by":"auto","created_at":"2025-10-08 07:07:49","extension":"tiff","order_by":12,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":39814914,"visible":true,"origin":"","legend":"","description":"","filename":"figure2.tiff","url":"https://assets-eu.researchsquare.com/files/rs-7654899/v1/7e32ce8ec886e348c8a8eaea.tiff"},{"id":93009175,"identity":"c9572854-b3a0-48c7-b115-0ab6c41865d2","added_by":"auto","created_at":"2025-10-08 07:07:49","extension":"tiff","order_by":13,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":4504304,"visible":true,"origin":"","legend":"","description":"","filename":"figure3.tiff","url":"https://assets-eu.researchsquare.com/files/rs-7654899/v1/c51ef69560819cedec72f267.tiff"},{"id":93010983,"identity":"41657eb6-b174-4932-a903-63207a1339df","added_by":"auto","created_at":"2025-10-08 07:15:49","extension":"png","order_by":14,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":310995,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefigure1.png","url":"https://assets-eu.researchsquare.com/files/rs-7654899/v1/d8588390b733e4e4a7ceaa6b.png"},{"id":93010984,"identity":"c6486e32-ca81-4f0d-90d6-b9dee2ce8362","added_by":"auto","created_at":"2025-10-08 07:15:49","extension":"png","order_by":15,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":4614339,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefigure2.png","url":"https://assets-eu.researchsquare.com/files/rs-7654899/v1/46cd20231a7fec2025f59cf9.png"},{"id":93009173,"identity":"c14c4e33-9c81-4ff3-abcd-f87a16a1002a","added_by":"auto","created_at":"2025-10-08 07:07:49","extension":"png","order_by":16,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":765303,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefigure3.png","url":"https://assets-eu.researchsquare.com/files/rs-7654899/v1/37fccaafa831dccc4676d688.png"},{"id":93010979,"identity":"970892ee-6099-46d2-99fb-c3faf0dad01f","added_by":"auto","created_at":"2025-10-08 07:15:48","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":8813046,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSchematic image of article selection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA PubMed search using the selected keywords was conducted. Articles were included that matched the specified criteria.\u003c/p\u003e","description":"","filename":"figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-7654899/v1/47a0835cbdbf3a017f7747bc.png"},{"id":93009165,"identity":"7e419068-ef8d-4b99-bb1e-46a302ccc42f","added_by":"auto","created_at":"2025-10-08 07:07:49","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":6560158,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eForest plots of overall survival\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eForest plots of 1- to 5-year overall survival for each radiotherapy modality.\u003c/p\u003e","description":"","filename":"figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-7654899/v1/4026c0d779e02ae4cb1ebc45.png"},{"id":93009167,"identity":"d7cb7794-492a-4742-a064-1e7772c4035c","added_by":"auto","created_at":"2025-10-08 07:07:49","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":13478579,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eForest plots of local control\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eForest plots of 1- to 5-year local control for each radiotherapy modality.\u003c/p\u003e","description":"","filename":"figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-7654899/v1/4e823fd903981643e0f1f0e4.png"},{"id":97673907,"identity":"e02199bf-9f58-4e3f-8d90-c23fde740237","added_by":"auto","created_at":"2025-12-08 09:41:52","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":29151717,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7654899/v1/a70f22ce-b318-4c58-b534-e02bc724637d.pdf"},{"id":93010982,"identity":"fe92bc33-24ae-4e64-961a-412c4c9d0859","added_by":"auto","created_at":"2025-10-08 07:15:49","extension":"tiff","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":4385560,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Figure 1. Forest plots of overall survival of studies since 2015\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eForest plots of 1- to 5-year overall survival for each radiotherapy modality.\u003c/p\u003e","description":"","filename":"SIfig1.tiff","url":"https://assets-eu.researchsquare.com/files/rs-7654899/v1/b980fd0536b958924de93178.tiff"},{"id":93009172,"identity":"95c90706-a5cc-4c47-9609-c53462dad095","added_by":"auto","created_at":"2025-10-08 07:07:49","extension":"tiff","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":3477050,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Figure 2. Forest plots of local control of studies since 2015\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eForest plots of 1- to 5-year local control for each radiotherapy modality.\u003c/p\u003e","description":"","filename":"SIfig2.tiff","url":"https://assets-eu.researchsquare.com/files/rs-7654899/v1/3179ff6bd7ec14b092198cb1.tiff"},{"id":93010980,"identity":"1255d9a5-d880-4908-a13a-baf5803d37a4","added_by":"auto","created_at":"2025-10-08 07:15:48","extension":"xlsx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":21664,"visible":true,"origin":"","legend":"","description":"","filename":"metaEWSSITable.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7654899/v1/238c515b00dc0fffe210928a.xlsx"}],"financialInterests":"","formattedTitle":"Systematic review and meta-analysis of photon radiotherapy versus proton beam therapy for pediatric Ewing sarcoma: TRP-Ewing sarcoma 2024","fulltext":[{"header":"Introduction","content":"\u003cp\u003eEwing sarcoma (EWS) is a common solid malignancy in children, adolescents and young adults, with onset typically occurring during the teenage years [1,2]. It primarily affects bone or soft tissue and can arise in various locations, including the extremities, pelvis, spine, and trunk. Approximately 25% of cases present with metastatic disease at the time of diagnosis [1,3]. Multimodal treatment is standard for EWS, involving induction chemotherapy followed by local treatment with surgery and/or radiotherapy (RT), along with postoperative chemotherapy. While several chemotherapy regimens are available, the EuroEwing 2012 trial demonstrated that interval-compressed VDC-IE therapy, administered every two weeks, offered superior outcomes compared to the traditional European protocol [4]. As a result, interval-compressed VDC-IE has become the global standard of care. In the Children’s Oncology Group report, event-free survival for patients with localized disease exceeds 75% [5], although the prognosis for patients with metastatic or relapsed disease remains poor [6-8]. Multiple studies are in progress on the role of high-dose chemotherapy with autologous stem cell transplantation and molecular-targeted therapies in refractory or relapsed cases [6,9,10].\u003c/p\u003e\n\u003cp\u003eIn contrast, strategies for local control continue to be a topic of discussion, given the diverse sites of tumor presentation. Surgery, or a combination of surgery and RT, is generally preferred over definitive RT alone, provided the tumor is resectable [11,12]. This is particularly true for pelvic tumors, where total surgical resection is often challenging due to anatomical constraints and the need to preserve tissue function. In such cases, RT plays a critical role in management [13].\u003c/p\u003e\n\u003cp\u003eThe use of proton beam therapy (PBT) for pediatric cancers has been increasingly reported in recent years. Proton beams generate Bragg peaks at specific depths depending on their energy, which limits radiation exposure to tissues beyond the target area. This property enables PBT to reduce irradiation of surrounding normal tissues. Consequently, PBT has been shown to minimize both acute and late adverse effects, such as secondary neoplasms, making it an increasingly preferred option for children and young patients. Previous meta-analyses comparing PBT and conventional photon RT across various pediatric malignancies have generally found no significant differences in clinical outcomes between the two modalities [14-17]. While reports on the use of PBT for EWS are gradually increasing, its comparative efficacy to photon RT remains unclear. Therefore, we performed a meta-analysis of existing studies to assess whether there are differences in local control (LC) and overall survival (OS) between photon RT and PBT in pediatric EWS.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eSelection criteria for meta-analysis\u003c/p\u003e\n\u003cp\u003eThe review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [18]. Only articles published in English were included. Two independent reviewers screened all extracted articles. The inclusion criteria were as follows: (1) clinically diagnosed Ewing sarcoma, (2) treatment with RT (photon RT or PBT), (3) availability of data on OS or LC rate with RT, and (4) inclusion of at least 10 cases.\u003c/p\u003e\n\u003cp\u003eA PubMed search was conducted using the terms “Ewing” AND (“radiotherapy” OR “proton”) AND (“children” OR “pediatrics”) for publications from 1990 to 2022, yielding 913 articles. Of these, 183 articles that described the treatment outcome of RT for EWS were selected based on their title or abstract. 108 articles were identified that reported OS, progression-free survival (PFS) or LC rate either in the abstract or full text. Finally, 38 results from 36 articles (8 PBT, 30 photon RT) were included after excluding studies with significant biases in patient characteristics or overlapping publication periods from the same center\u0026nbsp;[2,12,13,19-52]. If different modalities were discussed within a single article, they were treated as separate results. The included articles\u0026nbsp;are listed in Supplementary Table 1. Figure 1 illustrates the summarization of the manuscript selection process. Data extracted from the selected studies included: authors, year of publication, country, study design, number of patients, number of deaths, all recurrences, local recurrences, follow-up period, 1- to 5-year OS and LC rates, age, male-to-female ratio, rates of concurrent chemotherapy and surgery, and treatment modality (photon RT vs. PBT). If the 1- to 5-year OS and LC rates were not directly reported, these rates were estimated from the figures. Within the limits specified in the manuscript, the irradiation method of photon RT was either Three-Dimensional Conformal Radiation Therapy (3D-CRT) or Intensity Modulated Radiation Therapy (IMRT).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eStatistical analysis\u003c/p\u003e\n\u003cp\u003eRandom-effects meta-analyses were conducted to assess the 1- to 5-year OS and LC rates for both photon RT and PBT, and forest plots were generated. In cases where studies had missing accuracy data, these values were imputed based on the survival probability, the number of cases, the risk set size at each year, and the mean dropout rate [53]. Heterogeneity in each meta-analysis was evaluated by I-square statistics. To compare the treatment modalities, random-effects meta-regression was performed with modality as the explanatory variable. All analyses were conducted using R (R Core Team, Vienna, Austria) and its accompanying meta package [54]. Differences in radiation dose by modality were assessed using the Mann-Whitney U test in SPSS Statistics version 28.0 (IBM Corporation, Tokyo, Japan).\u003c/p\u003e"},{"header":"Abbreviation","content":"\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eConfidence interval\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eEWS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eEwing sarcoma\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eLC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eLocal control\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eOS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eOverall survival\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePBT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eProton beam therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eRCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eRandomized controlled trial\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eRT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eRadiotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTRP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTsukuba review project\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Results","content":"\u003cp\u003eFigures 2 and 3 display the forest plots for each modality regarding the 1- to 5-year OS and LC rates, respectively.\u003c/p\u003e\n\u003cp\u003eA meta-analysis of the 38 results from 36 articles (8 for PBT and 28 for photon RT) showed the following 1- to 5-year OS rates (95% confidence interval (CI)) for PBT vs. photon RT, respectively: at 1-year OS, 94.3% (89.0%-97.1%) vs. 87.6% (83.7%-90.7%) (p=0.5480); at 2-years OS, 87.3% (80.7%-91.8%) vs. 75.8% (69.9%-80.7%) (p=0.3834); at 3-years OS, 82.0% (72.3%-88.6%) vs. 70.2% (64.2%-75.4%) (p=0.2456); at 4-years OS, 78.2% (68.1%-85.4%) vs. 64.8% (59.0%-70.0%) (p=0.3543); and at 5-years OS,76.3% (65.8%-83.9%) vs. 61.2% (57.0%-65.1%) (p=0.0008\u0026lt;0.05).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eResult of meta-analysis of the 1- to 5-year LC rates (95% CI) for PBT vs. photon RT, respectively, were as follows: at 1-year LC, 98.1% (93.6%-99.4%) vs. 93.2% (90.8%-95.0%) (p=0.2063); at 2-years LC, 91.7% (80.5%-96.6%) vs. 86.6% (83.6%-89.0%) (p=0.1042); at 3-years LC, 89.0% (79.6%-94.2%) vs. 83.6% (80.3%-86.4%) (p=0.0151); at 4-years LC, 88.2% (75.8%-94.5%) vs. 82.0% (78.2%-85.1%) (p=0.0363); and at 5-years LC, 83.1% (68.7%-91.3%) vs. 79.7% (75.4%-83.4%) (p=0.4745).\u003c/p\u003e\n\u003cp\u003eMeta-regression analysis\u0026nbsp;was conducted using modality (photon RT vs. PBT), age, male-to-female ratio, concurrent chemotherapy rate, and concurrent surgery rate as risk factors. The median age was 13.3 years (range 9.8-23) in the photon RT group and 10.0 years (range 5.9-16) in PBT group. The respective percentages (median) for each factor (photon RT vs. PBT) were: male-to-female ratio, 46.2%-69.8% (55.9%) vs. 47.1%-63.8% (50.3%); concurrent chemotherapy, 88.4%-100% (100%) vs. 100% (100%); and concurrent surgery, 0%-100% (50.2%) vs. 24.0%-100% (94.1%), respectively. The total doses for photon RT ranged from 44.7 to 56.1 Gy (median 52.2 Gy), and for PBT, it ranged from 50.4 to 59.4 GyE (median 54.9 GyE) with no significant difference between the two modalities (p=0.079), and thus, these were excluded from further analysis. The meta-regression analysis identified a significant better OS associated with a higher male rate at 1-,4-and 5-year OS, and with concurrent surgery at 4-, 5-year OS. No significant risk factors for LC were identified (Table 1). Furthermore, the analysis showed that PBT was significantly associated with better 5-year OS and 3-, 4-year LC rates.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe considered that advancements in chemotherapy regimens and radiological techniques might influence the outcomes, so we performed a re-analysis limiting the studies to those published in 2015 or later (Supplementary Figures 1, 2) [12,13,30-52]. A meta-analysis of the 27 results from 25 articles (7 for PBT and 20 for photon RT) revealed a significant difference between PBT and photon RT only in the 5-year OS rate (95% CI); with PBT showing 78.1% (65.6%-86.5%) compared to 65.2% (60.9%-69.2%) for photon RT (p=0.0034\u0026lt;0.05). No significant differences were observed for other OS or LC rates. The meta-regression analysis identified a significant association between treatment modality of RT and improved 5-year OS in favor of PBT (Supplementary Table 2).\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe conducted a meta-analysis comparing the treatment outcomes of photon RT and PBT in pediatric EWS. Significant differences were observed only in the 5-year OS rate, with no clear distinction in OS and LC rates at other time points. For studies published from 2015 onwards, the 5-year EFS rates were 65% for photon RT and 78% for PBT, while the 5-year LC rates were around 80% for both modalities. Although the analysis included reports with metastases or various primary tumor sites, it is evident that better outcomes have been achieved in recent years. Inadequate local treatment, such as intralesional resection, increases the risk of local extension and recurrence [19], with poor prognosis after recurrence, as demonstrated by a 6-month EFS of only 12.7%\u0026nbsp;[8]. When planning local therapy, the feasibility of complete resection and the response to induction chemotherapy are crucial factors. Achieving complete resection should be the goal whenever possible; otherwise, effective RT should be used in cases where complete resection is unachievable. PBT is increasingly replacing photon RT in the treatment of pediatric solid tumors. However, conducting RCTs to compare PBT with photon RT remains challenging, making the results of this study particularly significant.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the context of RT for EWS, particularly with PBT, the treatment strategy has not yet been clearly defined, and several aspects remain open for discussion. The first point for discussion regarding RT is the timing of its administration. RT has traditionally been delivered either as definitive RT without surgery or as postoperative RT. However, preoperative RT is increasingly becoming the method of choice. European studies have shown that the local failure rate in patients treated with preoperative RT, particularly those with large tumors or poor clinical responses to induction chemotherapy, was 5.3% [55]. This outcome was non-inferior to the local recurrence rate observed in low-risk patients treated with surgery alone. In the AEWS1031 trial, 7.4% of participants who underwent combined modality local therapy received preoperative RT with a dose of 36 Gy to the tumor and a 1 cm margin [56]. The 3-year cumulative incidence of local failure in patients receiving preoperative RT was 12.5%, and R0 resection rates improved with lower doses and smaller target volumes, alongside better pathological responses. A single-center study in the UK reported that using PBT as preoperative RT for pelvic localized EWS also improved local recurrence-free survival compared to postoperative RT\u0026nbsp;[48]. Furthermore, in the same study, complications related to RT, such as wound issues or infections, did not differ significantly between modalities. Based on these findings, preoperative RT could be considered in cases where marginal resection is expected. PBT may be particularly advantageous in preoperative settings, as it limits normal tissue toxicity and reduces the delay in post-irradiation recovery before surgery.\u003c/p\u003e\n\u003cp\u003eSecondly, the optimal irradiation dose for EWS has not yet been established. While the standard definitive RT dose for EWS is typically between 50-60 Gy, studies have reported that using higher doses, such as 60 Gy or more, can enhance the therapeutic efficacy of RT. In a retrospective study, Kacar et al. found that a median dose of 64.8 Gy resulted in a 5-year local failure rate of 6.6% for tumors larger than 8 cm [58]. Laskar et al. conducted a randomized controlled trial (RCT) comparing 55.8 Gy and 70.2 Gy doses in nonmetastatic unresectable EWS/primitive neuroectodermal tumors. The study reported a statistically significant improvement in the high-dose group, with a 5-year LC rate of 76.4% [52]. Although acute skin toxicity was more common in the high-dose group, late toxic effects did not differ between the two groups. These findings suggest that high-dose RT is feasible with acceptable levels of toxicity and functional outcomes.\u003c/p\u003e\n\u003cp\u003eA third point of debate is whether the use of PBT in EWS increases side effects, a concern that remains insufficiently addressed in the literature. Lex et al. reported that, in primary pelvic cases, no significant association between RT type and toxicity, such as radiation dermatitis or avascular necrosis, was observed [58]. Rhabdomyosarcoma is one of the tumors treated with a combination of chemotherapy and RT, like EWS.\u0026nbsp;Suzuki et al. conducted a single-center, retrospective analysis of side effects associated with chemotherapy with or without PBT for rhabdomyosarcoma [59]. They found that when PBT was combined with chemotherapy, the duration of opioid use for managing dermatitis or mucositis was longer than when chemotherapy alone was administered. However, PBT was not associated with the duration of fever or the highest C-reactive protein levels. Notably, grade 4 or higher nonhematological toxicities were not observed. Based on these findings, the authors concluded that PBT is feasible for children when appropriate supportive care is provided.\u003c/p\u003e\n\u003cp\u003eFurthermore, secondary malignancy is a significant late complication following RT. In EWS, the 30-year cumulative incidence of secondary malignancies has been reported to be 10.1% [60]. Among the PBT studies included in this analysis, only Rombi et al. reported that 4 out of 30 patients developed secondary malignancies: 3 cases of acute myeloid leukemia (AML) and 1 case of myelodysplastic syndrome (MDS) [26]. In this study, the development of secondary hematological malignancies was attributed to chemotherapy, particularly alkylating agents. However, the development of solid tumors was not reported in any of the PBT studies included in this analysis. Most of the articles collected in this study had relatively short follow-up periods, with the median follow-up for PBT studies being 46.2 months (range: 27.5-54.6 months), and all studies reported follow-up of less than 5 years. Given the short follow-up duration, it is not possible to draw conclusions regarding the development of solid secondary malignancies associated with RT.\u003c/p\u003e\n\u003cp\u003eThis study has several limitations. First, the number of included studies was relatively small (36 studies). Furthermore, many of these reports involved a limited number of patients, primarily due to the rarity of the disease. Second, only one of the studies included in this analysis was a prospective RCT, while the remaining studies were retrospective in nature. Third, four of the eight studies involving PBT were conducted at the same institution, which may introduce sample bias.\u003c/p\u003e\n\u003cp\u003eIn conclusion, our analysis suggests that there is no significant difference between photon RT and PBT in the treatment of EWS. Among local therapies, PBT is likely to become an increasingly important modality as further data on RT are gathered. Reports on long-term outcomes and treatment-related toxicity are urgently needed.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgement:\u003c/strong\u003e We would like to thank all the children with Ewing sarcoma, their family members, and the collaborating medical staff. We would also like to thank Thomas Mayers (Medical English Communications Center, University of Tsukuba) for English language editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclarations\u003c/strong\u003e\u003c/p\u003e\n\u003cp id=\"_Toc472330565\"\u003e\u003cstrong\u003eConflict of interest statement\u003c/strong\u003e\u003cstrong\u003e:\u0026nbsp;\u003c/strong\u003eThe authors have no conflicts of interest to declare.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval:\u0026nbsp;\u003c/strong\u003eNot required.\u003c/p\u003e\n\u003cp id=\"_Toc472330568\"\u003e\u003cstrong\u003eFunding sources\u003c/strong\u003e\u003cstrong\u003e:\u0026nbsp;\u003c/strong\u003eThis work was supported by institutional funds only.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u0026nbsp;\u003c/strong\u003eConception/design: MM, YO, SH. Collection and/or assembly of data: HF, MM, SH, KN, YL, YO, HH, TI, TS, MI, RS, HT, SS. Data analysis and interpretation: MM, KM. Manuscript writing: KN, HF. MM and HS supervised the management of the research and the overall structure of the manuscript.\u0026nbsp;\u003cstrong\u003eAll authors\u003c/strong\u003emade substantial contributions to the study concept or the data analysis or interpretation; drafted the manuscript or revised it critically for important intellectual content; approved the final version of the manuscript to be published; and agreed to be accountable for all aspects of the work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eavailability\u003c/strong\u003e\u003cstrong\u003es\u003c/strong\u003e\u003cstrong\u003etatement:\u0026nbsp;\u003c/strong\u003eAll data generated or analyzed during this study are included in this article. Further enquiries can be directed to the corresponding author.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eEsiashvili N, Goodman M, Marcus RB Jr (2008) Changes in incidence and survival of Ewing sarcoma patients over the past 3 decades: Surveillance Epidemiology and End Results data. J Pediatr Hematol Oncol 30:425-430. https://doi.org/10.1097/MPH.0b013e31816e22f3\u003c/li\u003e\n \u003cli\u003eNakata K, Ito Y, Magadi W, et al (2018) Childhood cancer incidence and survival in Japan and England: A population-based study (1993-2010) Cancer Sci 109:422-434. https://doi.org/ 10.1111/cas.13457\u003c/li\u003e\n \u003cli\u003eShi J, Yang J, Ma X, et al (2020) Risk factors for metastasis and poor prognosis of Ewing sarcoma: a population based study. J Orthop Surg Res 15:88. https://doi.org/10.1186/s13018-020-01607-8\u003c/li\u003e\n \u003cli\u003eBrennan B, Kirton L, Berard PM, et al (2022) Comparison of two chemotherapy regimens in patients with newly diagnosed Ewing sarcoma (EE2012): an open-label, randomised, phase 3 trial. Lancet 400:1513-1521. https://doi.org/10.1016/S0140-6736(22)01790-1\u003c/li\u003e\n \u003cli\u003eLeavey PJ, Laack NN, Krailo MD, et al (2021) Phase III Trial Adding Vincristine-Topotecan-Cyclophosphamide to the Initial Treatment of Patients with Nonmetastatic Ewing Sarcoma: A Children\u0026apos;s Oncology Group Report. J Clin Oncol 39:4029-4038. https://doi.org/10,1200/JCO.21.00358\u003c/li\u003e\n \u003cli\u003eLadenstein R, P\u0026ouml;tschger U, Le Deley MC, et al (2010) Primary disseminated multifocal Ewing sarcoma: results of the Euro-EWING 99 trial. J Clin Oncol 28:3284-3291. https://doi.org/10.1200/JCO.2009.22.9864\u003c/li\u003e\n \u003cli\u003eLeavey PJ, Mascarenhas L, Marina N, et al (2008) Prognostic factors for patients with Ewing sarcoma (EWS) at first recurrence following multi-modality therapy: A report from the Children\u0026apos;s Oncology Group. Pediatr Blood Cancer 51:334-338. https://doi.org/10.1200/pbc.21618\u003c/li\u003e\n \u003cli\u003eCollier AB 3\u003csup\u003erd\u003c/sup\u003e, Krailo MD, Dang HM, et al (2021) Outcome of patients with relapsed or progressive Ewing sarcoma enrolled on cooperative group phase 2 clinical trials: A report from the Children\u0026apos;s Oncology Group. Pediatr Blood Cancer 68: e29333. https://doi.org/10.1002/pbc.29333\u003c/li\u003e\n \u003cli\u003eDuBois SG, Krailo MD, Glade-Bender J, et al (2023) Randomized Phase III Trial of Ganitumab With Interval-Compressed Chemotherapy for Patients With Newly Diagnosed Metastatic Ewing Sarcoma: A Report From the Children\u0026apos;s Oncology Group. J Clin Oncol 41:2098-2107. https://doi.org/10.1200/JCO.22.01815\u003c/li\u003e\n \u003cli\u003eReed DR, Grohar P, Rubin E, et al (2023) Children\u0026apos;s Oncology Group\u0026apos;s 2023 blueprint for research: Bone tumors. Pediatr Blood Cancer 70: e30583. https://doi.org/10.1002/pbc.30583\u003c/li\u003e\n \u003cli\u003eHeesen P, Rnft A, Bhadri V, et al (2023) Association between local treatment modalities and event-free survival, overall survival, and local recurrence in patients with localised Ewing Sarcoma. Report from the Ewing 2008 trial. Eur J Cancer 192:113260. https://doi.org/10.1016/j.ejca.2023.113260\u003c/li\u003e\n \u003cli\u003eAhmed SK, Randall RL, DuBois SG, et al (2017) Identification of Patients With Localized Ewing Sarcoma at Higher Risk for Local Failure: A Report From the Children\u0026apos;s Oncology Group. Int J Radiat Oncol Biol Phys 99:1286-1294. https://doi.org/10.1016/j.ijrobp.2017.08.020\u003c/li\u003e\n \u003cli\u003eAndreou D, Ranft A, Gosheger G, et al (2020) Which Factors Are Associated with Local Control and Survival of Patients with Localized Pelvic Ewing\u0026apos;s Sarcoma? A Retrospective Analysis of Data from the Euro-EWING99 Trial. Clin Orthop Relat Res 478:290-302. https://doi.org/10.1097/CORR.0000000000000962\u003c/li\u003e\n \u003cli\u003eNakamura M, Mizumoto M, Saito T, et al (2024) A systematic review and meta-analysis of radiotherapy and particle beam therapy for skull base chondrosarcoma: TRP-chondrosarcoma 2024. Front Oncol 14:1380716. https://doi.org/10.3389/fonc.2024.1380716\u003c/li\u003e\n \u003cli\u003eSaito T, Mizumoto M, Oshiro Y, et al (2024) Systematic Review and Meta-Analysis of Particle Beam Therapy versus Photon Radiotherapy for Skull Base Chordoma: TRP-Chordoma 2024. Cancers (Basel) 16:2569. https://doi.org/10.3390/cancers16142569\u003c/li\u003e\n \u003cli\u003eMizumoto M, Hosaka S, Nakai K, et al (2024) Systematic review and meta-analysis of photon radiotherapy versus proton beam therapy for pediatric intracranial ependymoma: TRP-ependymoma 2024. Heliyon 10: e40372. https://doi.org/10.1016/j.heliyon.2024.e40372\u003c/li\u003e\n \u003cli\u003eFukushima H, Mizumoto M, Hosaka S, et al (2025) Systematic review and meta-analysis of photon radiotherapy versus proton beam therapy for pediatric rhabdomyosarcoma: TRP-rhabdomyosarcoma 2024. Int J Clin Oncol 2025 Jun 10. Online ahead of print. https://doi.org/10.1007/s10147-025-02794-2\u003c/li\u003e\n \u003cli\u003eMoher D, Liberati A, Tetzlaff J, et al (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6: e1000097. https://doi.org/10.1371/journal.pmed.1000097\u003c/li\u003e\n \u003cli\u003eSchuck A, Ahrens S, Schorlemer I, et al (2005) Radiotherapy in Ewing tumors of the vertebrae: treatment results and local relapse analysis of the CESS 81/86 and EICESS 92 trials. Int J Radiat Oncol Biol Phys 63:1562-1567. https://doi.org/10.1016/j.ijrobp.2005.05.036\u003c/li\u003e\n \u003cli\u003eYock TI, Krailo M, Fryer CJ, et al (2006) Local control in pelvic Ewing sarcoma: analysis from INT-0091--a report from the Children\u0026apos;s Oncology Group. J Clin Oncol 24:3838-3843. https://doi.org/10.1200/JCO.2006.05.9188.\u003c/li\u003e\n \u003cli\u003eRodr\u0026iacute;guez-Galindo C, Nabid F, Liu T, et al (2008) Prognostic factors for local and distant control in Ewing sarcoma family of tumors. Ann Oncol 19:814-820. https://doi.org/10.1093/annonc/mdm521\u003c/li\u003e\n \u003cli\u003eIntelicato DJ, Keole SR, Shahlaee AH, et al (2008) Definitive radiotherapy for ewing tumors of extremities and pelvis: long-term disease control, limb function, and treatment toxicity. Int J Radiat Oncol Biol Phys 72:871-877. https://doi.org/10.1016/j.ijrobp.2008.02.023\u003c/li\u003e\n \u003cli\u003eIntelicato DJ, Keole SR, Shahlaee AH, et al (2010) Spinal and paraspinal Ewing tumors. Int J Radiat Oncol Biol Phys 76:1463-1471. https://doi.org/10.1016/j.ijrobp.2009.03.042\u003c/li\u003e\n \u003cli\u003eSari N, Toğral G, Cetindağ MF et al (2010) Treatment results of the Ewing sarcoma of bone and prognostic factors. Pediatr Blood Cancer 54:19-24 https://doi.org/10.1002/pbc.22278\u003c/li\u003e\n \u003cli\u003eIntelicato DJ, Keole SR, Lagmay JP, et al (2011) Chest wall Ewing sarcoma family of tumors: long-term outcomes. Int J Radiat Oncol Biol Phys 81:158-166. https://doi.org/10.1016/j.ijrobp.2010.04.066\u003c/li\u003e\n \u003cli\u003eLopez JL, Cabrera P, Ordo\u0026ntilde;ez R, et al (2011) Role of radiation therapy in the multidisciplinary management of Ewing\u0026apos;s Sarcoma of bone in pediatric patients: An effective treatment for local control. Rep Pract Oncol Radiother 16:103-109. https://doi.org/10.1016/j.rpor.2011.01.006\u003c/li\u003e\n \u003cli\u003eRombi B, DeLaney TF, MacDonald SM, et al (2012) Proton radiotherapy for pediatric Ewing\u0026apos;s sarcoma: initial clinical outcomes. Int J Radiat Oncol Biol Phys 82:1142-1148. https://doi.org/10.1016/j.ijrobp.2011.03.038\u003c/li\u003e\n \u003cli\u003eVogin G, Helfre S, Glorion C, et al (2013) Local control and sequelae in localised Ewing tumours of the spine: a French retrospective study. Eur J Cancer 49:1314-1323. https://doi.org/10.1016/j.ejca.2012.12.005\u003c/li\u003e\n \u003cli\u003eRaciborska A, Bliska K, Drabki K, et al (2014) Validation of a multi-modal treatment protocol for Ewing sarcoma--a report from the polish pediatric oncology group. Pediatr Blood Cancer 61:2170-2174. https://doi.org/10.1002/pbc.25167\u003c/li\u003e\n \u003cli\u003eDuBois SG, Krailo MD, Gebhardt MC, et al (2015) Comparative evaluation of local control strategies in localized Ewing sarcoma of bone: a report from the Children\u0026apos;s Oncology Group. Cancer 121:467-475. https://doi.org/10.1002/cncr.29065\u003c/li\u003e\n \u003cli\u003eChoi Y, Lin DH, Lee SH, et al (2015) Role of Radiotherapy in the Multimodal Treatment of Ewing Sarcoma Family Tumors. Cancer Res Treat 47:904-912. https://doi.org/10.4143/crt.2014.158\u003c/li\u003e\n \u003cli\u003eBedetti B, Wiebe K, Ranft A, et al (2015) Local control in Ewing sarcoma of the chest wall: results of the EURO-EWING 99 trial. Ann Surg Oncol 22:2853-2859. https://doi.org/10.1245/s10434-015-4630-0\u003c/li\u003e\n \u003cli\u003eNing MS, Perkins SM, Borinstein SC, et al (2016) Role of radiation in the treatment of non-metastatic osseous Ewing sarcoma. J Med Imaging Radiat Oncol 60:119-128. https://doi.org/10.1111/1754-9485.12389\u003c/li\u003e\n \u003cli\u003eGrevener K, Haveman LM, Ranft A, et al (2016) Management and Outcome of Ewing Sarcoma of the Head and Neck. Pediatr Blood Cancer 63:604-610. https://doi.org/10.1002/pbc.25830\u003c/li\u003e\n \u003cli\u003eDaw NC, Laack NN, Mcllvaine EJ, et al (2016) Local Control Modality and Outcome for Ewing Sarcoma of the Femur: A Report From the Children\u0026apos;s Oncology Group. Ann Surg Oncol 23:3541-3547. https://doi.org/10.1245/s10434-016-5269-1\u003c/li\u003e\n \u003cli\u003eTalleur AC, Navid F, Spunt SL, 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 96:119-126. https://doi.org/10.1016/j.ijrobp.2016.04.001\u003c/li\u003e\n \u003cli\u003eHamilton SN, Carlson R, Hasan H, et al (2017) Long-term Outcomes and Complications in Pediatric Ewing Sarcoma. Am J Clin Oncol 40:423-428. https://doi.org/10.1097/COC.0000000000000176\u003c/li\u003e\n \u003cli\u003eWan W, Lou Y, Hu Z, et al (2017) Factors affecting survival outcomes of patients with non-metastatic Ewing\u0026apos;s sarcoma family tumors in the spine: a retrospective analysis of 63 patients in a single center. J Neurooncol 131:313-320. https://doi.org/10.1007/s11060-016-2295-6\u003c/li\u003e\n \u003cli\u003eAhmed SK, Robinson SI, Arndt CAS, et al (2017) Pelvis Ewing sarcoma: Local control and survival in the modern era. Pediatr Blood Cancer 64. https://doi.org/10.1002/pbc.26504\u003c/li\u003e\n \u003cli\u003eWeber DC, Murray FR, Correia D, et al (2017) Pencil beam scanned protons for the treatment of patients with Ewing sarcoma. Pediatr Blood Cancer 64. https://doi.org/10.1002/pbc.26688\u003c/li\u003e\n \u003cli\u003eAsh S, Yaniv I, Toledano H, et al (2019) Improved Outcome in Local Ewing Sarcoma With an Intensified Pilot Treatment Protocol SCMCIE 94. J Pediatr Hematol Oncol 41:105-111. https://doi.org/10.1097/MPH.0000000000001384\u003c/li\u003e\n \u003cli\u003eMartin E, Radomski S, Harley EH (2019) Pediatric Ewing sarcoma of the head and neck: A retrospective survival analysis. Int J Pediatr Otorhinolaryngol 117:138-142. https://doi.org/10.1016/j.ijporl.2018.11.026\u003c/li\u003e\n \u003cli\u003eSeitz G, Urla C, Sparber-Sauer M, et al (2019) Treatment and outcome of patients with thoracic tumors of the Ewing sarcoma family: A report from the Cooperative Weichteilsarkom Studiengruppe CWS-81, -86, -91, -96, and -2002P trials. Pediatr Blood Cancer 66: e27884. https://doi.org/10.1002/pbc.27884\u003c/li\u003e\n \u003cli\u003eKharod SM, Indelicato DJ, Rotondo RL, et al (2020) Outcomes following proton therapy for Ewing sarcoma of the cranium and skull base. Pediatr Blood Cancer 67: e28080. https://doi.org/10.1002/pbc.28080\u003c/li\u003e\n \u003cli\u003eTorabi SJ, Izreig S, Kasle DA, et al (2020) Clinical characteristics and treatment-associated survival of head and neck Ewing sarcoma. Laryngoscope 130:2385-2392. https://doi.org/10.1002/lary.28412\u003c/li\u003e\n \u003cli\u003eUezono H, Indelicato DJ, Rotondo RL, et al (2020) Treatment Outcomes After Proton Therapy for Ewing Sarcoma of the Pelvis. Int J Radiat Oncol Biol Phys 107:974-981. https://doi.org/10.1016/j.ijrobp.2020.04.043\u003c/li\u003e\n \u003cli\u003eGuder WK, Hardes J, Nottrott M, et al (2020) Pelvic Ewing sarcoma: a retrospective outcome analysis of 104 patients who underwent pelvic tumor resection at a single supra-regional center. J Orthop Surg Res 15:534. https://doi.org/10.1186/s13018-020-02028-3\u003c/li\u003e\n \u003cli\u003eLex JR, Kurisunkal V, Kaneuchi Y, et al (2021) Pelvic Ewing sarcoma: Should all patients receive pre-operative radiotherapy, or should it be delivered selectively? Eur J Surg Oncol 47:2618-2626. https://doi.org/0.1016/j.ejso.2021.05.027\u003c/li\u003e\n \u003cli\u003eIndelicato DJ, Vega RBM, Viviers E, et al (2022) Modern Therapy for Spinal and Paraspinal Ewing Sarcoma: An Update of the University of Florida Experience. Int J Radiat Oncol Biol Phys 113:161-165. https://doi.org/10.1016/j.ijrobp.2022.01.007\u003c/li\u003e\n \u003cli\u003eIndelicato DJ, Vega RBM, Viviers E, et al (2022) Modern Therapy for Chest Wall Ewing Sarcoma: An Update of the University of Florida Experience. Int J Radiat Oncol Biol Phys 113:345-354. https://doi.org/10.1016/j.ijrobp.2022.02.011\u003c/li\u003e\n \u003cli\u003eWorawongsakul R, Steinmeier T, Lin YL, et al (2022) Proton Therapy for Primary Bone Malignancy of the Pelvic and Lumbar Region - Data From the Prospective Registries ProReg and KiProReg. Front Oncol 12:805051. https://doi.org/10.3389/fonc.2022.805051\u003c/li\u003e\n \u003cli\u003eLaskar S, Sinha S, Chatterjee A, et al (2022) Radiation Therapy Dose Escalation in Unresectable Ewing Sarcoma: Final Results of a Phase 3 Randomized Controlled Trial. Int J Radiat Oncol Biol Phys 113:996-1002. https://doi.org/10.1016/j.ijrobp.2022.04.024\u003c/li\u003e\n \u003cli\u003eMaruo K, Yamaguchi Y, Ishii R, et al Simple imputation method for meta-analysis of survival rates when precision information is missing. Research Synthesis Methods https://doi.org/10.1017/rsm.2025.10024 ,in press.\u003c/li\u003e\n \u003cli\u003eBalduzzi S, R\u0026uuml;cker G, Schwarzer G (2019) How to perform a meta-analysis with R: a practical tutorial. Evid Based Ment Health. 22:153-160. https://doi.org/10.1136/ebmental-2019-300117\u003c/li\u003e\n \u003cli\u003eSchuck A, Ahrens S, Pauluseen M, et al (2003) Local therapy in localized Ewing tumors: results of 1058 patients treated in the CESS 81, CESS 86, and EICESS 92 trials. Int J Radiat Oncol Biol Phys 55:168-177. https://doi.org/10.1016/s0360-3016(02)03797-5\u003c/li\u003e\n \u003cli\u003eIndelicato DJ, Callan AK, Ahmed SK, et al (2025) Preoperative Radiotherapy in Patients With Localized Ewing Sarcoma Enrolled on AESFT1031: A Report From the Children\u0026apos;s Oncology Group. Pediatr Blood Cancer 2025 May 25: e31820. Online ahead of print. https://doi.org/10.1002/pbc.31820\u003c/li\u003e\n \u003cli\u003eEaton BR, Claude L, Indelicato DJ, et al (2021) Ewing sarcoma. Pediatr Blood Cancer 68: e28355. https://doi.org/10.1002/pbc.28355\u003c/li\u003e\n \u003cli\u003eKacar M, Nagel MB, Liang J, et al (2024) Radiation therapy dose escalation achieves high rates of local control with tolerable toxicity profile in pediatric and young adult patients with Ewing sarcoma. Cancer 130:1836-1843. https://doi.org/10.1002/cncr.35196\u003c/li\u003e\n \u003cli\u003eSuzuki R, Fukushima H, Okuwaki H, et al (2021) Proton beam therapy with concurrent chemotherapy is feasible in children with newly diagnosed rhabdomyosarcoma. Rep Pract Oncol Radiother 26:616-625. https://doi.org/10.5603/RPOR.a2021.0082\u003c/li\u003e\n \u003cli\u003eFriedman DL, Whitton J, Leisenring W, et al (2010) Subsequent neoplasms in 5-year survivors of childhood cancer: the Childhood Cancer Survivor Study. J Natl Cancer Inst 102(14):1083-1095. https://doi.org/10.1093/jnci/djq238\u003c/li\u003e\n\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":"Ewing sarcoma, radiotherapy modality, proton beam therapy, meta-analysis","lastPublishedDoi":"10.21203/rs.3.rs-7654899/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7654899/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground: Advances in multimodal treatment strategies and chemotherapy have led to improved outcomes for patients with Ewing sarcoma (EWS). Proton beam therapy (PBT) has increasingly been utilized in pediatric oncology to minimize late toxicities associated with conventional treatments; however, studies specifically addressing the use of PBT in EWS remain limited.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMethods: We conducted a meta-analysis to compare the efficacy of photon radiotherapy (RT) and PBT in the treatment of pediatric EWS. We analyzed English-language articles published between 1990 and 2022 that included at least 10 patients and described RT treatment protocols. The primary endpoints were overall survival (OS) and local control (LC).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eResults: A total of 38 studies from 36 articles (8 reporting PBT and 30 reporting photon RT) were included in the meta-analysis. PBT showed better 5-year OS and 4- and 3-year LC rates compared to photon RT. In analyses restricted to studies published since 2015, only the 5-year OS remained significantly different. No associations were found between OS or LC and variables such as age, sex ratio, or the rate of concurrent chemotherapy or surgery.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDiscussion: The observed differences across the entire study period may be attributed to improvements in treatment protocols, including interval-compressed chemotherapy, and recent advancements in supportive care and radiation technology, which could have influenced outcomes. Conclusion: PBT appears to be non-inferior to photon RT in the treatment of pediatric EWS. Further studies are needed to assess long-term outcomes and the potential treatment-related toxicities of PBT.\u003c/p\u003e","manuscriptTitle":"Systematic review and meta-analysis of photon radiotherapy versus proton beam therapy for pediatric Ewing sarcoma: TRP-Ewing sarcoma 2024","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-08 07:07:44","doi":"10.21203/rs.3.rs-7654899/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":"5f4c0fe5-968b-44f4-9374-a185e1f2587c","owner":[],"postedDate":"October 8th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-12-08T00:26:47+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-08 07:07:44","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7654899","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7654899","identity":"rs-7654899","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}