Carbon Ion Radiotherapy for Unresectable Primary or Recurrent Soft Tissue Sarcomas: Long-Term Outcomes based on the Local Effect Model System

Carbon Ion Radiotherapy for Unresectable Primary or Recurrent Soft Tissue Sarcomas: Long-Term Outcomes based on the Local Effect Model System | 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 Carbon Ion Radiotherapy for Unresectable Primary or Recurrent Soft Tissue Sarcomas: Long-Term Outcomes based on the Local Effect Model System Ping Li, Yongqiang Li, Cihang Bao, Xin Cai, Zheng Wang, Qing Zhang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7817850/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 16 You are reading this latest preprint version Abstract Background The application of carbon ion radiotherapy (CIRT) for unresectable primary or recurrent soft tissue sarcoma (STS) remains controversial and existing data are limited. We herein present our institutional experience with CIRT for unresectable primary or recurrent STS. Methods We retrospectively evaluated the outcomes of CIRT in unresectable primary or recurrent STS patients at our center. We assessed the 4 - and 5 - year local control (LC), overall survival (OS), distant metastasis free survival (DMFS), progression free survival (PFS), as well as acute and late toxicities. Additionally, we analyzed the prognostic factors associated with the treatment outcomes. Results Between June 2015 and August 2022, 48 consecutive patients with unresectable primary or recurrent STS were treated with CIRT at our center. The median follow-up duration was 48.6 months. The 4-year LC, OS, DMFS, and PFS rates were 65.8%, 59.7%, 50.3%, and 36.7%, respectively. The 5-year LC, OS, DMFS, and PFS rates were 60.3%, 54.7%, 44.0%, and 28.0%, respectively. The median survival time was 67.3 months. Late toxicities included grade 3 dermatitis (n = 2, 4.2%), grade 3 arthrofibrosis (n = 1, 2.1%), and grade 4 neuropathy (n = 1, 2.1%). Patients who received a higher prescribed dose (BED ≥ 129 Gy) exhibited significantly better LC ( p = 0.010) and PFS ( p = 0.004) compared to those who received a lower prescribed dose. A pre-CIRT neutrophil-to-lymphocyte ratio (NLR) ≥ 3 was associated was significantly associated with inferior DMFS ( p = 0.020). Conclusions In patients with unresectable primary or recurrent STS, CIRT may serve as a potentially safe and effective treatment option. Carbon Ion Radiotherapy Soft tissue sarcoma Local Effect Model Neutrophil-to-lymphocyte ratio Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Soft tissue sarcomas (STS) are a relatively uncommon and highly heterogeneous group of malignancies, accounting for approximately 1% of cancers diagnosed in adults ( 1 ). These tumors are predominantly located in the extremities, retroperitoneum, and trunk. Complete surgical resection remains the standard treatment for patients with localized STS; however, achieving complete resection is often challenging or infeasible due to large tumor size or involvement of adjacent vital structures, particularly in retroperitoneal sarcoma (RPS) ( 2 ). The management of patients with STS who are unsuitable for surgery or who experience recurrence after surgery is challenging. Currently, no standard treatment exists for these types of STS. Radiotherapy may serve as a local treatment option for unresectable primary or recurrent STS; however, STS are considered to be a group of malignancies that are highly resistant to conventional irradiation. carbon ion radiotherapy (CIRT) is a specialized treatment that offers unique physical and biological advantages over conventional radiation therapies( 3 ). Carbon ions exhibit a higher linear energy transfer (LET), leading to greater relative biological effectiveness (RBE) and more potent tumor cell killing. Furthermore, the Bragg peak phenomenon enables precise dose distribution, thereby minimizing damage to surrounding critical organs. These attributes render CIRT particularly effective for treating radio-resistant tumors and those located in close proximity to critical structures (4). Despite its potential, the application of CIRT in STS, particularly in unresectable cases, remains limited. Imai et al. demonstrated that CIRT provides effective tumor control in unresectable STS, reporting a 5-year local control (LC) rate of 65% ( 5 ). However, the CIRT in their study was based on the Microdosimetric Kinetic Model (MKM), which is primarily applied in Japanese facilities. In contrast, European centers and our institution primarily employ the Local Effect Model (LEM). Emerging research indicates substantial differences in clinical outcomes between these two models ( 6 , 7 ). The optimal treatment dose and corresponding clinical outcomes for STS under the LEM model remain to be fully elucidated. This retrospective study aims to evaluate the efficacy and safety of CIRT in patients with unresectable STS based on the LEM model. Furthermore, we investigated prognostic factors influencing outcomes following CIRT for STS, with a specific focus on the neutrophil-to-lymphocyte ratio (NLR). As a well-established biomarker of tumor-associated inflammation, NLR has been shown to correlate with prognosis in numerous malignancies( 8 ). However, its prognostic significance within the specific context of CIRT for STS has not yet been conclusively established. Patients and methods Study population A consecutive cohort of patients with histologically confirmed unresectable primary or recurrent STS undergoing CIRT at the Shanghai Proton and Heavy Ion Center (SPHIC) between June 2015 and August 2022 was retrospectively analyzed. Inclusion criteria comprised patients aged 14 years or older with histologically confirmed unresectable primary or recurrent STS undergoing definitive CIRT. Exclusion criteria included: 1) lymph node metastasis; 2) distant metastasis. Each patient underwent complete blood counts (CBC) testing before and after CIRT. This study was approved by the Ethics Committee of Shanghai Proton and Heavy Ion Center (No. 1810-27-02). Informed consent was obtained from all individual participants included in the study. Carbon ion radiotherapy CIRT was administered with definitive intent. A simulation computed tomography (CT) scan with 2 mm slice thickness was performed, with patients positioned either supine or prone based on the tumor's anatomical location. The gross tumor volume (GTV) was delineated on the simulation CT or, when available, on T2-weighted magnetic resonance imaging (MRI) fused with the simulation CT. A clinical target volume (CTV) margin of 5–30 mm was then added, with adjustments made to protect critical structures including the bowel, bones, bladder, and rectum. The CTV was prescribed to receive at least 95% of the prescribed dose. The planning target volume (PTV) included the CTV plus a 3-5mm margin. CIRT was administered once daily for 5 days per week. The prescribed doses were based on the RBE-weighted dose (D RBE ), with the RBE calculated using the LEM model within the Siemens Syngo treatment planning system. The total radiation dose ranged from 45 to 80.8 Gy, with a median of 70.4 Gy. Dose per fraction ranged from 3 to 4.6 Gy, with a median of 4 Gy. Thirteen patients received a total dose of 72 Gy delivered in 18 fractions. Follow up and evaluation Following completion of CIRT, patients underwent follow-up assessments every three months for the first three years and every six months thereafter. Follow-up assessments included physical examinations, routine blood tests, and MRI or CT scans of the lesion area. An annual chest CT scan was recommended. PET/CT and other examinations were performed based on clinical evidence of metastasis, recurrence, or other concurrent conditions. Acute and late toxicities were classified according to the highest grade observed within three months (acute) and after three months (late) following the initiation of CIRT. The follow-up period was calculated from the initial date of CIRT. CBCs were obtained, with particular attention to the absolute neutrophil and lymphocyte counts. The NLR was calculated by dividing the absolute neutrophil count by the absolute lymphocyte count. LC was defined as the absence of tumor progression or recurrence within the radiotherapy field. Progression free survival (PFS) was determined by the absence of local or distant disease progression. Distant metastasis free survival (DMFS) was defined as the absence of disease progression outside the radiotherapy field. Overall survival (OS) was calculated as the proportion of patients remaining alive at a specific time interval from the start of RT until the time of the event. Statistical analyses Median follow-up was estimated using the reverse Kaplan-Meier method. LC, PFS, DMFS, and OS were estimated using the Kaplan-Meier method. The log-rank test was employed for univariate analysis. The following factors were evaluated: patient age, tumor location, history of previous radiotherapy, metal implants, radiation dose, tumor volume, and NLR before and after treatment. After consulting with statisticians, we omitted multivariate analysis in this study owing to the limited number of cases and events. A p-value < 0.05 was considered statistically significant. All statistical analyses were conducted using GraphPad Prism 9. Results A cohort of 48 patients treated with CIRT between June 2015 and August 2022 was included in this study. The median age of these patients was 53.5 years (range: 16–86 years). There were 30 males and 18 females. Of the 48 patients, 38 (79.2%) had recurrent tumor after resection, 8 (16.7%) with primary unresectable tumor, and 2 (4.2%) had residual tumor after resection (R2 resection). Of the 40 patients who had recurrence or residual tumor after surgery, 22 (55.0%) underwent at least two resections. Most tumors were located in retroperitoneum and pelvis (75.0%). The histological subtype included liposarcoma (20.8%), leiomyosarcoma (10.4%), synovial sarcoma (8.3%), undifferentiated pleomorphic sarcoma (6.3%), malignant peripheral nerve sheath tumor (6.3%), myxofibrosarcoma (6.3%) and other histologies with fewer than 3 cases each (41.7%). Among the 48 patients, 9 (18.8%) had previously received in-field radiotherapy, 5 (10.4%) patients had metal implants within the irradiation field. The median follow up was 48.6 months. Twenty patients (41.7%) had no evidence of local recurrence or distant metastases at the time of death or last follow-up. Across the entire cohort, 30 patients experienced disease progression, 8 patients developed local recurrence, 14 patients had distant metastases, and 8 patients exhibited both local and distant relapses. The median time to local recurrence was 23.8 months (range: 6.6–87.0 months) among the 16 patients. Eleven of the 16 local recurrences (68.8%) occurred within 2 years after CIRT. The 4- and 5-year LC rates were 65.8% and 60.3% (Fig. 1 a), respectively. The median LC was 87 months. The 4-year LC for tumors in retroperitoneum and pelvis, trunk, and extremities were 56.4% and 91.7%, respectively. Eighteen patients died. Among these, 11 patients died due to distant metastasis, 4 succumbed to local progression, 2 deaths were attributed to unknown causes, and 1 patient died from another disease (Myelodysplastic Syndrome, MDS). The median DMFS, PFS and OS were 54.7, 24.3 and 67.3 months, respectively. The 4-year DMFS, PFS and OS were 50.3%, 36.7% and 59.7%, respectively. The 5-year DMFS, PFS and OS were 44.0%, 28.0% and 54.7%, respectively. (Fig. 1 b-d). In univariate analysis, radiation dose demonstrated a significant impact on both LC and PFS. Patients who were administered a higher prescribed dose (BED ≥ 129 Gy, α/β = 5) demonstrated significantly superior LC ( p = 0.011) and PFS ( p = 0.004) compared with those who received a lower prescribed dose. The 5-year LC was 41.7% for patients in the BED < 129 Gy group, compared with 74.0% for those in the BED ≥ 129 Gy group. The mean tumor volume was 148.6 cc (range: 5.5-2957.2 cc). A tumor size less than 150cc was correlated with better PFS ( p = 0.014), although it was not significantly associated with better LC ( p = 0.322). The median survival for patients with tumor size less than 150 cc and those with tumors 150 cc or greater was 50.4 months and 22.8 months, respectively. The pre-CIRT NLR of 3 or higher was associated with worse DMFS ( p = 0.020), whereas a post-CIRT NLR of 3 or higher was not significantly correlated with DMFS ( p = 0.568). Other parameters were not significantly correlated with clinical outcomes. The most frequently observed acute toxicity was radiation dermatitis. Grade 2 and grade 3 acute radiation dermatitis were observed in two patients each (4.2%), and all patients completed the planned radiotherapy course. Late toxicities included grade 2 dermatitis in six patients (12.5%) and grade 3 dermatitis in two patients (4.2%), primarily localized to the limb and vulvar region, respectively. Additional late complications included one case of grade 2 arthrofibrosis and one case of grade 3 arthrofibrosis. Late neurological toxicities were observed in three patients: two cases of grade 2 neuropathy (4.2%) and one case of grade 4 neuropathy (2.1%). This grade 4 neuropathy was observed in a patient undergoing CIRT followed by surgical resection. All grade ≥ 2 acute and late toxicities were exclusively observed in patients received a BED ≥ 129 Gy. Notably, following multidisciplinary team (MDT) review, three patients with tumors presenting high surgical resection difficulty received neoadjuvant CIRT followed by surgery. The first case involved a patient with a Capicua transcriptional repressor (CIC) - rearranged sarcoma that recurred two months postoperatively, presenting with multiple tumors, the largest of which measured 15*17 cm. The patient received CIRT (72 Gy / 18 fractions) followed by tumor resection one month later. At the latest follow-up (42.7 months), the patient remained disease-free. However, grade 4 late neuropathy presented as foot numbness and pain, ultimately requiring distal amputation followed by prosthetic rehabilitation. The patient currently exhibits normal ambulation and functional activity (Fig. 4 ). To preserve limb function, the second patient underwent preoperative CIRT with a total dose of 72 Gy delivered in 18 fractions. One month post-CIRT, the patient underwent complete surgical resection of the tumor. At the most recent follow-up (32.3 months), the patient remained disease-free with preserved limb function. The third case involved a patient with recurrent pelvic low-grade fibromyxoid sarcoma who received CIRT (70.4 Gy / 16 fractions). Tumor resection was performed two months post-CIRT. Unfortunately, local recurrence developed at 11.1 months after surgery, followed by lung metastasis at 14.2 months after surgery. Metal implants within the radiation field were observed in this patient, potentially associated with tumor recurrence. Discussion Surgical resection remains the standard curative-intent treatment for localized STS. However, population-based studies indicate that 15 to 55% of patients are considered ineligible for surgery due to anatomical limitations (e.g., tumor proximity to neurovascular bundles) or medical comorbidities.( 9 ) Moreover, the management of locally recurrent disease presents significant therapeutic dilemmas, as these patients often face prohibitive reoperation risks or experience disease recurrence even after surgery. Carbon ions exhibit higher LET and RBE, enhancing tumor cell killing while minimizing damage to surrounding normal tissues via the Bragg peak effect ( 3 ). This renders CIRT particularly effective for treating radioresistant tumors or those located near critical structures. Previous studies have demonstrated promising LC rates with CIRT for STS, such as the 5-year LC rate of 65% reported by Imai et al. ( 4 ). In a study reported by Serizawa et al., among 24 patients with unresectable RPS received CIRT, the 5-year LC and OS rates were 69% and 50%, respectively. These results were superior to previous outcomes from photon therapy. However, these studies were primarily based on the MKM, which is predominantly used in Japanese facilities. In contrast, European centers and our institution utilize the LEM, which may yield different clinical outcomes ( 5 , 6 ). This study aims to fill this knowledge gap by evaluating the efficacy and safety of CIRT based on the LEM model. Our study included 48 patients with unresectable primary or recurrent STS who were treated with CIRT at SPHIC. The median follow-up was 48.6 months, and the overall results demonstrated favorable LC and survival outcomes. The 4-year and 5-year LC rates were 65.8% and 60.3%, respectively, indicating that CIRT can provide durable LC and consistent with those reported by Imai et al. Furthermore, the 4-year and 5-year OS rates were 58.9% and 53.6%, respectively. The median survival time was 67.3 months. Previous study ( 10 ) from the MGH included 112 patients underwent photon therapy and reported the 5-year LC, DFS, and OS were 45%, 24%, and 35%, respectively. Allignet et al ( 9 ) report that, in 116 unresectable STS patients treated with definitive photon therapy, 3-year local failure (LF), PFS and OS were 43.2%, 16.6% and 34%, respectively. Median OS was 21.4 months. Our results are quite higher than those results. Systematic review also ( 11 ) showed that definitive photon therapy achieves 5-year LC rates of 28–73% in unresectable STS, while particle therapies achieve rates of 52–69%. Regarding toxicities, all grade ≥ 2 toxicities occurred in patients who received a BED ≥ 129 Gy. Previous studies have also shown that radiation-induced neuropathy significantly increases when a long length of sacral nerves is exposed to CIRT doses > 70 Gy ( 12 ). These findings suggest that while higher doses are associated with better LC, they may also increase the risk of toxicity. Therefore, careful dose optimization and individualized treatment planning are essential to balance efficacy and safety. Several factors have been identified as potential predictors of clinical outcomes. Higher prescribed radiation doses (BED ≥ 129 Gy) were significantly associated with improved LC and PFS (LC: p = 0.011; PFS: p = 0.004). This finding highlights the importance of dose escalation in CIRT, which may be particularly critical for radio-resistant STS. While dose-response relationships are well established in photon radiotherapy( 10 ), comparable evidence for CIRT remains limited and inconsistent ( 5 ). This discrepancy likely originate from fundamental differences in radiobiological modeling approaches, where the conversion factor increases with decreasing prescribed dose. In this study, the predominant dose fractionation regimen in our cohort was 72 Gy delivered in 18 fractions (BED = 129.6Gy, α/β = 5). Notably, Japanese protocols typically employ 70.4 Gy in 16 fractions (BED = 132.4 Gy, α/β = 5). It should be noted that Japan typically delivers four fractions per week, whereas our center delivers five fractions per week, though both approaches maintain comparable therapeutic ratios. Tumor volume emerged as an independent prognostic factor, with lesions < 150 cc demonstrating superior PFS outcomes ( p = 0.014). This suggests that larger tumor volumes may pose a greater challenge for effective LC, potentially due to increased biological complexity or anatomical constraints near organs at risk. To the best of our knowledge, this is the first study to evaluate the association between NLR and prognosis in STS patients who underwent CIRT. An elevated pre-CIRT NLR (≥ 3) predicted worse DMFS ( p = 0.020), indicating that tumor-associated inflammation may influence the metastatic potential of STS. Several studies have investigated the prognostic value of NLR in various cancer types, demonstrating that an elevated NLR is associated with reduced OS and an increased risk of locoregional recurrence ( 13 , 14 ). Studies have also identified the NLR as an independent prognostic factor for OS in RPS and synovial sarcoma ( 15 , 16 ). Barcellini et al.( 17 ), showed that ACC patients with higher pre-CIRT levels of NLR had a predictable decrease in DFS. However, the post-CIRT NLR lost its prognostic value ( p = 0.568), our research findings are inconsistent with those of Matris et al.( 18 ), who used hypofractionated radiotherapy (30 Gy in 5 fractions) and showed that higher post-RT NLR and a value ≥ 4 was associated with worse DFS and DMFS. Therefore, the relationship between post-CIRT NLR and therapeutic efficacy after CIRT remains unclear, which may be related to the radiation field coverage of lymphocytes during CIRT. Preclinical evidence indicates carbon ions reduce myeloid-derived suppressor cells (MDSCs) and enhance antigen presentation, potentially resetting the immune contexture ( 19 , 20 ). Three patients in our study underwent multidisciplinary evaluation and received neoadjuvant CIRT followed by surgical resection due to the large tumor size and proximity to critical organs. Our study is the first, to our knowledge, to report the effect of neoadjuvant CIRT in unresectable STS. Two of these patients achieved disease-free survival at their latest follow-up, highlighting the potential role of CIRT in a multimodal treatment strategy. This approach may be particularly beneficial for patients with tumors that are initially deemed unresectable or those with recurrent disease after previous surgery. It should be noted that all three patients received preoperative radiotherapy with a radical dose, rather than the conventional prophylactic radiation dose. One patient developed grade 4 late neurological toxicity, potentially associated with extensive tumor encasement of the nerve, as both CIRT and surgical intervention may induce neurotoxicity. Further studies are needed to explore the optimal sequencing and integration of CIRT with surgery and other modalities. Despite providing promising results into the efficacy and safety of CIRT for unresectable primary or recurrent STS, this study has several limitations. First, as a single-center retrospective analysis, the study design may inherently introduce selection bias and confounding factors. Second, the small sample size (n = 48) and limited number of clinical events reduced statistical power, precluding multivariate analyses to adjust for potential confounders. Third, the absence of a direct comparator group hinders conclusive comparisons regarding the relative advantages of CIRT in terms of LC and toxicity profiles. Future prospective, multicenter studies with larger cohorts and integrated biomarker analyses are essential to validate these findings, optimize patient stratification, and refine therapeutic strategies. Conclusion In conclusion, our study demonstrates that CIRT based on the LEM model is an effective and relatively safe treatment option for patients with unresectable primary or recurrent STS. Higher radiation doses and smaller tumor volumes were associated with better clinical outcomes, while systemic inflammation (as indicated by NLR) may influence metastatic potential. Future research should focus on optimizing treatment protocols, exploring the role of CIRT in multimodal strategies, and validating these findings in larger cohorts. Additionally, further investigation into the differences between the MKM and LEM models is warranted to better understand their clinical implications and guide treatment decisions. Declarations Ethics approval and consent to participate This study was conducted in compliance with the Declaration of Helsinki– Ethical Principles for Medical Research Involving Human Participants. This study was approved by the Ethics Committee of Shanghai Proton and Heavy Ion Center (No. 1810-27-02). Informed consent was obtained from all individual participants included in the study. Consent for publication Not applicable. Funding This study was provided by the Scientific Research Program of Shanghai Pudong New Area Health Commission (No. PW2021A-41), Pudong New Area Science and Technology Development Foundation (No. PKJ2023-Y42). And the Shanghai Municipal Health Bureau, Shanghai, People’s Republic of China (No. 20224Y0273). Data availability The datasets used and/or analysed during the current study available from the corresponding author on reasonable request. Competing interests The authors declare no competing interests References Gamboa AC, Gronchi A, Cardona K. Soft-tissue sarcoma in adults: An update on the current state of histiotype-specific management in an era of personalized medicine. CA: a cancer journal for clinicians. 2020;70(3):200-29. Raut CP, Callegaro D, Miceli R, Barretta F, Rutkowski P, Blay JY, et al. Predicting Survival in Patients Undergoing Resection for Locally Recurrent Retroperitoneal Sarcoma: A Study and Novel Nomogram from TARPSWG. 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Guthrie GJK, Charles KA, Roxburgh CSD, Horgan PG, McMillan DC, Clarke SJ. The systemic inflammation-based neutrophil–lymphocyte ratio: Experience in patients with cancer. Critical Reviews in Oncology/Hematology. 2013;88(1):218-30. Allignet B, Waissi W, Geets X, Dufresne A, Brahmi M, Ray-Coquard I, et al. Long-term outcomes after definitive radiotherapy with modern techniques for unresectable soft tissue sarcoma. Radiotherapy and oncology. 2022;173:55-61. Kepka L, DeLaney TF, Suit HD, Goldberg SI. Results of radiation therapy for unresected soft-tissue sarcomas. International journal of radiation oncology, biology, physics. 2005;63(3):852-9. Allignet B, Sunyach MP, Geets X, Waissi W. Is there a place for definitive radiotherapy in the treatment of unresectable soft-tissue sarcoma? A systematic review. Acta oncologica (Stockholm, Sweden). 2022;61(6):720-9. Nachankar A, Schafasand M, Hug E, Martino G, Góra J, Carlino A, et al. 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García-Ortega DY, Álvarez-Cano A, Sánchez-Llamas LA, Caro-Sanchez CHS, Martínez-Said H, Luna-Ortiz K, et al. Neutrophil/lymphocyte ratio is associated with survival in synovial sarcoma. Surgical oncology. 2018;27(3):551-5. Barcellini A, Fontana G, Filippini DM, Ronchi S, Bonora M, Vischioni B, et al. Exploring the role of neutrophil-to-lymphocyte ratio and blood chemistry in head and neck adenoid cystic carcinomas treated with carbon ion radiotherapy. Radiotherapy and oncology. 2022;177:143-51. Martinez C, Asso RN, Rastogi N, Freeman CR, Cury FL. Neutrophil-to-lymphocyte ratio for the prediction of soft tissue sarcomas response to pre-operative radiation therapy. Radiotherapy and oncology. 2024;195:110239. Zhou H, Yang P, Li H, Zhang L, Li J, Zhang T, et al. Carbon ion radiotherapy boosts anti-tumour immune responses by inhibiting myeloid-derived suppressor cells in melanoma-bearing mice. Cell death discovery. 2021;7(1):332. Sudo M, Tsutsui H, Fujimoto J. Carbon Ion Irradiation Activates Anti-Cancer Immunity. Int J Mol Sci. 2024;25(5). Tables Table 1. Patients’ characteristics Characteristics No. of patients Median age (range), y 53.5 (16-86) y Male : female ratio 30:18 Tumor type Primary tumor without resection 8 Recurrent tumor after resection 38 Residual tumor after resection 2 Tumor site Retroperitoneum 19 Pelvis 17 Extremities 10 Trunk 2 Tumor size (range), cm3 ~100 15 100-200 14 200-500 11 500-1000 5 1000~ 3 Histology Liposarcoma 10 Leiomyosarcoma 5 Synovial sarcoma 4 UPS 3 MPNST 3 Myxofibrosarcoma 3 Others 20 Metal implant Yes 5 No 43 Re-irradiation Yes 9 No 39 Surgery Times 0 8 1 18 2 15 ≥3 7 MPNST, malignant peripheral nerve sheath tumor; UPS, undifferentiated pleomorphic sarcoma. Table 2 ． Univariate analysis Variables LC DMFS PFS OS HR P value HR P value HR P value HR P value Age ( <55y vs. ≥55y ) 1.657 (0.622-4.414) 0.320 1.010 (0.438-2.329) 0.982 0.964 (0.477-1.949) 0.918 0.678 (0.268-1.714) 0.408 Tumor location (retroperitoneum and pelvis vs. trunk and extremities) 2.977 (1.020-8.688) 0.129 1.364 (0.541-3.439) 0.536 1.174 (0.518-2.661) 0.710 2.054 (0.743-5.679) 0.243 Previous radiotherapy (yes vs. no) 0.453 (0.105-1.964) 0.427 0.766 (0.207-2.833) 0.715 1.007 (0.351-2.885) 0.990 2.746 (0.565-13.35) 0.059 Metal implants (yes vs. no) 0.442 (0.104-1.887) 0.410 1.238 (0.331-4.633) 0.729 0.774 (0.264-2.275) 0.671 0.445 (0.106-1.875) 0.416 Radiation dose (BED<129 Gy vs. BED≥129 Gy) 3.579 (1.305-9.817) 0.011 1.800 (0.753-4.306) 0.158 2.702 (1.284-5.683) 0.004 2.395 (0.931-6.159) 0.060 Tumor volume (GTV<150cc vs. GTV≥150cc) 0.619 (0.231-1.659) 0.322 0.546 (0.236-1.268) 0.153 0.421 (0.205-0.864) 0.014 0.493 (0.196-1.241) 0.146 NLR before treatment (NLR＜3 vs. NLR≥3) 0.926 (0.343-2.500) 0.878 0.396 (0.162-0.968) 0.020 0.590 (0.283-1.231) 0.129 0.704 (0.269-1.843) 0.452 NLR after treatment (NLR＜3 vs. NLR≥3) 1.008 (0.365-2.779) 0.988 0.782 (0.339-1.806) 0.568 0.724 (0.357-1.466) 0.375 0.722 (0.286-1.823) 0.498 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 02 Dec, 2025 Reviews received at journal 28 Nov, 2025 Reviews received at journal 24 Nov, 2025 Reviewers agreed at journal 24 Nov, 2025 Reviews received at journal 23 Nov, 2025 Reviewers agreed at journal 23 Nov, 2025 Reviewers agreed at journal 22 Nov, 2025 Reviews received at journal 18 Nov, 2025 Reviewers agreed at journal 16 Nov, 2025 Reviewers agreed at journal 16 Nov, 2025 Reviewers agreed at journal 16 Nov, 2025 Reviewers invited by journal 14 Nov, 2025 Editor invited by journal 23 Oct, 2025 Editor assigned by journal 23 Oct, 2025 Submission checks completed at journal 22 Oct, 2025 First submitted to journal 22 Oct, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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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-7817850","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":549812463,"identity":"82de6433-65cb-4923-a106-e602c9c7bbf7","order_by":0,"name":"Ping Li","email":"","orcid":"","institution":"Shanghai Proton and Heavy Ion Center","correspondingAuthor":false,"prefix":"","firstName":"Ping","middleName":"","lastName":"Li","suffix":""},{"id":549812464,"identity":"bb22a7f3-e1ff-414d-a8d4-1d1323bca9ed","order_by":1,"name":"Yongqiang Li","email":"","orcid":"","institution":"Shanghai Proton and Heavy Ion Center","correspondingAuthor":false,"prefix":"","firstName":"Yongqiang","middleName":"","lastName":"Li","suffix":""},{"id":549812465,"identity":"ad3fcdbf-fbbe-4a06-a92f-2d7059b79dfd","order_by":2,"name":"Cihang Bao","email":"","orcid":"","institution":"Shanghai Proton and Heavy Ion Center","correspondingAuthor":false,"prefix":"","firstName":"Cihang","middleName":"","lastName":"Bao","suffix":""},{"id":549812466,"identity":"a168248a-66d5-434a-8517-cec44bb6337b","order_by":3,"name":"Xin Cai","email":"","orcid":"","institution":"Shanghai Proton and Heavy Ion Center","correspondingAuthor":false,"prefix":"","firstName":"Xin","middleName":"","lastName":"Cai","suffix":""},{"id":549812467,"identity":"534d7c20-ad5b-46a6-a131-71d1a73c149e","order_by":4,"name":"Zheng Wang","email":"","orcid":"","institution":"Shanghai Proton and Heavy Ion Center","correspondingAuthor":false,"prefix":"","firstName":"Zheng","middleName":"","lastName":"Wang","suffix":""},{"id":549812468,"identity":"fe813292-0e4c-4ef9-906d-f78e3c0beb93","order_by":5,"name":"Qing Zhang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/UlEQVRIie3SMWrDMBSA4WcEyqLYq4IHX0Em4HopvYpKIXv2UDxpavfmDh00hXYzPHAWF68eMgQMIUtB4DVDVTfpptbdOugfhBD6kEAC8Pn+Y2QYy89ZCUHB/0SoHEngmzBhyYi94XaKRzjtkqvoue+XL3kCk8fuCKudk8wwXOTADunr0/smXtc8Ldg2y6E6OIlAlgngGOj2bUOmikvgCyqCAn8hAm90W3f9WDLfg8Rb3TxAfCZk/xOZ2VNAlninW5rFa8VTxSoKsnKTsKnnxpzwWjfY9Ut1n0QTRYxZuYl9EWovY7Pj8KwULituQswwicrzT4DLis/n8/m++gDioFcSQCQBaQAAAABJRU5ErkJggg==","orcid":"","institution":"Shanghai Proton and Heavy Ion Center","correspondingAuthor":true,"prefix":"","firstName":"Qing","middleName":"","lastName":"Zhang","suffix":""}],"badges":[],"createdAt":"2025-10-09 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07:09:26","extension":"xml","order_by":17,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":82892,"visible":true,"origin":"","legend":"","description":"","filename":"869353fb06ec493bbb38284e8d34b05c1structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7817850/v1/14d46e38cf7815c699bc9be8.xml"},{"id":96794177,"identity":"1caf9e6d-8d40-446b-8f22-70f81ab83a1d","added_by":"auto","created_at":"2025-11-26 07:09:26","extension":"html","order_by":18,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":91196,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7817850/v1/5ad4e915685d479dc47db5fb.html"},{"id":96794168,"identity":"9fea6f5b-123d-4ced-ab7a-8b87001c874a","added_by":"auto","created_at":"2025-11-26 07:09:26","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":548373,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier analysis of local control (a), distant metastasis free survival (b), progression free survival (c), and overall survival (d) stratified by biologically effective dose (BED) in 48 patients treated with carbon ion radiotherapy.\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-7817850/v1/dc3d1b76f09b3570e41c93fe.png"},{"id":96794166,"identity":"15d9034f-e5f7-4730-a73c-1a4de45d75d8","added_by":"auto","created_at":"2025-11-26 07:09:26","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":470882,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier analysis of local control (a) and progression-free survival (b) stratified by biologically effective dose (BED) in patients undergoing carbon ion radiotherapy.\u003c/p\u003e","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-7817850/v1/78330e9ffebdfe9fb99f35a6.png"},{"id":96915121,"identity":"0b4eaad4-9e3d-45e7-9d98-671322c25172","added_by":"auto","created_at":"2025-11-27 14:06:52","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":392923,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier analysis of distant metastasis free survival stratified by neutrophil-to-lymphocyte ratio in patients undergoing carbon ion radiotherapy.\u003c/p\u003e","description":"","filename":"fig3.png","url":"https://assets-eu.researchsquare.com/files/rs-7817850/v1/c52e9a17d11caf2355f77d97.png"},{"id":96916856,"identity":"4f680a89-39e8-42e9-8601-689a47420341","added_by":"auto","created_at":"2025-11-27 14:08:58","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":4699349,"visible":true,"origin":"","legend":"\u003cp\u003eA patient with a CIC - rearranged sarcoma that recurred two months postoperatively, presenting with multiple tumors. The patient received CIRT (72 Gy / 18 fractions) followed by tumor resection one month later. A and B: Clinical photographs of the skin at the lesion site before (A) and 3 years after CIRT (B). C and F: Axial (C) and coronal (F) dose distribution of the CIRT treatment plan. The CTV was prescribed to receive at least 95% of the prescribed dose. D and E: MRI before (D) and 3 years after CIRT (E).\u003c/p\u003e","description":"","filename":"fig4.png","url":"https://assets-eu.researchsquare.com/files/rs-7817850/v1/107fad455668af9789de171c.png"},{"id":96923188,"identity":"3872b49c-bb55-4932-b321-70bc3d59746d","added_by":"auto","created_at":"2025-11-27 14:21:06","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":6658487,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7817850/v1/63558ba7-d760-4e11-8e13-fc21fdccc0b0.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Carbon Ion Radiotherapy for Unresectable Primary or Recurrent Soft Tissue Sarcomas: Long-Term Outcomes based on the Local Effect Model System","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSoft tissue sarcomas (STS) are a relatively uncommon and highly heterogeneous group of malignancies, accounting for approximately 1% of cancers diagnosed in adults (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). These tumors are predominantly located in the extremities, retroperitoneum, and trunk. Complete surgical resection remains the standard treatment for patients with localized STS; however, achieving complete resection is often challenging or infeasible due to large tumor size or involvement of adjacent vital structures, particularly in retroperitoneal sarcoma (RPS) (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). The management of patients with STS who are unsuitable for surgery or who experience recurrence after surgery is challenging. Currently, no standard treatment exists for these types of STS.\u003c/p\u003e\u003cp\u003eRadiotherapy may serve as a local treatment option for unresectable primary or recurrent STS; however, STS are considered to be a group of malignancies that are highly resistant to conventional irradiation. carbon ion radiotherapy (CIRT) is a specialized treatment that offers unique physical and biological advantages over conventional radiation therapies(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Carbon ions exhibit a higher linear energy transfer (LET), leading to greater relative biological effectiveness (RBE) and more potent tumor cell killing. Furthermore, the Bragg peak phenomenon enables precise dose distribution, thereby minimizing damage to surrounding critical organs. These attributes render CIRT particularly effective for treating radio-resistant tumors and those located in close proximity to critical structures (4).\u003c/p\u003e\u003cp\u003eDespite its potential, the application of CIRT in STS, particularly in unresectable cases, remains limited. Imai et al. demonstrated that CIRT provides effective tumor control in unresectable STS, reporting a 5-year local control (LC) rate of 65% (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). However, the CIRT in their study was based on the Microdosimetric Kinetic Model (MKM), which is primarily applied in Japanese facilities. In contrast, European centers and our institution primarily employ the Local Effect Model (LEM). Emerging research indicates substantial differences in clinical outcomes between these two models (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). The optimal treatment dose and corresponding clinical outcomes for STS under the LEM model remain to be fully elucidated. This retrospective study aims to evaluate the efficacy and safety of CIRT in patients with unresectable STS based on the LEM model. Furthermore, we investigated prognostic factors influencing outcomes following CIRT for STS, with a specific focus on the neutrophil-to-lymphocyte ratio (NLR). As a well-established biomarker of tumor-associated inflammation, NLR has been shown to correlate with prognosis in numerous malignancies(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). However, its prognostic significance within the specific context of CIRT for STS has not yet been conclusively established.\u003c/p\u003e"},{"header":"Patients and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy population\u003c/h2\u003e\u003cp\u003eA consecutive cohort of patients with histologically confirmed unresectable primary or recurrent STS undergoing CIRT at the Shanghai Proton and Heavy Ion Center (SPHIC) between June 2015 and August 2022 was retrospectively analyzed. Inclusion criteria comprised patients aged 14 years or older with histologically confirmed unresectable primary or recurrent STS undergoing definitive CIRT. Exclusion criteria included: 1) lymph node metastasis; 2) distant metastasis. Each patient underwent complete blood counts (CBC) testing before and after CIRT. This study was approved by the Ethics Committee of Shanghai Proton and Heavy Ion Center (No. 1810-27-02). Informed consent was obtained from all individual participants included in the study.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eCarbon ion radiotherapy\u003c/h3\u003e\n\u003cp\u003eCIRT was administered with definitive intent. A simulation computed tomography (CT) scan with 2 mm slice thickness was performed, with patients positioned either supine or prone based on the tumor's anatomical location. The gross tumor volume (GTV) was delineated on the simulation CT or, when available, on T2-weighted magnetic resonance imaging (MRI) fused with the simulation CT. A clinical target volume (CTV) margin of 5\u0026ndash;30 mm was then added, with adjustments made to protect critical structures including the bowel, bones, bladder, and rectum. The CTV was prescribed to receive at least 95% of the prescribed dose. The planning target volume (PTV) included the CTV plus a 3-5mm margin.\u003c/p\u003e\u003cp\u003eCIRT was administered once daily for 5 days per week. The prescribed doses were based on the RBE-weighted dose (D\u003csub\u003eRBE\u003c/sub\u003e), with the RBE calculated using the LEM model within the Siemens Syngo treatment planning system. The total radiation dose ranged from 45 to 80.8 Gy, with a median of 70.4 Gy. Dose per fraction ranged from 3 to 4.6 Gy, with a median of 4 Gy. Thirteen patients received a total dose of 72 Gy delivered in 18 fractions.\u003c/p\u003e\n\u003ch3\u003eFollow up and evaluation\u003c/h3\u003e\n\u003cp\u003eFollowing completion of CIRT, patients underwent follow-up assessments every three months for the first three years and every six months thereafter. Follow-up assessments included physical examinations, routine blood tests, and MRI or CT scans of the lesion area. An annual chest CT scan was recommended. PET/CT and other examinations were performed based on clinical evidence of metastasis, recurrence, or other concurrent conditions. Acute and late toxicities were classified according to the highest grade observed within three months (acute) and after three months (late) following the initiation of CIRT. The follow-up period was calculated from the initial date of CIRT. CBCs were obtained, with particular attention to the absolute neutrophil and lymphocyte counts. The NLR was calculated by dividing the absolute neutrophil count by the absolute lymphocyte count. LC was defined as the absence of tumor progression or recurrence within the radiotherapy field. Progression free survival (PFS) was determined by the absence of local or distant disease progression. Distant metastasis free survival (DMFS) was defined as the absence of disease progression outside the radiotherapy field. Overall survival (OS) was calculated as the proportion of patients remaining alive at a specific time interval from the start of RT until the time of the event.\u003c/p\u003e\n\u003ch3\u003eStatistical analyses\u003c/h3\u003e\n\u003cp\u003eMedian follow-up was estimated using the reverse Kaplan-Meier method. LC, PFS, DMFS, and OS were estimated using the Kaplan-Meier method. The log-rank test was employed for univariate analysis. The following factors were evaluated: patient age, tumor location, history of previous radiotherapy, metal implants, radiation dose, tumor volume, and NLR before and after treatment. After consulting with statisticians, we omitted multivariate analysis in this study owing to the limited number of cases and events. A p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. All statistical analyses were conducted using GraphPad Prism 9.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eA cohort of 48 patients treated with CIRT between June 2015 and August 2022 was included in this study. The median age of these patients was 53.5 years (range: 16\u0026ndash;86 years). There were 30 males and 18 females. Of the 48 patients, 38 (79.2%) had recurrent tumor after resection, 8 (16.7%) with primary unresectable tumor, and 2 (4.2%) had residual tumor after resection (R2 resection). Of the 40 patients who had recurrence or residual tumor after surgery, 22 (55.0%) underwent at least two resections. Most tumors were located in retroperitoneum and pelvis (75.0%). The histological subtype included liposarcoma (20.8%), leiomyosarcoma (10.4%), synovial sarcoma (8.3%), undifferentiated pleomorphic sarcoma (6.3%), malignant peripheral nerve sheath tumor (6.3%), myxofibrosarcoma (6.3%) and other histologies with fewer than 3 cases each (41.7%). Among the 48 patients, 9 (18.8%) had previously received in-field radiotherapy, 5 (10.4%) patients had metal implants within the irradiation field.\u003c/p\u003e\u003cp\u003eThe median follow up was 48.6 months. Twenty patients (41.7%) had no evidence of local recurrence or distant metastases at the time of death or last follow-up. Across the entire cohort, 30 patients experienced disease progression, 8 patients developed local recurrence, 14 patients had distant metastases, and 8 patients exhibited both local and distant relapses. The median time to local recurrence was 23.8 months (range: 6.6\u0026ndash;87.0 months) among the 16 patients. Eleven of the 16 local recurrences (68.8%) occurred within 2 years after CIRT. The 4- and 5-year LC rates were 65.8% and 60.3% (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea), respectively. The median LC was 87 months. The 4-year LC for tumors in retroperitoneum and pelvis, trunk, and extremities were 56.4% and 91.7%, respectively. Eighteen patients died. Among these, 11 patients died due to distant metastasis, 4 succumbed to local progression, 2 deaths were attributed to unknown causes, and 1 patient died from another disease (Myelodysplastic Syndrome, MDS). The median DMFS, PFS and OS were 54.7, 24.3 and 67.3 months, respectively. The 4-year DMFS, PFS and OS were 50.3%, 36.7% and 59.7%, respectively. The 5-year DMFS, PFS and OS were 44.0%, 28.0% and 54.7%, respectively. (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb-d).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eIn univariate analysis, radiation dose demonstrated a significant impact on both LC and PFS. Patients who were administered a higher prescribed dose (BED\u0026thinsp;\u0026ge;\u0026thinsp;129 Gy, α/β\u0026thinsp;=\u0026thinsp;5) demonstrated significantly superior LC (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.011) and PFS (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004) compared with those who received a lower prescribed dose. The 5-year LC was 41.7% for patients in the BED\u0026thinsp;\u0026lt;\u0026thinsp;129 Gy group, compared with 74.0% for those in the BED\u0026thinsp;\u0026ge;\u0026thinsp;129 Gy group. The mean tumor volume was 148.6 cc (range: 5.5-2957.2 cc). A tumor size less than 150cc was correlated with better PFS (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.014), although it was not significantly associated with better LC (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.322). The median survival for patients with tumor size less than 150 cc and those with tumors 150 cc or greater was 50.4 months and 22.8 months, respectively. The pre-CIRT NLR of 3 or higher was associated with worse DMFS (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.020), whereas a post-CIRT NLR of 3 or higher was not significantly correlated with DMFS (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.568). Other parameters were not significantly correlated with clinical outcomes.\u003c/p\u003e\u003cp\u003eThe most frequently observed acute toxicity was radiation dermatitis. Grade 2 and grade 3 acute radiation dermatitis were observed in two patients each (4.2%), and all patients completed the planned radiotherapy course. Late toxicities included grade 2 dermatitis in six patients (12.5%) and grade 3 dermatitis in two patients (4.2%), primarily localized to the limb and vulvar region, respectively. Additional late complications included one case of grade 2 arthrofibrosis and one case of grade 3 arthrofibrosis. Late neurological toxicities were observed in three patients: two cases of grade 2 neuropathy (4.2%) and one case of grade 4 neuropathy (2.1%). This grade 4 neuropathy was observed in a patient undergoing CIRT followed by surgical resection. All grade\u0026thinsp;\u0026ge;\u0026thinsp;2 acute and late toxicities were exclusively observed in patients received a BED\u0026thinsp;\u0026ge;\u0026thinsp;129 Gy.\u003c/p\u003e\u003cp\u003eNotably, following multidisciplinary team (MDT) review, three patients with tumors presenting high surgical resection difficulty received neoadjuvant CIRT followed by surgery. The first case involved a patient with a Capicua transcriptional repressor (CIC) - rearranged sarcoma that recurred two months postoperatively, presenting with multiple tumors, the largest of which measured 15*17 cm. The patient received CIRT (72 Gy / 18 fractions) followed by tumor resection one month later. At the latest follow-up (42.7 months), the patient remained disease-free. However, grade 4 late neuropathy presented as foot numbness and pain, ultimately requiring distal amputation followed by prosthetic rehabilitation. The patient currently exhibits normal ambulation and functional activity (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). To preserve limb function, the second patient underwent preoperative CIRT with a total dose of 72 Gy delivered in 18 fractions. One month post-CIRT, the patient underwent complete surgical resection of the tumor. At the most recent follow-up (32.3 months), the patient remained disease-free with preserved limb function. The third case involved a patient with recurrent pelvic low-grade fibromyxoid sarcoma who received CIRT (70.4 Gy / 16 fractions). Tumor resection was performed two months post-CIRT. Unfortunately, local recurrence developed at 11.1 months after surgery, followed by lung metastasis at 14.2 months after surgery. Metal implants within the radiation field were observed in this patient, potentially associated with tumor recurrence.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eSurgical resection remains the standard curative-intent treatment for localized STS. However, population-based studies indicate that 15 to 55% of patients are considered ineligible for surgery due to anatomical limitations (e.g., tumor proximity to neurovascular bundles) or medical comorbidities.(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e) Moreover, the management of locally recurrent disease presents significant therapeutic dilemmas, as these patients often face prohibitive reoperation risks or experience disease recurrence even after surgery.\u003c/p\u003e\u003cp\u003eCarbon ions exhibit higher LET and RBE, enhancing tumor cell killing while minimizing damage to surrounding normal tissues via the Bragg peak effect (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). This renders CIRT particularly effective for treating radioresistant tumors or those located near critical structures. Previous studies have demonstrated promising LC rates with CIRT for STS, such as the 5-year LC rate of 65% reported by Imai et al. (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). In a study reported by Serizawa et al., among 24 patients with unresectable RPS received CIRT, the 5-year LC and OS rates were 69% and 50%, respectively. These results were superior to previous outcomes from photon therapy. However, these studies were primarily based on the MKM, which is predominantly used in Japanese facilities. In contrast, European centers and our institution utilize the LEM, which may yield different clinical outcomes (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). This study aims to fill this knowledge gap by evaluating the efficacy and safety of CIRT based on the LEM model.\u003c/p\u003e\u003cp\u003eOur study included 48 patients with unresectable primary or recurrent STS who were treated with CIRT at SPHIC. The median follow-up was 48.6 months, and the overall results demonstrated favorable LC and survival outcomes. The 4-year and 5-year LC rates were 65.8% and 60.3%, respectively, indicating that CIRT can provide durable LC and consistent with those reported by Imai et al. Furthermore, the 4-year and 5-year OS rates were 58.9% and 53.6%, respectively. The median survival time was 67.3 months. Previous study (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e) from the MGH included 112 patients underwent photon therapy and reported the 5-year LC, DFS, and OS were 45%, 24%, and 35%, respectively. Allignet et al (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e) report that, in 116 unresectable STS patients treated with definitive photon therapy, 3-year local failure (LF), PFS and OS were 43.2%, 16.6% and 34%, respectively. Median OS was 21.4 months. Our results are quite higher than those results. Systematic review also (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e) showed that definitive photon therapy achieves 5-year LC rates of 28\u0026ndash;73% in unresectable STS, while particle therapies achieve rates of 52\u0026ndash;69%.\u003c/p\u003e\u003cp\u003eRegarding toxicities, all grade\u0026thinsp;\u0026ge;\u0026thinsp;2 toxicities occurred in patients who received a BED\u0026thinsp;\u0026ge;\u0026thinsp;129 Gy. Previous studies have also shown that radiation-induced neuropathy significantly increases when a long length of sacral nerves is exposed to CIRT doses\u0026thinsp;\u0026gt;\u0026thinsp;70 Gy (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). These findings suggest that while higher doses are associated with better LC, they may also increase the risk of toxicity. Therefore, careful dose optimization and individualized treatment planning are essential to balance efficacy and safety.\u003c/p\u003e\u003cp\u003eSeveral factors have been identified as potential predictors of clinical outcomes. Higher prescribed radiation doses (BED\u0026thinsp;\u0026ge;\u0026thinsp;129 Gy) were significantly associated with improved LC and PFS (LC: \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.011; PFS: \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004). This finding highlights the importance of dose escalation in CIRT, which may be particularly critical for radio-resistant STS. While dose-response relationships are well established in photon radiotherapy(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e), comparable evidence for CIRT remains limited and inconsistent (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). This discrepancy likely originate from fundamental differences in radiobiological modeling approaches, where the conversion factor increases with decreasing prescribed dose. In this study, the predominant dose fractionation regimen in our cohort was 72 Gy delivered in 18 fractions (BED\u0026thinsp;=\u0026thinsp;129.6Gy, α/β\u0026thinsp;=\u0026thinsp;5). Notably, Japanese protocols typically employ 70.4 Gy in 16 fractions (BED\u0026thinsp;=\u0026thinsp;132.4 Gy, α/β\u0026thinsp;=\u0026thinsp;5). It should be noted that Japan typically delivers four fractions per week, whereas our center delivers five fractions per week, though both approaches maintain comparable therapeutic ratios. Tumor volume emerged as an independent prognostic factor, with lesions\u0026thinsp;\u0026lt;\u0026thinsp;150 cc demonstrating superior PFS outcomes (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.014). This suggests that larger tumor volumes may pose a greater challenge for effective LC, potentially due to increased biological complexity or anatomical constraints near organs at risk.\u003c/p\u003e\u003cp\u003eTo the best of our knowledge, this is the first study to evaluate the association between NLR and prognosis in STS patients who underwent CIRT. An elevated pre-CIRT NLR (\u0026ge;\u0026thinsp;3) predicted worse DMFS (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.020), indicating that tumor-associated inflammation may influence the metastatic potential of STS. Several studies have investigated the prognostic value of NLR in various cancer types, demonstrating that an elevated NLR is associated with reduced OS and an increased risk of locoregional recurrence (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Studies have also identified the NLR as an independent prognostic factor for OS in RPS and synovial sarcoma (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Barcellini et al.(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e), showed that ACC patients with higher pre-CIRT levels of NLR had a predictable decrease in DFS. However, the post-CIRT NLR lost its prognostic value (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.568), our research findings are inconsistent with those of Matris et al.(\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e), who used hypofractionated radiotherapy (30 Gy in 5 fractions) and showed that higher post-RT NLR and a value\u0026thinsp;\u0026ge;\u0026thinsp;4 was associated with worse DFS and DMFS. Therefore, the relationship between post-CIRT NLR and therapeutic efficacy after CIRT remains unclear, which may be related to the radiation field coverage of lymphocytes during CIRT. Preclinical evidence indicates carbon ions reduce myeloid-derived suppressor cells (MDSCs) and enhance antigen presentation, potentially resetting the immune contexture (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThree patients in our study underwent multidisciplinary evaluation and received neoadjuvant CIRT followed by surgical resection due to the large tumor size and proximity to critical organs. Our study is the first, to our knowledge, to report the effect of neoadjuvant CIRT in unresectable STS. Two of these patients achieved disease-free survival at their latest follow-up, highlighting the potential role of CIRT in a multimodal treatment strategy. This approach may be particularly beneficial for patients with tumors that are initially deemed unresectable or those with recurrent disease after previous surgery. It should be noted that all three patients received preoperative radiotherapy with a radical dose, rather than the conventional prophylactic radiation dose. One patient developed grade 4 late neurological toxicity, potentially associated with extensive tumor encasement of the nerve, as both CIRT and surgical intervention may induce neurotoxicity. Further studies are needed to explore the optimal sequencing and integration of CIRT with surgery and other modalities.\u003c/p\u003e\u003cp\u003eDespite providing promising results into the efficacy and safety of CIRT for unresectable primary or recurrent STS, this study has several limitations. First, as a single-center retrospective analysis, the study design may inherently introduce selection bias and confounding factors. Second, the small sample size (n\u0026thinsp;=\u0026thinsp;48) and limited number of clinical events reduced statistical power, precluding multivariate analyses to adjust for potential confounders. Third, the absence of a direct comparator group hinders conclusive comparisons regarding the relative advantages of CIRT in terms of LC and toxicity profiles. Future prospective, multicenter studies with larger cohorts and integrated biomarker analyses are essential to validate these findings, optimize patient stratification, and refine therapeutic strategies.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, our study demonstrates that CIRT based on the LEM model is an effective and relatively safe treatment option for patients with unresectable primary or recurrent STS. Higher radiation doses and smaller tumor volumes were associated with better clinical outcomes, while systemic inflammation (as indicated by NLR) may influence metastatic potential. Future research should focus on optimizing treatment protocols, exploring the role of CIRT in multimodal strategies, and validating these findings in larger cohorts. Additionally, further investigation into the differences between the MKM and LEM models is warranted to better understand their clinical implications and guide treatment decisions.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate\u003c/p\u003e\n\u003cp\u003eThis study was conducted in compliance with the Declaration of Helsinki\u0026ndash; Ethical Principles for Medical Research Involving Human Participants. This study was approved by the Ethics Committee of Shanghai Proton and Heavy Ion Center (No. 1810-27-02). Informed consent was obtained from all individual participants included in the study.\u003c/p\u003e\n\n\u003cp\u003eConsent for publication\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eThis study was provided by the Scientific Research Program of Shanghai Pudong New Area Health Commission (No. PW2021A-41), Pudong New Area Science and Technology Development Foundation (No. PKJ2023-Y42). And the Shanghai Municipal Health Bureau, Shanghai, People\u0026rsquo;s Republic of China (No. 20224Y0273).\u003c/p\u003e\n\n\u003cp\u003eData availability\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study available from the corresponding author on reasonable request.\u003c/p\u003e\n\n\u003cp\u003eCompeting interests\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests\u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eGamboa AC, Gronchi A, Cardona K. Soft-tissue sarcoma in adults: An update on the current state of histiotype-specific management in an era of personalized medicine. CA: a cancer journal for clinicians. 2020;70(3):200-29.\u003c/li\u003e\n\u003cli\u003eRaut CP, Callegaro D, Miceli R, Barretta F, Rutkowski P, Blay JY, et al. Predicting Survival in Patients Undergoing Resection for Locally Recurrent Retroperitoneal Sarcoma: A Study and Novel Nomogram from TARPSWG. Clinical cancer research. 2019;25(8):2664-71.\u003c/li\u003e\n\u003cli\u003eTinganelli W, Durante M. Carbon Ion Radiobiology. Cancers (Basel). 2020;12(10).\u003c/li\u003e\n\u003cli\u003eIoakeim-Ioannidou M, Rose M, Chen YL, MacDonald SM. The Use of Proton and Carbon Ion Radiation Therapy for Sarcomas. Seminars in radiation oncology. 2024;34(2):207-17.\u003c/li\u003e\n\u003cli\u003eImai R, Kamada T, Araki N. Carbon ion radiotherapy for unresectable localized axial soft tissue sarcoma. Cancer medicine. 2018;7(9):4308-14.\u003c/li\u003e\n\u003cli\u003eMolinelli S, Bonora M, Magro G, Casale S, Dale JE, Fossati P, et al. RBE-weighted dose in carbon ion therapy for ACC patients: Impact of the RBE model translation on treatment outcomes. Radiotherapy and oncology. 2019;141:227-33.\u003c/li\u003e\n\u003cli\u003eGrosshagauer S, Fossati P, Schafasand M, Carlino A, Poljanc K, Radakovits T, et al. Organs at risk dose constraints in carbon ion radiotherapy at MedAustron: Translations between LEM and MKM RBE models and preliminary clinical results. Radiotherapy and oncology. 2022;175:73-8.\u003c/li\u003e\n\u003cli\u003eGuthrie GJK, Charles KA, Roxburgh CSD, Horgan PG, McMillan DC, Clarke SJ. The systemic inflammation-based neutrophil\u0026ndash;lymphocyte ratio: Experience in patients with cancer. Critical Reviews in Oncology/Hematology. 2013;88(1):218-30.\u003c/li\u003e\n\u003cli\u003eAllignet B, Waissi W, Geets X, Dufresne A, Brahmi M, Ray-Coquard I, et al. Long-term outcomes after definitive radiotherapy with modern techniques for unresectable soft tissue sarcoma. Radiotherapy and oncology. 2022;173:55-61.\u003c/li\u003e\n\u003cli\u003eKepka L, DeLaney TF, Suit HD, Goldberg SI. Results of radiation therapy for unresected soft-tissue sarcomas. International journal of radiation oncology, biology, physics. 2005;63(3):852-9.\u003c/li\u003e\n\u003cli\u003eAllignet B, Sunyach MP, Geets X, Waissi W. Is there a place for definitive radiotherapy in the treatment of unresectable soft-tissue sarcoma? A systematic review. Acta oncologica (Stockholm, Sweden). 2022;61(6):720-9.\u003c/li\u003e\n\u003cli\u003eNachankar A, Schafasand M, Hug E, Martino G, G\u0026oacute;ra J, Carlino A, et al. Sacral-Nerve-Sparing Planning Strategy in Pelvic Sarcomas/Chordomas Treated with Carbon-Ion Radiotherapy. Cancers. 2024;16(7).\u003c/li\u003e\n\u003cli\u003eTempleton AJ, McNamara MG, \u0026Scaron;eruga B, Vera-Badillo FE, Aneja P, Oca\u0026ntilde;a A, et al. Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: a systematic review and meta-analysis. Journal of the National Cancer Institute. 2014;106(6):dju124.\u003c/li\u003e\n\u003cli\u003eMoldoveanu D, Pravongviengkham V, Best G, Mart\u0026iacute;nez C, Hijal T, Meguerditchian AN, et al. Dynamic Neutrophil-to-Lymphocyte Ratio: A Novel Prognosis Measure for Triple-Negative Breast Cancer. Annals of surgical oncology. 2020;27(10):4028-34.\u003c/li\u003e\n\u003cli\u003eFiore M, Ljevar S, Pasquali S, Morelli D, Callegaro D, Sanfilippo R, et al. Preoperative Neutrophil-to-Lymphocyte Ratio and a New Inflammatory Biomarkers Prognostic Index for Primary Retroperitoneal Sarcomas: Retrospective Monocentric Study. Clinical cancer research. 2023;29(3):614-20.\u003c/li\u003e\n\u003cli\u003eGarc\u0026iacute;a-Ortega DY, \u0026Aacute;lvarez-Cano A, S\u0026aacute;nchez-Llamas LA, Caro-Sanchez CHS, Mart\u0026iacute;nez-Said H, Luna-Ortiz K, et al. Neutrophil/lymphocyte ratio is associated with survival in synovial sarcoma. Surgical oncology. 2018;27(3):551-5.\u003c/li\u003e\n\u003cli\u003eBarcellini A, Fontana G, Filippini DM, Ronchi S, Bonora M, Vischioni B, et al. Exploring the role of neutrophil-to-lymphocyte ratio and blood chemistry in head and neck adenoid cystic carcinomas treated with carbon ion radiotherapy. Radiotherapy and oncology. 2022;177:143-51.\u003c/li\u003e\n\u003cli\u003eMartinez C, Asso RN, Rastogi N, Freeman CR, Cury FL. Neutrophil-to-lymphocyte ratio for the prediction of soft tissue sarcomas response to pre-operative radiation therapy. Radiotherapy and oncology. 2024;195:110239.\u003c/li\u003e\n\u003cli\u003eZhou H, Yang P, Li H, Zhang L, Li J, Zhang T, et al. Carbon ion radiotherapy boosts anti-tumour immune responses by inhibiting myeloid-derived suppressor cells in melanoma-bearing mice. Cell death discovery. 2021;7(1):332.\u003c/li\u003e\n\u003cli\u003eSudo M, Tsutsui H, Fujimoto J. Carbon Ion Irradiation Activates Anti-Cancer Immunity. Int J Mol Sci. 2024;25(5).\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1. Patients\u0026rsquo; characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 55.9055%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;Characteristics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44.0945%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo. of patients\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 55.9055%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMedian age (range), y\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44.0945%;\"\u003e\n \u003cp\u003e53.5 (16-86) y\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 55.9055%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMale : female ratio\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44.0945%;\"\u003e\n \u003cp\u003e30:18\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 55.9055%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTumor type\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44.0945%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 55.9055%;\"\u003e\n \u003cp\u003e\u0026nbsp;Primary tumor without resection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44.0945%;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 55.9055%;\"\u003e\n \u003cp\u003e\u0026nbsp;Recurrent tumor after resection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44.0945%;\"\u003e\n \u003cp\u003e38\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 55.9055%;\"\u003e\n \u003cp\u003e\u0026nbsp;Residual tumor after resection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44.0945%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 55.9055%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTumor site\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44.0945%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 55.9055%;\"\u003e\n \u003cp\u003e\u0026nbsp;Retroperitoneum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44.0945%;\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 55.9055%;\"\u003e\n \u003cp\u003e\u0026nbsp;Pelvis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44.0945%;\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 55.9055%;\"\u003e\n \u003cp\u003e\u0026nbsp;Extremities\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44.0945%;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 55.9055%;\"\u003e\n \u003cp\u003e\u0026nbsp;Trunk\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44.0945%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 55.9055%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTumor size (range), cm3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44.0945%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 55.9055%;\"\u003e\n \u003cp\u003e\u0026nbsp; ~100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44.0945%;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 55.9055%;\"\u003e\n \u003cp\u003e100-200\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44.0945%;\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 55.9055%;\"\u003e\n \u003cp\u003e200-500\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44.0945%;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 55.9055%;\"\u003e\n \u003cp\u003e500-1000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44.0945%;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 55.9055%;\"\u003e\n \u003cp\u003e1000~\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44.0945%;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 55.9055%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHistology\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44.0945%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 55.9055%;\"\u003e\n \u003cp\u003eLiposarcoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44.0945%;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 55.9055%;\"\u003e\n \u003cp\u003eLeiomyosarcoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44.0945%;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 55.9055%;\"\u003e\n \u003cp\u003e\u0026nbsp; Synovial sarcoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44.0945%;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 55.9055%;\"\u003e\n \u003cp\u003e\u0026nbsp; UPS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44.0945%;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 55.9055%;\"\u003e\n \u003cp\u003e\u0026nbsp; MPNST\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44.0945%;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 55.9055%;\"\u003e\n \u003cp\u003e\u0026nbsp; Myxofibrosarcoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44.0945%;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 55.9055%;\"\u003e\n \u003cp\u003e\u0026nbsp; Others\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44.0945%;\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 55.9055%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMetal implant\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44.0945%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 55.9055%;\"\u003e\n \u003cp\u003e\u0026nbsp; Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44.0945%;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 55.9055%;\"\u003e\n \u003cp\u003e\u0026nbsp; No\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44.0945%;\"\u003e\n \u003cp\u003e43\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 55.9055%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRe-irradiation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44.0945%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 55.9055%;\"\u003e\n \u003cp\u003e\u0026nbsp; Yes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44.0945%;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 55.9055%;\"\u003e\n \u003cp\u003e\u0026nbsp; No\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44.0945%;\"\u003e\n \u003cp\u003e39\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 55.9055%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSurgery Times\u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44.0945%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 55.9055%;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44.0945%;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 55.9055%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44.0945%;\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 55.9055%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44.0945%;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 55.9055%;\"\u003e\n \u003cp\u003e\u0026ge;3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 44.0945%;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eMPNST, malignant peripheral nerve sheath tumor; UPS, undifferentiated pleomorphic sarcoma.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eTable 2\u003c/strong\u003e\u003cstrong\u003e．\u003c/strong\u003e\u003cstrong\u003eUnivariate\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;analysis\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"933\" class=\"fr-table-selection-hover\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 226px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariables\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 180px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLC\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 178px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDMFS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePFS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 180px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 121px;\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eAge ( \u0026lt;55y vs. \u0026ge;55y )\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e1.657 (0.622-4.414)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.320\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 121px;\"\u003e\n \u003cp\u003e1.010 (0.438-2.329)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.982\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e0.964 (0.477-1.949)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.918\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e0.678 (0.268-1.714)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.408\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eTumor location (retroperitoneum and pelvis vs. trunk and extremities)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e2.977 (1.020-8.688)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.129\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 121px;\"\u003e\n \u003cp\u003e1.364 (0.541-3.439)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.536\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e1.174 (0.518-2.661)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.710\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e2.054 (0.743-5.679)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.243\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003ePrevious radiotherapy (yes vs. no)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e0.453 (0.105-1.964)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.427\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 121px;\"\u003e\n \u003cp\u003e0.766 (0.207-2.833)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.715\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e1.007 (0.351-2.885)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.990\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e2.746 (0.565-13.35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.059\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eMetal implants (yes vs. no)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e0.442 (0.104-1.887)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.410\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 121px;\"\u003e\n \u003cp\u003e1.238 (0.331-4.633)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.729\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e0.774 (0.264-2.275)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.671\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e0.445 (0.106-1.875)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.416\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eRadiation dose (BED\u0026lt;129 Gy vs. BED\u0026ge;129 Gy)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e3.579 (1.305-9.817)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.011\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 121px;\"\u003e\n \u003cp\u003e1.800 (0.753-4.306)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.158\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e2.702 (1.284-5.683)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.004\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e2.395 (0.931-6.159)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.060\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eTumor volume (GTV\u0026lt;150cc vs. GTV\u0026ge;150cc)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e0.619 (0.231-1.659)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.322\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 121px;\"\u003e\n \u003cp\u003e0.546 (0.236-1.268)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.153\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e0.421 (0.205-0.864)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.014\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e0.493 (0.196-1.241)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.146\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eNLR before treatment (NLR＜3 vs. NLR\u0026ge;3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e0.926 (0.343-2.500)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.878\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 121px;\"\u003e\n \u003cp\u003e0.396 (0.162-0.968)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.020\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e0.590 (0.283-1.231)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.129\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e0.704 (0.269-1.843)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.452\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 226px;\"\u003e\n \u003cp\u003eNLR after treatment (NLR＜3 vs. NLR\u0026ge;3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e1.008 (0.365-2.779)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.988\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 121px;\"\u003e\n \u003cp\u003e0.782 (0.339-1.806)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.568\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 113px;\"\u003e\n \u003cp\u003e0.724 (0.357-1.466)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.375\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 123px;\"\u003e\n \u003cp\u003e0.722 (0.286-1.823)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e0.498\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Carbon Ion Radiotherapy, Soft tissue sarcoma, Local Effect Model, Neutrophil-to-lymphocyte ratio","lastPublishedDoi":"10.21203/rs.3.rs-7817850/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7817850/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe application of carbon ion radiotherapy (CIRT) for unresectable primary or recurrent soft tissue sarcoma (STS) remains controversial and existing data are limited. We herein present our institutional experience with CIRT for unresectable primary or recurrent STS.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e\u003cp\u003eWe retrospectively evaluated the outcomes of CIRT in unresectable primary or recurrent STS patients at our center. We assessed the 4 - and 5 - year local control (LC), overall survival (OS), distant metastasis free survival (DMFS), progression free survival (PFS), as well as acute and late toxicities. Additionally, we analyzed the prognostic factors associated with the treatment outcomes.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e\u003cp\u003eBetween June 2015 and August 2022, 48 consecutive patients with unresectable primary or recurrent STS were treated with CIRT at our center. The median follow-up duration was 48.6 months. The 4-year LC, OS, DMFS, and PFS rates were 65.8%, 59.7%, 50.3%, and 36.7%, respectively. The 5-year LC, OS, DMFS, and PFS rates were 60.3%, 54.7%, 44.0%, and 28.0%, respectively. The median survival time was 67.3 months. Late toxicities included grade 3 dermatitis (n\u0026thinsp;=\u0026thinsp;2, 4.2%), grade 3 arthrofibrosis (n\u0026thinsp;=\u0026thinsp;1, 2.1%), and grade 4 neuropathy (n\u0026thinsp;=\u0026thinsp;1, 2.1%). Patients who received a higher prescribed dose (BED\u0026thinsp;\u0026ge;\u0026thinsp;129 Gy) exhibited significantly better LC (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.010) and PFS (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004) compared to those who received a lower prescribed dose. A pre-CIRT neutrophil-to-lymphocyte ratio (NLR)\u0026thinsp;\u0026ge;\u0026thinsp;3 was associated was significantly associated with inferior DMFS (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.020).\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusions\u003c/b\u003e\u003c/p\u003e\u003cp\u003eIn patients with unresectable primary or recurrent STS, CIRT may serve as a potentially safe and effective treatment option.\u003c/p\u003e","manuscriptTitle":"Carbon Ion Radiotherapy for Unresectable Primary or Recurrent Soft Tissue Sarcomas: Long-Term Outcomes based on the Local Effect Model System","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-26 07:09:21","doi":"10.21203/rs.3.rs-7817850/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-12-02T19:32:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-28T09:14:07+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-24T09:42:01+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"327181916889228870810167120895914470454","date":"2025-11-24T07:34:53+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-23T10:48:21+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"339070152460421947185138518951546362297","date":"2025-11-23T10:29:54+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"19555566660142189267316004638854030011","date":"2025-11-22T17:58:22+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-19T00:53:57+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"257776581031167573750297916468808356637","date":"2025-11-17T04:20:16+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"153387629692013956016202995748388334303","date":"2025-11-17T01:41:35+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"303085838697626288287468675775092119141","date":"2025-11-16T05:53:37+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-11-14T10:03:34+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-10-23T13:53:19+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-23T12:24:50+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-10-22T15:16:13+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cancer","date":"2025-10-22T14:28:29+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"3ea45c19-c2ad-44d2-809e-51d12605cb76","owner":[],"postedDate":"November 26th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-18T10:23:40+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-26 07:09:21","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7817850","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7817850","identity":"rs-7817850","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}