The impact of resection margins in primary resection of high grade soft tissue sarcomas: a single-center analysis of 203 patients

The impact of resection margins in primary resection of high grade soft tissue sarcomas: a single-center analysis of 203 patients | 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 The impact of resection margins in primary resection of high grade soft tissue sarcomas: a single-center analysis of 203 patients Julian Miles Steffens, Tymoteusz Budny, Georg Gosheger, Marieke Vaal, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4808552/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: The World Health Organization’s (WHO) classification of tumors contains around 80 entities of soft tissue sarcomas (STS). Till now surgery is the standard treatment for patients with localized STS but the adequacy of resection margins in soft tissue sarcomas (STS) remains a topic of intense discussion. Methods: This single-center study retrospectively reviewed 203 patients with primary high-grade soft tissue sarcoma, including a follow-up period of at least 24 months unless a local recurrence occurred earlier (1-170 months). Patients with prior resection, secondary STS, metastasis at presentation or those who required amputational surgery were excluded from the study. Patients were categorized based on their margin thickness: positive (n = 13, 6.4%), 0–1 mm (n = 67, 33.0%), 1–5 mm (n = 70, 34.5%), and > 5 mm (n = 27, 13.3%). Results: A total of 64 out of 203 (31.5%) patients developed a local recurrence. The estimated 5-year local recurrence-free survival (LRFS) was 11.5% (CI 4–25%) for positive margins, 58% (CI 51–64%) for margins 0–1 mm, 76% (CI 70–81%) for margins > 1–5 mm, and 93% (CI 88–98%) for margins > 5 mm. No local recurrences occurred in patients with margins > 5 mm and adjuvant radiotherapy. Margin status significantly influenced the development of distant metastasis and overall survival. Adjuvant radiotherapy improved both local control and overall survival. Conclusions: To minimize the risk of local recurrence (LR) and achieve near-complete local control, a resection margin greater than 5 mm should be attained. When adjuvant radiotherapy is applied, the likelihood of LR decreases even more. In scenarios where preserving critical structures is essential, a resection margin of less than 5 mm can be acceptable for ensuring local control. Achieving an R0 resection is imperative for ensuring distant metastasis-free survival and overall survival. soft-tissue sarcoma resection margin local recurrence distant metastasis overall survival Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 1. Introduction The World Health Organization’s (WHO) classification of tumors includes approximately 80 entities of soft tissue sarcomas. To date, surgery remains the standard treatment for patients with localized STS, simultaneously trying to preserve the limb and an acceptable function(1). In 1980, Enneking et al.(2) categorized resection margins into four grades: intralesional, marginal, wide, and radical. However, due to the qualitative nature of this system, it has become more common to define surgical margins using metric units. According to the 2021 European Society of Medical Oncology (ESMO) Guidelines(3) surgery should feature an “ en bloc wide excision with R0 margins”. While there is a consensus on the importance of wide excision for local control of STS (4–13), there remains a controversial discussion regarding the optimal margin distance to minimize the risk of local recurrence (5,6,9,10,12). The studies addressing this issue have shown heterogeneous results, often due to the inclusion of low-grade STS and re-resections. Additionally, margin assessment remains complex, and an appropriate classification system for resection margins in STS has yet to be established(4,10,14,15). According to the literature, prognostic factors for distant metastases and overall survival are even harder to assess and a consensus is yet to be agreed upon. To date, LR is the only independent prognostic factor for OS that has been consistently identified.(13,16–20) The present study aims to further explore the optimal resection margin to accomplish local control of STSs, and to gain deeper insight into potential risk factors for distant metastases and overall survival. 2. Materials and Methods A retrospective single-center study was conducted on 619 patients diagnosed with high-grade soft tissue sarcomas (STS) who underwent primary surgery at a specialized sarcoma center between 2008 and 2018. Ethical approval was obtained from the local ethics committee (2023-070-f-S). 2.1. Staging and Grading Prior to surgery, patients received standardized staging methods: MRI images were used to define the size and location of the tumor and CT scans of the chest served to detect distant metastasis. Open biopsies were performed to determine the tumor’s entity according to the latest WHO classification of Tumours of Soft Tissue and Bone.(21) Histopathological analysis was conducted at the same center. Margin thickness was assessed using the R-classification system(22), categorized as R0 if the tumor did not reach the intact barrier or resection margins, and R1 if there was microscopic tumor contamination or resection alongside the pseudo-capsule. Tumor grading was conducted using the FNCLCC (Fédération Nationale des Centres de Lutte Contre le Cancer) system. 2.2. Follow-up and Exclusion criteria A follow-up of at least 24 months including MRI and CT scans was required (n = 359) if the study’s main end point (LR) was not reached earlier. The imaging followed a strict scheme of MRIs of the tumor site as well as a low-dose lung-CT every 3 months for the first two years. The intervals were then extended to 6 months and from the 6th year on to 12 months. If patients remained tumor-free for more than 10 years, follow-up was completed. If contaminated margins remained and the patients underwent re-resection (n = 108), they were excluded from this study. Patients presenting with secondary STS, metastasis at presentation (n = 29) or those who required amputational surgery (n = 14) were also excluded. Tumors of the bone such as Ewing-sarcoma or osteosarcoma, tumors which derived from soft tissue but originated from within the bone and gastrointestinal-stroma tumors (GIST) or retroperitoneal STS were not included in this study. In total the number of eligible patients was n = 203. 2.3. Variables The following tumor characteristics were obtained: entity, margin thickness, grading, staging, tumor size, and the depth meaning subfascial or superficial. Further, treatment-associated data was collected from the patient’s file such as neoadjuvant or adjuvant therapy. Comorbidities and risk factors including hypertension, obesity and smoking were noted. Each patient was discussed separately in a multimodal tumor board consisting of several experts from different subjects. Most commonly they advised for an adjuvant treatment in sarcomas that were great in size, aggressive in nature or had a close or contaminated resection margin. In a limited number of cases neoadjuvant therapy was applied, mainly for downsizing tumors close to critical structures (major nerves, vessels or bone). In tumors that were resected with a margin wider than 10mm, further therapy was rarely indicated. However, each advise remained an individual decision and was based on the patient’s general health and preferences. 2.4. Statistics The occurrence of local recurrence marked the study’s main endpoint, others being distant-metastasis-free survival (DMFS) and overall survival. For statistical analysis, Local-recurrence-free-survival, DMFS and OS were calculated according to the Kaplan–Meier method(23) looking at a time span of 5 years for LRFS and DMFS and 10 years for OS. Significance analysis was performed using the log-rank test for nominal factors or the Cox regression model(24) in a bivariate setting for metric covariates. Significant predictor variables were selected for multivariate analysis (Cox regression). To maximize the patient numbers within subgroups, these factors were further refined through backwards: Wald method with an exclusion probability of 0.10. A p-value of less than 0.05 was considered statistically significant. The data analysis software used was SPSS Statistics Version: 28.0.1.1 (14). 3. Results Among the 203 eligible patients in our cohort, comprising 107 males and 96 females, the median age at the time of surgery was 60 years (range: 19–91 years). Tumor grades were distributed as FNCLCC grade 2 in 55 cases (27%) and grade 3 in 143 cases (70%), with 5 cases (3%) where eventual tumor grade determination was not possible due to histological subtypes not aligning with the FNCLCC grading scale or grading difficulties. The most prevalent tumor types were Liposarcoma, followed by Undifferentiated Pleomorphic Sarcoma and Spindle Cell Sarcoma (Table 2 ). Local recurrences were observed in 64 patients, and distant metastases were detected in 75 patients. In 13 cases (6%), non-adequate resection with positive margins persisted, while the majority showed negative margins (Table 1 ). Table 1 Patient characteristics in total and within subgroups. Margin width Positive 0.1-1mm > 1-5mm > 5mm Total Gender - Male - Female 6 (46%) 7 (54%) 38 (57%) 29 (43%) 34 (49%) 36 (51%) 18 (67%) 9 (33%) 107 (53%) 96 (47%) Age at surgery (median and range) 71 (19–81) years 62 (21–91) years 61 (19–83) years 58 (22–87) years 60 (19–91) years Duration of surgery (median and range) 173 (85–480) min. 114 (30–509) min. 99 (39–458) min 105 (34–235) min 105 (30–509) min Depth - Superficial - Subfascial 1 (8%) 12 (92%) 7 (11%) 56 (89%) 7 (10%) 62 (90%) 7 (26%) 20 (74%) 25 (13%) 169 (87%) Size of tumor (median) 138 (23–288) mm 103 (22–251) mm 88 (27–301) mm 88 (8-175) mm 96(8-301) mm Exulcerating - Yes - No 0 13 (100%) 2 (3%) 65 (97%) 1 (1%) 69 (99%) 3 (11%) 24 (89%) 6 (3%) 197 (97%) Tumor site - Right arm - Left arm - Right leg - Left leg - Trunk 3 (23%) 1 (8%) 3 (23%) 4 (31%) 2 (15%) 4 (6%) 11 (16%) 30 (44%) 20 (30%) 2 (3%) 4 (6%) 4 (6%) 30 (43%) 28 (40%) 4 (6%) 5 (19%) 1 (4%) 10 (37%) 9 (33%) 2 (7%) 17 (8%) 20 (10%) 81 (40%) 74 (37%) 11 (5%) Tumor Stage - II - IIIA - IIIB 1 (8%) 3 (23%) 9 (69%) 7 (11%) 27 (44%) 28 (45%) 10 (14%) 37 (54%) 21 (31%) 5 (19%) 13 (48%) 9 (33%) 27 (14%) 88 (46%) 76(40%) Radiotherapy (RTx) - Adj. - Neoadj. - No 6 (46%) 4 (31%) 3 (23%) 52 (78%) 6 (9%) 9 (13%) 58 (83%) 4 (6%) 8 (11%) 20 (74%) 1 (4%) 6 (22%) 155 (76%) 17 (8%) 31 (15%) Chemotherapy (CTx) - Adj. - Neoadj. - No - 1 (8%) 12 (92%) 18 (28%) 2 (3%) 44 (69%) 25 (37%) 4 (6%) 39 (57%) 14 (52%) 0 (0%) 13 (48%) 66 (33%) 9 (5%) 122 (62%) Wound healing complication - Yes - No 5 (42%) 7 (58% 14 (21%) 51 (79%) 13 (19%) 56 (81%) 7 (26%) 20 (74%) 45 (23%) 154 (77%) Obesity / BMI (kg/m 2 ) - 40 - 5 (39%) 5 (39%) 1 (8%) 1 (8%) 1 (8%) 1 (2%) 22 (33%) 27 (42%) 11 (17%) 2 (3%) 1 (2%) 2 (3%) 20 (31%) 23 (36%) 14 (22%) 2 (3%) 3 (4%) - 7 (28%) 13 (52%) - 4 (16%) 1 (4%) 3 (2%) 61 (33%) 73 (40%) 31 (17%) 10 (5%) 6 (3%) Smoking - Yes - No 3 (25%) 9 (75%) 14 (22%) 49 (78%) 12 (19%) 50 (81%) 4 (16%) 21 (84%) 36 (20%) 144 (80%) High blood pressure - Yes - No 7 (54%) 6 (46%) 32 (49%) 33 (51%) 29 (45%) 36 (55%) 15 (58%) 11 (42%) 90 (48%) 98 (52%) Local recurrence - Yes - No 11 (85%) 2 (15%) 27 (40%) 40 (60%) 19 (27%) 51 (73%) 4 (15%) 23 (85%) 64 (31%) 139 (69%) Distant metastasis - Yes - No 8 (67%) 4 (33%) 30 (47%) 34 (53%) 23 (34%) 45 (66%) 9 (33%) 18 (67%) 75 (38%) 121 (62%) Follow-Up (median and range) 13 (3–78) months 37 (1-154) months 45 (3-151) months 55 (24–152) months 46 (1-170) months Overall survival (median and range) 22 (4-153) months 119 (2-191) months 98 (6-192) months 124 (28–189) months 96 (2-192) months Table 2 Histological subtypes and grading of the STSs Histological subtype G2 G3 LR All All patients* 55 143 64 203 (100%) Undifferentiated sarcoma (UPS)** 17 79 34 97 (48%) Liposarcoma* 18 17 6 36 (18%) Myxofibrosarcoma 8 16 9 24 (12%) Synovial sarcoma 5 10 5 15 (7%) Rhabdomyosarcoma 1 8 3 9 (4%) Leiomyosarcoma 2 5 3 7 (3%) Malignant peripheral nerve sheath tumor (MPNST) 0 4 0 4 (2%) Fibrosarcoma 1 1 2 2 (1%) Clear cell sarcoma 0 1 0 1 (1%) Others* 3 2 2 8 (4%) 3.1. Prognostic factors for local recurrence (LR) Table 3 Cox proportional hazard analysis for LR Covariates Hazard ratio 95% confidence interval p-value Age at surgery 1.017 1.000–1.035 0.048 Margin width in mm 0 0,1–1 > 1–5 > 5 1 0.304 0.178 0.054 0.143–0.646 0,079–0.401 0.016–0.183 < 0.001 0.002 < 0.001 < 0.001 Radiotherapy No. RTx Neoadj. RTx Adj. RTx 1 1.229 0.232 0.564–2.678 0.126–0.426 < 0.001 0.605 < 0.001 The estimated overall 5-year local recurrence-free survival (LRFS) rate was 70%. Out of 203 patients, 55 (27.1%) developed a local recurrence within this period. The estimated 5-year LRFS for positive margins was 11.5% (CI 4–25%), for margins ≥ 0.1-1 mm it was 58% (CI 51–64%), for margins > 1–5 mm it was 76% (CI 70–81%), and for margins > 5 mm it was 93% (CI 88–98%). Both margin width and adjuvant radiotherapy had a highly significant positive impact on LRFS (Table 3 , Figs. 1 and 2), with the hazard ratio decreasing as the diameter of the surrounding non-reactive tissue increased. Patients who did not receive radiotherapy had a fourfold higher risk of developing local recurrence compared to those who received adjuvant radiotherapy (p 5 mm and adjuvant radiotherapy was applied. In patients who received adjuvant radiotherapy, the estimated 5-year LRFS was 25% (CI 5–45%) for positive margins, 67% (CI 60–74%) for margins ≥ 0.1-1 mm, 81% (CI 71–87%) for margins > 1–5 mm, and 100% for margins > 5 mm. There was a significant difference in LRFS between patients with resection margins of ≥ 0–1 mm and > 1–5 mm (p = 0.07), and this difference showed a trend when adjuvant radiotherapy was applied (p = 0.137). Patients with resection margins > 5 mm and adjuvant radiotherapy had a significantly superior outcome compared to those with margins > 1–5 mm and adjuvant radiotherapy (p = 0.023). The effect of neoadjuvant therapy was not significant. No significant differences were found between the R- and UICC-classification systems regarding the cumulative incidence of local recurrence in R0 or R1 resections (p = 0.944, Fig. 5 ). Neither tumor grading (p = 0.962) nor risk factors such as high blood pressure (p = 0.323), smoking (p = 0.233), and obesity (p = 0.509) influenced LRFS. However, wound healing complications (p = 0.049), chemotherapy (p = 0.043), staging (p = 0.032), and tumor size (p = 0.007) showed a trend toward influencing local control in bivariate analysis but were later excluded through backward selection using the Wald method. In multivariate Cox proportional-hazards regression analysis, age at surgery, adjuvant radiotherapy, and margin width were identified as significant factors (Table 3 ). 3.2. Prognostic factors for distant metastasis (DM) Table 4 Cox proportional hazard analysis for DM Covariates Hazard ratio 95% confidence interval p-value Margin status R0 R1 1 1.477 0.669–3.261 0.335 Radiotherapy No RTx Neoadj. RTx Adj. RTx 1 1.439 1.735 0.547–3.783 0.798–3.772 0.373 0.164 0.461 Chemotherapy No CTx Neoadj. CTx Adj. CTx 1 1.627 0.491 0.635–4.167 0.269–0.895 0.026 0.311 0.020 Local recurrence No Yes 1 3.328 1.947–5.551 < 0.001 The estimated 5-year DMFS was 60.8% (CI 57–65%); 71 (34.9%) patients developed distant metastases within a five-year span. In bivariate analysis the covariates margin status (p = 0.004), margin width (p = 0.006), tumor size (p = 0.044), local recurrence (p < 0.001) and chemotherapy (p = 0.006) showed significant associations with DMFS whereas tumor stage and radiotherapy demonstrated trends (p = 0.066 and p = 0.067, respectively). Notably, when negative resection margins were achieved, the metric resection width no longer significantly influenced metastasis-free survival (p = 0.163). Comparing margins greater than 5mm to margins between 0.1 and 1 mm did not show significant differences in DMFS (p = 0.143). The estimated 5-year DMFS rates were as follows: 31.3% (CI: 17–45%) for positive margins, 47.4% (CI: 40–54%) for margins between 0.1 and 1mm, 66.8% (CI: 61–73%) for margins between > 1-5mm, and 68.2% (CI: 58–78%) for margins greater than 5mm (Fig. 3 ). In multivariate analysis, both local recurrence (p < 0.001; HR 3.288, CI: 1.947–5.551) and adjuvant chemotherapy (p = 0.020; HR 0.491, CI: 0.269–0.895) remained significant. Adjuvant chemotherapy demonstrated a potential to reduce the risk of developing distant metastasis by more than 2. When LR was removed as an independent covariate in the subsequent Cox regression on the premise that it is closely associated with margin width and adjuvant RTx, margin status became a significant factor (p = 0.021, HR 2.475, CI: 1.148–5.336). However, radiotherapy did not exhibit any influence on DMFS in either analysis. Chemotherapy showed similar results when local recurrence was included or excluded as a covariate. Furthermore, no significant changes were observed when analyzing only patients who received adjuvant radiotherapy. 3.3. Prognostic factors for overall survival (OS) Table 5 Cox proportional hazard analysis for OS Covariates Hazard ratio 95% confidence interval p-value Age at surgery 1.018 1.000–1.037 0.056 Margin status R0 R1 1 1.482 0.643–3.416 0.356 Radiotherapy No RTx Neoadj. RTx Adj. RTx 1 0.555 0.482 0.232–1.329 0.243–0.954 0.108 0.186 0.036 Chemotherapy No CTx Neoadj. CTx Adj. CTx 1 0.637 0.419 0.215–1.888 0.213–0.823 0.032 0.416 0.012 Local recurrence No Yes 1 2.765 1.655–4.620 < 0.001 Distant metastasis No Yes 1 8.705 4.915–15.418 < 0.001 Wound healing complications No Yes 2.247 1.255–4.021 0.006 Mean OS was 96 months (Range: 2–192 months) with an estimated 10-year-overall-survival rate of 60% (CI 57–64%). Within this timeframe, 77 (38%) people died, of which 48 (62%) were confirmed tumor-related deaths. The Log-Rank test and respectively the bivariate Cox-regression showed a significant correlation for several variables: staging (p = 0.002), margin width (p = 0.003), margin status, local recurrence, distant metastasis, radiotherapy, and chemotherapy (p < 0.001 for each variable), tumor depth (p = 0.032), wound-healing complications (p = 0.002), duration of surgery (p = 0.008), age at surgery (p = 0,013) and tumor size (p = 0.001). As with DMFS: if negative margins are achieved, there was no significant correlation between OS and the metrical margin width (p = 0.458). Again, the examined risk factors obesity (p 0,889), high blood pressure (0,115) and smoking (0,863) did not appear to contribute to OS. In multivariate Cox-Analysis (Table 4 ) local recurrence (HR 2,765; 1,655–4,620) and distant metastasis (HR 8,705; 4,915–15,418) were identified as the worst prognostic factors decreasing chances of long-time survival by almost 3 and 9 times respectively. In addition, patients who received either adjuvant radio- (HR 0,482; CI 0,243–0,954) or chemotherapy (HR 0,419, CI 0,213–0,823) showed a superior outcome in terms of OS compared to those who did not receive adjuvant therapy. In contrast, both neoadjuvant radio- and chemotherapy demonstrated a trend but could not signigicantly improve OS. Wound healing complication was also identified as an independent prognostic factor for OS (HR 2,247; CI 1,255–4,021). However, When LR was excluded from the Cox analysis, as was done when analyzing DMFS, resection margins and adjuvant radiotherapy gained a stronger influence (p = 0.094 and 0.003, respectively) while adjuvant CTx remained almost unchanged. 4. Discussion There is a broad consensus on the fact that positive margins increase the risk of local recurrence (4–13) and that radiotherapy can improve local control(25–28). When it comes to an adequate resection margin, however, there is still some dissent. This is mostly due to the rarity of soft tissue sarcomas which only account for approximately 1% of new malignant neoplasms in adults. Hence, to reach enough cases, studies about STS often encompass heterogenous patient populations with varied tumor entities, grades and treatments across different institutions and therefore different surgeons, procedures and pathologists. Moreover, they integrate re-resections, whoops procedures, LR, and DM at presentation. Dickinson et al. categorized (5) 303 patients based on achieved surgical margins: contaminated, <1mm but clear, 1-4mm, 5-9mm and 10-19mm. They concluded that “the margin can safely be as narrow as 1mm in terms of low local recurrence rates”. However, their study did not consider critical factors such as tumor size and resection difficulty and included previously treated patients. Bilgeri et al. categorized all R0-patients, including those who presented with LR and DM, into four categories: 10mm and found that wider margins were associated with better outcomes up to 5mm, beyond which there was no significant improvement in LRFS and overall survival (10). In a broader pooled study population including patients with both low- and high-grade STS, McKee et al. demonstrated that those with microscopically positive margins and close negative margins (1–9 mm) were at increased risk for LR and distant metastases compared to patients with clear margins measuring ≥ 10 mm. Having said this, the study is further limited by its low percentage of adjuvant radiotherapy (38%) and its inclusion of re-resections.(6) In the most selective study Fujiwara et al. were able to show that in a cohort composed only of patients with infiltrative STS, a surgical margin of greater than 10mm was associated with an improved LR-free survival.(9) Albeit these findings are limited because not all negative margins could retrospectively be sorted into the right category.(10) In a prospective study including all types of STS and previously treated patients, Sampo et al.(12) reported that the LRFS correlated with increasing surgical margin as far as 4cm and indicated that a surgical margin of 2-3cm provided “reasonable local control”. Consistent with previous research, our findings demonstrated that negative margins are significantly superior to positive margins, with a hazard ratio (HR) of nearly 8 (HR 7.845; CI 3.984–14.450). Adjuvant radiotherapy also played an important role in achieving local control, reducing the HR of local recurrence (LR) by more than threefold (Table 3 ). Additionally, our study showed a direct correlation between local recurrence-free survival (LRFS) and margin width (Figs. 1 and 2): larger surrounding non-reactive tissue in the tumor specimen was associated with longer LRFS. Radio- and chemotherapy, as well as tumor stage, were relatively evenly distributed among the subgroups. Patients with resection margins > 5mm had the best 5-year LRFS at 93%, followed by those with margins of > 1-5mm at 76%. Our 5-year LRFS is slightly lower than most reports in the literature but aligns closely with studies focusing exclusively on high-grade soft tissue sarcomas (STS), particularly those examining wide resection margins (10,29). Notably, in our study, no LR occurred when the margin was > 5mm and adjuvant radiotherapy was applied, a result significantly superior to patients with margins < 5mm and adjuvant radiotherapy (p ≤ 0.023). Age at surgery attained statistical significance in both uni- and multivariate analysis concerning LR, although it only slightly increased the HR. Duration of surgery, considered a composite measure of tumor characteristics such as size, depth, and stage, was significant in bivariate analysis, not aligning with expectations since individual tumor characteristics did not independently reach significance. It becomes apparent that there is more to predict LRFS than only metric treatment options. Proximity to vascular bundles, nerves or fascia has become a more critical decision-factor in recent years. Kawaguchi et al.(7) first suggested that certain barriers such as the above have a stronger resistance against STS infiltration than normal tissue. O’Donnell et al.(30) emphasized the impact of different clinical settings in patients with positive margins on LRFS and supported the practice of close dissection for the preservation of critical structures even when this leads to microscopically positive margins. They hypothesized that the infiltration of critical structures can hint to a more aggressive nature of the tumor in general. However, this must be weighed against the potential risk of proposing an untrue or falsely assessed surgical barrier which led to the worst 5-year LRFS in their study. Our findings support that the question of what constitutes adequacy should be considered in context but that there is a good chance of achieving local control when a resection margin of more than 5mm can be achieved, particularly when coupled with adjuvant radiotherapy, which is standard practice in most cases. Table 6 Overview over the literature: resection margins and their impact on LR in STS patients Reference Nr. of patients Resection margin categories Impact on LR Limitations Dickinson I.C. et al., ANZ J Surgery 2006 303 Contaminated, < 1, 1–4, 5–9 and 10-19mm margin can safely be as narrow as 1mm Including re-resections, no respect to tumor size and difficulty of resection Bilgeri A. et al., Cancers (Basel). 2020 305 Contaminated, 5 and > 10mm A margin of > 5mm is sufficient, wider margins do not benefit the patients Including re-resections; margin, tumor size and age are linked to RTx and CTx. McKee MD et al., J Surg Oncol. 2004 111 Contaminated, 1–9 and > 10mm Margins > 10mm are optimal for extremity resections Including low-grade STS and re-resections, low percentage of adj. RTx and CTx Fujiwara T et al., Eur J Surg Oncol. 2020 305 Contaminated, 0.1–0.9, 1.0-1.9, 2.0-4.9, 5.0-9.9 and > 10mm A margin of > 10mm is advocated not all negative margins could retrospectively be sorted into the right WHO-category Kainhofer V et al., Eur J Surg Oncol. 2016 265 UICC- and R-Classification R0 resections are superior when classified according to the UICC-classification Including low and high-grade STS and re-resections; treatment for atypical liposarcomas changed during the second half Gundle KR et al., J Clin Oncol. 2018 2217 R-Classification, R + 1-Classification and TMCC classification An R + 1mm classification reduced LR-differences between R1 and R0, but the R-classification best determined the risk of LR Single-center study, treatment protocol has changed over the years; tumor sampling errors cannot be ruled out Sampo M et al., Br J Surg. 2008 270 2.0mm A surgical margin of 2-3cm provided reasonable local control, even without the use of radiotherapy Including low and high-grade STS as well as post radiation STS and patients who received amputation. Our findings 207 Contaminated, 0.1-1, > 1–5 and > 5mm A margin of > 5mm is advised Anatomical boundaries could not be evaluated, treatment protocol has shifted over the years R vs. UICC-Classification In 2016, Kainhofer et al. (4) initiated a discourse regarding the prognostic significance of various classifications of resection widths in patients with STS. They primarily focused on the R-classification as suggested by the American Joint Committee on Cancer (AJCC)(22) and the R + 1 classification suggested by the International Union against Cancer (UICC)(31). Their results favored the UICC-classification. However, two years later, Gundle et al. (14) conducted a comparative assessment of both systems and determined that the R-classification was more adept at assessing the risk of local recurrence (LR) within a competitive risk framework. Our findings cautiously align with this perspective, as we observed no enhancement in LRFS with the R + 1 (UICC) classification when juxtaposed with the traditional R-classification (Fig. 5 ). While study results are relatively consistent on how resection width and margin status relate to LRFS, an association with DMFS remains questionable (13,19). It must be said that neither the present, nor one of the studies mentioned above demonstrate any statistically significant correlation between the quantitative resection margin and metastasis free survival, underscoring the necessity for further research into this topic. While this study could show that margin width and subsequently margin status were independent risk factors in univariate analysis, their significance waned in a multivariate setting. In contrast, adjuvant chemotherapy and LR had a decisive impact on DMFS: as shown in the LRFS-analyses, there is an inverse relationship between LR and resection width. Analyzing the present study, LR itself proves to be a significant predictor for DM but the causal association has been described as weak by Trovik et al.(13) before. The authors argue that since inadequate margins were the highest risk factor for LR, inadequate margins should also be a significant prognostic factor for DM in an analysis not including LR. However, the authors did not show this in their analysis. Upon removing LR from Cox regression analysis in the present study, margin status assumed critical importance (p = 0.021), highlighting its role in influencing DMFS. Radiotherapy, while significant for LR, did not retain significance for DMFS, suggesting a nuanced interplay between treatment modalities and metastatic behavior in STS. Thus, the present study underlines that negative margins are vital in the prevention of both LR and DM Moreover, larger-scale studies investigating the interaction between surgical resection margins, (neo-)adjuvant therapy, and the biological properties of STS are imperative for devising effective treatment strategies aimed at prolonging DMFS Similarly, the impact of margin status on OS remains discussible. While a meta-analysis by Jang et al (11) and a recent study by Bilgeri et al.(10) concluded that margin status does affect OS, Jang et al. acknowledged several studies that showed contradictory results.(19,33–35) However, they acknowledged the low number of participants in the mentioned studies. The latest by Chouliaras et al.(8) could not find any correlation either. In another approach, Willeumier et al. argued that due to the aggressive nature of high-grade STS and its decrease in the 5-year survival rate it is difficult to determine the effect of surgical margin on survival(29) and that the effect will manifest over a longer time on patients who escape early DM(11,26), which is why we set the endpoint for OS at 10 years. While margin status could not uphold its significance in a multivariate setting, the major prognostic factors for OS were LR and DM with a HR of 2,8 and 8,7, respectively. Given the pivotal role of both local recurrence (LR) and distant metastases (DM) as primary prognostic factors for overall survival (OS), it follows that margin status should significantly influence OS as well. Upon excluding LR and DM in a Cox-regression analysis with respect to OS, we observed that R1-resection emerged as a negative prognostic factor (p = 0.045, HR 2.209). This underscored the importance of achieving negative margins to optimize OS Additionally, the findings in the present study suggest that adjuvant radiotherapy and chemotherapy can improve OS, highlighting the potential benefits of adjunctive therapies in enhancing survival outcomes. While specific details on adjuvant radiotherapy and chemotherapy were not collected in this study, optimizing the administration of these therapies akin to Schliemann et al(36) in R0-resected high-grade STS patients is important. Interestingly, OS was influenced by wound-healing complications. However, these were mostly noted in patients with positive margins (42%) whereas in other subgroups, only around a fifth of the patients developed wound-healing complications (19%, 21%, 26%). Interestingly, we observed that OS was influenced by wound-healing complications, with a higher incidence noted in patients with positive margins (42%) compared to other subgroups (19%, 21%, 26%). This disparity may be attributed to several factors, including the advanced age of patients with positive margins, their tendency to receive less adjuvant therapy, and the larger average tumor size among patients with wound-healing complications as the tumor might have been in proximity of critical structures. Limitations of our study We acknowledge the following limitations in our study. There was an uneven distribution of patients receiving neo- or adjuvant chemotherapy within the subgroups, and the overall numbers were small. Additionally, exact histopathological resection margins were untraceable in 26 patients, limiting our analysis to 177 patients when grouped by resection width. However, when we analyzed by resection status, all 203 patients could be included. To minimize distortions, we established strict inclusion criteria. However, our cohort still included patients with various soft tissue sarcoma (STS) entities, and we could not account for anatomical barriers beyond the superficial or subfascial location of tumors. 5. Conclusions In conclusion, the present study underlines the significance of achieving margins greater than 5 mm, preferably coupled with adjuvant radiotherapy. The highest 5-year local recurrence-free survival (LRFS) rate was observed in patients meeting these criteria. Moreover, the attainment of negative margins remains important for optimizing distant metastasis-free survival (DMFS) and overall survival (OS). Abbreviations WHO World health organization STS Soft tissue sarcoma ESMO European Society of Medical Oncology LR Local recurrence DM Distant metastases OS Overall survival GIST Gastrointestinal-stroma tumors DMFS Distant-metasis-free survival LRFS Local-recurrence-free survival FNCLCC Fédération Nationale des Centres de Lutte Contre le Cancer Adj. Adjuvant Neoadj. Neoadjuvant RTx Radiotherapy CTx Chemotherapy UICC International Union against Cancer AJCC American Joint Committee on Cancer TMCC Toronto margin context classification CI Confidence interval Declarations Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Ethics approval and consent to participate The study protocol was approved by the regional ethics committee (reference no.: 2023-070-f-S). All participants gave written informed consent. Consent for publication Not applicable Competing interests The authors declare that they have no competing interests. Funding The APC was funded by the Open Access Publishing Funds of the Westphalian Wilhelms University of Muenster Acknowledgements Not applicable Author Contribution Conceptualization, N.D. and T.B.; methodology, J.M.S., N.D. and T.B.; software, J.M.S.; validation, G.G., N. D. and T.B.; formal analysis, N.D. and T.B.; investigation, J.M.S.; N.E.;resources, G.G.; data curation, J.M.S.; writing manuscript, J.M.S., N.E.; review and editing, N.D., T.B., A.L., N.E., M.D.; visualization, J.M.S.; supervision, N.D, T.B., A.R.; project administration, N.D.; References Bernstein MJ. Limb-Sparing Treatment of Adult Soft-Tissue Sarcomas and Osteosarcomas. JAMA [Internet]. 1985 Oct 4 [cited 2022 Oct 17];254(13):1791–4. Available from: https://jamanetwork.com/journals/jama/fullarticle/400790 Enneking WF, Spanier SS, Goodman MA. A System for the Surgical Staging of Musculoskeletal Sarcoma. Clin Orthop Relat Res. 1980;153:106ff. Gronchi A, Miah AB, Dei Tos AP, Abecassis N, Bajpai J, Bauer S, et al. Soft tissue and visceral sarcomas: ESMO–EURACAN–GENTURIS Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology [Internet]. 2021 [cited 2022 Oct 14];32:1348–65. Available from: https://doi.org/10.1016/j.annonc.2021.07.006 Kainhofer V, Smolle MA, Szkandera J, Liegl-Atzwanger B, Maurer-Ertl W, Gerger A, et al. The width of resection margins influences local recurrence in soft tissue sarcoma patients. European Journal of Surgical Oncology. 2016 Jun 1;42(6):899–906. Dickinson IC, Whitwell DJ, Battistuta D, Thompson B, Strobel N, Duggal A, et al. SURGICAL MARGIN AND ITS INFLUENCE ON SURVIVAL IN SOFT TISSUE SARCOMA. ANZ J Surg [Internet]. 2006 Mar 1 [cited 2022 Oct 12];76(3):104–9. Available from: https://onlinelibrary.wiley.com/doi/full/10.1111/j.1445-2197.2006.03615.x Mckee MD, Liu DF, Brooks JJ, Gibbs JF, Driscoll DL, Kraybill WG. The Prognostic Significance of Margin Width for Extremity and Trunk Sarcoma. J Surg Oncol [Internet]. 2004;85:68–76. Available from: https://onlinelibrary.wiley.com/doi/10.1002/jso.20009 Kawaguchi N, Ahmed AR, Matsumoto S, Manabe J, Matsushita Y. The Concept of Curative Margin in Surgery for Bone and Soft Tissue Sarcoma. Clin Orthop Relat . 2004;419:165–72. Chouliaras K, Patel N, Senehi R, Ethun CG, Poultsides G, Grignol V, et al. Impact of resection margin on outcomes in high-grade soft tissue sarcomas of the extremity—A USSC analysis. J Surg Oncol. 2021 Feb 1;123(2):479–88. Fujiwara T, Stevenson J, Parry M, Tsuda Y, Tsoi K, Jeys L. What is an adequate margin for infiltrative soft-tissue sarcomas? European Journal of Surgical Oncology. 2020 Feb 1;46(2):277–81. Bilgeri A, Klein A, Lindner LH, Nachbichler S, Knösel T, Birkenmaier C, et al. The effect of resection margin on local recurrence and survival in high grade soft tissue sarcoma of the extremities: How far is far enough? Cancers (Basel). 2020 Sep 1;12(9):1–13. Jang WY, Kim HS, Han I. Impact of surgical margin on survival in extremity soft tissue sarcoma: A systematic review and meta-analysis. Medicine [Internet]. 2021 Jan 1 [cited 2022 Oct 12];100(3):e24124. Available from: /pmc/articles/PMC7837970/ Sampo M, Tarkkanen M, Huuhtanen R, Tukiainen E, Böhling T, Blomqvist C. Impact of the smallest surgical margin on local control in soft tissue sarcoma. British Journal of Surgery [Internet]. 2008 Jan 14 [cited 2022 Oct 12];95(2):237–43. Available from: https://academic.oup.com/bjs/article/95/2/237/6142608 Trovik CS, Bauer HCF, Alvegaê Rd C TA, Anderson H, Blomqvist C, Berlin È, et al. Surgical margins, local recurrence and metastasis in soft tissue sarcomas: 559 surgically-treated patients from the Scandinavian Sarcoma Group Register. Eur J Cancer [Internet]. 2000;36:710–6. Available from: www.ejconline.com Gundle KR, Kafchinski L, Gupta S, Griffin AM, Dickson BC, Chung PW, et al. Analysis of Margin Classification Systems for Assessing the Risk of Local Recurrence After Soft Tissue Sarcoma Resection. J Clin Oncol [Internet]. 2018 [cited 2022 Nov 2];36. Available from: https://doi.org/10.1200/JCO.2017. Sambri A, Caldari E, Fiore M, Zucchini R, Giannini C, Pirini MG, et al. Margin Assessment in Soft Tissue Sarcomas: Review of the Literature. Cancers (Basel) [Internet]. 2021 Apr 1 [cited 2024 Mar 4];13(7). Available from: https://pubmed.ncbi.nlm.nih.gov/33918457/ Eilber FC, Rosen G, Nelson SD, Selch M, Dorey F, Eckardt J, et al. High-Grade Extremity Soft Tissue Sarcomas: Factors Predictive of Local Recurrence and its Effect on Morbidity and Mortality. Ann Surg [Internet]. 2003 Feb [cited 2022 Nov 25];237(2):218. Available from: /pmc/articles/PMC1522131/ Stojadinovic A, Leung DHY, Hoos A, Jaques DP, Lewis JJ, Brennan MF. Analysis of the Prognostic Significance of Microscopic Margins in 2,084 Localized Primary Adult Soft Tissue Sarcomas. Ann Surg [Internet]. 2002 [cited 2022 Nov 25];235(3):424. Available from: /pmc/articles/PMC1422449/ Gronchi A, Miceli R, Fiore M, Collini P, Lozza L, Grosso F, et al. Extremity soft tissue sarcoma: Adding to the prognostic meaning of local failure. Ann Surg Oncol. 2007 May;14(5):1583–90. Gronchi A, Casali PG, Mariani L, Miceli R, Fiore M, Lo Vullo S, et al. Status of surgical margins and prognosis in adult soft tissue sarcomas of the extremities: A series of patients treated at a single institution. Journal of Clinical Oncology. 2005 Jan 1;23(1):96–104. Kaytan Saglam E, Yaman Ağaoğlu F, Cosar R, Eralp Y. Prognostic Factors in Localized Soft-Tissue Sarcomas Article in. Am J Clin Oncol [Internet]. 2003 [cited 2023 Apr 19]; Available from: https://www.researchgate.net/publication/10626166 WHO Classification of Tumours Editorial Boar, WHO Classification of Tumours Editorial Board.Soft Tissue and BoneTumours.3. 5th ed. Lyon: IARC; 2020. Available athttps://publications.iarc.fr/588. Accessed May 1 2021. Soft Tissue and Bone Tumours WHO Classification of Tumours. 5th ed. WHO Classification of Tumours Editorial Board, editor. Vol. 3. 2020. Tunn PU, Kettelhack C, Dürr HR. Standardized Approach to the Treatment of Adult Soft Tissue Sarcoma of the Extremities. In: Tunn PU, editor. Treatment of Bone and Soft Tissue Sarcomas [Internet]. Berlin, Heidelberg: Springer Berlin Heidelberg; 2009. p. 211–28. Available from: https://doi.org/10.1007/978-3-540-77960-5_13 Kaplan EL, Meier P. Nonparametric Estimation from Incomplete Observations. J Am Stat Assoc [Internet]. 1958 Jun 1;53(282):457–81. Available from: https://www.tandfonline.com/doi/abs/10.1080/01621459.1958.10501452 Cox DR. Regression Models and Life-Tables. Journal of the Royal Statistical Society: Series B (Methodological). 1972 Jan;34(2):187–202. DeLaney TF, Kepka L, Goldberg SI, Hornicek FJ, Gebhardt MC, Yoon SS, et al. Radiation Therapy for Control of Soft-Tissue Sarcomas Resected With Positive Margins. International Journal of Radiation Oncology*Biology*Physics. 2007 Apr 1;67(5):1460–9. Gronchi A, Verderio P, De Paoli A, Ferraro A, Tendero O, Majó J, et al. Quality of surgery and neoadjuvant combined therapy in the ISG-GEIS trial on soft tissue sarcomas of limbs and trunk wall. Annals of Oncology. 2013;24(3):817–23. Yang JC, Chang AE, Baker AR, Sindelar WF, Danforth DN, Topalian SL, et al. Randomized Prospective Study of the Benefit of Adjuvant Radiation Therapy in the Treatment of Soft Tissue Sarcomas of the Extremity. Vol. 16, J Clin Oncol. 1998. Rivera D. Long-Term Results of a Prospective Randomized Trial of Adjuvant Brachytherapy in So Tissue Sarcoma. 1996. Willeumier J, Fiocco M, Nout R, Dijkstra S, Aston W, Pollock R, et al. High-grade soft tissue sarcomas of the extremities: surgical margins influence only local recurrence not overall survival. International Orthopaedics (SICOT). 2015;(39):935–41. O’donnell PW, Griffin AM, Eward WC, Sternheim A, Catton CN, Chung PW, et al. The Effect of the Setting of a Positive Surgical Margin in Soft Tissue Sarcoma. Cancer [Internet]. 2014 [cited 2024 Mar 4];120:2866–75. Available from: https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.28793 Wittekind C, Compton CC, Greene FL, Sobin LH. TNM residual tumor classification revisited. Cancer [Internet]. 2002 May 1 [cited 2022 Nov 4];94(9):2511–6. Available from: https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.10492 Goldstein NS, Soman A, Sacksner J. Disparate surgical margin lengths of colorectal resection specimens between in vivo and in vitro measurements. The effects of surgical resection and formalin fixation on organ shrinkage. Am J Clin Pathol [Internet]. 1999 [cited 2024 Mar 4];111(3):349–51. Available from: https://pubmed.ncbi.nlm.nih.gov/10078110/ Popov P, Tukiainen E, Asko-Seljaavaara S, Huuhtanen R, Virolainen M, Virkkunen P, et al. Soft tissue sarcomas of the lower extremity: Surgical treatment and outcome. European Journal of Surgical Oncology. 2000;26(7):679–85. Tanabe KK, Pollock RE, Ellis LM, Murphy A, Sherman N, Romsdahl MM. Influence of Surgical Margins on Outcome in Patients with Preoperatively Irradiated Extremity Soft Tissue Sarcomas. [cited 2022 Oct 31]; Available from: https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/1097-0142 Bonvalot S, Levy A, Terrier P, Tzanis D, Bellefqih S, Le Cesne A, et al. Primary Extremity Soft Tissue Sarcomas: Does Local Control Impact Survival? Ann Surg Oncol. 2017 Jan 1;24(1):194–201. Schliemann C, Kerkhoff A, Hesse P, Bröckling S, Hardes J, Streitbürger A, et al. Adjuvant chemotherapy—Radiotherapy—Chemotherapy sandwich protocol in resectable soft tissue sarcoma: An updated single-center analysis of 104 cases. PLoS One [Internet]. 2018 May 1 [cited 2023 May 9];13(5). Available from: /pmc/articles/PMC5963910/ Albertsmeier M, Rauch A, Roeder F, Hasenhütl S, Pratschke S, Kirschneck M, et al. External Beam Radiation Therapy for Resectable Soft Tissue Sarcoma: A Systematic Review and Meta-Analysis. Ann Surg Oncol [Internet]. 2018 Mar 1 [cited 2024 Mar 4];25(3):754–67. Available from: https://pubmed.ncbi.nlm.nih.gov/28895107/ Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4808552","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":333656378,"identity":"cb4e972c-cfb6-4067-9abd-49552642350c","order_by":0,"name":"Julian Miles Steffens","email":"","orcid":"","institution":"University Hospital Münster","correspondingAuthor":false,"prefix":"","firstName":"Julian","middleName":"Miles","lastName":"Steffens","suffix":""},{"id":333656379,"identity":"4181f33b-64e6-4429-8131-587d7833b19a","order_by":1,"name":"Tymoteusz Budny","email":"","orcid":"","institution":"University Hospital Münster","correspondingAuthor":false,"prefix":"","firstName":"Tymoteusz","middleName":"","lastName":"Budny","suffix":""},{"id":333656380,"identity":"8776fecf-e875-4cb1-ab46-ad0ed2cab86c","order_by":2,"name":"Georg Gosheger","email":"","orcid":"","institution":"University Hospital Münster","correspondingAuthor":false,"prefix":"","firstName":"Georg","middleName":"","lastName":"Gosheger","suffix":""},{"id":333656381,"identity":"13b93f45-1f98-46dc-8470-b43091ff6e66","order_by":3,"name":"Marieke Vaal","email":"","orcid":"","institution":"University Hospital Münster","correspondingAuthor":false,"prefix":"","firstName":"Marieke","middleName":"","lastName":"Vaal","suffix":""},{"id":333656382,"identity":"13de0ff2-bec8-4013-802a-b81b7e5054ab","order_by":4,"name":"Anna Maria Rachbauer","email":"","orcid":"","institution":"University Hospital Münster","correspondingAuthor":false,"prefix":"","firstName":"Anna","middleName":"Maria","lastName":"Rachbauer","suffix":""},{"id":333656383,"identity":"b46b3b0f-36dd-48f4-b03a-42e08ed3c20f","order_by":5,"name":"Andrea Laufer","email":"","orcid":"","institution":"University Hospital Münster","correspondingAuthor":false,"prefix":"","firstName":"Andrea","middleName":"","lastName":"Laufer","suffix":""},{"id":333656384,"identity":"adb82aed-21b0-408e-91b5-19083a1dd122","order_by":6,"name":"Nina Myline Engel","email":"","orcid":"","institution":"University Hospital Essen","correspondingAuthor":false,"prefix":"","firstName":"Nina","middleName":"Myline","lastName":"Engel","suffix":""},{"id":333656385,"identity":"ee65a27c-b7b6-499d-a783-d48f9b5f0062","order_by":7,"name":"Niklas Deventer","email":"data:image/png;base64,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","orcid":"","institution":"University Hospital Münster","correspondingAuthor":true,"prefix":"","firstName":"Niklas","middleName":"","lastName":"Deventer","suffix":""}],"badges":[],"createdAt":"2024-07-26 13:52:50","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4808552/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4808552/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":63887793,"identity":"e8183d0c-8dfb-4591-8ef7-a81759b87817","added_by":"auto","created_at":"2024-09-03 11:39:35","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":36522,"visible":true,"origin":"","legend":"\u003cp\u003eCumulative incidence of LR for margin width\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4808552/v1/600821f17bfa68e7763d5646.png"},{"id":63886689,"identity":"01e0ff19-0e67-4d1c-b146-c023b8137ff0","added_by":"auto","created_at":"2024-09-03 11:31:35","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":32393,"visible":true,"origin":"","legend":"\u003cp\u003eSeparately for patients with ajduvant RTx\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4808552/v1/c85d96cf8b13d3d4690263cc.png"},{"id":63886690,"identity":"4a391bae-97b3-47fa-bc63-b43d20f0545f","added_by":"auto","created_at":"2024-09-03 11:31:35","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":57559,"visible":true,"origin":"","legend":"\u003cp\u003eCumulative incidence of DMFS for margin width\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4808552/v1/6542217c856a320a4f24722d.png"},{"id":63886693,"identity":"a4422e7a-dae4-40aa-843f-a4d44ba3ffa7","added_by":"auto","created_at":"2024-09-03 11:31:35","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":62371,"visible":true,"origin":"","legend":"\u003cp\u003eCumulative incidence of OS for margin width\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-4808552/v1/48da2514cfd44739b2ab1712.png"},{"id":63886692,"identity":"d2163568-2f3c-4138-b46f-33cd0e4962d8","added_by":"auto","created_at":"2024-09-03 11:31:35","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":48312,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier curve depicting LR rates of the 3 possible resection margin combinations.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-4808552/v1/def4a1b3b5775d0cddef432c.png"},{"id":77714696,"identity":"fd70eece-5f0c-41a7-9c0a-69bc5bc69104","added_by":"auto","created_at":"2025-03-04 13:47:00","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1379841,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4808552/v1/51d4380d-eeaa-4798-8ca1-a805d6e8b5ae.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"The impact of resection margins in primary resection of high grade soft tissue sarcomas: a single-center analysis of 203 patients","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eThe World Health Organization\u0026rsquo;s (WHO) classification of tumors includes approximately 80 entities of soft tissue sarcomas. To date, surgery remains the standard treatment for patients with localized STS, simultaneously trying to preserve the limb and an acceptable function(1). In 1980, Enneking et al.(2) categorized resection margins into four grades: intralesional, marginal, wide, and radical. However, due to the qualitative nature of this system, it has become more common to define surgical margins using metric units. According to the 2021 European Society of Medical Oncology (ESMO) Guidelines(3) surgery should feature an \u0026ldquo;\u003cem\u003een bloc\u003c/em\u003e wide excision with R0 margins\u0026rdquo;. While there is a consensus on the importance of wide excision for local control of STS (4\u0026ndash;13), there remains a controversial discussion regarding the optimal margin distance to minimize the risk of local recurrence (5,6,9,10,12). The studies addressing this issue have shown heterogeneous results, often due to the inclusion of low-grade STS and re-resections. Additionally, margin assessment remains complex, and an appropriate classification system for resection margins in STS has yet to be established(4,10,14,15). According to the literature, prognostic factors for distant metastases and overall survival are even harder to assess and a consensus is yet to be agreed upon. To date, LR is the only independent prognostic factor for OS that has been consistently identified.(13,16\u0026ndash;20) The present study aims to further explore the optimal resection margin to accomplish local control of STSs, and to gain deeper insight into potential risk factors for distant metastases and overall survival.\u003c/p\u003e"},{"header":"2. Materials and Methods","content":"\u003cp\u003eA retrospective single-center study was conducted on 619 patients diagnosed with high-grade soft tissue sarcomas (STS) who underwent primary surgery at a specialized sarcoma center between 2008 and 2018. Ethical approval was obtained from the local ethics committee (2023-070-f-S).\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Staging and Grading\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003ePrior to surgery, patients received standardized staging methods: MRI images were used to define the size and location of the tumor and CT scans of the chest served to detect distant metastasis. Open biopsies were performed to determine the tumor\u0026rsquo;s entity according to the latest WHO classification of Tumours of Soft Tissue and Bone.(21) Histopathological analysis was conducted at the same center. Margin thickness was assessed using the R-classification system(22), categorized as R0 if the tumor did not reach the intact barrier or resection margins, and R1 if there was microscopic tumor contamination or resection alongside the pseudo-capsule. Tumor grading was conducted using the FNCLCC (F\u0026eacute;d\u0026eacute;ration Nationale des Centres de Lutte Contre le Cancer) system.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2. Follow-up and Exclusion criteria\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eA follow-up of at least 24 months including MRI and CT scans was required (n\u0026thinsp;=\u0026thinsp;359) if the study\u0026rsquo;s main end point (LR) was not reached earlier. The imaging followed a strict scheme of MRIs of the tumor site as well as a low-dose lung-CT every 3 months for the first two years. The intervals were then extended to 6 months and from the 6th year on to 12 months. If patients remained tumor-free for more than 10 years, follow-up was completed. If contaminated margins remained and the patients underwent re-resection (n\u0026thinsp;=\u0026thinsp;108), they were excluded from this study. Patients presenting with secondary STS, metastasis at presentation (n\u0026thinsp;=\u0026thinsp;29) or those who required amputational surgery (n\u0026thinsp;=\u0026thinsp;14) were also excluded. Tumors of the bone such as Ewing-sarcoma or osteosarcoma, tumors which derived from soft tissue but originated from within the bone and gastrointestinal-stroma tumors (GIST) or retroperitoneal STS were not included in this study. In total the number of eligible patients was n\u0026thinsp;=\u0026thinsp;203.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3. Variables\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eThe following tumor characteristics were obtained: entity, margin thickness, grading, staging, tumor size, and the depth meaning subfascial or superficial. Further, treatment-associated data was collected from the patient\u0026rsquo;s file such as neoadjuvant or adjuvant therapy. Comorbidities and risk factors including hypertension, obesity and smoking were noted. Each patient was discussed separately in a multimodal tumor board consisting of several experts from different subjects. Most commonly they advised for an adjuvant treatment in sarcomas that were great in size, aggressive in nature or had a close or contaminated resection margin. In a limited number of cases neoadjuvant therapy was applied, mainly for downsizing tumors close to critical structures (major nerves, vessels or bone). In tumors that were resected with a margin wider than 10mm, further therapy was rarely indicated. However, each advise remained an individual decision and was based on the patient\u0026rsquo;s general health and preferences.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4. Statistics\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eThe occurrence of local recurrence marked the study\u0026rsquo;s main endpoint, others being distant-metastasis-free survival (DMFS) and overall survival. For statistical analysis, Local-recurrence-free-survival, DMFS and OS were calculated according to the Kaplan\u0026ndash;Meier method(23) looking at a time span of 5 years for LRFS and DMFS and 10 years for OS. Significance analysis was performed using the log-rank test for nominal factors or the Cox regression model(24) in a bivariate setting for metric covariates. Significant predictor variables were selected for multivariate analysis (Cox regression). To maximize the patient numbers within subgroups, these factors were further refined through backwards: Wald method with an exclusion probability of 0.10. A p-value of less than 0.05 was considered statistically significant. The data analysis software used was SPSS Statistics Version: 28.0.1.1 (14).\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eAmong the 203 eligible patients in our cohort, comprising 107 males and 96 females, the median age at the time of surgery was 60 years (range: 19\u0026ndash;91 years). Tumor grades were distributed as FNCLCC grade 2 in 55 cases (27%) and grade 3 in 143 cases (70%), with 5 cases (3%) where eventual tumor grade determination was not possible due to histological subtypes not aligning with the FNCLCC grading scale or grading difficulties. The most prevalent tumor types were Liposarcoma, followed by Undifferentiated Pleomorphic Sarcoma and Spindle Cell Sarcoma (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Local recurrences were observed in 64 patients, and distant metastases were detected in 75 patients. In 13 cases (6%), non-adequate resection with positive margins persisted, while the majority showed negative margins (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient characteristics in total and within subgroups.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMargin width\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.1-1mm\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;1-5mm\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;5mm\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003cp\u003e- Male\u003c/p\u003e \u003cp\u003e- Female\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (46%)\u003c/p\u003e \u003cp\u003e7 (54%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e38 (57%)\u003c/p\u003e \u003cp\u003e29 (43%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e34 (49%)\u003c/p\u003e \u003cp\u003e36 (51%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e18 (67%)\u003c/p\u003e \u003cp\u003e9 (33%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e107 (53%)\u003c/p\u003e \u003cp\u003e96 (47%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at surgery (median and range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e71 (19\u0026ndash;81) years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e62 (21\u0026ndash;91) years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e61 (19\u0026ndash;83) years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e58 (22\u0026ndash;87) years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e60 (19\u0026ndash;91) years\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration of surgery (median and range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e173 (85\u0026ndash;480) min.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e114 (30\u0026ndash;509) min.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e99 (39\u0026ndash;458) min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e105 (34\u0026ndash;235) min\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e105\u003c/p\u003e \u003cp\u003e(30\u0026ndash;509) min\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDepth\u003c/p\u003e \u003cp\u003e- Superficial\u003c/p\u003e \u003cp\u003e- Subfascial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (8%)\u003c/p\u003e \u003cp\u003e12 (92%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (11%)\u003c/p\u003e \u003cp\u003e56 (89%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (10%)\u003c/p\u003e \u003cp\u003e62 (90%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7 (26%)\u003c/p\u003e \u003cp\u003e20 (74%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e25 (13%)\u003c/p\u003e \u003cp\u003e169 (87%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSize of tumor (median)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e138 (23\u0026ndash;288) mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e103 (22\u0026ndash;251) mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e88 (27\u0026ndash;301) mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e88 (8-175) mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e96(8-301) mm\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExulcerating\u003c/p\u003e \u003cp\u003e- Yes\u003c/p\u003e \u003cp\u003e- No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003cp\u003e13 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (3%)\u003c/p\u003e \u003cp\u003e65 (97%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (1%)\u003c/p\u003e \u003cp\u003e69 (99%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3 (11%)\u003c/p\u003e \u003cp\u003e24 (89%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6 (3%)\u003c/p\u003e \u003cp\u003e197 (97%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor site\u003c/p\u003e \u003cp\u003e- Right arm\u003c/p\u003e \u003cp\u003e- Left arm\u003c/p\u003e \u003cp\u003e- Right leg\u003c/p\u003e \u003cp\u003e- Left leg\u003c/p\u003e \u003cp\u003e- Trunk\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (23%)\u003c/p\u003e \u003cp\u003e1 (8%)\u003c/p\u003e \u003cp\u003e3 (23%)\u003c/p\u003e \u003cp\u003e4 (31%)\u003c/p\u003e \u003cp\u003e2 (15%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (6%)\u003c/p\u003e \u003cp\u003e11 (16%)\u003c/p\u003e \u003cp\u003e30 (44%)\u003c/p\u003e \u003cp\u003e20 (30%)\u003c/p\u003e \u003cp\u003e2 (3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (6%)\u003c/p\u003e \u003cp\u003e4 (6%)\u003c/p\u003e \u003cp\u003e30 (43%)\u003c/p\u003e \u003cp\u003e28 (40%)\u003c/p\u003e \u003cp\u003e4 (6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5 (19%)\u003c/p\u003e \u003cp\u003e1 (4%)\u003c/p\u003e \u003cp\u003e10 (37%)\u003c/p\u003e \u003cp\u003e9 (33%)\u003c/p\u003e \u003cp\u003e2 (7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e17 (8%)\u003c/p\u003e \u003cp\u003e20 (10%)\u003c/p\u003e \u003cp\u003e81 (40%)\u003c/p\u003e \u003cp\u003e74 (37%)\u003c/p\u003e \u003cp\u003e11 (5%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor Stage\u003c/p\u003e \u003cp\u003e- II\u003c/p\u003e \u003cp\u003e- IIIA\u003c/p\u003e \u003cp\u003e- IIIB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (8%)\u003c/p\u003e \u003cp\u003e3 (23%)\u003c/p\u003e \u003cp\u003e9 (69%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (11%)\u003c/p\u003e \u003cp\u003e27 (44%)\u003c/p\u003e \u003cp\u003e28 (45%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 (14%)\u003c/p\u003e \u003cp\u003e37 (54%)\u003c/p\u003e \u003cp\u003e21 (31%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5 (19%)\u003c/p\u003e \u003cp\u003e13 (48%)\u003c/p\u003e \u003cp\u003e9 (33%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e27 (14%)\u003c/p\u003e \u003cp\u003e88 (46%)\u003c/p\u003e \u003cp\u003e76(40%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRadiotherapy (RTx)\u003c/p\u003e \u003cp\u003e- Adj.\u003c/p\u003e \u003cp\u003e- Neoadj.\u003c/p\u003e \u003cp\u003e- No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (46%)\u003c/p\u003e \u003cp\u003e4 (31%)\u003c/p\u003e \u003cp\u003e3 (23%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e52 (78%)\u003c/p\u003e \u003cp\u003e6 (9%)\u003c/p\u003e \u003cp\u003e9 (13%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e58 (83%)\u003c/p\u003e \u003cp\u003e4 (6%)\u003c/p\u003e \u003cp\u003e8 (11%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e20 (74%)\u003c/p\u003e \u003cp\u003e1 (4%)\u003c/p\u003e \u003cp\u003e6 (22%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e155 (76%)\u003c/p\u003e \u003cp\u003e17 (8%)\u003c/p\u003e \u003cp\u003e31 (15%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChemotherapy (CTx)\u003c/p\u003e \u003cp\u003e- Adj.\u003c/p\u003e \u003cp\u003e- Neoadj.\u003c/p\u003e \u003cp\u003e- No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003cp\u003e1 (8%)\u003c/p\u003e\u003cp\u003e12 (92%)\u003c/p\u003e\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18 (28%)\u003c/p\u003e \u003cp\u003e2 (3%)\u003c/p\u003e \u003cp\u003e44 (69%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e25 (37%)\u003c/p\u003e \u003cp\u003e4 (6%)\u003c/p\u003e \u003cp\u003e39 (57%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e14 (52%)\u003c/p\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003cp\u003e13 (48%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e66 (33%)\u003c/p\u003e \u003cp\u003e9 (5%)\u003c/p\u003e \u003cp\u003e122 (62%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWound healing complication\u003c/p\u003e \u003cp\u003e- Yes\u003c/p\u003e \u003cp\u003e- No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (42%)\u003c/p\u003e \u003cp\u003e7 (58%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (21%)\u003c/p\u003e \u003cp\u003e51 (79%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13 (19%)\u003c/p\u003e \u003cp\u003e56 (81%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7 (26%)\u003c/p\u003e \u003cp\u003e20 (74%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e45 (23%)\u003c/p\u003e \u003cp\u003e154 (77%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eObesity / BMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003cp\u003e- \u0026lt;\u0026thinsp;18,5\u003c/p\u003e \u003cp\u003e- 18,5\u0026ndash;24,9\u003c/p\u003e \u003cp\u003e- 25\u0026ndash;29,9\u003c/p\u003e \u003cp\u003e- 30\u0026ndash;34,9\u003c/p\u003e \u003cp\u003e- 35\u0026ndash;39,9\u003c/p\u003e \u003cp\u003e- \u0026gt;\u0026thinsp;40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e- \u003c/p\u003e \u003cp\u003e5 (39%)\u003c/p\u003e \u003cp\u003e5 (39%)\u003c/p\u003e \u003cp\u003e1 (8%)\u003c/p\u003e \u003cp\u003e1 (8%)\u003c/p\u003e \u003cp\u003e1 (8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (2%)\u003c/p\u003e \u003cp\u003e22 (33%)\u003c/p\u003e \u003cp\u003e27 (42%)\u003c/p\u003e \u003cp\u003e11 (17%)\u003c/p\u003e \u003cp\u003e2 (3%)\u003c/p\u003e \u003cp\u003e1 (2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (3%)\u003c/p\u003e \u003cp\u003e20 (31%)\u003c/p\u003e \u003cp\u003e23 (36%)\u003c/p\u003e \u003cp\u003e14 (22%)\u003c/p\u003e \u003cp\u003e2 (3%)\u003c/p\u003e \u003cp\u003e3 (4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003cp\u003e7 (28%)\u003c/p\u003e \u003cp\u003e13 (52%)\u003c/p\u003e \u003cp\u003e-\u003c/p\u003e \u003cp\u003e4 (16%)\u003c/p\u003e \u003cp\u003e1 (4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3 (2%)\u003c/p\u003e \u003cp\u003e61 (33%)\u003c/p\u003e \u003cp\u003e73 (40%)\u003c/p\u003e \u003cp\u003e31 (17%)\u003c/p\u003e \u003cp\u003e10 (5%)\u003c/p\u003e \u003cp\u003e6 (3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoking\u003c/p\u003e \u003cp\u003e- Yes\u003c/p\u003e \u003cp\u003e- No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (25%)\u003c/p\u003e \u003cp\u003e9 (75%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14 (22%)\u003c/p\u003e \u003cp\u003e49 (78%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12 (19%)\u003c/p\u003e \u003cp\u003e50 (81%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4 (16%)\u003c/p\u003e \u003cp\u003e21 (84%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e36 (20%)\u003c/p\u003e \u003cp\u003e144 (80%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHigh blood pressure\u003c/p\u003e \u003cp\u003e- Yes\u003c/p\u003e \u003cp\u003e- No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (54%)\u003c/p\u003e \u003cp\u003e6 (46%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32 (49%)\u003c/p\u003e \u003cp\u003e33 (51%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29 (45%)\u003c/p\u003e \u003cp\u003e36 (55%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e15 (58%)\u003c/p\u003e \u003cp\u003e11 (42%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e90 (48%)\u003c/p\u003e \u003cp\u003e98 (52%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLocal recurrence\u003c/p\u003e \u003cp\u003e- Yes\u003c/p\u003e \u003cp\u003e- No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (85%)\u003c/p\u003e \u003cp\u003e2 (15%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27 (40%)\u003c/p\u003e \u003cp\u003e40 (60%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e19 (27%)\u003c/p\u003e \u003cp\u003e51 (73%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4 (15%)\u003c/p\u003e \u003cp\u003e23 (85%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e64 (31%)\u003c/p\u003e \u003cp\u003e139 (69%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDistant metastasis\u003c/p\u003e \u003cp\u003e- Yes\u003c/p\u003e \u003cp\u003e- No\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (67%)\u003c/p\u003e \u003cp\u003e4 (33%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30 (47%)\u003c/p\u003e \u003cp\u003e34 (53%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e23 (34%)\u003c/p\u003e \u003cp\u003e45 (66%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9 (33%)\u003c/p\u003e \u003cp\u003e18 (67%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e75 (38%)\u003c/p\u003e \u003cp\u003e121 (62%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFollow-Up \u003c/p\u003e \u003cp\u003e(median and range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (3\u0026ndash;78) months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37 (1-154) months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e45 (3-151) months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e55 (24\u0026ndash;152) months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e46 (1-170)\u003c/p\u003e \u003cp\u003emonths\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOverall survival (median and range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (4-153) months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e119 (2-191) months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e98 (6-192) months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e124 (28\u0026ndash;189) months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e96 (2-192)\u003c/p\u003e \u003cp\u003emonths\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eHistological subtypes and grading of the STSs\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistological subtype\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eG2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eG3\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAll\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAll patients*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e143\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e203 (100%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUndifferentiated sarcoma (UPS)**\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e97 (48%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLiposarcoma*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e36 (18%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMyxofibrosarcoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e24 (12%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSynovial sarcoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e15 (7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRhabdomyosarcoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9 (4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeiomyosarcoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7 (3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMalignant peripheral nerve sheath tumor (MPNST)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4 (2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFibrosarcoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 (1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClear cell sarcoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (1%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOthers*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8 (4%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e3.1. Prognostic factors for local recurrence (LR)\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCox proportional hazard analysis for LR\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCovariates\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eHazard ratio\u003c/span\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e95% confidence interval\u003c/span\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003ep-value\u003c/span\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.000\u0026ndash;1.035\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.048\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMargin width in mm\u003c/p\u003e \u003cp\u003e0\u003c/p\u003e \u003cp\u003e0,1\u0026ndash;1\u003c/p\u003e \u003cp\u003e\u0026gt;\u0026thinsp;1\u0026ndash;5\u003c/p\u003e \u003cp\u003e\u0026gt;\u0026thinsp;5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e0.304\u003c/p\u003e \u003cp\u003e0.178\u003c/p\u003e \u003cp\u003e0.054\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.143\u0026ndash;0.646\u003c/p\u003e \u003cp\u003e0,079\u0026ndash;0.401\u003c/p\u003e \u003cp\u003e0.016\u0026ndash;0.183\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e0.002\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRadiotherapy\u003c/p\u003e \u003cp\u003eNo. RTx\u003c/p\u003e \u003cp\u003eNeoadj. RTx\u003c/p\u003e \u003cp\u003eAdj. RTx\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e1.229\u003c/p\u003e \u003cp\u003e0.232\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.564\u0026ndash;2.678\u003c/p\u003e \u003cp\u003e0.126\u0026ndash;0.426\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003cp\u003e0.605\u003c/p\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eThe estimated overall 5-year local recurrence-free survival (LRFS) rate was 70%. Out of 203 patients, 55 (27.1%) developed a local recurrence within this period. The estimated 5-year LRFS for positive margins was 11.5% (CI 4\u0026ndash;25%), for margins\u0026thinsp;\u0026ge;\u0026thinsp;0.1-1 mm it was 58% (CI 51\u0026ndash;64%), for margins\u0026thinsp;\u0026gt;\u0026thinsp;1\u0026ndash;5 mm it was 76% (CI 70\u0026ndash;81%), and for margins\u0026thinsp;\u0026gt;\u0026thinsp;5 mm it was 93% (CI 88\u0026ndash;98%). Both margin width and adjuvant radiotherapy had a highly significant positive impact on LRFS (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, Figs.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and 2), with the hazard ratio decreasing as the diameter of the surrounding non-reactive tissue increased. Patients who did not receive radiotherapy had a fourfold higher risk of developing local recurrence compared to those who received adjuvant radiotherapy (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; HR 0.232; CI 0.126\u0026ndash;0.426). Notably, no local recurrences occurred in our study when the margin was \u0026gt;\u0026thinsp;5 mm and adjuvant radiotherapy was applied.\u003c/p\u003e \u003cp\u003eIn patients who received adjuvant radiotherapy, the estimated 5-year LRFS was 25% (CI 5\u0026ndash;45%) for positive margins, 67% (CI 60\u0026ndash;74%) for margins\u0026thinsp;\u0026ge;\u0026thinsp;0.1-1 mm, 81% (CI 71\u0026ndash;87%) for margins\u0026thinsp;\u0026gt;\u0026thinsp;1\u0026ndash;5 mm, and 100% for margins\u0026thinsp;\u0026gt;\u0026thinsp;5 mm. There was a significant difference in LRFS between patients with resection margins of \u0026ge;\u0026thinsp;0\u0026ndash;1 mm and \u0026gt;\u0026thinsp;1\u0026ndash;5 mm (p\u0026thinsp;=\u0026thinsp;0.07), and this difference showed a trend when adjuvant radiotherapy was applied (p\u0026thinsp;=\u0026thinsp;0.137). Patients with resection margins\u0026thinsp;\u0026gt;\u0026thinsp;5 mm and adjuvant radiotherapy had a significantly superior outcome compared to those with margins\u0026thinsp;\u0026gt;\u0026thinsp;1\u0026ndash;5 mm and adjuvant radiotherapy (p\u0026thinsp;=\u0026thinsp;0.023). The effect of neoadjuvant therapy was not significant.\u003c/p\u003e \u003cp\u003eNo significant differences were found between the R- and UICC-classification systems regarding the cumulative incidence of local recurrence in R0 or R1 resections (p\u0026thinsp;=\u0026thinsp;0.944, Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e5\u003c/span\u003e). Neither tumor grading (p\u0026thinsp;=\u0026thinsp;0.962) nor risk factors such as high blood pressure (p\u0026thinsp;=\u0026thinsp;0.323), smoking (p\u0026thinsp;=\u0026thinsp;0.233), and obesity (p\u0026thinsp;=\u0026thinsp;0.509) influenced LRFS. However, wound healing complications (p\u0026thinsp;=\u0026thinsp;0.049), chemotherapy (p\u0026thinsp;=\u0026thinsp;0.043), staging (p\u0026thinsp;=\u0026thinsp;0.032), and tumor size (p\u0026thinsp;=\u0026thinsp;0.007) showed a trend toward influencing local control in bivariate analysis but were later excluded through backward selection using the Wald method. In multivariate Cox proportional-hazards regression analysis, age at surgery, adjuvant radiotherapy, and margin width were identified as significant factors (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.2. Prognostic factors for distant metastasis (DM)\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCox proportional hazard analysis for DM\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCovariates\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eHazard ratio\u003c/span\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e95% confidence interval\u003c/span\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003ep-value\u003c/span\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMargin status\u003c/p\u003e \u003cp\u003eR0\u003c/p\u003e \u003cp\u003eR1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e1.477\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.669\u0026ndash;3.261\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.335\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRadiotherapy\u003c/p\u003e \u003cp\u003eNo RTx\u003c/p\u003e \u003cp\u003eNeoadj. RTx\u003c/p\u003e \u003cp\u003eAdj. RTx\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e1.439\u003c/p\u003e \u003cp\u003e1.735\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.547\u0026ndash;3.783\u003c/p\u003e \u003cp\u003e0.798\u0026ndash;3.772\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.373\u003c/p\u003e \u003cp\u003e0.164\u003c/p\u003e \u003cp\u003e0.461\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChemotherapy\u003c/p\u003e \u003cp\u003eNo CTx\u003c/p\u003e \u003cp\u003eNeoadj. CTx\u003c/p\u003e \u003cp\u003eAdj. CTx\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e1.627\u003c/p\u003e \u003cp\u003e0.491\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.635\u0026ndash;4.167\u003c/p\u003e \u003cp\u003e0.269\u0026ndash;0.895\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.026\u003c/b\u003e\u003c/p\u003e \u003cp\u003e0.311\u003c/p\u003e \u003cp\u003e\u003cb\u003e0.020\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLocal recurrence\u003c/p\u003e \u003cp\u003eNo\u003c/p\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e3.328\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.947\u0026ndash;5.551\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eThe estimated 5-year DMFS was 60.8% (CI 57\u0026ndash;65%); 71 (34.9%) patients developed distant metastases within a five-year span. In bivariate analysis the covariates margin status (p\u0026thinsp;=\u0026thinsp;0.004), margin width (p\u0026thinsp;=\u0026thinsp;0.006), tumor size (p\u0026thinsp;=\u0026thinsp;0.044), local recurrence (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and chemotherapy (p\u0026thinsp;=\u0026thinsp;0.006) showed significant associations with DMFS whereas tumor stage and radiotherapy demonstrated trends (p\u0026thinsp;=\u0026thinsp;0.066 and p\u0026thinsp;=\u0026thinsp;0.067, respectively). Notably, when negative resection margins were achieved, the metric resection width no longer significantly influenced metastasis-free survival (p\u0026thinsp;=\u0026thinsp;0.163). Comparing margins greater than 5mm to margins between 0.1 and 1 mm did not show significant differences in DMFS (p\u0026thinsp;=\u0026thinsp;0.143). The estimated 5-year DMFS rates were as follows: 31.3% (CI: 17\u0026ndash;45%) for positive margins, 47.4% (CI: 40\u0026ndash;54%) for margins between 0.1 and 1mm, 66.8% (CI: 61\u0026ndash;73%) for margins between \u0026gt;\u0026thinsp;1-5mm, and 68.2% (CI: 58\u0026ndash;78%) for margins greater than 5mm (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e3\u003c/span\u003e). In multivariate analysis, both local recurrence (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; HR 3.288, CI: 1.947\u0026ndash;5.551) and adjuvant chemotherapy (p\u0026thinsp;=\u0026thinsp;0.020; HR 0.491, CI: 0.269\u0026ndash;0.895) remained significant. Adjuvant chemotherapy demonstrated a potential to reduce the risk of developing distant metastasis by more than 2. When LR was removed as an independent covariate in the subsequent Cox regression on the premise that it is closely associated with margin width and adjuvant RTx, margin status became a significant factor (p\u0026thinsp;=\u0026thinsp;0.021, HR 2.475, CI: 1.148\u0026ndash;5.336). However, radiotherapy did not exhibit any influence on DMFS in either analysis. Chemotherapy showed similar results when local recurrence was included or excluded as a covariate. Furthermore, no significant changes were observed when analyzing only patients who received adjuvant radiotherapy.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.3. Prognostic factors for overall survival (OS)\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCox proportional hazard analysis for OS\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCovariates\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eHazard ratio\u003c/span\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e95% confidence interval\u003c/span\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003ep-value\u003c/span\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.000\u0026ndash;1.037\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.056\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMargin status\u003c/p\u003e \u003cp\u003eR0\u003c/p\u003e \u003cp\u003eR1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e1.482\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.643\u0026ndash;3.416\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.356\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRadiotherapy\u003c/p\u003e \u003cp\u003eNo RTx\u003c/p\u003e \u003cp\u003eNeoadj. RTx\u003c/p\u003e \u003cp\u003eAdj. RTx\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e0.555\u003c/p\u003e \u003cp\u003e0.482\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.232\u0026ndash;1.329\u003c/p\u003e \u003cp\u003e0.243\u0026ndash;0.954\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.108\u003c/p\u003e \u003cp\u003e0.186\u003c/p\u003e \u003cp\u003e\u003cb\u003e0.036\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChemotherapy\u003c/p\u003e \u003cp\u003eNo CTx\u003c/p\u003e \u003cp\u003eNeoadj. CTx\u003c/p\u003e \u003cp\u003eAdj. CTx\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e0.637\u003c/p\u003e \u003cp\u003e0.419\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.215\u0026ndash;1.888\u003c/p\u003e \u003cp\u003e0.213\u0026ndash;0.823\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.032\u003c/b\u003e\u003c/p\u003e \u003cp\u003e0.416\u003c/p\u003e \u003cp\u003e\u003cb\u003e0.012\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLocal recurrence\u003c/p\u003e \u003cp\u003eNo\u003c/p\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e2.765\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.655\u0026ndash;4.620\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDistant metastasis\u003c/p\u003e \u003cp\u003eNo\u003c/p\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003cp\u003e8.705\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.915\u0026ndash;15.418\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWound healing complications\u003c/p\u003e \u003cp\u003eNo\u003c/p\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.247\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.255\u0026ndash;4.021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.006\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eMean OS was 96 months (Range: 2\u0026ndash;192 months) with an estimated 10-year-overall-survival rate of 60% (CI 57\u0026ndash;64%). Within this timeframe, 77 (38%) people died, of which 48 (62%) were confirmed tumor-related deaths. The Log-Rank test and respectively the bivariate Cox-regression showed a significant correlation for several variables: staging (p\u0026thinsp;=\u0026thinsp;0.002), margin width (p\u0026thinsp;=\u0026thinsp;0.003), margin status, local recurrence, distant metastasis, radiotherapy, and chemotherapy (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 for each variable), tumor depth (p\u0026thinsp;=\u0026thinsp;0.032), wound-healing complications (p\u0026thinsp;=\u0026thinsp;0.002), duration of surgery (p\u0026thinsp;=\u0026thinsp;0.008), age at surgery (p\u0026thinsp;=\u0026thinsp;0,013) and tumor size (p\u0026thinsp;=\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003eAs with DMFS: if negative margins are achieved, there was no significant correlation between OS and the metrical margin width (p\u0026thinsp;=\u0026thinsp;0.458). Again, the examined risk factors obesity (p 0,889), high blood pressure (0,115) and smoking (0,863) did not appear to contribute to OS.\u003c/p\u003e \u003cp\u003eIn multivariate Cox-Analysis (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e) local recurrence (HR 2,765; 1,655\u0026ndash;4,620) and distant metastasis (HR 8,705; 4,915\u0026ndash;15,418) were identified as the worst prognostic factors decreasing chances of long-time survival by almost 3 and 9 times respectively. In addition, patients who received either adjuvant radio- (HR 0,482; CI 0,243\u0026ndash;0,954) or chemotherapy (HR 0,419, CI 0,213\u0026ndash;0,823) showed a superior outcome in terms of OS compared to those who did not receive adjuvant therapy. In contrast, both neoadjuvant radio- and chemotherapy demonstrated a trend but could not signigicantly improve OS. Wound healing complication was also identified as an independent prognostic factor for OS (HR 2,247; CI 1,255\u0026ndash;4,021). However, When LR was excluded from the Cox analysis, as was done when analyzing DMFS, resection margins and adjuvant radiotherapy gained a stronger influence (p\u0026thinsp;=\u0026thinsp;0.094 and 0.003, respectively) while adjuvant CTx remained almost unchanged.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eThere is a broad consensus on the fact that positive margins increase the risk of local recurrence (4\u0026ndash;13) and that radiotherapy can improve local control(25\u0026ndash;28). When it comes to an adequate resection margin, however, there is still some dissent. This is mostly due to the rarity of soft tissue sarcomas which only account for approximately 1% of new malignant neoplasms in adults. Hence, to reach enough cases, studies about STS often encompass heterogenous patient populations with varied tumor entities, grades and treatments across different institutions and therefore different surgeons, procedures and pathologists. Moreover, they integrate re-resections, whoops procedures, LR, and DM at presentation.\u003c/p\u003e \u003cp\u003eDickinson et al. categorized (5) 303 patients based on achieved surgical margins: contaminated, \u0026lt;1mm but clear, 1-4mm, 5-9mm and 10-19mm. They concluded that \u0026ldquo;the margin can safely be as narrow as 1mm in terms of low local recurrence rates\u0026rdquo;. However, their study did not consider critical factors such as tumor size and resection difficulty and included previously treated patients. Bilgeri et al. categorized all R0-patients, including those who presented with LR and DM, into four categories: \u0026lt;1mm, 1-5mm, 5-10mm and \u0026gt;\u0026thinsp;10mm and found that wider margins were associated with better outcomes up to 5mm, beyond which there was no significant improvement in LRFS and overall survival (10).\u003c/p\u003e \u003cp\u003eIn a broader pooled study population including patients with both low- and high-grade STS, McKee et al. demonstrated that those with microscopically positive margins and close negative margins (1\u0026ndash;9 mm) were at increased risk for LR and distant metastases compared to patients with clear margins measuring\u0026thinsp;\u0026ge;\u0026thinsp;10 mm. Having said this, the study is further limited by its low percentage of adjuvant radiotherapy (38%) and its inclusion of re-resections.(6) In the most selective study Fujiwara et al. were able to show that in a cohort composed only of patients with infiltrative STS, a surgical margin of greater than 10mm was associated with an improved LR-free survival.(9) Albeit these findings are limited because not all negative margins could retrospectively be sorted into the right category.(10) In a prospective study including all types of STS and previously treated patients, Sampo et al.(12) reported that the LRFS correlated with increasing surgical margin as far as 4cm and indicated that a surgical margin of 2-3cm provided \u0026ldquo;reasonable local control\u0026rdquo;.\u003c/p\u003e \u003cp\u003eConsistent with previous research, our findings demonstrated that negative margins are significantly superior to positive margins, with a hazard ratio (HR) of nearly 8 (HR 7.845; CI 3.984\u0026ndash;14.450). Adjuvant radiotherapy also played an important role in achieving local control, reducing the HR of local recurrence (LR) by more than threefold (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Additionally, our study showed a direct correlation between local recurrence-free survival (LRFS) and margin width (Figs.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and 2): larger surrounding non-reactive tissue in the tumor specimen was associated with longer LRFS. Radio- and chemotherapy, as well as tumor stage, were relatively evenly distributed among the subgroups. Patients with resection margins\u0026thinsp;\u0026gt;\u0026thinsp;5mm had the best 5-year LRFS at 93%, followed by those with margins of \u0026gt;\u0026thinsp;1-5mm at 76%. Our 5-year LRFS is slightly lower than most reports in the literature but aligns closely with studies focusing exclusively on high-grade soft tissue sarcomas (STS), particularly those examining wide resection margins (10,29). Notably, in our study, no LR occurred when the margin was \u0026gt;\u0026thinsp;5mm and adjuvant radiotherapy was applied, a result significantly superior to patients with margins\u0026thinsp;\u0026lt;\u0026thinsp;5mm and adjuvant radiotherapy (p\u0026thinsp;\u0026le;\u0026thinsp;0.023).\u003c/p\u003e \u003cp\u003eAge at surgery attained statistical significance in both uni- and multivariate analysis concerning LR, although it only slightly increased the HR. Duration of surgery, considered a composite measure of tumor characteristics such as size, depth, and stage, was significant in bivariate analysis, not aligning with expectations since individual tumor characteristics did not independently reach significance.\u003c/p\u003e \u003cp\u003eIt becomes apparent that there is more to predict LRFS than only metric treatment options. Proximity to vascular bundles, nerves or fascia has become a more critical decision-factor in recent years. Kawaguchi et al.(7) first suggested that certain barriers such as the above have a stronger resistance against STS infiltration than normal tissue. O\u0026rsquo;Donnell et al.(30) emphasized the impact of different clinical settings in patients with positive margins on LRFS and supported the practice of close dissection for the preservation of critical structures even when this leads to microscopically positive margins. They hypothesized that the infiltration of critical structures can hint to a more aggressive nature of the tumor in general. However, this must be weighed against the potential risk of proposing an untrue or falsely assessed surgical barrier which led to the worst 5-year LRFS in their study. Our findings support that the question of what constitutes adequacy should be considered in context but that there is a good chance of achieving local control when a resection margin of more than 5mm can be achieved, particularly when coupled with adjuvant radiotherapy, which is standard practice in most cases.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab6\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eOverview over the literature: resection margins and their impact on LR in STS patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNr. of patients\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eResection margin categories\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eImpact on LR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLimitations\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDickinson I.C. et al., ANZ J Surgery 2006\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e303\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eContaminated, \u0026lt;\u0026thinsp;1, 1\u0026ndash;4, 5\u0026ndash;9 and 10-19mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003emargin can safely be as narrow as 1mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIncluding re-resections, no respect to tumor size and difficulty of resection\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBilgeri A. et al., Cancers (Basel). 2020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e305\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eContaminated, \u0026lt;\u0026thinsp;1, 1\u0026ndash;5, \u0026gt;\u0026thinsp;5 and \u0026gt;\u0026thinsp;10mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eA margin of \u0026gt;\u0026thinsp;5mm is sufficient, wider margins do not benefit the patients\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIncluding re-resections; margin, tumor size and age are linked to RTx and CTx.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMcKee MD et al., J Surg Oncol. 2004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e111\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eContaminated, 1\u0026ndash;9 and \u0026gt;\u0026thinsp;10mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMargins\u0026thinsp;\u0026gt;\u0026thinsp;10mm are optimal for extremity resections\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIncluding low-grade STS and re-resections, low percentage of adj. RTx and CTx\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFujiwara T et al., Eur J Surg Oncol. 2020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e305\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eContaminated, 0.1\u0026ndash;0.9, 1.0-1.9, 2.0-4.9, 5.0-9.9 and \u0026gt;\u0026thinsp;10mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eA margin of \u0026gt;\u0026thinsp;10mm is advocated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003enot all negative margins could retrospectively be sorted into the right WHO-category\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKainhofer V et al., Eur J Surg Oncol. 2016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e265\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eUICC- and R-Classification\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eR0 resections are superior when classified according to the UICC-classification\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIncluding low and high-grade STS and re-resections; treatment for atypical liposarcomas changed during the second half\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGundle KR et al., J Clin Oncol. 2018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2217\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eR-Classification, R\u0026thinsp;+\u0026thinsp;1-Classification and TMCC classification\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAn R\u0026thinsp;+\u0026thinsp;1mm classification reduced LR-differences between R1 and R0, but the R-classification best determined the risk of LR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSingle-center study, treatment protocol has changed over the years; tumor sampling errors cannot be ruled out\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSampo M et al., Br J Surg. 2008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e270\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.4, 0.4-2.0, \u0026gt;\u0026thinsp;2.0mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eA surgical margin of 2-3cm provided reasonable local control, even without the use of radiotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIncluding low and high-grade STS as well as post radiation STS and patients who received amputation.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOur findings\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e207\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eContaminated, 0.1-1, \u0026gt;\u0026thinsp;1\u0026ndash;5 and \u0026gt;\u0026thinsp;5mm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eA margin of \u0026gt;\u0026thinsp;5mm is advised\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAnatomical boundaries could not be evaluated, treatment protocol has shifted over the years\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003e\u003cem\u003eR vs. UICC-Classification\u003c/em\u003e\u003c/p\u003e\u003cp\u003eIn 2016, Kainhofer et al. (4) initiated a discourse regarding the prognostic significance of various classifications of resection widths in patients with STS. They primarily focused on the R-classification as suggested by the American Joint Committee on Cancer (AJCC)(22) and the R\u0026thinsp;+\u0026thinsp;1 classification suggested by the International Union against Cancer (UICC)(31). Their results favored the UICC-classification. However, two years later, Gundle et al. (14) conducted a comparative assessment of both systems and determined that the R-classification was more adept at assessing the risk of local recurrence (LR) within a competitive risk framework. Our findings cautiously align with this perspective, as we observed no enhancement in LRFS with the R\u0026thinsp;+\u0026thinsp;1 (UICC) classification when juxtaposed with the traditional R-classification (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eWhile study results are relatively consistent on how resection width and margin status relate to LRFS, an association with DMFS remains questionable (13,19).\u003c/p\u003e \u003cp\u003eIt must be said that neither the present, nor one of the studies mentioned above demonstrate any statistically significant correlation between the quantitative resection margin and metastasis free survival, underscoring the necessity for further research into this topic. While this study could show that margin width and subsequently margin status were independent risk factors in univariate analysis, their significance waned in a multivariate setting. In contrast, adjuvant chemotherapy and LR had a decisive impact on DMFS: as shown in the LRFS-analyses, there is an inverse relationship between LR and resection width. Analyzing the present study, LR itself proves to be a significant predictor for DM but the causal association has been described as weak by Trovik et al.(13) before. The authors argue that since inadequate margins were the highest risk factor for LR, inadequate margins should also be a significant prognostic factor for DM in an analysis not including LR. However, the authors did not show this in their analysis. Upon removing LR from Cox regression analysis in the present study, margin status assumed critical importance (p\u0026thinsp;=\u0026thinsp;0.021), highlighting its role in influencing DMFS. Radiotherapy, while significant for LR, did not retain significance for DMFS, suggesting a nuanced interplay between treatment modalities and metastatic behavior in STS. Thus, the present study underlines that negative margins are vital in the prevention of both LR and DM Moreover, larger-scale studies investigating the interaction between surgical resection margins, (neo-)adjuvant therapy, and the biological properties of STS are imperative for devising effective treatment strategies aimed at prolonging DMFS\u003c/p\u003e \u003cp\u003eSimilarly, the impact of margin status on OS remains discussible. While a meta-analysis by Jang et al (11) and a recent study by Bilgeri et al.(10) concluded that margin status does affect OS, Jang et al. acknowledged several studies that showed contradictory results.(19,33\u0026ndash;35) However, they acknowledged the low number of participants in the mentioned studies. The latest by Chouliaras et al.(8) could not find any correlation either. In another approach, Willeumier et al. argued that due to the aggressive nature of high-grade STS and its decrease in the 5-year survival rate it is difficult to determine the effect of surgical margin on survival(29) and that the effect will manifest over a longer time on patients who escape early DM(11,26), which is why we set the endpoint for OS at 10 years. While margin status could not uphold its significance in a multivariate setting, the major prognostic factors for OS were LR and DM with a HR of 2,8 and 8,7, respectively. Given the pivotal role of both local recurrence (LR) and distant metastases (DM) as primary prognostic factors for overall survival (OS), it follows that margin status should significantly influence OS as well. Upon excluding LR and DM in a Cox-regression analysis with respect to OS, we observed that R1-resection emerged as a negative prognostic factor (p\u0026thinsp;=\u0026thinsp;0.045, HR 2.209). This underscored the importance of achieving negative margins to optimize OS Additionally, the findings in the present study suggest that adjuvant radiotherapy and chemotherapy can improve OS, highlighting the potential benefits of adjunctive therapies in enhancing survival outcomes. While specific details on adjuvant radiotherapy and chemotherapy were not collected in this study, optimizing the administration of these therapies akin to Schliemann et al(36) in R0-resected high-grade STS patients is important.\u003c/p\u003e \u003cp\u003eInterestingly, OS was influenced by wound-healing complications. However, these were mostly noted in patients with positive margins (42%) whereas in other subgroups, only around a fifth of the patients developed wound-healing complications (19%, 21%, 26%). Interestingly, we observed that OS was influenced by wound-healing complications, with a higher incidence noted in patients with positive margins (42%) compared to other subgroups (19%, 21%, 26%). This disparity may be attributed to several factors, including the advanced age of patients with positive margins, their tendency to receive less adjuvant therapy, and the larger average tumor size among patients with wound-healing complications as the tumor might have been in proximity of critical structures.\u003c/p\u003e \u003cp\u003e \u003cem\u003eLimitations of our study\u003c/em\u003e \u003c/p\u003e \u003cp\u003eWe acknowledge the following limitations in our study. There was an uneven distribution of patients receiving neo- or adjuvant chemotherapy within the subgroups, and the overall numbers were small. Additionally, exact histopathological resection margins were untraceable in 26 patients, limiting our analysis to 177 patients when grouped by resection width. However, when we analyzed by resection status, all 203 patients could be included. To minimize distortions, we established strict inclusion criteria. However, our cohort still included patients with various soft tissue sarcoma (STS) entities, and we could not account for anatomical barriers beyond the superficial or subfascial location of tumors.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e"},{"header":"5. Conclusions","content":"\u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eIn conclusion, the present study underlines the significance of achieving margins greater than 5 mm, preferably coupled with adjuvant radiotherapy. The highest 5-year local recurrence-free survival (LRFS) rate was observed in patients meeting these criteria. Moreover, the attainment of negative margins remains important for optimizing distant metastasis-free survival (DMFS) and overall survival (OS).\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e"},{"header":"Abbreviations","content":"\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.88235294117647%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eWHO\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"82.11764705882354%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eWorld health organization\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.88235294117647%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSTS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"82.11764705882354%\" valign=\"top\"\u003e\n \u003cp\u003eSoft tissue sarcoma\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.88235294117647%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eESMO\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"82.11764705882354%\" valign=\"top\"\u003e\n \u003cp\u003eEuropean Society of Medical Oncology\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.88235294117647%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eLR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"82.11764705882354%\" valign=\"top\"\u003e\n \u003cp\u003eLocal recurrence\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.88235294117647%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eDM\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"82.11764705882354%\" valign=\"top\"\u003e\n \u003cp\u003eDistant metastases\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.88235294117647%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eOS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"82.11764705882354%\" valign=\"top\"\u003e\n \u003cp\u003eOverall survival\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.88235294117647%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eGIST\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"82.11764705882354%\" valign=\"top\"\u003e\n \u003cp\u003eGastrointestinal-stroma tumors\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.88235294117647%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eDMFS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"82.11764705882354%\" valign=\"top\"\u003e\n \u003cp\u003eDistant-metasis-free survival\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.88235294117647%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eLRFS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"82.11764705882354%\" valign=\"top\"\u003e\n \u003cp\u003eLocal-recurrence-free survival\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.88235294117647%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eFNCLCC\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"82.11764705882354%\" valign=\"top\"\u003e\n \u003cp\u003eF\u0026eacute;d\u0026eacute;ration Nationale des Centres de Lutte Contre le Cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.88235294117647%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAdj.\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"82.11764705882354%\" valign=\"top\"\u003e\n \u003cp\u003eAdjuvant\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.88235294117647%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eNeoadj.\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"82.11764705882354%\" valign=\"top\"\u003e\n \u003cp\u003eNeoadjuvant\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.88235294117647%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eRTx\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"82.11764705882354%\" valign=\"top\"\u003e\n \u003cp\u003eRadiotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.88235294117647%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCTx\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"82.11764705882354%\" valign=\"top\"\u003e\n \u003cp\u003eChemotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.88235294117647%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eUICC\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"82.11764705882354%\" valign=\"top\"\u003e\n \u003cp\u003eInternational Union against Cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.88235294117647%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAJCC\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"82.11764705882354%\" valign=\"top\"\u003e\n \u003cp\u003eAmerican Joint Committee on Cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.88235294117647%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTMCC\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"82.11764705882354%\" valign=\"top\"\u003e\n \u003cp\u003eToronto margin context classification\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.88235294117647%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCI\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"82.11764705882354%\" valign=\"top\"\u003e\n \u003cp\u003eConfidence interval\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study protocol was approved by the regional ethics committee (reference no.:\u0026nbsp;2023-070-f-S).\u0026nbsp;All participants gave written informed consent.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe APC was funded by the Open Access Publishing Funds of the Westphalian Wilhelms University of Muenster\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization, N.D. and T.B.; methodology, J.M.S., N.D. and T.B.; software, J.M.S.; validation, G.G., N. D. and T.B.; formal analysis, N.D. and T.B.; investigation, J.M.S.; N.E.;resources, G.G.; data curation, J.M.S.; writing manuscript, J.M.S., N.E.; review and editing, N.D., T.B., A.L., N.E., M.D.; visualization, J.M.S.; supervision, N.D, T.B., A.R.; project administration, N.D.;\u003c/p\u003e"},{"header":"References","content":"\n\u003col\u003e\n\u003cli\u003eBernstein MJ. Limb-Sparing Treatment of Adult Soft-Tissue Sarcomas and Osteosarcomas. JAMA [Internet]. 1985 Oct 4 [cited 2022 Oct 17];254(13):1791\u0026ndash;4. Available from: https://jamanetwork.com/journals/jama/fullarticle/400790\u003c/li\u003e\n\u003cli\u003eEnneking WF, Spanier SS, Goodman MA. A System for the Surgical Staging of Musculoskeletal Sarcoma. Clin Orthop Relat Res. 1980;153:106ff. \u003c/li\u003e\n\u003cli\u003eGronchi A, Miah AB, Dei Tos AP, Abecassis N, Bajpai J, Bauer S, et al. Soft tissue and visceral sarcomas: ESMO\u0026ndash;EURACAN\u0026ndash;GENTURIS Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology [Internet]. 2021 [cited 2022 Oct 14];32:1348\u0026ndash;65. Available from: https://doi.org/10.1016/j.annonc.2021.07.006\u003c/li\u003e\n\u003cli\u003eKainhofer V, Smolle MA, Szkandera J, Liegl-Atzwanger B, Maurer-Ertl W, Gerger A, et al. The width of resection margins influences local recurrence in soft tissue sarcoma patients. European Journal of Surgical Oncology. 2016 Jun 1;42(6):899\u0026ndash;906. \u003c/li\u003e\n\u003cli\u003eDickinson IC, Whitwell DJ, Battistuta D, Thompson B, Strobel N, Duggal A, et al. SURGICAL MARGIN AND ITS INFLUENCE ON SURVIVAL IN SOFT TISSUE SARCOMA. ANZ J Surg [Internet]. 2006 Mar 1 [cited 2022 Oct 12];76(3):104\u0026ndash;9. Available from: https://onlinelibrary.wiley.com/doi/full/10.1111/j.1445-2197.2006.03615.x\u003c/li\u003e\n\u003cli\u003eMckee MD, Liu DF, Brooks JJ, Gibbs JF, Driscoll DL, Kraybill WG. The Prognostic Significance of Margin Width for Extremity and Trunk Sarcoma. J Surg Oncol [Internet]. 2004;85:68\u0026ndash;76. Available from: https://onlinelibrary.wiley.com/doi/10.1002/jso.20009\u003c/li\u003e\n\u003cli\u003eKawaguchi N, Ahmed AR, Matsumoto S, Manabe J, Matsushita Y. The Concept of Curative Margin in Surgery for Bone and Soft Tissue Sarcoma. Clin Orthop Relat . 2004;419:165\u0026ndash;72. \u003c/li\u003e\n\u003cli\u003eChouliaras K, Patel N, Senehi R, Ethun CG, Poultsides G, Grignol V, et al. Impact of resection margin on outcomes in high-grade soft tissue sarcomas of the extremity\u0026mdash;A USSC analysis. J Surg Oncol. 2021 Feb 1;123(2):479\u0026ndash;88. \u003c/li\u003e\n\u003cli\u003eFujiwara T, Stevenson J, Parry M, Tsuda Y, Tsoi K, Jeys L. What is an adequate margin for infiltrative soft-tissue sarcomas? European Journal of Surgical Oncology. 2020 Feb 1;46(2):277\u0026ndash;81. \u003c/li\u003e\n\u003cli\u003eBilgeri A, Klein A, Lindner LH, Nachbichler S, Kn\u0026ouml;sel T, Birkenmaier C, et al. The effect of resection margin on local recurrence and survival in high grade soft tissue sarcoma of the extremities: How far is far enough? Cancers (Basel). 2020 Sep 1;12(9):1\u0026ndash;13. \u003c/li\u003e\n\u003cli\u003eJang WY, Kim HS, Han I. Impact of surgical margin on survival in extremity soft tissue sarcoma: A systematic review and meta-analysis. Medicine [Internet]. 2021 Jan 1 [cited 2022 Oct 12];100(3):e24124. Available from: /pmc/articles/PMC7837970/\u003c/li\u003e\n\u003cli\u003eSampo M, Tarkkanen M, Huuhtanen R, Tukiainen E, B\u0026ouml;hling T, Blomqvist C. Impact of the smallest surgical margin on local control in soft tissue sarcoma. British Journal of Surgery [Internet]. 2008 Jan 14 [cited 2022 Oct 12];95(2):237\u0026ndash;43. Available from: https://academic.oup.com/bjs/article/95/2/237/6142608\u003c/li\u003e\n\u003cli\u003eTrovik CS, Bauer HCF, Alvega\u0026ecirc; Rd C TA, Anderson H, Blomqvist C, Berlin \u0026Egrave;, et al. Surgical margins, local recurrence and metastasis in soft tissue sarcomas: 559 surgically-treated patients from the Scandinavian Sarcoma Group Register. Eur J Cancer [Internet]. 2000;36:710\u0026ndash;6. Available from: www.ejconline.com\u003c/li\u003e\n\u003cli\u003eGundle KR, Kafchinski L, Gupta S, Griffin AM, Dickson BC, Chung PW, et al. Analysis of Margin Classification Systems for Assessing the Risk of Local Recurrence After Soft Tissue Sarcoma Resection. J Clin Oncol [Internet]. 2018 [cited 2022 Nov 2];36. Available from: https://doi.org/10.1200/JCO.2017.\u003c/li\u003e\n\u003cli\u003eSambri A, Caldari E, Fiore M, Zucchini R, Giannini C, Pirini MG, et al. Margin Assessment in Soft Tissue Sarcomas: Review of the Literature. Cancers (Basel) [Internet]. 2021 Apr 1 [cited 2024 Mar 4];13(7). Available from: https://pubmed.ncbi.nlm.nih.gov/33918457/\u003c/li\u003e\n\u003cli\u003eEilber FC, Rosen G, Nelson SD, Selch M, Dorey F, Eckardt J, et al. High-Grade Extremity Soft Tissue Sarcomas: Factors Predictive of Local Recurrence and its Effect on Morbidity and Mortality. Ann Surg [Internet]. 2003 Feb [cited 2022 Nov 25];237(2):218. Available from: /pmc/articles/PMC1522131/\u003c/li\u003e\n\u003cli\u003eStojadinovic A, Leung DHY, Hoos A, Jaques DP, Lewis JJ, Brennan MF. Analysis of the Prognostic Significance of Microscopic Margins in 2,084 Localized Primary Adult Soft Tissue Sarcomas. Ann Surg [Internet]. 2002 [cited 2022 Nov 25];235(3):424. Available from: /pmc/articles/PMC1422449/\u003c/li\u003e\n\u003cli\u003eGronchi A, Miceli R, Fiore M, Collini P, Lozza L, Grosso F, et al. Extremity soft tissue sarcoma: Adding to the prognostic meaning of local failure. Ann Surg Oncol. 2007 May;14(5):1583\u0026ndash;90. \u003c/li\u003e\n\u003cli\u003eGronchi A, Casali PG, Mariani L, Miceli R, Fiore M, Lo Vullo S, et al. Status of surgical margins and prognosis in adult soft tissue sarcomas of the extremities: A series of patients treated at a single institution. Journal of Clinical Oncology. 2005 Jan 1;23(1):96\u0026ndash;104. \u003c/li\u003e\n\u003cli\u003eKaytan Saglam E, Yaman Ağaoğlu F, Cosar R, Eralp Y. Prognostic Factors in Localized Soft-Tissue Sarcomas Article in. Am J Clin Oncol [Internet]. 2003 [cited 2023 Apr 19]; Available from: https://www.researchgate.net/publication/10626166\u003c/li\u003e\n\u003cli\u003eWHO Classification of Tumours Editorial Boar, WHO Classification of Tumours Editorial Board.Soft Tissue and BoneTumours.3. 5th ed. Lyon: IARC; 2020. Available athttps://publications.iarc.fr/588. Accessed May 1 2021. Soft Tissue and Bone Tumours WHO Classification of Tumours. 5th ed. WHO Classification of Tumours Editorial Board, editor. Vol. 3. 2020. \u003c/li\u003e\n\u003cli\u003eTunn PU, Kettelhack C, D\u0026uuml;rr HR. Standardized Approach to the Treatment of Adult Soft Tissue Sarcoma of the Extremities. In: Tunn PU, editor. Treatment of Bone and Soft Tissue Sarcomas [Internet]. Berlin, Heidelberg: Springer Berlin Heidelberg; 2009. p. 211\u0026ndash;28. Available from: https://doi.org/10.1007/978-3-540-77960-5_13\u003c/li\u003e\n\u003cli\u003eKaplan EL, Meier P. Nonparametric Estimation from Incomplete Observations. J Am Stat Assoc [Internet]. 1958 Jun 1;53(282):457\u0026ndash;81. Available from: https://www.tandfonline.com/doi/abs/10.1080/01621459.1958.10501452\u003c/li\u003e\n\u003cli\u003eCox DR. Regression Models and Life-Tables. Journal of the Royal Statistical Society: Series B (Methodological). 1972 Jan;34(2):187\u0026ndash;202. \u003c/li\u003e\n\u003cli\u003eDeLaney TF, Kepka L, Goldberg SI, Hornicek FJ, Gebhardt MC, Yoon SS, et al. Radiation Therapy for Control of Soft-Tissue Sarcomas Resected With Positive Margins. International Journal of Radiation Oncology*Biology*Physics. 2007 Apr 1;67(5):1460\u0026ndash;9. \u003c/li\u003e\n\u003cli\u003eGronchi A, Verderio P, De Paoli A, Ferraro A, Tendero O, Maj\u0026oacute; J, et al. Quality of surgery and neoadjuvant combined therapy in the ISG-GEIS trial on soft tissue sarcomas of limbs and trunk wall. Annals of Oncology. 2013;24(3):817\u0026ndash;23. \u003c/li\u003e\n\u003cli\u003eYang JC, Chang AE, Baker AR, Sindelar WF, Danforth DN, Topalian SL, et al. Randomized Prospective Study of the Benefit of Adjuvant Radiation Therapy in the Treatment of Soft Tissue Sarcomas of the Extremity. Vol. 16, J Clin Oncol. 1998. \u003c/li\u003e\n\u003cli\u003eRivera D. Long-Term Results of a Prospective Randomized Trial of Adjuvant Brachytherapy in So Tissue Sarcoma. 1996. \u003c/li\u003e\n\u003cli\u003eWilleumier J, Fiocco M, Nout R, Dijkstra S, Aston W, Pollock R, et al. High-grade soft tissue sarcomas of the extremities: surgical margins influence only local recurrence not overall survival. International Orthopaedics (SICOT). 2015;(39):935\u0026ndash;41. \u003c/li\u003e\n\u003cli\u003eO\u0026rsquo;donnell PW, Griffin AM, Eward WC, Sternheim A, Catton CN, Chung PW, et al. The Effect of the Setting of a Positive Surgical Margin in Soft Tissue Sarcoma. Cancer [Internet]. 2014 [cited 2024 Mar 4];120:2866\u0026ndash;75. Available from: https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.28793\u003c/li\u003e\n\u003cli\u003eWittekind C, Compton CC, Greene FL, Sobin LH. TNM residual tumor classification revisited. Cancer [Internet]. 2002 May 1 [cited 2022 Nov 4];94(9):2511\u0026ndash;6. Available from: https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.10492\u003c/li\u003e\n\u003cli\u003eGoldstein NS, Soman A, Sacksner J. Disparate surgical margin lengths of colorectal resection specimens between in vivo and in vitro measurements. The effects of surgical resection and formalin fixation on organ shrinkage. Am J Clin Pathol [Internet]. 1999 [cited 2024 Mar 4];111(3):349\u0026ndash;51. Available from: https://pubmed.ncbi.nlm.nih.gov/10078110/\u003c/li\u003e\n\u003cli\u003ePopov P, Tukiainen E, Asko-Seljaavaara S, Huuhtanen R, Virolainen M, Virkkunen P, et al. Soft tissue sarcomas of the lower extremity: Surgical treatment and outcome. European Journal of Surgical Oncology. 2000;26(7):679\u0026ndash;85. \u003c/li\u003e\n\u003cli\u003eTanabe KK, Pollock RE, Ellis LM, Murphy A, Sherman N, Romsdahl MM. Influence of Surgical Margins on Outcome in Patients with Preoperatively Irradiated Extremity Soft Tissue Sarcomas. [cited 2022 Oct 31]; Available from: https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/1097-0142\u003c/li\u003e\n\u003cli\u003eBonvalot S, Levy A, Terrier P, Tzanis D, Bellefqih S, Le Cesne A, et al. Primary Extremity Soft Tissue Sarcomas: Does Local Control Impact Survival? Ann Surg Oncol. 2017 Jan 1;24(1):194\u0026ndash;201. \u003c/li\u003e\n\u003cli\u003eSchliemann C, Kerkhoff A, Hesse P, Br\u0026ouml;ckling S, Hardes J, Streitb\u0026uuml;rger A, et al. Adjuvant chemotherapy\u0026mdash;Radiotherapy\u0026mdash;Chemotherapy sandwich protocol in resectable soft tissue sarcoma: An updated single-center analysis of 104 cases. PLoS One [Internet]. 2018 May 1 [cited 2023 May 9];13(5). Available from: /pmc/articles/PMC5963910/\u003c/li\u003e\n\u003cli\u003eAlbertsmeier M, Rauch A, Roeder F, Hasenh\u0026uuml;tl S, Pratschke S, Kirschneck M, et al. External Beam Radiation Therapy for Resectable Soft Tissue Sarcoma: A Systematic Review and Meta-Analysis. Ann Surg Oncol [Internet]. 2018 Mar 1 [cited 2024 Mar 4];25(3):754\u0026ndash;67. Available from: https://pubmed.ncbi.nlm.nih.gov/28895107/\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"soft-tissue sarcoma, resection margin, local recurrence, distant metastasis, overall survival","lastPublishedDoi":"10.21203/rs.3.rs-4808552/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4808552/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground:\u003c/h2\u003e \u003cp\u003eThe World Health Organization\u0026rsquo;s (WHO) classification of tumors contains around 80 entities of soft tissue sarcomas (STS). Till now surgery is the standard treatment for patients with localized STS but the adequacy of resection margins in soft tissue sarcomas (STS) remains a topic of intense discussion.\u003c/p\u003e\u003ch2\u003eMethods:\u003c/h2\u003e \u003cp\u003eThis single-center study retrospectively reviewed 203 patients with primary high-grade soft tissue sarcoma, including a follow-up period of at least 24 months unless a local recurrence occurred earlier (1-170 months). Patients with prior resection, secondary STS, metastasis at presentation or those who required amputational surgery were excluded from the study. Patients were categorized based on their margin thickness: positive (n\u0026thinsp;=\u0026thinsp;13, 6.4%), 0\u0026ndash;1 mm (n\u0026thinsp;=\u0026thinsp;67, 33.0%), 1\u0026ndash;5 mm (n\u0026thinsp;=\u0026thinsp;70, 34.5%), and \u0026gt;\u0026thinsp;5 mm (n\u0026thinsp;=\u0026thinsp;27, 13.3%).\u003c/p\u003e\u003ch2\u003eResults:\u003c/h2\u003e \u003cp\u003eA total of 64 out of 203 (31.5%) patients developed a local recurrence. The estimated 5-year local recurrence-free survival (LRFS) was 11.5% (CI 4\u0026ndash;25%) for positive margins, 58% (CI 51\u0026ndash;64%) for margins 0\u0026ndash;1 mm, 76% (CI 70\u0026ndash;81%) for margins\u0026thinsp;\u0026gt;\u0026thinsp;1\u0026ndash;5 mm, and 93% (CI 88\u0026ndash;98%) for margins\u0026thinsp;\u0026gt;\u0026thinsp;5 mm. No local recurrences occurred in patients with margins\u0026thinsp;\u0026gt;\u0026thinsp;5 mm and adjuvant radiotherapy. Margin status significantly influenced the development of distant metastasis and overall survival. Adjuvant radiotherapy improved both local control and overall survival.\u003c/p\u003e\u003ch2\u003eConclusions:\u003c/h2\u003e \u003cp\u003eTo minimize the risk of local recurrence (LR) and achieve near-complete local control, a resection margin greater than 5 mm should be attained. When adjuvant radiotherapy is applied, the likelihood of LR decreases even more. In scenarios where preserving critical structures is essential, a resection margin of less than 5 mm can be acceptable for ensuring local control. Achieving an R0 resection is imperative for ensuring distant metastasis-free survival and overall survival.\u003c/p\u003e","manuscriptTitle":"The impact of resection margins in primary resection of high grade soft tissue sarcomas: a single-center analysis of 203 patients","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-09-03 11:31:30","doi":"10.21203/rs.3.rs-4808552/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5884cbab-49c7-48d5-b8ab-6c66612ebd73","owner":[],"postedDate":"September 3rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-03-04T13:38:42+00:00","versionOfRecord":[],"versionCreatedAt":"2024-09-03 11:31:30","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4808552","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4808552","identity":"rs-4808552","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}