Preoperative hypofractionated radiotherapy in soft tissue sarcomas: institutional experience and clinical implications

Highlights

• •Preoperative hypofractionated RT achieved excellent tolerance and local control.
• •Favorable pathological response observed in 66.7% of treated soft-tissue sarcomas.
• •Major wound complications occurred in 29.2%, comparable to conventional RT.
• •Functional outcomes (MSTS, TESS) confirmed preserved postoperative limb function.
• •Supports hypofractionated RT as safe, efficient, and function-sparing alternative.

Abstract

Background

Conventional preoperative radiotherapy (RT) with 50 Gy in 25 fractions improves local control in soft tissue sarcomas (STS) but entails prolonged treatment and high rates of wound complications. Hypofractionated regimens may offer a shorter, more patient-convenient alternative while maintaining comparable outcomes, although they are not yet standard.

Materials and methods

We conducted an observational study of a prospective cohort of 24 patients with localized STS of the extremities or superficial trunk treated with preoperative hypofractionated RT between December 2021 and January 2025. Two regimens were used: moderately hypofractionated RT (MHFRT, 42.75 Gy/15 fx) and ultra-hypofractionated RT (UHFRT, 30 Gy/5 fx). Outcomes included acute toxicity, wound complications, pathological response, local control, and postoperative limb function using the Musculoskeletal Tumor Society (MSTS) and Toronto Extremity Salvage Score (TESS) scales.

Results

The median age was 68 years, and median tumor size 11.6 cm. All patients completed RT without interruption. A favorable pathological response (≥90% necrosis and/or ≤ 10% viable tumor) was achieved in 66.7%. Grade 1–2 dermatitis occurred in 66.7%, with no grade ≥ 3 toxicity. Major wound complications developed in 29.2%. Median MSTS and TESS scores were 26/30 (86.7%) and 88%, respectively. At 18 months median follow-up, 1- and 2-year local control rates were 100%.

Conclusions

Preoperative hypofractionated RT demonstrated excellent tolerance, high pathological response, and outstanding local control with acceptable wound-complication rates. Functional outcomes were favorable, supporting hypofractionated RT as a safe, efficient, and function-preserving alternative for localized STS in experienced centers. These findings provide real-world evidence supporting shorter preoperative RT schedules as a feasible and function-preserving approach in multidisciplinary sarcoma care.

Introduction

Soft tissue sarcomas (STS) are rare, heterogeneous mesenchymal tumors that account for less than 1% of all adult malignancies and most commonly arise in the extremities and superficial trunk [1], [2]. Standard management for localized STS combines limb-sparing surgery with with radiotherapy (RT), achieving local control rates exceeding 85–90% while facilitating functional preservation [3], [4].

Preoperative RT offers several advantages over postoperative treatment, including more accurate target delineation, lower total dose (typically 50 Gy in 25 fractions), and reduced late toxicities. In the landmark randomized trial comparing preoperative and postoperative radiotherapy for extremity soft tissue sarcomas, O’Sullivan et al. reported a significantly higher rate of acute wound complications in the preoperative arm (35% vs 17%, p = 0.01), while demonstrating a reduction in late radiation-related morbidity compared with postoperative treatment [3]. Subsequent analyses by Davis et al. further characterized late toxicity and functional outcomes, reporting lower rates of long-term morbidity such as edema, fibrosis, and joint stiffness following preoperative radiotherapy (48.2% vs 31.5%, p = 0.07) [4].

In the last decade, there has been growing interest in hypofractionation, an approach that delivers higher doses per fraction in fewer sessions, offering potential logistical, economic, and patient-centered benefits. The feasibility and safety of preoperative hypofractionated RT in STS have been demonstrated in multiple prospective studies, showing wound complications and local control rates comparable to conventional fractionation [[5], [6], [7], [8], [9], [10], [11], [12]].

Moderately hypofractionated schedules, such as the HYPORT-STS trial (42.75 Gy in 15 fractions), have reported acceptable toxicity profiles and local control rates of 93% at 30 months [7]. Conversely, ultra-hypofractionated regimens (UHFRT), such as 30 Gy in five fractions, have yielded promising preliminary results, although variability remains regarding postoperative wound toxicity and other functional outcomes [8]. Despite encouraging data, major guidelines have not adopted preoperative hypofractionation as a standard of care or as an alternative, largely due to the lack of phase III randomized evidence [[13], [14]]. As a result, systematic implementation into clinical practice remains controversial. Current recommendations continue to favor conventional fractionation, mainly because of the limited number of comparative high-level studies confirming therapeutic equivalence.

Beyond oncological control and toxicity, functional preservation is a critical outcome in the multidisciplinary management of soft tissue sarcomas of the extremities. The combination of limb-sparing surgery and radiotherapy aims not only to achieve local control, but also to maintain optimal postoperative function and quality of life. To objectively evaluate these aspects, validated instruments such as the Musculoskeletal Tumor Society (MSTS) score and the Toronto Extremity Salvage Score (TESS) are routinely used to assess physician- and patient-reported functional outcomes after treatment [[15], [16], [17], [18], [19]]. However, evidence on functional recovery following preoperative hypofractionated RT remains limited, and few studies have systematically incorporated these scales into outcome analysis. The present study therefore also explores functional outcomes using these tools, providing real-world data on postoperative limb function after hypofractionated preoperative RT.

Therefore, generating additional clinical evidence is essential to clarify its safety, oncological efficacy, and tolerability, particularly in centers that have already implemented this approach within multidisciplinary teams. Evaluating short- and medium-term outcomes will help determine its viability as a therapeutic alternative and inform future inclusion in clinical guidelines.

The present study contributes to this objective by analyzing a single-center experience with preoperative hypofractionated RT in patients with STS, providing real-world data on acute toxicity, pathological response, local control, and functional outcome during follow-up.

Materials and methods

Study design

This single-center, descriptive, observational study was based on a prospective cohort of patients with histologically confirmed localized soft tissue sarcoma (STS) who received preoperative hypofractionated radiotherapy (RT) between December 2021 and January 2025 at Fundación Jiménez Díaz University Hospital, Madrid, Spain.

Objectives

To evaluate pathological response, safety (acute toxicity and wound complications), local control (LC), and postoperative functional outcome of preoperative hypofractionated RT in patients with localized soft tissue sarcomas of the extremities and superficial trunk treated at our institution.

Study population

Inclusion criteria:

• ●Age ≥ 18 years.
• ●Histologically confirmed diagnosis of localized STS in the extremities or superficial trunk.
• ●Absence of distant metastases at the time of diagnosis.
• ●Multidisciplinary tumor board indication for preoperative RT.
• ●Availability of complete clinical, surgical, and histopathological data.

Exclusion criteria:

• •Histologies other than conventional adult-type soft tissue sarcoma (e.g., gastrointestinal stromal tumors, desmoid-type fibromatosis, Kaposi sarcoma, dermatofibrosarcoma protuberans, Ewing/PNET) and primary bone sarcomas.
• •Primary sites outside the extremities or superficial trunk (e.g., retroperitoneal/visceral, uterine, head and neck).
• •Distant metastases at diagnosis.
• •Prior radiotherapy to the index field.
• •Contraindications to radiotherapy (e.g., pregnancy, high-risk connective tissue disorders).
• •Incomplete clinical, surgical, or pathological data, or postoperative follow-up shorter than 6 months (unless an early event such as recurrence or death occurred).

Treatment regimens

Two preoperative hypofractionated RT regimens were used:

• 1.Ultra-hypofractionated RT (UHFRT): 30 Gy in five consecutive daily fractions (6 Gy/fraction).
• 2.Moderately hypofractionated RT (MHFRT): 42.75 Gy in 15 fractions (2.85 Gy/fraction) over three weeks.

The choice of regimen was based on tumor size: UHFRT schedule was applied to tumors measuring ≤ 8 cm, while the MHFRT regimen was preferred for lesions ≥ 8 cm. The 8-cm cut-off used to guide fractionation selection was pragmatic and volume-driven rather than arbitrary. Tumor size directly influences clinical target volume (CTV) expansion and, consequently, overall treatment volumes and dose distribution. As a result, fractionation was adapted to maintain acceptable dose homogeneity and organ-at-risk constraints across different target sizes. This size-adapted approach is consistent with previously established volume-based radiotherapy principles, including those applied in RTOG 0630 [20].

All patients underwent a planning CT scan before treatment using appropriate immobilization devices depending on the tumor site to ensure a comfortable and reproducible daily setup. Target delineation was performed by fusing the planning CT images with contrast-enhanced MRI, including T1-weighted post-gadolinium and T2-weighted sequences. Contrast-enhanced T1-weighted images were primarily used to define viable gross tumor volume (GTV), while T2-weighted sequences were reviewed as complementary information to better assess tumor extent, particularly in cases with heterogeneous signal intensity, infiltrative growth patterns, or poorly defined tumor–muscle interfaces. T2-weighted imaging aided in the identification of subtle tumor extension not clearly distinguishable on T1-weighted images alone, contributing to a more comprehensive assessment of tumor boundaries while avoiding unnecessary inclusion of surrounding normal tissues.

The clinical target volume (CTV) included the macroscopic tumor volume with an additional longitudinal margin of 2–3 cm and a radial margin of 1–1.5 cm, adjusted as needed near critical structures. Longitudinal margin selection was adapted according to tumor size, with smaller margins preferentially applied in tumors ≤ 8 cm and larger margins in tumors > 8 cm, following volume-based principles consistent with those described in RTOG 0630. The planning target volume (PTV) was generated by applying a 0.5 cm isotropic expansion around the CTV. Treatment plans were generated using either three-dimensional conformal radiotherapy (3DCRT) or intensity-modulated radiotherapy (IMRT/VMAT), depending on dosimetric considerations. Radiotherapy was delivered using an AGILITY linear accelerator (Elekta, Stockholm, Sweden) with 6 and 10 MV photon beams, five days per week. Daily setup verification was performed using image-guided radiotherapy (IGRT) with kV cone-beam CT (CBCT) in combination with surface-guided radiotherapy (SGRT) using the AlignRT system (Vision RT Ltd., London, United Kingdom).

The interval between RT completion and surgery was determined by the multidisciplinary tumor board, typically ≥ 4th week post-RT, based on oncological safety and tissue recovery criteria.

Systemic therapy was administered in a small subset of patients according to multidisciplinary team recommendations, primarily based on histological subtype and tumor grade. Three patients received concurrent chemotherapy during preoperative radiotherapy due to high-grade histology and perceived high-risk disease. In all three cases, moderately hypofractionated schedules were selected, as tumor volumes exceeded 8 cm in maximum diameter. No patients treated with ultra-hypofractionated regimens received concurrent systemic therapy. Radiotherapy fractionation was selected independently of systemic treatment considerations.

Surgery and pathological response assessment

Limb-sparing surgery was performed ≥ 4 weeks after RT completion. Surgical margins were classified as R0 (negative), R1 (microscopically positive), and R2 (macroscopically positive). All surgical specimens were reviewed by experienced soft tissue pathologists. Pathological evaluation included assessment of resection margins and the extent of post-neoadjuvant treatment histologic changes, encompassing necrosis, hyalinization, fibrosis, hemorrhage, inflammatory and histiocytic responses, and residual viable tumor cellularity. Pathological response was categorized according to the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group (EORTC–STBSG) recommendations: favorable pathological response was defined as ≥ 90% tumor necrosis and/or ≤ 10% viable tumor in the resected specimen [21].

Toxicity and surgical complications

Acute toxicity was prospectively assessed through weekly clinical evaluations during RT and for four weeks after completion. Adverse events were graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.

A major wound complication was defined as any postoperative event requiring medical or surgical intervention – such as reoperation, prolonged wound care, or hospitalization for infection, dehiscence, or other wound-related issues. Complications were recorded from surgery to 3 months postoperatively, which is the standard window for assessing early wound events following preoperative RT.

Follow-up

Patients were regularly monitored in outpatient clinics according to the institutional protocols. Each visit included a systematic clinical evaluation and imaging with MRI and/or CT, depending on the tumor location and the clinical context.

Follow-up was calculated from the completion of the entire oncological treatment, defined as preoperative RT (with or without chemotherapy) followed by surgery, until the date of the last documented clinical evaluation.

Local control (LC) was defined as the absence of recurrence within the previously irradiated fields. Local control rates were estimated at 1 and 2 years after surgery based on the clinical and radiological data available at the end of follow-up.

Functional outcome assessment

Postoperative functional outcomes were assessed using the Musculoskeletal Tumor Society (MSTS, 1993) score and the Toronto Extremity Salvage Score (TESS), both validated instruments for limb function after surgery +/- radiotherapy in soft tissue sarcomas [[15], [16]]. The MSTS score (range, 0–30) was completed by the treating physician, evaluating pain, function, emotional acceptance, support, gait/manual dexterity, and mobility. The TESS questionnaire (range, 0–100%) was self-administered by the patients and reflected perceived ability to perform daily activities. Higher scores in both scales indicate better functional status. Assessments were performed at 3, 6, 9 and 12 months after surgery during routine clinical follow-up.

Ethical considerations

The study was approved by the Institutional Ethics Committee of Fundación Jiménez Díaz University Hospital and conducted in accordance with the Declaration of Helsinki. All patients provided informed consent for treatment and data use. Data were entered into an anonymized database compliant with Spanish data-protection laws (Organic Law 3/2018) and the EU General Data Protection Regulation (Regulation (EU) 2016/679).

Statistical analysis

Statistical analyses were performed using SPSS® version 26 (IBM Corp., Armonk, NY). A descriptive analysis of the clinical, histological, and treatment-related variables was conducted. Quantitative variables are expressed as median ± standard deviation for normally distributed data or as median and interquartile range (IQR) when not normally distributed. Qualitative variables were summarized using frequency tables with absolute values (n) and percentages (%).

Results

Patient and tumor characteristics

Between December 2021 and January 2025, 24 patients with localized soft tissue sarcomas (STS) of the extremities or trunk were treated with preoperative hypofractionated RT. The main clinical and demographic characteristics of the patients and tumors are summarized in Table 1.

Table 1.

Baseline patient and tumor characteristics. Data are presented as absolute numbers and percentages. Tumor grade was determined according to the FNCLCC (Fédération Nationale des Centres de Lutte Contre le Cancer) system.

Parameter	Results [n (%) or median (range)]
Male/Female	10 (41.7%) / 14 (58.3%)
Age (median, years)	68 (31–89)
Local Recurrence / Distant metastases	0 (0%) / 2 (8.3%)
Tumor location
− Lower limbs	17 (70.8%)
− Upper limbs	5 (20.8%)
− Trunk	2 (8.3%)
Histology
− Myxofibrosarcoma	6 (25%)
− Myxoid liposarcoma	5 (20.3%)
− Well-differentiated liposarcoma	4 (16.7%)
− Dedifferentiated liposarcoma	1 (4.2%)
− Leiomyosarcoma	1 (4.2%)
− Undifferentiated pleomorphic sarcoma	1 (4.2%)
− Synovial sarcoma	1 (4.2%)
− Clear cell sarcoma	1 (4.2%)
− Other histologic subtypes	4 (16.7%)
Tumor size, median (cm) (range)	11.6 (6–14)
Tumor grade
− G1	7 (29.2%)
− G2	12 (50%)
− G3	4 (16.7%)
Preoperative chemotherapy
− Yes	3 (12.5%)
− No	21 (87.5%)
Surgical margins
− R0	17 (70.8%)
− R1	5 (20.3%)
− R2	2 (8.3%)

The median age was 68 years (range, 31–89 years), with 14 women (58.3%) and 10 men (41.7%). The median tumor size was 11.6 cm (range, 6–14 cm). The most common tumor site was the lower extremity (n = 17, 70.8% of cases). All patients presented with localized disease and subsequently underwent curative-intent surgery after radiotherapy. Histologically, multiple sarcoma subtypes were represented, with myxofibrosarcoma being the most common. The distribution of histological subtypes and grades according to the FNCLCC classification is illustrated in Fig. 1, showing a predominance of grade 1 and 2 tumors, consistent with low-to-moderate biological aggressiveness. This pattern may partly explain the high local control rates observed, as intermediate-grade sarcomas are typically more responsive to RT and have lower metastatic potential than high-grade sarcomas.

Fig. 1.

Distribution of histologic subtypes according to FNCLCC grade. Each bar represents the number of patients for each histologic subtype, color-coded according to the FNCLCC grading system (Grade 1 = orange; Grade 2 = light blue; Grade 3 = green. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Radiotherapy regimens

Among the 24 patients, 18 (75%) received moderately hypofractionated RT (MHFRT) of 42.75 Gy in 15 fractions, and six patients (25%) were treated with ultra-hypofractionated RT (UHFRT) of 30 Gy in five fractions. All patients completed the planned course of RT without any delays or interruptions. The median interval between RT completion and surgery was 7 weeks (range, 4–8). Three patients received concurrent chemotherapy with epirubicin and ifosfamide.

Pathological response

A favorable pathological response (fPR) was observed in 16 patients (66.7%). Among them, three patients (12.5%) achieved a pathological complete response (pCR). When comparing the regimens, no statistically significant differences were found between the groups.

• ●MHFRT: 13/18 patients (72.2%) achieved fPR.
• ●UHFRT: 3/6 patients (50%) achieved fPR.

These findings suggest that hypofractionated regimens may be effective in inducing tumor regression, although the limited sample size precludes definitive comparative conclusions.

Acute toxicity

A total of 16 patients (66.7%) experienced grade 1–2 radiation dermatitis, mainly erythema, dry desquamation, or mild exudation, all successfully managed with topical treatment. Five patients (31.2% of those with dermatitis) reported mild pain (grade 1), which was adequately controlled with first-line analgesics. No grade ≥ 3 acute skin toxicity was reported. Overall, these data indicate excellent tolerance to hypofractionated RT.

Surgical wound complications

Seven patients (29.2%) developed major wound complications that required medical or surgical intervention. The documented events included wound dehiscence requiring reoperation (n = 2), prolonged wound care (n = 3), and postoperative infection requiring hospitalization and intravenous antibiotics (n = 2 patients).

Despite these complications, wound healing delays did not interfere with oncologic follow-up or adjuvant treatment initiation. These results indicate that although local wound issues were not uncommon, they were manageable within a multidisciplinary setting and did not compromise the therapeutic course (Table 2).

Table 2.

Acute radiation-related toxicity (CTCAE v5) and postoperative surgical wound complications.

Acute radiation-related toxicity (CTCAE v5)
Toxicity	CTCAE v5 grade	No. of patients (%)
Radiation dermatitis	Grade 1–2	16 (66.7%)
Radiation dermatitis	Grade ≥ 3	0 (0%)
Pain	Grade 1	5 (31.2%)
Pain	Grade ≥ 2	0 (0%)
Postoperative surgical wound complications*
Complication	No. of patients (%)
Any major wound complication	7 (29.2%)
Wound dehiscence requiring reoperation	2 (8.3%)
Prolonged wound care	3 (12.5%)
Postoperative infection requiring hospitalization and IV antibiotics	2 (8.3%)

^*Surgical wound complications are reported descriptively and are not classified according to CTCAE v5.

Local control

With a median follow-up of 18 months (range, 3–38 months), local control (LC) at 1 and 2 years was 100%. No local recurrences were documented during the observation period. Two patients (8.3%) developed distant (pulmonary) metastases without impact on local control. At the time of analysis, no deaths had occurred in the cohort, further supporting the excellent early oncologic outcomes of preoperative hypofractionated RT in this cohort.

Functional outcomes

Functional evaluation was available for 20 of 24 patients (83%). The median MSTS score was 26/30 (range 24–28), corresponding to 86.7% functional preservation. The median TESS score was 88% (range 80–92), consistent with good self-reported functional recovery. No significant differences were observed between patients treated with moderately (MHFRT) versus ultra-hypofractionated (UHFRT) regimens. Patients who experienced major wound complications had slightly lower functional scores (median MSTS 24 vs 27, p = 0.09).

Discussion

The results of this study suggest that preoperative hypofractionated radiotherapy (HFRT), either with moderately or ultra-hypofractionated schedules, may represent a safe and effective alternative to conventional fractionation in patients with localized soft tissue sarcomas (STS) of the extremities and trunk.

The favorable pathological response rate (66.7%) observed in this series lies within the upper range reported in the literature, comparable to the 61.1% described by Montero et al. using 52.5 Gy in 15 fractions [5]. These findings are consistent with the hypothesis that soft tissue sarcomas are thought to have a relatively low α/β ratio [22], estimated to range from approximately 0.5 to 5.4, which renders them more responsive to higher doses per fraction. This radiobiological characteristic provides a plausible rationale for the use of hypofractionated regimens in this setting. In this context, higher per-fraction doses may enhance antitumor effects while maintaining acceptable normal-tissue toxicity, particularly when modern image-guided techniques and meticulous treatment planning are employed, as demonstrated in this study and in previously published reports [[5], [7], [9], [10], [11], [12]]. Nonetheless, this approach requires careful treatment planning and close monitoring to minimize the risk of complications in adjacent critical tissues.

In terms of safety, acute skin toxicity was mild in all cases, with no grade ≥3 events and grade 1–2 dermatitis occurring in 66.7% of patients. These results align with those of Guadagnolo et al. [7] and Kalbasi et al. [10], who reported similar tolerability with 42.75 Gy/15 fractions and 30 Gy/5 fractions, respectively. Excellent tolerance can be attributed not only to the fractionation schedule but also to the use of advanced RT techniques, such as IMRT or VMAT, which provide optimal dose conformity and sparing of surrounding normal tissues, supported by image guidance [20].

Importantly, major wound complications have also been reported in the context of hypofractionated preoperative radiotherapy. In a phase II trial of ultra-hypofractionated preoperative radiotherapy, Kalbasi et al. [10] reported major wound complication rates comparable to those historically described with conventional preoperative regimens. More recent institutional series have similarly shown acceptable rates of major wound complications following hypofractionated preoperative radiotherapy.

In the present study, the 29.2% rate of major wound complications is comparable to the 31% reported in the HYPORT-STS trial [7] and falls within the 24–42% range observed in other hypofractionated series [[5], [6], [9], [10], [11], [12]]. These findings suggest that the risk of major postoperative wound complications with hypofractionated preoperative radiotherapy is not higher than that associated with conventional fractionation, provided that adequate surgical timing (4–6 weeks after radiotherapy), careful patient selection, and appropriate reconstructive techniques are applied. Maintaining a balance between oncological efficacy and postoperative recovery is essential for the successful integration of hypofractionated preoperative radiotherapy into multidisciplinary sarcoma care.

The 100% 1- and 2-year local control rate is remarkable, exceeding the 85–95% typically reported with conventional preoperative RT [3], [4]. This may be explained by the biologically equivalent or even superior doses delivered by both hypofractionated regimens, achieving EQD2 values ≥49 Gy, which are comparable to the standard 50 Gy in 25 fractions [3], [4]. Comparable outcomes have been reported by Kalbasi et al. and Mayo et al., both showing LC rates above 94% at 2 years with 30 Gy/5 fractions regimens [10], [11].

Regarding patients with close or microscopically positive margins (R1/R2), no systematic radiotherapy boost was administered. Boost indication was individually discussed within the multidisciplinary tumor board, carefully weighing potential oncological benefit against the risk of increased toxicity. In the preoperative setting, particularly under hypofractionated regimens, the role of a boost is not well established and lacks robust supporting evidence. Moreover, in several cases with large tumors, the involved margins were adjacent to critical neurovascular structures, where dose escalation could have resulted in unacceptable morbidity. Therefore, a conservative approach was adopted, prioritizing functional preservation and toxicity avoidance.

Regarding functional outcomes, postoperative limb function in our cohort was systematically evaluated using both the Musculoskeletal Tumor Society (MSTS) and Toronto Extremity Salvage Score (TESS) scales [[15], [16]]. The median scores indicated satisfactory postoperative function, comparable to those reported in previous series using conventional preoperative RT [[17], [18]]. These findings support that hypofractionated preoperative radiotherapy does not compromise limb function or functional recovery when combined with limb-sparing surgery in multidisciplinary sarcoma care.

Exploratory analyses were performed to evaluate the relationship between key clinical and treatment-related variables and oncological outcomes, including age, sex, tumor size, anatomical location, histological subtype, delivered BED, surgical margins, and use of systemic therapy. Given the limited sample size, no formal statistical comparisons were conducted, and findings should be interpreted descriptively.

Overall, no clear differences in local control or early toxicity outcomes were observed across subgroups defined by age, sex, or tumor location. Larger tumor size and higher-grade histologies were more frequently associated with the use of moderately hypofractionated regimens, reflecting institutional selection criteria rather than differential oncological outcomes. Similarly, variations in delivered BED did not appear to translate into clinically meaningful differences in early local control within the available follow-up.

Patients with microscopically positive margins did not demonstrate an excess of local failures during the observation period, although longer follow-up is required to confirm the durability of these findings. The limited number of patients receiving concurrent systemic therapy precluded meaningful assessment of its impact on oncological outcomes.

Taken together, these observations suggest that the favorable local control and toxicity profiles observed in this cohort were consistent across a range of clinical and treatment-related variables. However, the exploratory nature of these analyses and the relatively short follow-up warrant cautious interpretation and underscore the need for prospective studies with larger patient populations.

As summarized in Table 3, the outcomes observed in the present study are consistent with those reported in other institutional series, showing comparable pathological response, wound complications, and local control rates. The present series reinforces the growing evidence supporting the feasibility, safety, and efficacy of preoperative HFRT for STS. The data support its consideration as a valid treatment option, particularly in centers where optimizing treatment time and resources is a clinical priority, without compromising oncological outcomes. Despite these encouraging results, HFRT is not yet considered the standard of care. Recent reviews and expert consensus statements emphasize the need for randomized evidence directly comparing hypofractionated and conventional RT schedules [[13], [14]]. The ongoing multicenter randomized phase II SCOPES trial (NCT04425967), led by Rick Hass, is comparing conventional 50 Gy in 25 fractions versus 42 Gy in 14 fractions of preoperative RT in extremity, trunk, and head-and-neck STS. In addition to SCOPES, other ongoing prospective clinical trials are currently evaluating preoperative hypofractionated radiotherapy in soft tissue sarcomas. Notably, the phase II HYPOSARC trial (NCT06022159), entitled “A Study to Evaluate Pre-operative Hypofractionated Radiation Therapy in Aged (≥70 Years) or ‘Fragile’ (≥65 Years) Patients with Limb or Trunk Soft Tissue Sarcoma,” is highly relevant to the present study, as it investigates short-course preoperative radiotherapy regimens and clinically meaningful endpoints in a vulnerable patient population. The results of this and other ongoing trials will be critical to further define the role of hypofractionated preoperative radiotherapy in routine clinical practice [[23], [24], [25]].

Table 3.

Summary of published studies evaluating preoperative hypofractionated radiotherapy in soft-tissue sarcomas. Only studies employing similar total doses and fractionation schedules (moderately and ultra-hypofractionated) were included for comparison.

Author (year)	Study design / n	Regimen (Gy/fx)	Pathologic response	Major wound complications	≥ G3 acute toxicity	Local control	Comments
Kalbasi et al., 2020.	Phase II, prospective (n = 50)	30 Gy / 5 fx	Not reported	32%	0%	94% (2 yr)	Benchmark ultra-HFRT trial; surgery within 0–7 days
HYPORT-STS (Guadagnolo et al., 2022).	Phase II, prospective (n = 120)	42.75 Gy / 15 fx	Not reported	31%	0%	93% (30 mo)	Moderate HFRT; multicenter U.S. trial
Bedi et al., 2022.	Phase II, prospective (n = 32)	30 Gy / 5 fx	≥ 50% necrosis in 41%	25%	Not reported	100% (1 yr)	Ultra-HFRT; immediate surgery (median 7 days)
Montero et al., 2023.	Prospective (n = 18)	52.5 Gy / 15 fx	61.1%	38.8%	0%	100% (14 mo)	Institutional experience; moderate HFRT
Mayo et al., 2023.	Retrospective (n = 22)	30 Gy / 5 fx	Not reported	41%	0% acute / 18.2% late	100% (2 yr)	UHFRT; heterogeneous histologies
Current series (2025).	Prospective observational (n = 24)	30 Gy / 5 fx or 42.75 Gy / 15 fx	66.7%	29.9%	0%	100% (1–2 yr)	Comparable outcomes; functional assessment (MSTS, TESS)

Our results may contribute to ongoing clinical and translational efforts aimed at optimizing sarcoma radiotherapy by integrating shorter, patient-centered preoperative RT schedules that enhance treatment efficiency without compromising functional outcomes.

Limitations

This study had several limitations. First, its single-center, observational design and the lack of randomization may introduce selection bias, and limit direct comparisons with conventional RT. Second, the small sample size (n = 24) restricts the statistical power of the findings. Third, the heterogeneity of histological subtypes and tumor grades may influence the treatment response, as radiosensitivity varies among sarcoma types.

A small number of patients received concurrent chemotherapy, exclusively within the moderately hypofractionated group and in the context of large, high-grade tumors. Although this may represent a potential confounding factor, the limited number of cases and their restriction to a single treatment group preclude meaningful comparative analysis.

Moreover, the median follow-up of 18 months, although sufficient for early toxicity and local control assessment, is short for evaluating late effects and long-term recurrence rates.

Finally, RT-regimen selection (moderate vs ultra-hypofractionation) was based on clinical factors such as tumor size and logistical considerations, potentially introducing selection bias and limiting intergroup comparisons.

These limitations underscore the need for prospective, controlled, multi-institutional studies with longer follow-up periods to validate and consolidate the present findings.

Conclusions

Preoperative hypofractionated radiotherapy (moderate or ultra-hypofractionated) for soft-tissue sarcomas of the extremities and trunk demonstrated excellent tolerance, a high rate of favorable pathological response, and outstanding 1–2 years local control in this institutional series.

Acute skin toxicity was mild in all cases, and the incidence of major wound complications remained within the expected range of conventional regimens. These findings support the radiobiological equivalence of hypofractionated and conventional schedules, providing adequate tumor control without increasing toxicity. However, the lack of randomization, small cohort size, and limited follow-up, preclude definitive conclusions regarding the therapeutic equivalence. Further prospective controlled trials with extended follow-up are warranted to better characterize late effects, functional outcomes, and quality of life.

In conclusion, preoperative HFRT appears to be safe, efficient, and promising alternative for STS management, particularly in experienced multidisciplinary centers seeking to optimize treatment delivery while maintaining oncologic excellence. Functional assessment using MSTS and TESS scales showed satisfactory postoperative limb preservation, comparable to outcomes reported with conventional preoperative RT. These results support that hypofractionated regimens preserve functional integrity while achieving excellent tumor control.

Conflict of interest

The authors declare that they have no known competing financial interest or personal relationships that could have appeared to influence the work reported in this paper.

Ethical approval

This study was approved by the Institutional Ethics Committee of Fundación Jiménez Díaz University Hospital and conducted in accordance with the Declaration of Helsinki. All patients provided informed consent for treatment and data use.

Author contributions

LG-G and IA conceived and designed the study. LG-G collected and analyzed the data. CM, JMB, NH, JAM-G, CVM, CGM, FLO, and LDC contributed to patient management and data interpretation. CMC-G assisted with data curation. LG-G drafted the manuscript, which all authors reviewed and approved.

Funding

This research did not receive any specific grants from funding agencies in the public, commercial or not-for-profit sectors.

Data availability

The datasets generated and analyzed during this study are not publicly available due to patient privacy regulations but may be obtained from the corresponding author upon reasonable request, in compliance with institutional and GDPR policies.