Preoperative Radiotherapy Remains Standard of Care for Soft Tissue Sarcoma, New ESTRO-ASTRO Guideline Confirms

An updated international clinical practice guideline from the European Society for Radiotherapy and Oncology (ESTRO) and the American Society for Radiation Oncology (ASTRO) establishes preoperative conventionally fractionated radiotherapy followed by surgery as the preferred treatment sequence for adult soft tissue sarcoma (STS) of the extremities and trunk wall, while providing detailed new guidance on dosing, imaging, target delineation, and emerging combination approaches.¹

The guideline was published in Radiotherapy and Oncology and represents the most comprehensive update to radiotherapy standards for this disease since prior guidance issued in 2012 and a 2021 ASTRO clinical practice guideline. Driven by advances in imaging, delivery techniques, and a growing body of trial data, the update addresses 13 key clinical questions and was developed by a task force of 16 international experts across radiation oncology, medical physics, and radiation therapy.

ESTRO convened 13 European experts alongside 3 specialists from ASTRO to conduct a systematic review following PRISMA guidelines, drawing on PubMed and Cochrane Library literature published through December 2024, with select 2025 studies incorporated during drafting to ensure the manuscript reflects the most current evidence. The panel evaluated evidence across treatment indications, sequencing, planning, target volume delineation, dosing, adverse event assessment, and organ-at-risk dose guidance. Recommendations were graded by strength and evidence quality using the ASTRO Clinical Practice Guideline Methodology framework.

Key Findings: Preop Beats Postop, Boosts Are Out, and Subtype Matters

Preoperative radiotherapy is recommended over postoperative treatment due to its more favorable late toxicity profile. Specifically, it is associated with lower rates of fibrosis, lymphedema, and joint stiffness and with equivalent oncological outcomes. The standard preoperative dose remains 50 to 50.4 Gy delivered in daily fractions of 1.8 to 2 Gy over 5 to 6 weeks.

When looking at postoperative boosts after preoperative radiotherapy, the guideline explicitly states that a boost following R1 (microscopically positive margin) resection is not recommended, noting that "multiple series have demonstrated local recurrence rates comparable to those achieved after preoperative radiotherapy and resections with negative margins"—particularly when positive margins involve neurovascular structures or the periosteum.

Subtype-specific guidance is also addressed. Myxoid liposarcoma, due to its distinct radiosensitivity, warrants preoperative radiotherapy, with a dose reduction to 36 Gy in select patients considered investigational but potentially viable. Myxofibrosarcoma, given its infiltrative behavior, may require wider clinical target volume margins of up to 4 cm longitudinally. For patients with hereditary cancer predisposition syndromes such as Li-Fraumeni or other germline TP53-related syndromes, radiotherapy is not absolutely contraindicated, but risk-benefit evaluation is essential.

Immunotherapy and Hypofractionation Are Coming—but Not Yet

The SU2C-SARC032 randomized phase 2 trial, published in The Lancet in 2024, demonstrated a significant disease-free survival benefit from adding anti–PD-1 immunotherapy (pembrolizumab) to preoperative radiotherapy for high-grade undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma.² The trial marked a significant step in integrating immunotherapy into STS management and a potentially promising new treatment option. The ESTRO guideline acknowledges this as a meaningful step, though it stops short of incorporating immunotherapy into routine recommendations pending further evidence.

Similarly, preoperative hypofractionation, with regimens ranging from 2.85 Gy × 15 fractions to ultrahypofractionated 5 to 8 Gy × 5 fractions, has shown promising local control in prospective single-arm studies. But, until head-to-head comparisons with conventional fractionation are complete, including the highly anticipated Dutch randomized phase 2 trial (NCT04425967) comparing 25 × 2 Gy vs 14 × 3 Gy, hypofractionation cannot be considered standard of care. The concern is not tumor control but late normal tissue toxicity, which increases substantially with higher fractional and total doses.

Takeaways for STS Management

Despite significant advances in imaging, planning, and personalized approaches over the past decade, the core principles of radiotherapy for STS remain stable. What has changed is the precision with which those principles can be applied and the emerging evidence that combination strategies may meaningfully improve outcomes for selected patients. As the guideline notes, "multidisciplinary evaluation at expert sarcoma centers remains essential for determining the optimal treatment approach for each patient." Clinicians treating STS should view this update not as a departure from established practice, but as a sharper, better-evidenced roadmap for executing it.

References

1. Roohani S, Spałek MJ, Aggerholm-Pedersen N, et al. ESTRO clinical practice guideline on radiotherapy for adult soft tissue sarcoma of the extremities and trunk wall – endorsed by ASTRO. Radiother Oncol. Published online April 16, 2026. doi:10.1016/j.radonc.2026.111535
2. Mowery YM, Ballman KV, Hong AM, et al. Safety and efficacy of pembrolizumab, radiation therapy, and surgery versus radiation therapy and surgery for stage III soft tissue sarcoma of the extremity (SU2C-SARC032): an open-label, randomised clinical trial. Lancet. 2024;404(10467):2053-2064. doi:10.1016/S0140-6736(24)01812-9