Should neoadjuvant radiotherapy be recommended for a localized soft‑tissue sarcoma with low‑ to intermediate‑Ki‑67, size >5 cm, deep to fascia, where clear surgical margins may be difficult?

Neoadjuvant Radiotherapy for Soft Tissue Sarcoma with Low to Intermediate Ki-67

For a localized soft tissue sarcoma >5 cm, deep to fascia, where clear surgical margins may be difficult, neoadjuvant radiotherapy at 50 Gy in 25 fractions is strongly recommended regardless of Ki-67 proliferation index, as the standard treatment algorithm is driven by tumor size, depth, and grade—not Ki-67 status. 1, 2

Treatment Algorithm Based on Tumor Characteristics

The decision for neoadjuvant radiotherapy should follow this hierarchy:

Primary Indications (Standard Treatment):

• Deep tumors >5 cm + intermediate-to-high grade (G2-3) → Neoadjuvant or adjuvant RT is standard 1
• Deep tumors >5 cm + low grade (G1) → RT should be discussed in multidisciplinary team, considering anatomical site and anticipated margin difficulty 1
• Borderline resectable tumors where negative margins are uncertain → Neoadjuvant RT strongly favored 1, 2

Ki-67 Does Not Alter This Algorithm: Ki-67 proliferation index is not mentioned in any major guideline (ESMO, SELNET, UK guidelines) as a decision point for radiotherapy 1. The treatment paradigm relies on tumor grade (histologic assessment), size, and depth—not proliferative markers 1.

Why Neoadjuvant Over Adjuvant in Your Scenario

For tumors where clear margins are anticipated to be difficult, neoadjuvant radiotherapy offers specific advantages:

• Smaller treatment volumes because the operative field is not yet contaminated, reducing normal tissue exposure 2, 3
• Better mitigation of R1 (microscopically positive) margins compared to postoperative RT 2
• Reduced long-term morbidity including lower rates of fibrosis, edema, pathological fractures, and joint stiffness 2, 3
• Facilitates limb-sparing surgery by potentially downsizing radiosensitive histologies (e.g., myxoid liposarcoma) 1, 4
• Lower total radiation dose (50 Gy preoperative vs. 60-66 Gy postoperative) due to better tumor oxygenation 2, 3

Standard Neoadjuvant Protocol

Dose and Fractionation:

• 50 Gy in 25-28 fractions (1.8-2 Gy per fraction) over 5-6 weeks 2, 1
• Alternative hypofractionated regimen: 50 Gy in 20 fractions (2.5 Gy per fraction) 2

Timing of Surgery:

• Perform definitive resection 4-8 weeks after RT completion to allow acute radiation effects to resolve while minimizing wound complications 2, 1

Post-Surgical Boost (if needed):

• R1 margins (microscopic positive): 16-18 Gy boost 2
• R2 margins (gross residual): 20-26 Gy boost 2
• Wide negative margins: No additional RT required 2

Critical Caveats and Pitfalls

Wound Complications: The primary trade-off of neoadjuvant RT is doubled risk of acute wound complications (35% vs. 17% with postoperative RT) 5, 3. Mitigate this by:

• Involving plastic surgery expertise for complex closures 1, 2
• Using modern IMRT techniques to reduce wound bed dose 2, 3
• Ensuring adequate 4-8 week interval between RT and surgery 2

When RT May Be Omitted:

• Compartmental resections that completely contain the tumor do not require RT 1, 2
• Truly superficial tumors <5 cm with wide margins achievable may be managed with surgery alone 1

Histology-Specific Considerations:

• Myxoid liposarcoma is highly radiosensitive and shows significant volume reduction with neoadjuvant RT, making it particularly suitable for this approach 1, 4
• Chemotherapy-insensitive subtypes (e.g., well-differentiated liposarcoma, clear cell sarcoma) should not receive neoadjuvant chemotherapy, but RT indications remain unchanged 1, 6

Multidisciplinary Requirements

Mandatory pre-treatment steps:

• Sarcoma multidisciplinary tumor board review involving pathology, radiology, surgery, and radiation oncology 1
• MRI of primary site to assess depth, resectability, and relationship to neurovascular structures 1, 6
• Chest CT for staging (pulmonary metastases) 1, 6
• Consider abdominal imaging for myxoid histologies due to unusual metastatic patterns 6

The decision must be made at a specialized sarcoma reference center, as inadvertent surgery outside expert centers leads to higher rates of positive margins and need for more aggressive adjuvant therapy 1.