For an adult with a large, high‑grade, borderline resectable primary peritoneal sarcoma and good performance status, when is neoadjuvant (pre‑operative) radiotherapy indicated and what are its advantages and disadvantages?

Preoperative Radiotherapy for Peritoneal Sarcoma: Indications and Trade-offs

For large, high-grade, borderline resectable primary peritoneal sarcomas, neoadjuvant radiotherapy should be considered as part of multimodality treatment, though the evidence supporting routine use is controversial and the decision must weigh theoretical advantages against proven lack of survival benefit in the only randomized trial. 1

When Neoadjuvant Radiotherapy Is Indicated

Borderline resectable tumors are the primary indication for considering preoperative radiotherapy in peritoneal/retroperitoneal sarcomas. 1 The UK guidelines specifically recommend preoperative treatment with chemotherapy and/or radiotherapy for patients with borderline resectable tumors depending on histology. 1

Specific Clinical Scenarios Favoring Neoadjuvant RT:

• Large tumors (>5 cm) where downsizing may facilitate complete resection with preservation of critical structures 1, 2
• High-grade (intermediate or high-grade) histology where local control is paramount 1, 3
• Radiosensitive subtypes, particularly myxoid liposarcoma, where significant tumor shrinkage is expected 1
• Situations where R0 resection appears unlikely without preoperative treatment 1

Technical Parameters When RT Is Used:

• Dose: 50 Gy in 25-28 fractions (1.8-2 Gy per fraction) delivered over 5-6 weeks 4
• Surgery timing: 4-8 weeks after completion of radiotherapy 4
• Advanced techniques (IMRT, image-guided RT, or proton therapy) should be employed when available 1

Advantages of Neoadjuvant Radiotherapy

Theoretical and Demonstrated Benefits:

• Defined tumor target with better visualization on imaging compared to postoperative surgical bed 1
• Displacement of adjacent bowel away from the radiation field, reducing gastrointestinal toxicity 1
• Potential reduction in tumor seeding at the time of surgery 1
• May render borderline resectable tumors more amenable to complete resection, particularly in radiosensitive histologies 1
• Lower total radiation dose required (50 Gy preoperatively vs 60-66 Gy postoperatively) 1, 4
• Smaller treatment volumes compared to postoperative radiotherapy 4

Supporting Evidence:

Two small prospective studies showed favorable 5-year outcomes after neoadjuvant RT: local recurrence-free survival of 60%, disease-free survival of 46%, and overall survival of 61% following R0/R1 resection. 1, 3 A meta-analysis of 11 studies indicated lower local recurrence rates with neoadjuvant versus adjuvant RT (OR 0.03, P=0.02). 1

Disadvantages and Limitations of Neoadjuvant Radiotherapy

Critical Evidence Against Routine Use:

The EORTC-62092 (STRASS) trial—the only large randomized phase III study—failed to demonstrate benefit. 1 In 266 patients with primary retroperitoneal sarcoma, neoadjuvant RT plus surgery showed median abdominal recurrence-free survival of 4.5 years versus 5 years with surgery alone (HR 1.01, P=0.95). 1

Acute and Perioperative Complications:

• High rate of severe acute toxicity: Grade 3-4 lymphopenia (77%), anemia (12%), and hypoalbuminemia (12%) in the STRASS neoadjuvant RT group 1
• Increased wound healing complications compared to surgery alone 1
• Potential for tumor progression during radiotherapy in less radiosensitive histologies 1
• Treatment delays of 5-6 weeks for RT delivery plus 4-8 weeks recovery before surgery 4

Long-term Toxicity Concerns:

• Risk of bowel toxicity remains significant despite modern techniques, given proximity of normal bowel to peritoneal tumors 1
• Late effects including renal dysfunction, cardiac effects, and fertility issues may occur 1

Evidence Quality Issues:

The STRASS trial has been criticized for: composite primary endpoint definitions, lack of R0 vs R1 resection reporting, higher toxicity than expected (possibly related to 65% protocol compliance), and study design limitations. 1 However, it remains the highest-quality randomized evidence available. 1

Current Guideline Recommendations

NCCN guidelines state that neoadjuvant RT is favored over adjuvant RT IF radiation is being considered, but emphasize this applies only to "highly selected cases" as part of multimodality therapy. 1 The panel generally discourages adjuvant RT for retroperitoneal/intra-abdominal sarcomas except where local recurrence would cause undue morbidity. 1

UK guidelines recommend preoperative radiotherapy for borderline resectable tumors depending on histology, with a dose of 50 Gy preoperatively. 1

Post-hoc Analysis Suggesting Potential Benefit:

Exploratory analysis of STRASS data suggested neoadjuvant RT may be favorable for certain patients with liposarcoma and may reduce local recurrence risk in selected subgroups. 1 This requires prospective validation. 1

Clinical Decision Algorithm

1. Confirm diagnosis with core needle biopsy before any treatment 5
2. Assess resectability at multidisciplinary sarcoma tumor board 5
3. If clearly resectable with anticipated negative margins: Proceed directly to surgery; RT is not routinely indicated 1
4. If borderline resectable:
   • Consider neoadjuvant RT (50 Gy/25-28 fractions) for liposarcoma or other radiosensitive histologies 1
   • Consider neoadjuvant chemotherapy ± RT for chemosensitive subtypes (synovial sarcoma, leiomyosarcoma) 1
   • Weigh risk of progression during RT against potential for improved resectability 1
5. If unresectable: RT may be used as primary treatment 1

Critical Pitfalls to Avoid

• Do not use RT as a substitute for adequate surgical resection—surgery with appropriate margins remains the cornerstone of treatment 1
• Do not routinely recommend neoadjuvant RT based solely on tumor size or grade—the STRASS trial showed no overall benefit 1
• Do not delay surgery excessively in non-radiosensitive histologies where progression risk is high 1
• Do not use adjuvant RT routinely—if RT is indicated, neoadjuvant approach is strongly preferred due to defined target and bowel displacement 1
• Ensure treatment at a specialized sarcoma center with experienced multidisciplinary team 1, 5