What is the recommended chemotherapy regimen for an adult with a retroperitoneal soft‑tissue sarcoma that is not immediately resectable or has high‑risk features?

Chemotherapy for Retroperitoneal Soft Tissue Sarcoma

For adults with high-risk retroperitoneal soft tissue sarcoma, neoadjuvant chemotherapy with doxorubicin plus ifosfamide (or doxorubicin plus dacarbazine for leiomyosarcoma) should be considered, though the evidence remains uncertain and is currently being evaluated in the ongoing STRASS II trial. 1

Current Evidence and Limitations

The role of chemotherapy in retroperitoneal sarcoma differs substantially from extremity sarcomas, and it is unclear if conclusions from extremity sarcoma trials are applicable to retroperitoneal/intra-abdominal sarcomas. 1

Key Evidence Gaps:

• Most randomized trials demonstrating chemotherapy benefits have focused on extremity and trunk wall sarcomas, not retroperitoneal tumors 1
• The STRASS II trial (NCT04031677) is specifically evaluating neoadjuvant chemotherapy in high-risk retroperitoneal sarcoma and will randomize 250 patients 1
• Current evidence is limited to retrospective data suggesting potential benefit in high-grade histologies and borderline resectable disease 2

Histology-Tailored Approach

The chemotherapy regimen should be modified based on histologic subtype: 1

For Leiomyosarcoma:

• Doxorubicin plus dacarbazine is the preferred regimen 1
• Leiomyosarcoma shows association with improved outcomes from combination chemotherapy in metastatic settings 1

For Dedifferentiated Liposarcoma and Other High-Grade Sarcomas:

• Doxorubicin plus ifosfamide is the standard regimen 1
• This represents the most promising chemotherapy combination for localized soft tissue sarcomas 3

For Well-Differentiated Liposarcoma:

• Chemotherapy is not recommended as these are low-grade tumors with minimal chemosensitivity 4

Clinical Decision Algorithm

Consider neoadjuvant chemotherapy if:

1. High-grade histology (Grade 2-3) with high risk of distant metastasis 1, 2
2. Borderline resectable disease where downsizing might facilitate complete resection 2
3. Patient is fit enough to tolerate intensive combination chemotherapy 5

Do NOT use chemotherapy for:

• Well-differentiated liposarcoma (Grade 1) 4
• Patients with poor performance status unable to tolerate intensive regimens 5

Dosing and Duration

Standard neoadjuvant regimen: 6, 3

• Three cycles of full-dose epirubicin (120 mg/m²) plus ifosfamide (9 g/m²) preoperatively
• Long-term data confirms three cycles are non-inferior to five cycles 6
• This represents the current standard tested in ongoing international trials 6

Important Caveats

Radiation Considerations:

• Neoadjuvant radiation does not reliably downsize retroperitoneal sarcomas 7
• 36.4% of tumors remained unchanged or increased in size with radiation 7
• Favorable RECIST responses are rare, with only one partial response observed in 22 patients 7
• The STRASS trial showed no benefit for preoperative radiotherapy in reducing 3-year local recurrences 2

Response Prediction:

• Leiomyosarcoma has the lowest response rates to chemotherapy 6
• Undifferentiated pleomorphic sarcoma has the highest response rates 6
• Response to neoadjuvant therapy is associated with better survival outcomes 6

Adjuvant vs. Neoadjuvant:

• Neoadjuvant chemotherapy is preferred over adjuvant when chemotherapy is used, as it allows assessment of tumor response and may facilitate resection 8, 3
• Recent trials demonstrate survival benefits specifically with neoadjuvant full-dose anthracycline plus ifosfamide for high-risk sarcomas 8, 3

Unresectable or Metastatic Disease

For advanced, unresectable, or metastatic retroperitoneal sarcoma: 1

• First-line: Doxorubicin-based combination regimens (doxorubicin or epirubicin with ifosfamide and/or dacarbazine) 1
• Alternative combinations: Gemcitabine plus docetaxel, gemcitabine plus dacarbazine 1
• Front-line combination chemotherapy shows positive association with overall survival 1
• Benefits beyond second-line therapy are very limited except in leiomyosarcoma 1