Management of Poor Response to Neoadjuvant VAC+IE in Ewing Sarcoma
Immediate Next Steps
For patients with poor response to VAC+IE neoadjuvant chemotherapy, proceed directly to local control with aggressive multimodal therapy (surgery with or without radiotherapy), followed by consideration of high-dose busulphan-melphalan chemotherapy with autologous stem cell rescue for those with large tumors (>200 mls) or poor radiological response. 1
Defining Poor Response
Poor response is characterized by:
- ≤90% tumor necrosis on histological examination 1
- Poor radiological response on MRI showing minimal tumor volume reduction 1
- Persistent FDG-PET activity indicating viable tumor 1
- Large residual tumor volume (>200 mls) 1
Local Control Strategy for Poor Responders
Surgical Approach
- Complete surgical resection remains the priority even with poor chemotherapy response, aiming for wide margins that include all tissues involved in the pre-chemotherapy tumor volume 1
- Multidisciplinary tumor board discussion is mandatory, with consideration of National Ewing MDT consultation 1
Radiotherapy Integration
Radiotherapy should be added to surgery in poor responders through one of these approaches 1:
- Preoperative radiotherapy for high-risk tumors with poor radiological response to induction chemotherapy 1
- Postoperative radiotherapy (40-45 Gy for microscopic residual, 50-60 Gy for macroscopic disease) if histological response shows ≤90% necrosis, even with negative surgical margins 1
- Definitive radiotherapy (50-60 Gy) if surgery would cause unacceptable morbidity 1
Systemic Therapy Intensification
High-Dose Chemotherapy Option
For poor responders with large tumors (>200 mls), high-dose busulphan-melphalan chemotherapy (BuMel HDT) with autologous stem cell rescue may be beneficial 1. This approach showed 5-year event-free survival of 72% in poor responders treated with HDT versus 33% in those who did not receive HDT 2.
Important caveat: HDT does not appear advantageous for patients with pulmonary metastases already receiving standard chemotherapy and whole lung irradiation 1
Consolidation Chemotherapy
Continue with consolidation chemotherapy using:
- IE/VC consolidation following VDC/IE induction, which has demonstrated better outcomes than VIDE induction with VAI or VAC consolidation 1
- Total treatment duration should be 28-49 weeks depending on regimen 1
Second-Line Options if Progressive Disease
If disease progresses during or immediately after VAC+IE, consider second-line regimens 1:
- High-dose ifosfamide (first choice for relapsed/refractory disease) 1
- Cyclophosphamide and topotecan 1
- Irinotecan and temozolomide ± multi-targeted kinase inhibitor 1
Critical Decision Points
When to Consider HDT with Stem Cell Rescue
- Tumor volume >200 mls after induction
- Poor radiological response on MRI
- Histological response ≤90% necrosis
- No pulmonary metastases (HDT not beneficial in this setting)
- Patient medically fit for intensive therapy
When to Intensify Radiotherapy
Add or increase radiotherapy dose if: 1
- Histological response ≤90% necrosis (even with negative margins)
- Surgical margins inadequate (R1 or R2 resection)
- Large tumor size
- High-risk anatomical location (pelvis, sacrum, rib)
- All pre-chemotherapy tumor volume tissues not excised
Common Pitfalls to Avoid
- Do not delay local control waiting for better chemotherapy response—proceed to surgery/radiotherapy after induction phase 1
- Do not rely on surgery alone in poor responders; combined modality (surgery + radiotherapy) improves local control 1, 3
- Do not use HDT indiscriminately—it is not beneficial for pulmonary metastases and utility following VDC/IE is not fully defined 1
- Do not underestimate the importance of histological response assessment—this guides postoperative radiotherapy decisions 1