What is the optimal management for a 4‑year‑old with recurrent orbital rhabdomyosarcoma, previously treated with multi‑agent chemotherapy, surgical excision and external‑beam radiotherapy 1.5 years ago, now with a positive margin involving the inferior orbital nerve?

Management of Recurrent Orbital Rhabdomyosarcoma with Positive Margins

For this 4-year-old with recurrent orbital rhabdomyosarcoma and positive margins at the inferior orbital nerve after prior multimodality therapy, salvage surgery (orbital exenteration or eye-sparing tumor excision) combined with systemic chemotherapy offers the best chance for long-term survival, with 71-92% disease-free survival rates reported in similar cases. 1, 2

Immediate Treatment Approach

Surgical Management

• Proceed with aggressive local surgical control as the primary intervention, choosing between orbital exenteration or eye-sparing tumor excision based on the extent of residual disease and involvement of critical structures 1, 2

• Orbital exenteration should be strongly considered given the positive margin at the inferior orbital nerve, as complete surgical clearance is critical for survival—the two deaths in refractory orbital rhabdomyosarcoma occurred in patients with tumor extending beyond operative margins 1

• Eye-sparing tumor excision may be attempted if complete resection with negative margins is technically feasible without compromising oncologic outcomes, though this is challenging with nerve involvement 1

• Surgical intervention should occur urgently, as the median time to relapse treatment in similar cases was 1.58 years, and this patient is already at 1.5 years post-initial treatment 2

Systemic Chemotherapy

• Administer intensive multi-agent salvage chemotherapy using combinations that include etoposide, doxorubicin, and ifosfamide, as these agents were used in 14, and 12 patients respectively in the largest series of recurrent orbital rhabdomyosarcoma with excellent outcomes 2

• Consider adding cyclophosphamide to the regimen, which was used in 7 of 24 relapsed patients 2

• Do NOT pursue high-dose chemotherapy with autologous stem cell transplant (HDT/ASCT), as there is no proven survival benefit in rhabdomyosarcoma, whether primary metastatic or relapsed disease 3, 4

Radiation Therapy Considerations

• Re-irradiation should be considered despite prior radiotherapy, as 4 of 6 patients who received post-relapse radiation therapy in the IRSG series had been previously irradiated and still achieved favorable outcomes 2

• Six patients received radiotherapy after relapse with successful salvage in the majority 2

• Radiation therapy to the orbital region carries a known risk for malignant transformation in other conditions, but in rhabdomyosarcoma the normal tissue response to radiotherapy is preserved, so standard doses should not be reduced 4

Expected Outcomes and Prognostic Factors

• The prognosis for recurrent orbital rhabdomyosarcoma is surprisingly favorable with aggressive re-treatment: 91.7% of patients survived sarcoma-free after relapse, with 82% alive ≥5 years after relapse in the largest pediatric series 2

• In another series of refractory orbital rhabdomyosarcoma, 71% (5 of 7) of children remained alive and disease-free at 3-11 years after salvage surgery 1

• The two critical negative prognostic factors are: (1) tumor extending beyond operative margins at exenteration, and (2) development of regional or distant metastasis 1

Critical Management Pitfalls to Avoid

• Do not delay surgical intervention while attempting additional chemotherapy alone—local surgical control is essential for cure in refractory disease 1, 2

• Do not assume the patient is incurable based on recurrence after full multimodality therapy—vigorous re-treatment with curative intent yields excellent long-term survival 2

• Do not use less aggressive chemotherapy regimens thinking the tumor is now resistant—intensive multi-agent salvage chemotherapy is required 2

• Do not pursue HDT/ASCT as this has no proven benefit and exposes the patient to unnecessary toxicity and treatment-related mortality (0-4% death rate) 3, 4

Multidisciplinary Team Requirements

• Immediate consultation with pediatric surgical oncology for surgical planning 3

• Pediatric oncology for systemic chemotherapy regimen design 3

• Radiation oncology for re-irradiation planning 3, 2

• Ophthalmology/oculoplastic surgery for surgical technique and functional preservation assessment 1

• All decisions should be made within a specialized sarcoma multidisciplinary team at a reference center with high volume experience 3

Monitoring During Treatment

• Severe hematologic toxicities are expected with salvage chemotherapy, including 83% grade 3-4 neutropenia, 60% thrombocytopenia, and 45% anemia 3

• Primary causes of treatment-related death are sepsis and anthracycline-related cardiotoxicity, requiring vigilant monitoring 3

• Response evaluation should occur after 2-3 cycles of chemotherapy using the same radiological examinations positive before treatment 3