What is the next step in management for a 19-year-old male with recurrent grade 3 ependymoma in the right frontal lobe after surgery and proton (particle) therapy?

Management of Recurrent Grade 3 Ependymoma After Surgery and Proton Therapy

For this 19-year-old with recurrent grade 3 frontal lobe ependymoma after prior surgery and proton therapy, the next step is re-irradiation using either hypofractionated stereotactic radiation or fractionated focal radiation therapy, as this approach is associated with significantly improved survival outcomes compared to chemotherapy alone. 1, 2

Treatment Algorithm for Recurrent Ependymoma

First Priority: Re-irradiation

Since the patient has already undergone repeat surgery (October 2025), the critical next decision is re-irradiation:

• Re-irradiation achieves durable responses in both adults and children with recurrent ependymoma 1
• Stereotactic hypofractionated re-irradiation after surgery is associated with significantly better overall survival (P = 0.030) and progression-free survival (P = 0.008) in multivariate analysis 2
• Alternative option: Full course fractionated re-irradiation can also achieve durable responses 1

Key Technical Considerations:

• For local relapses treated with hypofractionated focal radiotherapy, median PFS was 2.5 years versus 1.2 years for conventional fractionated radiotherapy (though not statistically significant, p = 0.2) 3
• Re-irradiation is safe and feasible, with radionecrosis occurring in only 15-19% of patients, and most cases not requiring intervention 3
• Combined radiation doses can reach median 111.6 Gy with acceptable toxicity when using modern techniques 4

Second Priority: Assess for Metastatic Disease

Before finalizing the re-irradiation plan, obtain:

• Craniospinal MRI with contrast 1
• CSF cytology (performed at least 2-3 weeks post-surgery) 1

If metastatic disease is present: Consider craniospinal irradiation (CSI) rather than focal re-irradiation, as CSI achieved 4-year event-free survival of 53% ± 20% for metastatic failures, with median PFS of 6.8 years versus 0.7 years for focal radiotherapy (p = 0.073) 3, 4

Third Priority: Chemotherapy (Only After Local Options Exhausted)

Chemotherapy should be considered ONLY when surgery and radiotherapy options have been exhausted 1

Critical Evidence Against Early Chemotherapy:

• Treatments including chemotherapy were associated with significantly worse overall survival (P = 0.028) and PFS (P = 0.033) in multivariate analysis 2
• Chemotherapy-naïve patients showed better responses than heavily pretreated patients 1

If chemotherapy becomes necessary (after exhausting local options):

• Temozolomide in standard schedule: 22% response rate (complete + partial), median PFS 9.69 months, median OS 30.55 months in chemo-naïve patients with grade II/III recurrent ependymoma 1
• Alternative: Platinum-based regimens (etoposide, vincristine, cyclophosphamide, platinum derivatives) showed 40-50% response rates in pediatric studies 1
• Temozolomide + lapatinib combination: Median PFS 25.3 weeks for grade III ependymomas, with responses correlating with higher ErbB2 expression 1

Critical Prognostic Factors

Extent of resection at recurrence matters:

• 5-year event-free survival after re-operation: 19% with gross total resection (GTR), 14% with incomplete resection, 8% without repeat surgery 1
• PFS was significantly better for patients with GTR before re-irradiation (14.7 vs 6.7 months, p = 0.05) 3

Common Pitfalls to Avoid

Do not use radiosurgery for recurrent ependymoma: Single-fraction radiosurgery resulted in significant brainstem toxicity and death in one series (median dose 18 Gy), with only 1 of 6 long-term survivors 4

Do not delay re-irradiation in favor of chemotherapy alone: The evidence clearly shows superior outcomes with re-irradiation compared to chemotherapy-based approaches 2

Do not assume local-only disease: Up to 32% of relapses have metastatic or combined (local + metastatic) components, requiring different treatment strategies 2

Specific Recommendation for This Patient

Given this patient is:

• 19 years old (young adult, treated as adult per guidelines)
• Grade 3 (anaplastic) ependymoma
• Already received second surgery
• Chemo-naïve
• Local recurrence in operated bed

Proceed with hypofractionated stereotactic re-irradiation to the tumor bed, as this offers the best chance for durable disease control 1, 3, 2

Reserve chemotherapy (temozolomide preferred given favorable toxicity profile) only if the patient experiences subsequent progression where further surgery or radiation is not feasible 1