What type of radiotherapy and dose is recommended for a recurrent grade 3 ependymoma at the operated bed 23 months after complete resection and proton beam therapy (PBT) with a dose of 56.8 Gy?

Re-irradiation with Fractionated Stereotactic Radiotherapy at 54-60 Gy

For this recurrent grade 3 frontal lobe ependymoma at the operative bed 23 months post-proton therapy, pursue maximal surgical re-resection first, followed by re-irradiation using fractionated stereotactic radiotherapy (FSRT) with doses of 54-60 Gy to the tumor bed, or hypofractionated stereotactic approaches with minimum doses of 21 Gy in 3 fractions or 25 Gy in 5 fractions. 1

Primary Treatment Algorithm

Step 1: Surgical Re-resection (First Priority)

• Attempt maximal surgical re-resection as the initial intervention, as extent of resection at recurrence is the single most critical prognostic factor determining survival 1
• Among patients undergoing re-operation, 5-year event-free survival is 19% with gross total resection, 14% with incomplete resection, and only 8% without repeat surgery 2, 3, 1
• Perform post-operative MRI within 48-72 hours to evaluate extent of resection 1

Step 2: Staging Before Re-irradiation

• Obtain craniospinal MRI with contrast and CSF cytology at least 2-3 weeks post-surgery to assess for metastatic disease 3, 1
• This staging is mandatory before finalizing the re-irradiation plan, as disseminated disease would alter the radiation field 1

Step 3: Re-irradiation Strategy

Re-irradiation achieves durable responses in both adults and children with recurrent ependymoma and should be administered regardless of resection extent in grade 3 tumors 2, 3, 1

Recommended Radiation Approaches:

Option 1: Fractionated Stereotactic Radiotherapy (FSRT) - Preferred

• Deliver focal fractionated re-irradiation with 54-60 Gy to the tumor bed using standard fractionation 1
• FSRT provides 76% local control at 3 years with minimal toxicity 4
• FSRT offers 89% 3-year local control with median event-free survival of 3.4 years in pediatric recurrent ependymoma 5

Option 2: Hypofractionated Stereotactic Approaches

• Minimum effective doses are 21 Gy in 3 fractions or 25 Gy in 5 fractions 4
• Lesions receiving ≥25 Gy/5 fractions or 21 Gy/3 fractions did not recur within 1 year 4
• These doses provide acceptable local control with minimal toxicity 4

Option 3: Stereotactic Radiosurgery (SRS)

• Single-fraction SRS with median margin dose of 15 Gy (range 9-25 Gy) achieves 66% 5-year local control 2
• SRS appears feasible for recurrent ependymoma with reasonable local control 6

Critical Pitfalls to Avoid

• Do not proceed directly to chemotherapy without attempting surgical resection, as extent of resection is the most powerful predictor of survival at recurrence 1
• Do not use photon-based proton beam therapy again - the patient already received 56.8 Gy with protons, necessitating stereotactic approaches to minimize overlap with previously irradiated volumes 4
• Monitor for brainstem toxicity and radiation necrosis, particularly given the frontal location and prior proton therapy exposure 2
• Radiation necrosis occurs in approximately 50% of patients receiving re-irradiation but is typically manageable with steroids 5, 6

Chemotherapy: Third-Line Option Only

Reserve chemotherapy only when both surgical and radiotherapy options have been exhausted 2, 3, 1

If chemotherapy becomes necessary:

• Temozolomide shows 22% response rate, median PFS of 9.69 months, and median OS of 30.55 months in chemo-naïve patients with grade II/III recurrent ependymoma 2, 3, 1
• Standard dosing: 150-200 mg/m² days 1-5 of 28-day cycles 1
• Responses occur only in chemotherapy-naïve patients and typically appear delayed 2, 1
• Do not expect temozolomide efficacy in heavily pretreated patients, as the modest activity relates to lack of MGMT promoter methylation in ependymoma cells 3, 1

Rationale for This Approach

The EANO guidelines emphasize that re-operation and re-irradiation are increasingly employed as standard salvage options for recurrent ependymomas, with both achieving durable responses 2. The frontal location allows for aggressive surgical re-resection without the anatomical constraints of posterior fossa tumors 2. Given prior full-dose proton therapy (56.8 Gy), stereotactic techniques are essential to deliver therapeutic doses while minimizing overlap with previously irradiated volumes 4. The 23-month recurrence interval suggests aggressive biology requiring both maximal cytoreduction and definitive re-irradiation 1.