What are the next modes of treatment for a recurrent grade 3 (G3) ependymoma in the right frontal lobe at the previously operated tumor bed?

Treatment of Recurrent Grade 3 Ependymoma in the Right Frontal Lobe

For recurrent grade 3 ependymoma at the operated tumor bed, pursue maximal safe re-resection followed by re-irradiation, as this combination achieves the most durable disease control and survival benefit. 1

Primary Treatment Strategy: Surgery First

Attempt maximal safe re-resection as the initial intervention, as extent of resection at recurrence is the most critical prognostic factor. 1 The 5-year event-free survival is 19% with gross total resection versus only 8% without repeat surgery. 1 Given the frontal lobe location, aggressive re-resection is typically feasible without devastating neurological consequences, unlike eloquent or deep-seated locations.

Pre-operative Staging Requirements

Before finalizing any treatment plan, obtain:

• Craniospinal MRI with contrast to assess for metastatic disease 1
• CSF cytology (performed at least 2-3 weeks post-surgery if already done) 2
• This staging determines whether focal re-irradiation versus craniospinal irradiation is needed 1

Re-irradiation: The Critical Second Step

Re-irradiation achieves durable responses in both adults and children with recurrent ependymoma and should be pursued after surgical resection. 1 The evidence demonstrates that re-irradiation provides meaningful disease control even in previously irradiated fields.

Re-irradiation Dosing Options

For focal recurrence without metastases:

• Fractionated stereotactic radiotherapy (FSRT): Minimum 21 Gy in 3 fractions or 25 Gy in 5 fractions 3
• Doses ≥25 Gy/5 fractions prevented recurrence within 1 year in anaplastic ependymoma 3
• FSRT achieved 76% local control at 3 years with minimal toxicity 3
• Avoid radiosurgery (single-fraction SRS) as it resulted in significant brainstem toxicity and death in one series, despite similar local control 4

For metastatic recurrence:

• Craniospinal irradiation (CSI) achieved 53% 4-year event-free survival in patients with metastatic failure 4
• CSI is the preferred approach when staging reveals disseminated disease 4

Common Pitfall: Radiosurgery Toxicity

Single-fraction radiosurgery carries unacceptable toxicity risk in recurrent ependymoma, particularly brainstem toxicity. 4 Always favor fractionated approaches (FSRT) over single-fraction SRS for re-irradiation. 3, 4

Chemotherapy: Third-Line After Surgery and Radiation Exhausted

Chemotherapy should only be considered when surgery and radiotherapy options have been exhausted, as it provides inferior disease control compared to local therapies. 1

Preferred Chemotherapy Regimens

Temozolomide is the preferred first-line systemic agent due to its favorable toxicity profile:

• Standard-schedule temozolomide achieved 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 1
• Temozolomide combined with lapatinib showed median PFS of 25.3 weeks for grade III ependymomas, with responses correlating to higher ErbB2 expression 2

Alternative chemotherapy options if temozolomide fails:

• Platinum-based regimens showed 40-50% response rates in pediatric studies 1
• Continuous oral etoposide was well tolerated and showed activity in small series of recurrent intramedullary ependymoma 2
• Bevacizumab can provide clinical benefit in some patients, though MRI changes may not meet formal response criteria 2

Limitation of Chemotherapy Efficacy

The modest activity of temozolomide against ependymoma likely relates to lack of MGMT promoter methylation in ependymoma cells. 2 Even when MGMT methylation is present, it may not correlate with temozolomide response. 2

Treatment Algorithm Summary

1. Obtain craniospinal MRI and CSF cytology to stage disease extent 1
2. Pursue maximal safe re-resection at the frontal lobe tumor bed 1
3. Administer re-irradiation:
   • Focal FSRT (≥25 Gy/5 fractions) if localized recurrence 3
   • CSI if metastatic disease present 4
4. Reserve chemotherapy (temozolomide preferred) for when surgical and radiation options exhausted 1
5. Consider repeat surgery and re-irradiation multiple times if technically feasible, as multiple procedures can achieve long-term control 5

Critical Caveat: Multiple Interventions

Do not assume a single re-operation or re-irradiation is the limit. Case reports demonstrate that multiple surgical resections combined with multiple stereotactic radiosurgery procedures can achieve long-term survival with good quality of life, even with extracranial metastasis. 5 Aggressive local control measures should be repeated as long as the tumor remains resectable and does not involve crucial structures. 5