Radiation Oncology/CNS/Ependymoma

Epidemiology

• 5-10% of pediatric brain tumors
• Primarily in infants and children <5 years
• Approximately 200 pediatric cases per year in USA

Location

• Glial tumors that arise from ependymal lining of the ventricular system
• May occur anywhere in the ventricular system or spinal canal
• 90% are in the brain
  • 1/3 supratentorial
  • 2/3 infratentorial, many arising from the 4th ventricle
  • Up to 50% may infiltrate into the brainstem
• 10% in the spine
  • Myxopapillary ependymomas are found almost exclusively in the conus and filum terminale and are the most common spinal tumors in this location.
• Location differs with age:
  • In young children: 90% intracranial, typically roof of 4th ventricle
  • In adolescents/adults: 75% spinal canal

Patterns of spread

• Spread is primarily local
  • In 50% of pts with posterior fossa tumors, a "tongue" of tumor may extend through the foramen magnum well into the cervical region
• Risk of leptomeningeal seeding is 5-10%

Presentation

• Since majority occur in 4th ventricle, symptoms are related to obstruction and subsequently increased intracranial pressure
• In spinal ependymomas, presentation is typically with sensory deficits (compared with astrocytomas, which tend to present with pain and motor symptoms)

Workup

• MRI of brain and spine: typically well-circumscribed, with displacement rather than invasion of brain parenchyma
• CSF cytology

Pathology

• Myxopapillary ependymoma (WHO grade I)
• Subependymoma (WHO grade I)
• Ependymoma (WHO grade II)
  • Cellular
  • Papillary
  • Clear cell
  • Tanycytic
• Anaplastic ependymoma (WHO grade III)

Treatment Overview

• No randomized studies
• Surgery is primary management
• Adjuvant RT is considered standard of care, although highly selected series report good outcomes with surgery alone
• Because recurrences tend to be local, RT is typically GTV plus 1-1.5 cm margin (per Perez, 4th edition)
• 5-year OS 50-65%, PFS 25-45%
• Recurrences typically local; median time to failure 1-2 years. About 20% isolated distant recurrences

Surgery

• Extent of surgery most important predictor of outcome
  • 5-year OS with GTR: 70-80%
  • 5-year OS with STR: 25-45%
• Gross total resection (GTR) achievable depending on location, overall 30-50%:
  • Supratentorial lesions: GTR ~80%
  • Infratentorial lesions: GTR "lower" rate (per Perez, 4th edition), BNI rate 70%
  • Spinal lesions: GTR close to 100%

• Barrow Neurological Institute; 2005 (1983-2002) PMID 15871504 -- "Is gross-total resection sufficient treatment for posterior fossa ependymomas?" (Rogers L, J Neurosurg. 2005 Apr;102(4):629-36.)
  • Retrospective. Posterior fossas ependymomas, no subependymomas or CNS dissemination. GTR in 71%. RT in 13/32 GTR and 12/13 STR. RT fields CSI + boost (n=6), rest posterior fossa or localized fields. Median F/U 5.5 years
  • Local control: Median LC: GTR alone 6.6 years vs. GTR+RT not yet reached; 10-year LC: GTR alone 50% vs. GTR+RT 100% (SS) vs. STR+RT 36% (SS), GTR alone comparable to STR+RT
  • 10-year OS: GTR alone 67% vs. GTR+RT 83% vs. STR+RT 43% (all NS)
  • Conclusion: Adjuvant RT significantly improves control after GTR

• BI Medical Center, NYC; 1998 PMID 9755311 -- "Treatment of intracranial ependymoma by surgery alone." (Hukin J, Pediatr Neurosurg. 1998 Jul;29(1):40-5.)
  • Prospective. 10 patients. Children >3 years, s/p GTR
  • Outcome: 7 free of disease, 3 recurred (2 salvaged with surgery and RT). No deaths. Overall median PFS 4 years, and OS 4.2 years
  • Conclusion: Deferral of RT after GTR of supratentorial ependymoma safe; recurrence salvageable

Radiation

Role of post-operative RT:

• Historically, ependymoma was believed to disseminate throughout the neuraxis, and CSI became the standard management approach
• However, more recent retrospective studies have shown that failure is primarily local in >90%
• Benefit for post-operative RT is based on retrospective studies. 5-yr EFS 45% vs 0% and 51-70% vs 13% PFS.

Dose response:
Evidence of a dose response above 45-50 Gy.

RT volume:
No evidence of need for extended-field or craniospinal radiation.
CTV margin around resection cavity is generally 1 cm.

Hyperfractionation:
In one study (POG 9132), HF RT produced better event-free survival for pts with incomplete resection. Dose was 69.6 Gy at 1.2 Gy BID.

Subependymoma

• Uncommon variant of ependymal tumors
• Histologically clusters of ependymal cells in an astrocyte-based matrix
• Clinically slow growing, with extremely low Ki-67
• Many discovered incidentally at autopsy
• Clinically symptomatic tumors present with CSF obstruction
• Gross total resection alone frequently leads to cure, but perioperative mortality can be high
• Role of adjuvant RT is not clear

Anaplastic Ependymoma

• HIT-SKK87 and HIT-SKK92 (1987-1992, 1992-1997)
  • HIT-SKK87: Low-risk (complete resection, M0) and age <2.5 received maintenance chemo only until RT at 3 years or progression. High-risk (subtotal resction, M+) and age 2.5-3 induction chemo / maintence chemo until RT at 3 years or progression
  • HIT-SKK92: Post-op chemo x3 cycles first, then if CR no RT. If PR and <18 months, then more chemo, if PR and >18 months, then RT.
  • RT given as CSI 35.2/22 Gy + 20/10 Gy boost; if no residual disease, reduced to CSI 24 Gy + PF boost to 55 Gy
  • 2005 PMID 16300848 -- "Role of radiotherapy in anaplastic ependymoma in children under age of 3 years: results of the prospective German brain tumor trials HIT-SKK 87 and 92." (Timmermann B, Radiother Oncol. 2005 Dec;77(3):278-85.)
    • Total 34 children enrolled. No RT given in 13 children, preventive RT in 9, salvage RT in 12
    • 3-year outcomes: PFS 27%, OS 56%. Positive predictive factors: higher age, M0, GTR, RT. If no RT, only 3/13 survived
  • Conclusion: Delaying RT jeopardized survival. Predominant failure primary tumor site; RT of neuraxis should be omitted in localized disease

Spine Ependymoma

• Rare tumors
• Gross total resection (~50%) leads to long-term control in >90%
• Subtotal resection can recur in 50-70% without adjuvant therapy; with adjuvant RT local control 60-100%
• RT dose seems to show a threshold effect, with worse control <45 Gy. However, radiation myelopathy becomes concerning >55 Gy, and with pediatric patients possibly as low as 40 Gy
• Field size is unclear, but commonly is +/- 2 vertebral bodies. In sacrum, need to cover nerve roots, so inferior edge at S4/S5 and lateral edges to SI joints

• Kaiser Permanente; 2007 (USA) PMID 17689025 -- "Outcomes in treatment for intradural spinal cord ependymomas." (Volpp PB, Int J Radiat Oncol Biol Phys. 2007 Nov 15;69(4):1199-204. Epub 2007 Aug 6.)
  • Retrospective. 23 patients (17 surgery alone, 5 surgery + RT, surgery + RT + chemo). Mean RT dose 45 Gy
  • Outcome: 9-year OS 64%, LC 96%
  • Recurrences: surgery alone: 12% recurred (1/17 locally, 1/17 distally). CMT 33% recurrence (both out-of-field)
  • Conclusion: En block total resection primary treatment, RT reserved for unfavorable characteristics (residual tumor, anaplastic features, piecemeal resection)

Reviews

• PMID 15049020, 2004 — "Review of radiotherapy dose and volume for intracranial ependymoma." Taylor RE. Pediatr Blood Cancer. 2004 May;42(5):457-60.