# Radiation Oncology/CNS/Ependymoma

* Front Page: Radiation Oncology | RTOG Trials | Randomized Trials

## 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.