Radiation Oncology Synopsis

PEDS: Ependymoma

Background

Intracranial ependymomas account for 5% - 10% of all pediatric CNS tumors. They arise from the ependymal cells of the ventricular floor as midline lesions. Pediatric ependymomas are more than 90% intracranial, as opposed to adult ependymomas which are predominantly in the spinal cord. More than 70% are found in the 4th Ventricle, predominantly in the cerebellar-pontine angle, foramen magnum and the cervical spine via the foramen of Lushka. 4th ventricle tumors extend caudally beyond the foramen magnum into the upper cervical spine via the foramen of Magendie and thence posteriorly form the cervicomedullar junction or from caudal growth through the foramen of Lushka.

Growth through the foramen magnum occurs in about 50% of fourth ventricle lesions.

Supratentorial ependymomas account for 1/3 of childhood presentations, occurring predominantly as extra-ventricular cerebral hemispheric tumors. Growth is commonly adjacent to the third or lateral ventricles.

Demographics

Ependymomas make up 10% of childhood brain tumors. In adults 5%. Most adult ependymomas are found in the spine, while in children they are found intracranially. They follow a bimodal age distribution with peaks at 5 years and at 35 years.

In children, 1/3 show up in those < 3 years with inferior disease control in this population.

In children 90% are found intracranially and only 10% are found in the cord. The posterior fossa is the most common site with 60% found in the floor of the 4th ventricle. 40% are supratentorial and are found in the lateral ventricle.

About 10% - 15% are found to have CSF seeding at diagnosis. Infratentorial sites appear to predispose to seeing, as do high grade tumors. Local failures also appear to predispose to CSF seeding.

There has been some controversy concerning the role of grade as a prognostic feature. Merchant's study of St. Jude data and multi-institutional reviews demonstrate that low grade tumors have higher rates of EFS-5 than higher grade or undifferentiated tumors.

Genetics

Spinal ependymomas are associated with NF2.

Chromosomal abnormalities are also noted, in particular, the long arm of Chromsome 22 loss (associated with NF-2) or loss of 6 or gain of 1q are rarely associated with 4th ventricle tumors but are seen in > 90% of supratentorial tumors.

Overexpression of erbB-2/erbB-4 is associated with poor outcomes in ependymoblastoma.

Pathology

There are a number of histologic grades associated with ependymoma subtypes in children:

Grade IV ependymoblastomas more commonly arise in the supratentorium.

The histologic pictures is that of perivascular pseudorosettes as a classic feature of ependymomas.

Myxopapillary ependymomas are most commonly associated with the conus medullaris/filum terminae region of the spinal cord.

The overall survival rates at 5 years are 55%, with 25% for infants < 1 year old, 46% for those aged 1 - 4 years, and > 70% for those over 5.

Signs and Symptoms

Ependymomas present more often in boys and have a non-specific presenting sign usually related to its site, which is commonly in the 4th venticle. These signs are associated with 4th ventricle obstruction and present with headaches, vomiting, and ataxia. Children presenting with cerebellar-pontine angle disease usually present with torticolis and CN deficits including unilateral hearing loss and facial weakness. MRI often shows a non-homogenously enhancing lesion. MRI is diagnostic when it reveals a soft tissue mass extending through the foramen of Luschka. CT often shows stippled calcifications.

Workup and Staging

The general workup for Pediatric Ependymoma is a CT of the head with particular interest in calcifications. (Aside from the usual H& P of course). Basic labs, and after MRI/CT, an LP once hydrocephalus can be ruled out to reduce the risk of herniation. LP is contraindicated with posterior fossa masses.

An MRI in follow up should be performed about 2 weeks after surgery (POD ≥ 14) to avoid post-surgical artifacts.

Treatment

The general treatment paradigm for ependymomas:

  1. Surgery: This is the primary therapy.
    • Is GTR enough? Avoiding radiation in children < 3 years is being investigated. Grade I and spinal/supratentorial GTR may be candidates for observation.
    • At present adjuvant RT for children > 3 and adjuvant chemotherapy for children < 3 years old.
  2. Radiation therapy:
    • If GTR:
      • Infratentorial sites: 59.4 Gy on protocol; 54 Gy off protocol
      • Supratentorial: 55.8 Gy
    • STR: for subtotal resection give 59.4Gy
    • Cranial-Spinal irradiation is indicated for leptomeningeal disease.
  3. Chemotherapy: Not robust. some data exist. Possible single agent CDDP or vincristine/cyclophosphamide.

Absent neuroaxis involvement (as evidenced by imaging studies, positive CSF or ependymoblastoma (WHO Grade IV) disease, CSI can be avoided. There have been multiple retrospective reviews which demonstrate that the primary pattern of failure is local, rather than CNS axis failure. Regardless of initial field size, spinal seeding is uncommon except in the setting of local failure. Whole brain radiation or cranio-spinal irradiation does not appear to affect survival when compared to local irradiation. The primary pattern of failure (> 90%) is local.

Summarizing: The general ependymoma treatment paradigm is maximum safe surgical resection followed by radiation therapy in children > 3 years old, and adjuvant chemotherapy in children under 3 years old.

Craniospinal irradiation should be performed if:

For all other diseases, local radiation should be sufficient.

Surgery

The single most important favorable prognostic indicator in ependymomas is the completeness of surgical resection. This correlates with local control closely for ependymomas. The difference in OS-5 between gross total resection and subtotal resection is 75% for GTR and 35% for STR. Grade does not appear to change this and the results are similar for both low grade and high grade disease.

Spinal disease which represents only 30% in children is the most amenable to complete resection. Supratentorial disase is the second most amenable followed by posterior fossa disease. Completeness of resection varies by these sites:

  1. Spinal Cord: 100% GTR
  2. Supratentorial Disease: 80% GTR
  3. Infratentorial Disease

Infratentorial tumors have a lower rate of successful resection than other sites. They as still managed the same way. Maximum safe resection is the first step, regardless of histologic grade. All patients get postoperative radiation therapy to the involved field to a dose of 59.4 Gy.

Supratentorial ependymomas are also managed with maximum safe resection with higher rates of gross total resection than infratentorial sites. Observation may be acceptable after GTR if not anaplastic or Grade IV disease.

Chemotherapy

The traditional role of chemotherapy as been to delay the use of radiation therapy until after age > 3. Chemotherapy has been used as a "bridge" treatment following maximum surgical resection. Chemotherapy has also been used in salvage settings after recurrence.

Chemotherapy agents include CDDP, VP16, temazolamide and nitrosurea. Response rates are 5% - 15%. Merchant (St. Jude's) has recently reported a new prospective trial that included many age < 3 treated with maximum safe surgical resection followed by conformal 3D post-operative radiation therapy with a 10 mm margin to 59.4 Gy. This trial suggests that radiation may be able to be given safely and effectively for patients under the age of 3. Merchant reports the following results:

Merchant concludes young age should not preclude young children aged 1 - 3 years from receiving radiation therapy. The safety of radiation therapy in infants < 1 year old remains uncertain.

Typical chemotherapy agents in ependymomas include cisplatinum, etoposide and cyclophosphamide.

Radiation Therapy

Post operative radiation therapy has been demonstrated to be effective in numerous studies.Typically the GTV is the tumor bed which according to ACNS 0121, "The GTV in most cases will be a contracted or collapsed tumor bed." A 10 mm expansion around the GTV is used to generate the CTV and the PTV is institution specific, generally 3 - 5 mm.

Radiation doses are:

The treatment volumes are established by the knowledge that ependymomas recur mostly locally, and the patterns of disease extension are typically known to follow the formen of Luschka, circumferentially around the brainstem to encase the basilar artery and into the foramen magnum to the upper spinal canal. Optimal planning requires MRI fusion with plannng CT.

A major reason infratentorial lesions should get adjuvant radiation therapy, regardless of histopathology (including subependymomas and myxopapillary ependymomas is due to the difficulty of obtaining a GTR due to the proximity of the 4th ventricle and CNS vesicles such as the basilar artery which leads to higher local recurrence with the omission of post-op radiation therapy.

A single POG study, POG 9132 suggested hyperfractionation may be better. EFS was better if 1.2 Gy BID was used to 69.6 Gy.

Ependymoblastomas (WHO Grade IV)

These tumors are treated differently, They are treated more like medulloblastomas. Cranio-spinal irradiation is given to 36 Gy with vincristine ± carboplatin. A boost to the cavity or gross residual disease is given to 45 - 50.4 Gy if the disease is in the spine and 54 - 59.4 Gy if cranial disease. This is followed by vincristine/cytoxan/prednisone 6 weeks after radiation.

Spinal Ependymomas

Radiation therapy is used with spinal ependymoma resection is incomplete or the histology is anaplastic ependymoma.

Spinal fields include 2 vertebral bodies or sacral nerve roots above and below the tumor to 45 - 50.4 Gy with a boost if below the cord to 54 - 59.4 Gy.

Recurrence

Recurrent ependymomas are treated similarly. Surgery remains the mainstay with radiation therapy modified based on prior radiation treatments. If there has been no prior radiation then post-op radiation is given, as is usual and customary. If there has been prior radiaiton therapy, then radiation fields are modified to treat with sterotactic radiotherapy or chemotherapy as second line.

Studies of Radiation after GTR

Several recent studies have demonstrated a benefit to radiation therapy postoperatively after gross total resection.

Rogers, 2005: This study showed the OS-10 after gross total resection improved with post operative radiation therapy from 67% to 83%.

ACNS0121 (Merchant, 2009, Lancet Oncology) updated the ACNS 0121 Phase II study data. All patients recieved conformal radiation therapy to 59.4 Gy for "near total resections" for all sites and grades and for R0 infratentorial lesions of all histologies. Well differentiated lesions with GTR were observed. Chemotherapy for subtotal resection was given.

The updated results of ACNS0121 demonstrated:


Prognosis

Supratentorial tumors are usually higher grade and have more sub-total resections. These tumors have a poorer prognosis than infratentorial tumors. The prognosis is also worse for those who have erbB-2/erbB-4 overexpression. Children < 4 have poorer outcomes than those older.

Toxicities

45 Gy is the commonly used spinal cord constraint. 50.4 Gy is the optic chiasm limit.

Crainiospinal MRI should be performed every 6 months for the first 2 years after treatment, then annually for 10 years. Later recurrences of > 12 years have been reported.