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