Pediatric brain tumors

Gliomas. Approximately three-quarters of pediatric brain tumors are gliomas. They are of neuroepithelial origin and frequently display morphological and/or biochemical characteristics of glial cells. Pediatric gliomas include the astroglial types found in adults as well as ependymomas and neuronal-glial tumors. Approximately 20% of childhood gliomas occur in the cerebellum, a site rarely affected in adults. More than 75% of pediatric cerebellar gliomas are pilocytic astrocytomas which are less infiltrative that cerebral gliomas, resulting in a 5 year survival rate of 95% following gross total resection. Infiltrative gliomas in children, regardless of their anatomic location, have the same poor prognosis as they have in adults.

Medulloblastoma, a highly malignant, morphologically undifferentiated neoplasm, comprises 20% of pediatric CNS tumors. The large majority of these tumors arise in or near the midline of the cerebellum. Medulloblastoma occurs primarily between the ages of 5 and 10 years and show a male to female preponderance of 2:1. Overall 5-year survival rates for medulloblastoma following surgery and adjuvant RT and CT have been reported to range from 60 to 85%. Long-term survival, however is frequently accompanied by detrimental physical and neuro-physcological sequelae produced by adjuvant radio-therapy and chemotherapy. The 10% to 30% of patients with tumor dissemination throughout the neuroaxis at time of diagnosis are less likely to respond to initial therapy and more likely to relapse within 5 years. There is no therapy that produces long-term remission in recurrent medulloblastoma. About 10% of medulloblastomas occur supratentorially in the cerebral hemispheres. Supratentorial tumors are more aggressive and less responsive than their cerebellar counterparts, with 5-year survival rates of less than 20%.

Treatment, resistance and recurrence. Post-surgical treatment for malignant gliomas and high-risk medulloblastomas usually consist of irradiation plus systematic chemotherapy. In children, an improvement in the disease free survival rate is observed when CT is combined with RT as compared to RT alone. Two important factors that affect the outcome of therapy are sensitivity of tumor cells and tumor burden at the time of treatment. Improved surgical methods allow for more extensive tumor resection, which will reduce the tumor burden at the start of therapy. Improving CT in young patients is of particular importance given the long-term effects of RT on physical and mental development. In the very young CT takes a more predominant role in brain tumor therapy with RT being reserved for recurrent tumors. DNA repair has been implicated as a critical determinant of tumor susceptibility to DNA damaging based CT. Of interest to our lab are; accessing the relationship between repair activity and tumor response to therapy, developing techniques to alter repair activities in vitro to evaluate the mechanistic relationship(s), developing techniques to alter repair activities in vivo to enhance the effectiveness of DNA damaging based therapies and develop new therapeutic protocols combing new and older chemotherapeutic and/or radiation therapies to exploit cellular response to DNA damage.