Faculty Bibliography

PURPOSE: To evaluate the feasibility of and response rate to an intensified induction chemotherapy regimen for young children with newly diagnosed high-risk or disseminated medulloblastomas. PATIENTS AND METHODS: From January 1997 to March 2003, 21 patients with high-risk or disseminated medulloblastoma were enrolled. After maximal surgical resection, patients were treated with five cycles of vincristine (0.05 mg/kg/wk x three doses per cycle for three cycles), cisplatin (3.5 mg/kg per cycle), etoposide (4 mg/kg/d x 2 days per cycle), cyclophosphamide (65 mg/kg/d x 2 days per cycle) with mesna, and methotrexate (400 mg/kg per cycle) with leucovorin rescue. Following induction chemotherapy, eligible patients underwent a single myeloablative chemotherapy cycle with autologous stem-cell rescue. RESULTS: Significant toxicities of this intensified regimen, including gastrointestinal and infectious toxicities, are described. Among the 21 patients enrolled, there were 17 complete responses (81%), two partial responses, one stable disease, and one progressive disease. The 3-year event-free survival and overall survival are 49% (95% CI, 27% to 72%) and 60% (95% CI, 36% to 84%), respectively. CONCLUSION: This intensified induction chemotherapy regimen is feasible and tolerable. With the majority of patients with disseminated medulloblastoma having M2 or M3 disease at diagnosis, the encouraging high response rate of this intensified induction regimen suggests that such an addition of methotrexate should be explored in future studies

Over the last decade, the results of 5 prospective clinical trials of intracranial low-grade glioma (LGG) have been published, 4 in adults with supratentorial LGG and 1 in children with infra- and supratentorial LGG. The data from the more than 1600 patients treated on these studies are summarized herein. European Organization for Research and Treatment of Cancer study 22845 randomized 311 adults to postoperative observation or radiation therapy (RT). There was no difference in the 5-year overall survival (OS) rate between the 2 arms. Irradiated patients had a significantly improved 5-year progression-free survival (PFS) rate. European Organization for Research and Treatment of Cancer study 22844 randomized 379 adults to low-dose (45 Gy) versus high-dose (59.4 Gy) RT. Similarly, an intergroup study conducted by the North Central Cancer Treatment Group, Radiation Therapy Oncology Group, and Eastern Cooperative Group randomized 203 adults to low-dose (50.4 Gy) versus high-dose (64.8 Gy) RT. There was no difference in the 5-year OS or PFS rates between the 2 dose groups in either study. A Southwest Oncology Group study randomized 54 adults with incompletely resected LGG to RT alone or RT plus CCNU (lomustine) chemotherapy. There was no difference in outcome between the 2 treatment arms. Important prognostic factors for OS in these 4 adult trials included extent of surgical resection, histology, tumor size, and age. An intergroup study of the Children's Cancer Group and Pediatric Oncology Group enrolled 660 pediatric patients with management based on the extent of surgical resection: Children who underwent gross total tumor resection were observed postoperatively, whereas those who had subtotal resection or biopsy were either observed or administered RT at the discretion of their physician. Survival was most impacted by several prognostic factors, primarily extent of resection. Besides extent of resection, other prognostic factors that were consistent in predicting survival in these 5 clinical trials included patient age and tumor location, size, and histology. The data from these 5 studies indicate that for intracranial LGG in adults, postoperative RT is associated with improved 5-year PFS but not OS rates compared to postoperative observation. Radiation doses of 45 to 54 Gy result in 5-year OS and PFS rates that are similar to those for higher doses. The strategies of chemotherapy alone and RT plus chemotherapy are under investigation. For pediatric LGG, extent of surgical resection is the most important prognostic factor associated with favorable 5-year OS and PFS. Radiation therapy and chemotherapy are generally used in the settings of incomplete resection and recurrent disease, and these strategies are being investigated in prospective clinical trials. The schemata from recently completed and ongoing studies in both adult and pediatric intracranial LGG are reviewed

PURPOSE: To assess the activity and tolerability of temozolomide in children with progressive low-grade gliomas (LGGs). PATIENTS AND METHODS: The authors reviewed the records of 13 children (6 months to 19 years old) with progressive LGGs and magnetic resonance imaging evidence of unresectable tumors who were treated with temozolomide at the authors' institution since 1999. RESULTS: Four patients received a 5-day regimen of temozolomide (150 mg/m2 per day) repeated every 28 days, and nine patients received a 42-day regimen (75 mg/m2 per day) repeated every 56 days. Three patients demonstrated partial responses to temozolomide, with a median time to maximal response of 5 months (range 4-12 months), and one had a minor response at 9 months. Four patients developed progression while on temozolomide, with a median time to progression of 7 months (range 1-12 months). Five patients had disease stabilization. Among the five patients with prior chemotherapy and/or radiation therapy, temozolomide was associated with disease stabilization in three and tumor response in one. In the three patients with neurofibromatosis type 1, two patients experienced tumor responses and one disease stabilization. Thrombocytopenia, nausea, emesis, and fatigue were the most common toxicities. Four patients discontinued therapy because of the side effects. CONCLUSIONS: Temozolomide is active in children with LGGs. It is effective in previously treated patients and in patients with neurofibromatosis type 1. The 42-day regimen appears less toxic than the 5-day regimen. Any impact on survival for these patients remains to be demonstrated