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Feasibility of Four Consecutive High-Dose Chemotherapy Cycles With Stem-Cell Rescue for Patients With Newly Diagnosed Medulloblastoma or Supratentorial Primitive Neuroectodermal Tumor After Craniospinal Radiotherapy: Results of a Collaborative Study

From the Department of Pediatrics, Baylor College of Medicine, Houston, TX; Departments of Hematology-Oncology and Biostatistics and Epidemiology, Division of Neurology, St Jude Children’s Research Hospital, and Department of Pediatrics, College of Medicine, University of Tennessee, Memphis, TN; and Department of Hematology Oncology, Royal Children’s Hospital, Melbourne, the Oncology Unit, The Children’s Hospital at Westmead, and The University of Sydney, Sydney, Australia.

Address reprint requests to Amar Gajjar, MD, Department of Hematology-Oncology, Rm 6024, St Jude Children’s Research Hospital, 332 North Lauderdale, Memphis, TN 38105-2794; email: amar.gajjar{at}stjude.org

PURPOSE: This study was designed to determine the feasibility and safety of delivering four consecutive cycles of high-dose cyclophosphamide, cisplatin, and vincristine, each followed by stem-cell rescue, every 4 weeks, after completion of risk-adapted craniospinal irradiation to children with newly diagnosed medulloblastoma or supratentorial primitive neuroectodermal tumor (PNET).

PATIENTS AND METHODS: Fifty-three patients, 19 with high-risk disease and 34 with average-risk disease, were enrolled onto this study. After surgical resection, high-risk patients were treated with topotecan in a 6-week phase II window followed by craniospinal radiation therapy and four cycles of high-dose cyclophosphamide (4,000 mg/m² per cycle), with cisplatin (75 mg/m² per cycle), and vincristine (two 1.5-mg/m² doses per cycle). Support with peripheral blood stem cells or bone marrow and with granulocyte colony-stimulating factor was administered after each cycle of high-dose chemotherapy. Treatment of average-risk patients consisted of surgical resection and craniospinal irradiation, followed by the same chemotherapy given to patients with high-risk disease. The expected duration of the chemotherapy was 16 weeks, with a cumulative cyclophosphamide dose of 16,000 mg/m² and a planned dose-intensity of 1,000 mg/m²/wk.

RESULTS: Fifty of the 53 patients commenced high-dose chemotherapy, and 49 patients completed all four cycles. The median length of chemotherapy cycles one through four was 28, 27, 29, and 28 days, respectively. Engraftment occurred at a median of 14 to 15 days after infusion of stem cells or autologous bone marrow. The intended dose-intensity of cyclophosphamide was 1,000 mg/m²/wk; the median delivered dose-intensity was 1,014, 1,023, 974, and 991 mg/m²/wk for cycles 1 through 4, respectively; associated median relative dose-intensity was 101%, 102%, 97%, and 99%. No deaths were attributable to the toxic effects of high-dose chemotherapy. Early outcome analysis indicates a 2-year progression-free survival of 93.6% ± 4.7% for the average-risk patients. For the high-risk patients, the 2-year progression-free survival is 73.7% ± 10.5% from the start of therapy and 84.2% ± 8.6% from the start of radiation therapy.

CONCLUSION: Administering four consecutive cycles of high-dose chemotherapy with stem-cell support after surgical resection and craniospinal irradiation is feasible in newly diagnosed patients with medulloblastoma/supratentorial PNET with aggressive supportive care. The early outcome results of this approach are very encouraging.

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