RESUMEN
High risk/recurrent CNS tumors have a poor prognosis. We studied tandem high dose chemotherapy (HDC) with hematopoietic progenitor stem cell rescues (HPCR) as potentially curative therapy. Twenty-four patients (mean age 6.8 years) were enrolled, 19 underwent HDC/HPCR. Diagnoses were medulloblastoma (n = 9), germ cell tumor (n = 4), high grade astrocytoma (n = 2), supratentorial PNET (n = 1), pineoblastoma (n = 2), or papillary meningioma (n = 1). Cytoreduction regimen #1 consisted of carboplatin (500 mg/m(2)) x 3 days, etoposide (250 mg/m(2)) x 3 days, and thiotepa (300 mg/m(2)) x 3 days. Patients without progression or excessive toxicity (n = 11), received regimen #2 with melphalan (60 mg/m(2)) x 3 days and cyclophosphamide (1,500 mg/m(2)) x 4 days. Projected overall/event-free survival for the 19 patients was 51/37% and 34/28% at 1 and 5 years, respectively. Toxicity was significant with six treatment related deaths including four with veno-occlusive disease. This regimen of sequential HDC/HPCR in high risk/recurrent CNS tumor patients is not feasible due to toxicity.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Sistema Nervioso Central/terapia , Trasplante de Células Madre Hematopoyéticas/métodos , Adolescente , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Neoplasias del Sistema Nervioso Central/mortalidad , Niño , Preescolar , Terapia Combinada , Ciclofosfamida/administración & dosificación , Etopósido/administración & dosificación , Etopósido/efectos adversos , Femenino , Humanos , Lactante , Estimación de Kaplan-Meier , Masculino , Melfalán/administración & dosificación , Melfalán/efectos adversos , Tiotepa/administración & dosificación , Tiotepa/efectos adversos , Acondicionamiento PretrasplanteRESUMEN
PURPOSE: To determine the toxicity profile, dose-limiting toxicities (DLT), and maximum tolerated dose (MTD) of ABT-751 administered orally once daily for 21 days, repeated every 28 days in a pediatric population. EXPERIMENTAL DESIGN: Patients who were < or = 18 years with relapsed or refractory solid tumors and who were able to swallow capsules were eligible. The starting dose was 75 mg/m(2)/d (n = 3) and was escalated to 100 (n = 6), 130 (n = 5), and 165 (n = 3) mg/m(2)/d in cohorts of three to six patients. The MTD was determined from DLTs occurring during the first treatment cycle. RESULTS: Nineteen children (median age, 13 years; range, 5-18 years) were enrolled, and 17 were evaluable for toxicity. Diagnoses included neuroblastoma (n = 9), sarcomas (n = 9), and other solid tumors (n = 1). DLTs included fatigue, sensory neuropathy, transient hypertension, neutropenia, thrombocytopenia, nausea, vomiting, dehydration, abdominal pain, and constipation. The MTD of ABT-751 administered daily for 21 days every 28 days was 100 mg/m(2)/d. Non-DLT at the MTD included bone marrow suppression, gastrointestinal toxicities (anorexia, abdominal pain, nausea, vomiting, and constipation), and sensory and motor neuropathies. The median number of cycles administered was one (range, one to five). Tolerance of repeated treatment cycles was poor. CONCLUSION: Fatigue, hematologic, and gastrointestinal toxicities limited the tolerability of ABT-751 administered to children on the once daily for 21 days every 28 days schedule. The MTD in children with solid tumors (100 mg/m(2)/d daily for 21 days) was similar to the recommended dose in adults with solid tumors (200 mg fixed dose) receiving the same dosing schedule.
Asunto(s)
Neoplasias/tratamiento farmacológico , Sulfonamidas/administración & dosificación , Sulfonamidas/efectos adversos , Moduladores de Tubulina/administración & dosificación , Moduladores de Tubulina/efectos adversos , Adolescente , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Humanos , Dosis Máxima Tolerada , Recurrencia Local de Neoplasia/tratamiento farmacológicoRESUMEN
PURPOSE: To determine the toxicity profile, dose-limiting toxicities, and maximum tolerated dose of ABT-751 administered orally once daily for 7 days, repeated every 21 days. EXPERIMENTAL DESIGN: Patients who were =18 years of age, with relapsed or refractory solid tumors, and who were able to swallow capsules were eligible. The starting dose was 100 mg/m(2)/d (n = 3) and was escalated to 130 mg/m(2)/d (n = 6), 165 mg/m(2)/d (n = 6), 200 mg/m(2)/d (n = 6), and 250 mg/m(2)/d (n = 2) in cohorts of three to six patients. The maximum tolerated dose was determined from dose-limiting toxicities occurring during the first treatment cycle. RESULTS: Twenty-four children (median age, 13 years; range, 4-18 years) were enrolled; 23 were evaluable for toxicity. Diagnoses included neuroblastoma (n = 8), sarcomas (n = 8), primary brain tumors (n = 2), Wilms' tumor (n = 2), and other solid tumors (n = 3). Dose-limiting toxicities (grade 3 sensory and motor neuropathy, grade 3 hypertension, and grade 3 fatigue) were observed in patients enrolled at the 250 mg/m(2)/d dose level. The maximum tolerated dose of ABT-751 administered daily for 7 days every 21 days was 200 mg/m(2)/d. Non-dose-limiting toxicities at the maximum tolerated dose included anemia, fatigue, peripheral sensory neuropathy, abdominal pain, nausea, constipation, anorexia, fever, and weight loss. Myelosuppression was minimal at the maximum tolerated dose. The median number of cycles administered is 2 (range, 1-50). No significant ABT-751-related cumulative toxicities were observed. CONCLUSION: ABT-751 is well tolerated in children. The recommended dose for phase 2 trials in solid tumors is 200 mg/m(2)/d administered orally, daily for 7 days every 21 days. This dose is >40% higher than the maximum tolerated dose in adults receiving the same dosing schedule.