RESUMO
PURPOSE: To assess the antitumor activity, toxicity, and plasma pharmacokinetics of the combination of melphalan and topotecan for superselective ophthalmic artery infusion (SSOAI) treatment of children with retinoblastoma. DESIGN: Single-center, prospective, clinical pharmacokinetic study. PARTICIPANTS: Twenty-six patients (27 eyes) with intraocular retinoblastoma. METHODS: Patients with an indication for SSOAI received melphalan (3-6 mg) and topotecan (0.5-1 mg; doses calculated by age and weight). Plasma samples were obtained for pharmacokinetic studies, and a population approach via nonlinear mixed effects modeling was used. Safety and efficacy were assessed and compared with historical cohorts of patients treated with melphalan single-agent SSOAI. MAIN OUTCOME MEASURES: Melphalan and topotecan pharmacokinetic parameters and efficacy and safety parameters. RESULTS: Twenty-seven eyes from 26 consecutive patients received 66 cycles of SSOAI melphalan and topotecan in combination. All 5 eyes treated as primary therapy responded to the combination chemotherapy and were preserved. Sixteen of the 22 eyes with relapsed or resistant tumors responded, but 3 of them ultimately underwent enucleation at a median of 8 months (range, 7.9-9.1 months). The incidence of grade III and IV neutropenia was 10.6% and 1.5%, respectively, which was comparable with historical controls of single-agent SSOAI melphalan. No episode of fever neutropenia was observed, and no patient required transfusion of blood products. The large variability in melphalan pharmacokinetics was explained by body weight (P <0.05). Concomitant topotecan administration did not influence melphalan pharmacokinetic parameters. There was no effect of the sequence of melphalan and topotecan administration in plasma pharmacokinetics. CONCLUSIONS: A regimen combining melphalan and topotecan for SSOAI treatment of retinoblastoma is active and well tolerated. This combination chemotherapy previously showed synergistic pharmacologic activity, and we herein provide evidence of not increasing the hematologic toxicity compared with single-agent melphalan.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Neoplasias da Retina/metabolismo , Retinoblastoma/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Pré-Escolar , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Lactente , Infusões Intra-Arteriais , Masculino , Melfalan/administração & dosagem , Melfalan/farmacocinética , Artéria Oftálmica/efeitos dos fármacos , Estudos Prospectivos , Neoplasias da Retina/tratamento farmacológico , Neoplasias da Retina/patologia , Retinoblastoma/tratamento farmacológico , Retinoblastoma/patologia , Topotecan/administração & dosagem , Topotecan/farmacocinéticaRESUMO
La Enfermedad de Caroli es una malformación congénita caracterizada por dilatación multifocal de los conductos biliares segmentarios, generalmente asociada con fibrosis hepática y colangitis recurrente. Se presenta el caso de una paciente femenina de 15 años de edad, con epigastralgia crónica, ictericia, fiebre, vómitos y pérdida de peso, con múltiples episodios de colangitis que ameritaron hospitalización y estudios paraclínicos (Eco y TC abdominal y PCRE) compatibles con síndrome hepatoesplénico, dilatación de las vías biliares intrahepáticas y litisiasis múltiple intrahepática. Inicialmente, en otro centro asistencial, se le practicó colecistostomia, apendicectomia y biopsia hepática, la cual reportó fibrosis portal y septal, colestasis y daño hepatocelular focal. Es referencia a nuestro centro, concluyéndose el diagnóstico de Enfermedad Caroli, por lo cual se le realizó una hepatoyeyuno anastomosis en Y de Roux y colocación de tutores a cada conducto hepático para drenaje y lavado con solución estéril heparinizada de las vías biliares intrahepáticas. La colangiografía a través de los tutores evidenció la indemnidad de la anastomosis y dilatación de las vías biliares intrahepáticas con obstrucción parcial de pequeños conductos biliares.