RESUMO
Local therapies are increasingly used for ocular preservation in retinoblastoma. In middle-income countries, these techniques pose specific challenges mostly related to more advanced disease at diagnosis. The Grupo de America Latina de Oncología Pediátrica (GALOP) developed a consensus document for the management of conservative therapy for retinoblastoma. Intra-arterial chemotherapy (OAC) is the preferred therapy, except for those with less advanced disease or age younger than 6 months. OAC allowed for a reduction in the use of external beam radiotherapy in our setting. Intravitreal chemotherapy is the preferred treatment for vitreous seeding. Enucleation is the treatment of choice for eyes with advanced disease.
Assuntos
Neoplasias da Retina , Retinoblastoma , Humanos , Lactente , Retinoblastoma/tratamento farmacológico , Neoplasias da Retina/tratamento farmacológico , Tratamento Conservador , Consenso , América do Sul , Estudos RetrospectivosRESUMO
BACKGROUND: The feasibility and results of intraarterial chemotherapy, also termed ophthalmic artery chemosurgery (OAC), for retinoblastoma in less developed countries have seldom been reported. PROCEDURE: A retrospective evaluation of a program of OAC in Argentina from 2010 to 2015. RESULTS: Ninety-seven eyes from 81 patients (61 bilateral) were analyzed. In 35 eyes, OAC was given as primary therapy and in 62 it was used for the treatment of tumors with partial response or those relapsing after systemic chemoreduction with focal therapy or external-beam radiotherapy. Twenty-two primarily treated eyes had group D and 13 groups B/C. A total of 400 procedures were carried out. Chemotherapy used included combinations of melphalan, carboplatin, and topotecan. There was no mortality associated with OAC. Toxicity included fever and neutropenia in five (1.25%), hypotension and bradycardia during anesthesia in two and femoral thrombosis in one, eyelid edema in nine, and neutropenia or thrombocytopenia in 28 cycles. With a median follow-up of 48.7 months (range 12-79), the 3-year probability of event-free survival (pEFS) (enucleation and/or radiotherapy were considered events) was comparable for patients who received first-line therapy and those treated at relapse (0.65 vs. 0.63, P = 0.5). In the former, the pEFS was 0.91 and 0.43 for groups B/C and D, respectively (P = 0.01). Two patients died of extraocular dissemination after refusal of enucleation. CONCLUSIONS: OAC was feasible with low toxicity. pEFS improved in all groups compared to the previous experience with systemic chemotherapy reducing the use of radiotherapy. The overall mortality associated with OAC is comparable to our previous experience with systemic chemoreduction.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Retina/tratamento farmacológico , Retinoblastoma/tratamento farmacológico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Argentina , Carboplatina/administração & dosagem , Criança , Pré-Escolar , Tratamento Conservador/métodos , Intervalo Livre de Doença , Estudos de Viabilidade , Feminino , Humanos , Infusões Intra-Arteriais , Masculino , Melfalan/administração & dosagem , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Artéria Oftálmica , Neoplasias da Retina/mortalidade , Retinoblastoma/mortalidade , Estudos Retrospectivos , Topotecan/administração & dosagem , Adulto JovemRESUMO
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
BACKGROUND: Treatment of eyes with retinoblastoma failing systemic chemoreduction and external beam radiotherapy is seldom efficacious. This study compares the efficacy and toxicity of intra-arterial ophthalmic artery chemotherapy (IAO) to our historical cohort of sequential periocular and systemic chemotherapy in such patients. PATIENTS AND METHODS: Eighteen eyes (15 consecutive patients) were retrospectively evaluated. Eight eyes received IAO for a median of four cycles (range: 2-9) including melphalan alone (n = 3) or after topotecan and carboplatin (n = 4) or topotecan and carboplatin without melphalan (n = 1). Ten eyes received a median of two cycles (range: 1-3) of periocular topotecan (n = 9) or carboplatin (n = 1) followed by intravenous topotecan and cyclophosphamide in three patients if at least stable disease was achieved. Both groups were comparable for disease extension and prior therapy. RESULTS: No extraocular dissemination or second malignancy occurred and all patients are alive. The probability of enucleation-free eye survival at 12 months was 0.87 (95% CI: 0.42-0.97) for the IAO group, compared to 0.1 (95% CI: 0.06-0.35) for the periocular group (P < 0.01). Ocular toxicity was mild and similar in both groups (mostly mild orbital edema). Systemic toxicity was low for IAO and periocular injection, but children who received sequentially intravenous chemotherapy (n = 12 cycles) had five episodes of grade 4 neutropenia, three of which resulted in hospitalizations. No case in the IAO group presented these complications. CONCLUSIONS: IAO is significantly superior to sequential periocular-intravenous topotecan-containing regimens in eyes with relapsed intraocular retinoblastoma with a more favorable toxicity profile.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias da Retina/tratamento farmacológico , Retinoblastoma/tratamento farmacológico , Terapia de Salvação , Administração Intravenosa , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Etoposídeo/administração & dosagem , Etoposídeo/uso terapêutico , Feminino , Humanos , Injeções Intra-Arteriais , Injeções Intraoculares , Masculino , Melfalan/administração & dosagem , Melfalan/efeitos adversos , Melfalan/uso terapêutico , Pessoa de Meia-Idade , Artéria Oftálmica , Neoplasias da Retina/patologia , Retinoblastoma/patologia , Estudos Retrospectivos , Topotecan/administração & dosagem , Topotecan/efeitos adversos , Topotecan/uso terapêutico , Resultado do Tratamento , Vincristina/administração & dosagem , Vincristina/uso terapêutico , Adulto JovemRESUMO
PURPOSE: To characterize melphalan pharmacokinetics after superselective ophthalmic artery infusion (SSOAI) in animals and children with retinoblastoma. METHODS: Vitreous and plasma samples of five Landrace pigs were obtained over a 4-hour period after SSOAI of melphalan (7 mg). Melphalan cytotoxicity was evaluated in retinoblastoma cell lines with and without topotecan. Plasma samples were obtained from 17 retinoblastoma patients after SSOAI of 3 to 6 mg of melphalan to one (n=14) or two eyes (n=3). Correlation between plasma pharmacokinetics and age, dosage, and systemic toxicity was studied in patients. RESULTS: In animals, melphalan peak vitreous levels were greater than its IC50 and resulted in 3-fold vitreous-to-plasma exposure. In patients, a large variability in pharmacokinetic parameters was observed and it was explained mainly by body weight (P<0.05). A significantly higher systemic area under the curve was obtained in children receiving more than 0.48 mg/kg for bilateral tandem infusions (P<0.05). These children had 50% probability of grades 3-4 neutropenia. Plasma concentrations after 2 and 4 hours of SSOAI were significantly higher in these children (P<0.05). A synergistic cytotoxic effect of melphalan and topotecan was evident in cell lines. CONCLUSIONS: Potentially active levels of melphalan after SSOAI were achieved in the vitreous of animals. Low systemic exposure was found in animals and children. Doses greater than 0.48 mg/kg, given for bilateral tandem infusions, were associated with significantly higher plasma levels and increased risk of neutropenia. Synergistic in vitro cytotoxicity between melphalan and topotecan favors combination treatment.
Assuntos
Melfalan/farmacocinética , Neoplasias da Retina/tratamento farmacológico , Retinoblastoma/tratamento farmacológico , Animais , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/farmacocinética , Linhagem Celular Tumoral , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Infusões Intra-Arteriais , Masculino , Melfalan/administração & dosagem , Neoplasias Experimentais , Artéria Oftálmica , Neoplasias da Retina/metabolismo , Neoplasias da Retina/patologia , Retinoblastoma/metabolismo , Retinoblastoma/patologia , Suínos , Corpo Vítreo/metabolismo , Corpo Vítreo/patologiaRESUMO
PURPOSE: To characterize the vitreous and plasma pharmacokinetics of topotecan after ophthalmic artery infusion (OAI) subsequent to superselective artery catheterization and to compare it with periocular injection (POI). METHODS: The ophthalmic artery of 4 pigs was catheterized and 1 mg of topotecan infused over a period of 30 minutes. The contralateral eye was subsequently used for administering topotecan by POI. Serial vitreous specimens were obtained by microdialysis and plasma samples collected and assayed for total and lactone topotecan. RESULTS: Maximum total topotecan concentration in the vitreous (median, range) was significantly higher after OAI compared with POI (131.8 ng/mL [112.9-138.7] vs. 13.6 ng/mL [5.5-15.3], respectively; P < 0.005). Median vitreous exposure calculated as area under the curve for total topotecan attained after OAI was significantly higher than after POI (299.8 ng·hour/mL [247.6-347.2] and 48.9 ng·hour/mL [11.8-63.4], respectively; P < 0.05). The vitreous to plasma exposure ratio was 29 after OAI and 3.4 after POI. Systemic exposure for total topotecan was low after both modalities of administration, with a trend to be lower after OAI compared with POI (10.6 ng·hour/mL [6.8-13.4] vs. 18.7 ng·hour/mL [6.3-21.7]; P = 0.54). CONCLUSION: Superselective OAI resulted in significantly higher vitreous concentrations and exposure and a trend toward lower systemic exposure than POI.
Assuntos
Artéria Oftálmica/metabolismo , Inibidores da Topoisomerase I/farmacocinética , Topotecan/farmacocinética , Corpo Vítreo/metabolismo , Animais , Área Sob a Curva , Disponibilidade Biológica , Cateterismo , Cromatografia Líquida de Alta Pressão , Infusões Intra-Arteriais , Injeções Intraoculares , Sus scrofaRESUMO
Objetivo. Resaltar la heterogeneidad de los aneurismas cerebrales en la población pediátrica. Material y método. 19 pacientes con 20 aneurismas intracraneanos fueron tratados en nuestro Hospital en los ultimos 6 años.Resultados. La edad media fue de 12 años (rango 10 meses a 17 años). 65 %de los aneurismas fueron saculares, 25% fusiformes, hubo un aneurisma infeccioso y otro lenticuloestriado distal. Los pacientes con aneurismas saculares fueron predominantemente varones y se manifestaron más comúnmente con hemorragia intracraneana (92%). Los aneurismas fusiformes se originaron posteriormente a una disección o fueron crónicos con trombo mural y ejerciendo efecto de masa. La terapéutica fue diferente según el tipo aneurismático. Conclusión. Los aneurismas pediátricos son un grupo heterogéneo de enfermedades arteriales intracraneanas con manifestaciones clínicas, morfología y terapéutica diferentes.(AU)
Assuntos
Aneurisma , Aneurisma Infectado , Aneurisma Intracraniano , PediatriaRESUMO
Objetivo. Resaltar la heterogeneidad de los aneurismas cerebrales en la población pediátrica. Material y método. 19 pacientes con 20 aneurismas intracraneanos fueron tratados en nuestro Hospital en los ultimos 6 años.Resultados. La edad media fue de 12 años (rango 10 meses a 17 años). 65 %de los aneurismas fueron saculares, 25% fusiformes, hubo un aneurisma infeccioso y otro lenticuloestriado distal. Los pacientes con aneurismas saculares fueron predominantemente varones y se manifestaron más comúnmente con hemorragia intracraneana (92%). Los aneurismas fusiformes se originaron posteriormente a una disección o fueron crónicos con trombo mural y ejerciendo efecto de masa. La terapéutica fue diferente según el tipo aneurismático. Conclusión. Los aneurismas pediátricos son un grupo heterogéneo de enfermedades arteriales intracraneanas con manifestaciones clínicas, morfología y terapéutica diferentes.
Assuntos
Aneurisma , Aneurisma Infectado , Aneurisma Intracraniano , PediatriaRESUMO
PURPOSE: This study aims to analyze the clinical and radiological findings, timing and type of treatment, and outcome in children under 1 year of age that presented with neurosurgical vascular malformations. METHODS: A retrospective review of 23 children under 1 year of age with neurosurgical vascular malformations was performed at a single institution between 1999 and 2009. RESULTS: The lesions found in this age group were: 10 vein of Galen aneurysmal malformations (VGAMs), 5 arteriovenous malformations (AVM), 2 pial arteriovenous fistulas (AVF; 1 in the brain and 1 in the spinal cord), 2 cavernous malformations, 2 dural sinus malformations (DSMs) in the posterior fossa with negative angiography which after surgery turned out to be embryonal malformations of dural sinuses, 1 sacular aneurysm, and 1 dural arteriovenous fistula (DAVF) that drained toward the vein of Galen. Of the 10 patients with VGAM, 8 presented choroidal type and 2 mural type. Two patients with choroidal VGAM were born in dramatically severe clinical condition; therefore, we decided to withhold aggressive treatment, and they died within 48 h after birth. The other eight patients with choroidal VGAM received endovascular treatment between 1 and 3 staged embolizations. In four of them, total occlusion was achieved and subtotal and partial in the others. One patient had complications and evolved with severe developmental delay. Another patient with partial occlusion died, and another patient with previous developmental delay stopped treatment because of parental decision making. Five patients evolved with normal development and one with mild delay. Only one patient required shunt. Hydrocephalus was solved after endovascular treatment in the rest of the patients. Regarding the five AVMs, four were treated with microsurgical approach achieving total resection of the lesion and normal developmental milestones except for one patient with brainstem AVM that was admitted with quadriparesis and coma. In the patient with basal ganglia AVM, the lesion spontaneously disappeared. From the two pial AVFs, the frontal one was microsurgically treated and the spinal one received endovascular session achieving 50% of lesion occlusion for which further treatment is needed. The two cavernous malformations were operated achieving total resection with normal development. The two children with DSM received surgical resection without complications and normal development. The rare case of sacular aneurysm at this age was occluded at the time of diagnostic procedure due to the bad clinical condition of the patient and the hematoma was removed immediately in the operating room. The only case of DAVF died of respiratory intercurrence after three sessions of endovascular treatment. CONCLUSIONS: In this neonatal age group (first year of life), we can find the whole range of neurosurgical vascular pathology: VGAM, AVM, cavernous malformation, DSM, pial AVF, DAVF, and sacular aneurysm. VGAM is the most frequent vascular malformation during the first year of age. The early treatment of vascular malformations prevents its adverse effects on a developing brain. A multidisciplinary team composed by endovascular and surgical specialists is necessary to discuss and treat each case.
Assuntos
Malformações Vasculares do Sistema Nervoso Central/diagnóstico por imagem , Malformações Vasculares do Sistema Nervoso Central/cirurgia , Embolização Terapêutica/métodos , Procedimentos Endovasculares/métodos , Procedimentos Neurocirúrgicos/métodos , Fatores Etários , Malformações Vasculares do Sistema Nervoso Central/classificação , Malformações Vasculares do Sistema Nervoso Central/terapia , Angiografia Cerebral , Procedimentos Endovasculares/efeitos adversos , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Procedimentos Neurocirúrgicos/efeitos adversos , Estudos Retrospectivos , Resultado do Tratamento , Malformações da Veia de Galeno/diagnóstico por imagem , Malformações da Veia de Galeno/cirurgiaRESUMO
PURPOSE: The objective of this article is to highlight the fact that cerebral aneurysms in children are heterogeneous unlike in the adult population. MATERIAL AND METHODS: This is a retrospective review of 17 children with intracranial aneurysms who were managed at a single institution from 2004 to 2009. RESULTS: The median age was 12 years (range 10 months-17 years). Sixty-five percent of the aneurysms were saccular and 24% were fusiform. There was one infectious and one distal lenticulostriate aneurysm. Patients with saccular aneurysms were predominantly male and presented more commonly with intracranial hemorrhage (91%). The fusiform aneurysms were dissecting in nature or chronic with intramural thrombus and mass effect. The treatment was dependent upon the type and location of the aneurysm. CONCLUSION: Pedriatic aneurysms are a heterogeneous group of intracranial arterial diseases with different etiologies, diverse morphology, and dissimilar clinical manifestations.