RESUMEN
BACKGROUND: Intra-arterial chemotherapy is a new retinoblastoma treatment associated with high rates of globe salvage that has been widely adopted for primary treatment of retinoblastoma but is less frequently used as secondary treatment for refractory retinoblastoma. This systematic review aims to summarize the reported outcomes of intra-arterial chemotherapy for refractory retinoblastoma. METHODS: We conducted a systematic review of studies published on PubMed, Medline, and Embase from 2011 to 2021 reporting globe salvage rates following intra-arterial chemotherapy for secondary treatment of refractory retinoblastoma. RESULTS: Our search yielded 316 studies, and 24 met inclusion criteria. The 24 included studies were comprised of 1366 patients and 1757 eyes. Among these, 1184 (67%) eyes received secondary indication treatment, and globe salvage was achieved for 776 of these 1184 eyes (64%). Sixteen studies reported cannulation success rates from 71.8 to 100%. Pooled analysis of subjects revealed 21 patients (2.6%) with metastatic disease and 26 deaths (3%) during study follow-up periods (7-74 months). The most common ocular complications were vitreous hemorrhage (13.2%), loss of eyelashes (12.7%), and periocular edema (10.5%). The most common systemic complications were nausea/vomiting (20.5%), neutropenia (14.1%), fever (8.2%), and bronchospasm (6.2%). CONCLUSIONS: Intra-arterial chemotherapy is associated with high rates of globe salvage and low rates of serious complications in patients with refractory retinoblastoma. Unfortunately, current literature is predominantly comprised of retrospective case studies, and further high-quality evidence is necessary to inform clinical practice.
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Resistencia a Antineoplásicos , Neoplasias de la Retina/tratamiento farmacológico , Retinoblastoma/tratamiento farmacológico , Terapia Recuperativa/métodos , Antineoplásicos/administración & dosificación , Espasmo Bronquial/inducido químicamente , Carboplatino/administración & dosificación , Edema/inducido químicamente , Pestañas/efectos de los fármacos , Neutropenia Febril/inducido químicamente , Humanos , Infusiones Intraarteriales/efectos adversos , Infusiones Intraarteriales/métodos , Melfalán/administración & dosificación , Metotrexato/administración & dosificación , Náusea/inducido químicamente , Neoplasias de la Retina/mortalidad , Neoplasias de la Retina/radioterapia , Retinoblastoma/mortalidad , Retinoblastoma/radioterapia , Terapia Recuperativa/efectos adversos , Terapia Recuperativa/estadística & datos numéricos , Topotecan/administración & dosificación , Hemorragia Vítrea/inducido químicamente , Vómitos/inducido químicamenteRESUMEN
Patients with retinoblastoma and central nervous system (CNS) involvement are rarely curable with available treatments. We designed a high-dose intra-arterial regimen targeting the ophthalmic artery and chiasm combined with intrathecal chemotherapy to treat a 4-year-old patient with retinoblastoma metastasized to the CNS. After three cycles of this regimen, including carboplatin, melphalan, and intrathecal topotecan, a partial response of the orbital tumor mass and chiasmatic lesion, and complete response in the cerebrospinal fluid and bone marrow were achieved. This new treatment strategy may be explored as a treatment component for patients with overt extraocular retinoblastoma and CNS dissemination.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Retina/tratamiento farmacológico , Retinoblastoma/tratamiento farmacológico , Carboplatino/administración & dosificación , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Neoplasias del Sistema Nervioso Central/secundario , Preescolar , Humanos , Infusiones Intraarteriales , Inyecciones Espinales , Masculino , Melfalán/administración & dosificación , Neoplasias de la Retina/patología , Retinoblastoma/secundario , Topotecan/administración & dosificaciónRESUMEN
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.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Retina/tratamiento farmacológico , Retinoblastoma/tratamiento farmacológico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Argentina , Carboplatino/administración & dosificación , Niño , Preescolar , Tratamiento Conservador/métodos , Supervivencia sin Enfermedad , Estudios de Factibilidad , Femenino , Humanos , Infusiones Intraarteriales , Masculino , Melfalán/administración & dosificación , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Arteria Oftálmica , Neoplasias de la Retina/mortalidad , Retinoblastoma/mortalidad , Estudios Retrospectivos , Topotecan/administración & dosificación , Adulto JovenRESUMEN
PURPOSE: Since combined strategy with cisplatin, etoposide, and irinotecan has shown the superiority to topotecan alone as second-line chemotherapy in patients with sensitive relapsed small-cell lung cancer, this study aimed to compare these two treatments based on JCOG0605 trail from Chinese cost-effectiveness perspective. METHODS: Basic medical information was derived from a multicenter, open-label, randomized phase III trial (JCOG0605). A Markov model including three health states: progression-free state, progressive disease (PD), and death, was developed to simulate the process of sensitive relapsed small-cell lung cancer. Cost was calculated from the perspective of Chinese society. Sensitivity analyses were applied to explore the impact of essential variables. RESULTS: Treatment with combination chemotherapy was estimated to increase costs by $6947.32 compared with topotecan alone, with a gain of 0.26 quality-adjusted life years (QALYs). Thus, the incremental cost-effective ratio was $26720.46/QALY for combination treatment versus monotherapy, which was beyond the threshold of 3 × the per capita GDP of China, $24423.00. The costs of PD state were the most influential factors to the model. CONCLUSION: The combination chemotherapy with cisplatin, etoposide, and irinotecan was not a cost-effectiveness choice for patients with sensitive relapsed SCLC in China from the cost-effectiveness perspective.
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Protocolos de Quimioterapia Combinada Antineoplásica/economía , Análisis Costo-Beneficio , Neoplasias Pulmonares/economía , Recurrencia Local de Neoplasia/economía , Carcinoma Pulmonar de Células Pequeñas/economía , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Cisplatino/administración & dosificación , Etopósido/administración & dosificación , Estudios de Seguimiento , Humanos , Irinotecán , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Pronóstico , Años de Vida Ajustados por Calidad de Vida , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/patología , Tasa de Supervivencia , Topotecan/administración & dosificaciónRESUMEN
OBJECTIVES: This work aimed to evaluate semisolid formulations containing topotecan (TPT) loaded nanostructured lipid carriers (NLC) for topical treatment of skin cancers, as TPT is effective against a variety of tumours. A formulation which increases TPT skin permeation would be extremely desirable. METHODS: TPT-NLC were prepared and incorporated in hydrogels with hydroxyethyl cellulose and chitosan (TPT-NLC-HEC and TPT-NLC-Ch, respectively). Control formulations were obtained by dispersing TPT in HEC and Ch hydrogels (TPT-HEC and TPT-Ch). KEY FINDINGS: TPT-NLC-HEC and TPT-NLC-Ch showed to maintain the drug and nanoparticle dispersions stable for up to 30 days. When nanoparticles were incorporated into gels, TPT release was significantly decreased (P < 0.05). Still, TPT-NLC-HEC increased 2.37 times permeation compared with TPT-HEC (11.9 and 5.0 µg/cm2 , respectively). Cell culture experiments with B16F10 melanoma demonstrated that nanoencapsulation significantly increased TPT cytotoxicity (P < 0.05). TPT-NLC was more toxic than free TPT, with IC50 value of 5.74 µg/ml, whereas free TPT had an IC50 > 20 µg/ml. As skin permeated values of TPT from developed formulation (TPT-NLC) were superior to melanoma IC50, it can be extrapolated that chemotherapeutic permeated amounts may be sufficient for a therapeutic effect. CONCLUSIONS: TPT-NLC-HEC may be a valuable tool for the topical treatment of skin cancers.
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Portadores de Fármacos/administración & dosificación , Melanoma Experimental/tratamiento farmacológico , Nanopartículas/administración & dosificación , Absorción Cutánea/fisiología , Neoplasias Cutáneas/tratamiento farmacológico , Topotecan/administración & dosificación , Administración Tópica , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/metabolismo , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Relación Dosis-Respuesta a Droga , Portadores de Fármacos/metabolismo , Hidrogeles/administración & dosificación , Hidrogeles/metabolismo , Lípidos/administración & dosificación , Melanoma Experimental/metabolismo , Ratones , Nanopartículas/metabolismo , Técnicas de Cultivo de Órganos , Absorción Cutánea/efectos de los fármacos , Neoplasias Cutáneas/metabolismo , Porcinos , Inhibidores de Topoisomerasa I/administración & dosificación , Inhibidores de Topoisomerasa I/metabolismo , Topotecan/metabolismo , Resultado del TratamientoRESUMEN
OBJECTIVES: We characterized and compared the in-vivo absorption of topotecan into the aqueous humor after instillation of aqueous and ointment formulations. METHODS: A lanolin/petrolatum ointment was used. New Zealand rabbits were instilled with topotecan solution (6 µg, group A), a single 10 µg dose of topotecan ointment (group B) or with five 10 µg doses of topotecan ointment (group C). Aqueous humor samples were collected at different times. Corneal samples were collected only for group A. Topotecan was quantified using HPLC, and pharmacokinetic parameters were calculated. Acute corneal epithelial toxicity was assessed after multiple instillations of topotecan ointment. KEY FINDINGS: Total topotecan maximum aqueous humor concentration (Cmax ) was 16.1, 69.9 and 287 ng/ml in group A, B and C, respectively. A single dose of topotecan ointment increased threefold and sevenfold the aqueous humor Cmax , and exposure compared to the aqueous formulation. Aqueous humor concentrations from group C eyes were substantially above the cytotoxic concentration for retinoblastoma cells. No corneal toxicity was evident after ointment instillation. CONCLUSIONS: Topotecan penetrated into the aqueous humor of the rabbit eye after multiple doses of an ointment in concentrations pharmacologically active against retinoblastoma cells without eliciting acute toxicity. Topotecan ointment may translate to the clinical treatment of anterior segment disseminated retinoblastoma.
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Soluciones Oftálmicas/administración & dosificación , Soluciones Oftálmicas/farmacocinética , Retinoblastoma/tratamiento farmacológico , Topotecan/administración & dosificación , Topotecan/farmacocinética , Cuerpo Vítreo/efectos de los fármacos , Administración Tópica , Animales , Humor Acuoso/efectos de los fármacos , Córnea/efectos de los fármacos , Conejos , Distribución TisularRESUMEN
PURPOSE: To review preclinical and clinical pharmacokinetic studies of the three most important chemotherapy drugs used for intraocular retinoblastoma and the contribution of the reported results to optimize treatment. METHODS: Systemic review of pharmacokinetic studies identified by a literature search at Pubmed using the keywords carboplatin, melphalan, topotecan, intravitreal, ophthalmic artery chemosurgery, pharmacokinetics, and retinoblastoma. RESULTS: A total of 21 studies were reviewed for assessing the preclinical and clinical pharmacokinetics of carboplatin, topotecan, and melphalan delivered by intravenous, periocular, ophthalmic artery, and intravitreal routes. Some preclinical studies were done before translation to the clinics. Others, despite encouraging preclinical data as reported for periocular topotecan did not correlate with clinical use. In addition, as was the case for melphalan after ophthalmic artery chemosurgery and despite nonfavorable preclinical information, some routes of drug delivery are clinically effective. Besides topotecan, complete knowledge of the pharmacokinetics of melphalan and carboplatin is still lacking. CONCLUSION: Pharmacokinetic knowledge of chemotherapy may aid to guide retinoblastoma treatment in favor of safety and efficacy. Nonetheless, results obtained in preclinical models should be translated with care to the clinics.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carboplatino/farmacocinética , Melfalán/uso terapéutico , Neoplasias de la Retina/tratamiento farmacológico , Retinoblastoma/tratamiento farmacológico , Topotecan/farmacocinética , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carboplatino/administración & dosificación , Carboplatino/uso terapéutico , Ensayos Clínicos como Asunto , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Humanos , Infusiones Intraarteriales , Inyecciones Intraoculares , Melfalán/administración & dosificación , Melfalán/farmacocinética , Topotecan/administración & dosificación , Topotecan/uso terapéuticoRESUMEN
INTRODUCTION: Intra-arterial chemotherapy is a novel therapeutic modality for retinoblastoma patients. Intra-arterial chemotherapy involves the administration of a super-selective drug through the ophthalmic artery, resulting in better ocular penetration and low systemic toxicity. OBJECTIVE: The aim of this report was to evaluate the feasibility of intra-arterial chemotherapy in a large referral center in Mexico City. METHODS: We included patients with bilateral retinoblastoma, one enucleation, and active disease in the other eye after at least two courses of systemic chemotherapy combined with topical treatments. All patients were treated with three courses of a combination of melphalan 4 mg and topotecan 1 mg. Patients were examined under general anesthesia three weeks after each chemotherapy cycle. RESULTS: From 14 eligible patients, three could not be treated due to inaccessibility of the ophthalmic artery. A complete response was observed in 5/11 patients, three in Stage C according to the International Classification for Intraocular Retinoblastoma, one in Stage D, and one in Stage B. The eyes of three patients were enucleated as a result of active/progressive disease, one in Stage B and two in Stage D. Eye preservation was 55% after a mean follow-up of 171 days (range 21-336). CONCLUSIONS: Super-selective intra-arterial chemotherapy is safe and effective for preventing the enucleation of 55% of affected eyes in this group of patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Retina/tratamiento farmacológico , Retinoblastoma/tratamiento farmacológico , Terapia Recuperativa/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Lactante , Inyecciones Intraarteriales , Estudios Longitudinales , Masculino , Melfalán/administración & dosificación , México , Arteria Oftálmica , Estudios Prospectivos , Neoplasias de la Retina/patología , Retinoblastoma/patología , Topotecan/administración & dosificación , Resultado del TratamientoRESUMEN
Treatment of retinoblastoma, the most common primary ocular malignancy in children, has greatly improved over the last decade. Still, new devices for chemotherapy are needed to achieve better tumor control. The aim of this project was to develop an ocular drug delivery system for topotecan (TPT) loaded in biocompatible hydrogels of poly(ε-caprolactone)-poly(ethyleneglycol)-poly(ε-caprolactone) block copolymers (PCL-PEG-PCL) for sustained TPT release in the vitreous humor. Hydrogels were prepared from TPT and synthesized PCL-PEG-PCL copolymers. Rheological properties and in vitro and in vivo TPT release were studied. Hydrogel cytotoxicity was evaluated in retinoblastoma cells as a surrogate for efficacy and TPT vitreous pharmacokinetics and systemic as well as ocular toxicity were evaluated in rabbits. The pseudoplastic behavior of the hydrogels makes them suitable for intraocular administration. In vitro release profiles showed a sustained release of TPT from PCL-PEG-PCL up to 7days and drug loading did not affect the release pattern. Blank hydrogels did not affect retinoblastoma cell viability but 0.4% (w/w) TPT-loaded hydrogel was highly cytotoxic for at least 7days. After intravitreal injection, TPT vitreous concentrations were sustained above the pharmacologically active concentration. One month after injection, animals with blank or TPT-loaded hydrogels showed no systemic toxicity or retinal impairment on fundus examination, electroretinographic, and histopathological assessments. These novel TPT-hydrogels can deliver sustained concentrations of active drug into the vitreous with excellent biocompatibility in vivo and pronounced cytotoxic activity in retinoblastoma cells and may become an additional strategy for intraocular retinoblastoma treatment.
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Hidrogeles/química , Topotecan/administración & dosificación , Topotecan/química , Animales , Línea Celular Tumoral , Preparaciones de Acción Retardada , Sistemas de Liberación de Medicamentos/métodos , Humanos , Poliésteres/química , Polietilenglicoles/química , Conejos , Retina/metabolismo , Retinoblastoma/tratamiento farmacológico , Topotecan/uso terapéuticoRESUMEN
Extraocular retinoblastoma is a major challenge worldwide, especially in developing countries. Current treatment involves the administration of systemic chemotherapy combined with radiation, but there is a clear need for improvement of chemotherapy bioavailability in the optic nerve. Our aim was to study the ophthalmic artery chemosurgery (OAC) local route for drug delivery assessing ocular and optic nerve exposure to chemotherapy and to compare it to exposure after intravenous infusion (IV) of the same dose in an animal model. Topotecan was used as a prototype drug that is active in retinoblastoma and based on the extensive knowledge of its pharmacokinetics in preclinical and clinical settings. Five Landrace pigs received 4mg of topotecan via OAC as performed in retinoblastoma patients. At the end of the infusion, the eyes were enucleated, the optic nerve and retina were dissected, and the vitreous and plasma were separated. After recovery and a wash-out period, the animals received a 30-min IV infusion of topotecan (4 mg). The remaining eye was enucleated and tissues and fluids were separated. All samples were stored until quantitation using HPLC. A significantly higher concentration of topotecan in the optic nerve, vitreous, and retina was obtained in eyes after OAC compared to IV infusion (p<0.05). The median (range) ratio between topotecan concentration attained after OAC to IV infusion in the optic nerve, retina and vitreous was 84(54-668), 143(49-200) and 246(56-687), respectively. However, topotecan systemic exposure after OAC and IV infusion remained comparable (p>0.05). The median optic nerve-to-plasma ratio after OAC and IV was 44 and 0.35, respectively. Topotecan OAC delivery attained an 80-fold higher concentration in the optic nerve compared to the systemic infusion of the same dose with similar plasma concentrations in a swine model. Patients with retinoblastoma extension into the optic nerve may benefit from OAC for tumor burden by increased chemotherapy bioavailability in the optic nerve without increasing systemic exposure or toxicity.
Asunto(s)
Arteria Oftálmica/cirugía , Nervio Óptico/metabolismo , Topotecan/farmacocinética , Animales , Infusiones Intraarteriales , Porcinos , Topotecan/administración & dosificaciónRESUMEN
PURPOSE: We report the response rate in children older than 18 months with stage 4 Neuroblastoma, using a modified dose-intensive, response-adaptive, induction mN7 protocol. METHODS: From 2005 to 2012, 24 patients were treated with the mN7 protocol. Phase 1 included five MSKCC N7 cycles and surgery and two high-dose cyclophosphamide-topotecan (HD-CT) cycles for those who did not achieve complete remission (CR) and negative bone marrow (BM) minimal residual disease (MRD) status (CR+MRD-). Phase 2 consisted of myeloablative doses of topotecan, thiotepa and carboplatin plus hyperfractionated RT. Phase 3 included isotretinoin and 3F8 immunotherapy plus GM-CSF. BM MRD was monitored using GD2 synthase, PHOX2B and cyclin D1 mRNAs. RESULTS: After 3 cycles, all patients showed BM complete histological clearance and 6 (25 %) were MRD-. Twenty of 21 s-look surgeries achieved macroscopic complete resection. After 5 cycles and surgery, (123)I-MIBG scan was negative in 15 (62.5 %) cases, BM disease by histology was negative in 23 (96 %) and 10 (42 %) patients were MRD-. Twelve (50 %) pts were in CR, 2 in very good partial response (VGPR), 9 partial response (PR) and one had progressive disease. With 2 HD-CT extra cycles, 17 (71 %) pts achieved CR+MRD- status moving to phase 2. Overall and event-free survival at 3 years for the 17 patients who achieved CR+MRD- is 65 and 53 %, respectively, median follow-up 47 months. Seven (29 %) patients never achieved CR+MRD-. Univariate Cox regression analysis shows CR+MRD- status after mN7 induction as the only statistically significant prognostic factor to predict overall survival. CONCLUSIONS: mN7 induction regimen produced a CR+MRD- rate of 71 %. CR+MRD- status following induction was the only predictive marker of long-term survival.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Médula Ósea/patología , Neoplasias Encefálicas/tratamiento farmacológico , Quimioterapia de Consolidación/métodos , Quimioterapia de Inducción/métodos , Neuroblastoma/tratamiento farmacológico , Procedimientos Neuroquirúrgicos , Carboplatino/administración & dosificación , Niño , Preescolar , Cisplatino/administración & dosificación , Estudios de Cohortes , Ciclofosfamida/administración & dosificación , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Etopósido/administración & dosificación , Femenino , Humanos , Inmunoterapia , Lactante , Isotretinoína/administración & dosificación , Masculino , Terapia Neoadyuvante , Estadificación de Neoplasias , Neuroblastoma/patología , Proyectos Piloto , Estudios Prospectivos , Radioterapia , Tiotepa/administración & dosificación , Topotecan/administración & dosificación , Resultado del Tratamiento , Vincristina/administración & dosificaciónRESUMEN
Intra-arterial chemotherapy (IAC) has proved to be an effective treatment for retinoblastoma, but can be very expensive in developing countries. We report 2 patients from Chile in whom IAC resulted in globe salvation. Both patients had their medical care provided by the public health system and had failed standard therapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/economía , Análisis Costo-Beneficio , Infusiones Intraarteriales/economía , Neoplasias de la Retina/tratamiento farmacológico , Retinoblastoma/tratamiento farmacológico , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Chile , Países en Desarrollo , Costos de los Medicamentos , Humanos , Lactante , Masculino , Melfalán/administración & dosificación , Neoplasias de la Retina/patología , Retinoblastoma/patología , Topotecan/administración & dosificaciónRESUMEN
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.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Neoplasias de la Retina/metabolismo , Retinoblastoma/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Niño , Preescolar , Cromatografía Líquida de Alta Presión , Femenino , Humanos , Lactante , Infusiones Intraarteriales , Masculino , Melfalán/administración & dosificación , Melfalán/farmacocinética , Arteria Oftálmica/efectos de los fármacos , Estudios Prospectivos , Neoplasias de la Retina/tratamiento farmacológico , Neoplasias de la Retina/patología , Retinoblastoma/tratamiento farmacológico , Retinoblastoma/patología , Topotecan/administración & dosificación , Topotecan/farmacocinéticaRESUMEN
OBJECTIVE: This retrospective analysis evaluates the clinical outcomes of extensive-stage small cell lung cancer (SCLC) patients who received second-line chemotherapy after platinum-based first-line chemotherapy, especially focusing on efficacy and toxicity between single-agent and combination chemotherapy. METHODS: We retrospectively reviewed 193 patients who received second-line chemotherapy for extensive-stage SCLC. Patients relapsing or progressing beyond 90 days were defined as sensitive recurrence patients, and below 90 days as refractory recurrence patients. Survival curves were plotted using the Kaplan-Meier method. The Cox proportional hazard model was used for multivariate analysis. RESULTS: 138 patients received combination chemotherapy and 55 received single-agent treatment. The objective response rate (ORR) was 25.4 % in the combination group and 9.1 % in the single-agent group (p = 0.012). The disease control rate (DCR) was 65.2 and 34.5 %, respectively, (p < 0.001). The progression-free survival (PFS) was 3.80 months in the combination group and 2.13 months in the single-agent group (p = 0.001). In the sensitive recurrence group, the median PFS was 3.80 months in combination group and 3.23 months in single-agent group (p = 0.092). In the refractory recurrence group, the median PFS was 2.83 and 1.30 months, respectively (p = 0.001). The grade III/IV toxicity in single-agent group is much lower than the combination group (56.4 vs. 74.6 %, p = 0.013). CONCLUSION: Our retrospective data suggest a potential role of prolonging the PFS for combination treatment in extensive-stage SCLC second-line treatment, especially for the refractory recurrence patients, but with more toxicity as compared to single-agent.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Terapia Recuperativa , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Anciano , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Docetaxel , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Estudios de Seguimiento , Humanos , Irinotecán , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Paclitaxel/administración & dosificación , Platino (Metal)/administración & dosificación , Pronóstico , Estudios Retrospectivos , Carcinoma Pulmonar de Células Pequeñas/patología , Tasa de Supervivencia , Taxoides/administración & dosificación , Topotecan/administración & dosificaciónRESUMEN
Treatment of intraocular retinoblastoma with vitreous seeding is a challenge. Different routes of chemotherapy administration have been explored in order to attaining pharmacological concentrations into the posterior chamber. Intravitreal drug injection is a promissing route for maximum bioavailability to the vitreous but it requires a well defined dose for achieving tumor control while limited toxicity to the retina. Topotecan proved to be a promising agent for retinoblastoma treatment due to its pharmacological activity and limited toxicity. High and prolonged concentrations were achieved in the rabbit vitreous after 5 µg of intravitreal topotecan. However, whether a lower dose could achieve potentially therapeutic levels remained to be determined. Thus, we here study the pharmacokinetics of topotecan after 0.5 µg and the toxicity profile of intravitreal topotecan in the rabbit eye as a potential treatment of retinoblastoma. A cohort of rabbits was used to study topotecan disposition in the vitreous after a single dose of 0.5 µg of intravitreal topotecan. In addition, an independent cohort of non-tumor bearing rabbits was employed to evaluate the clinical and retinal toxicity after four weekly injections of two different doses of intravitreal topotecan (Group A, 5 µg/dose; Group B, 0.5 µg/dose) to the right eye of each animal. The same volume (0.1 ml) of normal saline was administered to the left eye as control. A third group of rabbits (Group C) served as double control (both eyes injected with normal saline). Animals were weekly evaluated for clinical and hematologic values and ocular evaluations were performed with an inverse ophthalmoscope to establish potential topotecan toxicity. Weekly controls included topotecan quantitation in plasma of all rabbits. Electroretinograms (ERGs) were recorded before and after topotecan doses. One week after the last injection, topotecan concentrations were measured in vitreous of all eyes and samples for retinal histology were obtained. Our results indicate that topotecan shows non linear pharmacokinetics after a single intravitreal dose in the range of 0.5-5 µg in the rabbit. Vitreous concentration of lactone topotecan was close to the concentration assumed to be therapeutically active after 5 h of 0.5 µg intravitreal administration. Eyes injected with four weekly doses of topotecan (0.5 or 5 µg/dose) showed no significant differences in their ERG wave amplitudes and implicit times in comparison with control (p > 0.05). Animals showed no weight, hair loss or significant changes in hematologic values during the study period. There were no significant histologic damage of the retinas exposed to topotecan treatments. After intravitreal administration no topotecan could be detected in plasma during the follow-up period nor in the vitreous of treated and control animals after 1 week of the last injection. The present data shows that four weekly intravitreal injection of 5 µg of topotecan is safe for the rabbit eye. Despite multiple injections of 0.5 µg of topotecan are also safe to the rabbit eye, lactone topotecan vitreous concentrations were potentially active only after 5 h of the administration. We postulate promising translation to clinics for retinoblastoma treatment.
Asunto(s)
Neoplasias de la Retina/tratamiento farmacológico , Retinoblastoma/tratamiento farmacológico , Inhibidores de Topoisomerasa I/administración & dosificación , Inhibidores de Topoisomerasa I/toxicidad , Topotecan/administración & dosificación , Topotecan/toxicidad , Animales , Esquema de Medicación , Electrorretinografía , Inyecciones Intravítreas , Modelos Biológicos , Dinámicas no Lineales , Oftalmoscopía , Conejos , Retina/efectos de los fármacos , Retina/metabolismo , Retina/patología , Inhibidores de Topoisomerasa I/farmacocinética , Topotecan/farmacocinética , Cuerpo Vítreo/metabolismoRESUMEN
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.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias de la Retina/tratamiento farmacológico , Retinoblastoma/tratamiento farmacológico , Terapia Recuperativa , Administración Intravenosa , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Etopósido/administración & dosificación , Etopósido/uso terapéutico , Femenino , Humanos , Inyecciones Intraarteriales , Inyecciones Intraoculares , Masculino , Melfalán/administración & dosificación , Melfalán/efectos adversos , Melfalán/uso terapéutico , Persona de Mediana Edad , Arteria Oftálmica , Neoplasias de la Retina/patología , Retinoblastoma/patología , Estudios Retrospectivos , Topotecan/administración & dosificación , Topotecan/efectos adversos , Topotecan/uso terapéutico , Resultado del Tratamiento , Vincristina/administración & dosificación , Vincristina/uso terapéutico , Adulto JovenRESUMEN
Primitive neuroectodermal tumor (PNET) is most common in the second decade of life. Congenital PNET is very rare. Ocular metastasis of PNET is likewise exceedingly rare; with only 5 previously published cases. We report an unusual congenital PNET of the face, which metastasized to subcutis, eyes, and brain. The primary tumor responded to chemotherapy (vincristine/doxorubicin/cyclophosphamide) with metachronous progression of ocular lesions. A therapeutic trial of intraocular bevacizumab showed no efficacy on intraocular lesions. Eventually the patient developed cerebral metastasis, and second line therapy with topotecan/cyclophosphamide was initiated. The tumor progressed and the patient died after acute herniation.
Asunto(s)
Neoplasias del Ojo/secundario , Tumores Neuroectodérmicos Primitivos/congénito , Tumores Neuroectodérmicos Primitivos/patología , Neoplasias de los Tejidos Blandos/congénito , Neoplasias de los Tejidos Blandos/patología , Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bevacizumab , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Neoplasias del Ojo/terapia , Cara/patología , Resultado Fatal , Humanos , Recién Nacido , Masculino , Tumores Neuroectodérmicos Primitivos/terapia , Neoplasias de los Tejidos Blandos/terapia , Topotecan/administración & dosificación , Vincristina/administración & dosificaciónRESUMEN
INTRODUCTION: Cervical cancer is the third most prevalent cancer in females worldwide. When advanced, the disease requires primary radiation concurrent with chemotherapy. However, chemotherapy alone is the standard treatment for recurrent/persistent/metastatic disease. AREAS COVERED: Areas covered in this review include the treatment of advanced cervical cancer with gemcitabine as radiosensitizer, either alone or in combination with cisplatin. The use of gemcitabine for recurrent/persistent/metastatic cervical cancer is also reviewed. EXPERT OPINION: Statistically significantly better survival rates are achieved with cisplatin doublets against cisplatin alone, in the management of recurrent/persistent/metastatic cervical cancer. The choice of the cisplatin doublet with paclitaxel, vinorelbine, gemcitabine and topotecan arms should be based on physician preference, pre-existing morbidity and patient-related factors. In advanced disease, a recently reported Phase III trial establishes the novel regimen of concurrent gemcitabine plus cisplatin and external radiation, followed by brachytherapy and two adjuvant 21-day cycles of gemcitabine plus cisplatin, as significantly improving survival outcomes when compared with the current standard of care. The increased acute toxicity of this regimen is clear; however, this should not deter its incorporation into clinical practice, in that the toxicity is predictable and manageable; nevertheless, the occurrence of late toxicity and survival at longer follow-up time are reasonable concerns in this regimen.
Asunto(s)
Desoxicitidina/análogos & derivados , Fármacos Sensibilizantes a Radiaciones/farmacocinética , Neoplasias del Cuello Uterino/tratamiento farmacológico , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Braquiterapia , Cisplatino/administración & dosificación , Cisplatino/farmacocinética , Ensayos Clínicos como Asunto , Desoxicitidina/administración & dosificación , Desoxicitidina/farmacocinética , Femenino , Humanos , Metástasis de la Neoplasia , Paclitaxel/administración & dosificación , Paclitaxel/farmacocinética , Fármacos Sensibilizantes a Radiaciones/administración & dosificación , Tasa de Supervivencia , Topotecan/administración & dosificación , Topotecan/farmacocinética , Vinblastina/administración & dosificación , Vinblastina/análogos & derivados , Vinblastina/farmacocinética , Vinorelbina , GemcitabinaRESUMEN
Topotecan is an important cytotoxic drug that has gained broad acceptance in clinical use for the treatment of refractory ovarian and small-cell lung cancer. The lactone active form of topotecan can be hydrolyzed in vivo, decreasing the drug's therapeutic efficacy. Lipid encapsulation may promote in vivo stabilization by removing topotecan from aqueous media. Earlier reports of topotecan lipid nanoencapsulation have focused on liposomal encapsulation; however, the higher stability and cost-effectiveness of solid lipid nanoparticles (SLN) highlight the potential of these nanoparticles as an advantageous carrier for topotecan. The initial motivation for this work was to develop, for the first time, solid lipid nanoparticles and nanostructured lipid carriers (NLC) with a high drug loading for topotecan. A microemulsion technique was employed to prepare SLNs and NLCs and produced homogeneous, small size, negatively charged lipid nanoparticles with high entrapment efficiency and satisfactory drug loading. However, low recovery of topotecan was observed when the microemulsion temperature was high and in order to obtain high quality nanoparticles, and precise control of the microemulsion temperature is critical. Nanoencapsulation sustained topotecan release and improved its chemical stability and cytotoxicity. Surprisingly, there were no significant differences between the NLCs and SLNs, and both are potential carriers for topotecan delivery.
Asunto(s)
Sistemas de Liberación de Medicamentos , Nanopartículas/química , Inhibidores de Topoisomerasa I/química , Topotecan/química , Supervivencia Celular/fisiología , Preparaciones de Acción Retardada , Portadores de Fármacos/química , Composición de Medicamentos , Evaluación Preclínica de Medicamentos , Estabilidad de Medicamentos , Emulsiones/química , Liofilización , Humanos , Células K562 , Lípidos/química , Nanopartículas/administración & dosificación , Nanopartículas/toxicidad , Nanoestructuras/análisis , Nanoestructuras/química , Nanoestructuras/toxicidad , Tamaño de la Partícula , Solubilidad , Propiedades de Superficie , Temperatura , Inhibidores de Topoisomerasa I/administración & dosificación , Inhibidores de Topoisomerasa I/metabolismo , Inhibidores de Topoisomerasa I/toxicidad , Topotecan/administración & dosificación , Topotecan/metabolismo , Topotecan/toxicidad , Azul de TripanoRESUMEN
Purpose. Intravenous or periocular topotecan has been proposed as new treatment modality for patients with advanced intraocular retinoblastoma, but systemic topotecan lactone exposure induced by both approaches may cause toxicity. The purpose of this study was to develop a topotecan-loaded ocular delivery system to minimize systemic exposure and achieve selective transscleral penetration. Methods. Biocompatible polymer implants containing low (0.3 mg) or high (2.3 mg) topotecan load were manufactured and characterized in vitro. Adrenaline (500 mug) was coloaded to induce local vasoconstriction in vivo in 2 of 4 animal groups. Implants were inserted into the episclera of rabbits, and topotecan (lactone and total) concentrations in ocular tissues and plasma were determined over a period of 48 hours. Results. In vitro, implants released 30% to 50% of the loaded drug within 48 hours and 45% to 70% by day 10. In vivo, topotecan lactone was highly accumulated in locally exposed ocular tissues (ranging from 10(5) to 10(6) ng/g in sclera and choroid and 10(2) to10(3) ng/g in retina) over 48 hours with all the formulations studied. Low vitreous topotecan lactone levels (approximately 5 ng/mL) were found in animals receiving concomitant local vasoconstriction and high load implants. Topotecan lactone concentrations in plasma and in contralateral eyes were minimal or undetectable as a marker of tissue selectivity of the proposed strategy. Conclusions. These studies may contribute to improving the efficacy and safety of chemotherapy treatments for retinoblastoma and may support the role of the local vasculature and tissues promoting drug clearance and local accumulation during transscleral drug delivery.