RESUMEN
Merbarone, a nonsedating derivative of thiobarbituric acid, has demonstrated excellent activity against certain murine tumors, including L1210 and P388 leukemias, B16 melanoma, and M5076 sarcoma. Preclinical studies suggested that the antitumor effects of this drug were schedule dependent, since repeated dosing increased killing of tumor cells when compared to intermittent injections. We have completed a Phase I clinical and pharmacological study of merbarone in which the drug was administered both as a 2-h infusion and as a continuous i.v. infusion over 24 h. In view of the increased toxicity observed in animals following bolus injections and the possibility of schedule-dependent anticancer activity, a schedule of drug administration daily for 5 days was selected. Fifty patients with advanced cancer were treated at dose levels that ranged from 100 to 1500 mg/m2/day. When the drug was administered by peripheral vein, phlebitis was observed at the infusion site at daily doses greater than or equal to 150 mg/m2. Therefore, all patients who received drug doses greater than or equal to 200 mg/m2 were treated by continuous i.v. infusion using central venous catheters. Renal insufficiency, initially observed at a dose of 1000 mg/m2/day, was the dose-limiting toxic reaction at 1500 mg/m2/day. Three of five patients treated at the highest dose level were unable to complete the infusion due to this effect. Marked hypouricemia was observed in all patients. Other toxic effects were mild and included nausea, fatigue, leukopenia, thrombocytopenia, and anorexia. Alopecia was noted in several patients who received doses greater than or equal to 1000 mg/m2/day. No major antitumor effects were observed. Dose-dependent, steady-state plasma concentrations of merbarone were reached within 24-48 h after beginning the continuous i.v. infusion. Elimination of drug from plasma followed a two-compartment model, with a t1/2 alpha of 4.2 h and a t1/2 beta of 15.3 h. Renal excretion of merbarone and its major metabolites accounted for less than 30% of the administered dose. We conclude that merbarone is relatively well tolerated with few constitutional symptoms. The current formulation of the drug causes phlebitis when administered by peripheral vein, and renal insufficiency is commonly observed at daily doses which exceed 1250 mg/m2. The recommended dose for extended Phase II evaluation is 1000 mg/m2/day daily for 5 days administered by central venous catheter.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Tiobarbitúricos/uso terapéutico , Adulto , Anciano , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Creatinina/sangre , Esquema de Medicación , Evaluación de Medicamentos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/metabolismo , Tiobarbitúricos/efectos adversos , Tiobarbitúricos/farmacocinética , Tiobarbitúricos/farmacología , Ácido Úrico/sangreRESUMEN
Seventy previously untreated patients with stage II, III, and IV intermediate- or high-grade lymphoma were treated with methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B) between September 1985 and November 1987. Forty-nine of these patients had diffuse large-cell lymphoma (DLCL), and eight of these patients were human immunodeficiency virus (HIV)-positive. Complete responses were achieved in 54% of all patients and 52% of those with DLCL. With follow-up extending to 36 months, 45% of all DLCL patients are alive, and 50% are still living, if the HIV-positive patients are excluded from the analysis. Chemotherapy was quite toxic. Seventy-five percent of patients had severe mucositis, 42% had peripheral neuropathy, 50% required hospitalization, and 54% experienced leukopenia with a WBC count below 1,000/microL. Seven percent (five patients) died of toxicity related to the chemotherapy. Our analysis of prognostic parameters indicated that B symptoms, a performance status below 80, and, to a lesser extent, elevation of serum lactic acid dehydrogenase (LDH) (in HIV-negative DLCL patients) were associated with an inferior survival. Advanced age, sex, and bulky disease were not found to have a statistically significant effect on survival. Our preliminary results indicate that MACOP-B chemotherapy is an effective regimen for high- and intermediate-grade lymphomas. However, the survival for patients with DLCL treated with MACOP-B is no different than that achieved with previous regimens at our institution.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma no Hodgkin/tratamiento farmacológico , Adolescente , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bleomicina/administración & dosificación , Bleomicina/efectos adversos , Trasplante de Médula Ósea , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Femenino , Estudios de Seguimiento , Seropositividad para VIH/epidemiología , Humanos , Leucovorina/administración & dosificación , Leucovorina/efectos adversos , Linfoma no Hodgkin/mortalidad , Linfoma no Hodgkin/patología , Masculino , Metotrexato/administración & dosificación , Metotrexato/efectos adversos , Persona de Mediana Edad , Estadificación de Neoplasias , Prednisona/administración & dosificación , Prednisona/efectos adversos , Pronóstico , Ensayos Clínicos Controlados Aleatorios como Asunto , Inducción de Remisión , Factores de Tiempo , Vincristina/administración & dosificación , Vincristina/efectos adversosRESUMEN
The clinical features and laboratory results of 63 patients with or at risk for AIDS with lymphoid neoplasias seen from November 1980 through November 1986 are reviewed. Forty-three had systemic non-Hodgkin's lymphoma (NHL), nine had primary large cell lymphomas of the brain, 11 had Hodgkin's disease (HD), and one had plasmacytoma evolving to myeloma. Those with systemic NHL included 40 (93%) with intermediate or high-grade histologies, 35 (81%) with advanced stage (III, IV), and 28 (65%) with extranodal disease at presentation (predominantly marrow and meninges). Overall survival was short (median, 10.5 months from diagnosis) with the majority of deaths attributable to AIDS-related opportunistic infections (OI). However, 17 patients with diffuse NHL achieved a complete clinical remission, and nine now have been disease-free for more than 1 year (median follow-up, 28 months; range, 12 to 73 months). Early stage and lack of systemic symptoms were features associated with prolonged disease-free survival. Primary brain NHL was a uniformly lethal manifestation of AIDS, being diagnosed at postmortem in seven of nine severely immunosuppressed homosexual men. As with NHL, a propensity towards advanced disease and extranodal involvement was also observed in HD, suggesting that the atypical clinical behavior of HD may be an additional epiphenomenon of AIDS. This experience tends to argue for the use of intensive therapy in at least some patients with AIDS-related systemic NHL since it has resulted in a proportion of long-term disease-free survivors.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/complicaciones , Neoplasias Encefálicas/complicaciones , Enfermedad de Hodgkin/complicaciones , Linfoma no Hodgkin/complicaciones , Adulto , Antineoplásicos/administración & dosificación , Neoplasias Encefálicas/tratamiento farmacológico , Enfermedad de Hodgkin/tratamiento farmacológico , Humanos , Linfoma no Hodgkin/tratamiento farmacológico , Linfoma no Hodgkin/patología , PronósticoRESUMEN
In recent years the literature has described a highly lethal "multicentric" variant of classic Castleman's disease (CD) with similar hyperplastic angio-follicular morphologic features. A 44-year-old man who was not known to be part of any established high-risk group for the acquired immune deficiency syndrome (AIDS) presented with clinical and laboratory features similar to "multicentric" CD. Serologic testing revealed antibody to the human immunodeficiency virus (HIV) by Western blot analysis. It is suggested that "multicentric" CD may be part of the clinicopathologic spectrum of HIV infection, and there should be a high index of suspicion for HIV in patients presenting with generalized lymphadenopathy and histopathologic features of CD.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/diagnóstico , Enfermedad de Castleman/diagnóstico , Adulto , Anticuerpos Antivirales/análisis , Enfermedad de Castleman/patología , Diagnóstico Diferencial , VIH/inmunología , Anticuerpos Anti-VIH , Humanos , Neoplasias Pulmonares/etiología , Ganglios Linfáticos/patología , Masculino , Infecciones Oportunistas/etiología , Sarcoma de Kaposi/etiologíaRESUMEN
The spectrum of neoplastic disease seen in patients with the acquired immune deficiency syndrome (AIDS) is similar to that seen in several congenital and iatrogenic immunodeficiency states and provides a human model for studying neoplastic transformation in the immune compromised host. High grade lymphoid neoplasia, particularly of the central nervous system (CNS), as well as a virulent form of Kaposi's sarcoma (KS) and several types of squamous cell carcinomas, are appearing at an alarming rate in patients with AIDS. There is substantial serologic, pathologic and molecular evidence linking cytomegalovirus (CMV) to KS and Epstein-Barr virus (EBV) to squamous cell carcinoma and high-grade B-cell non-Hodgkin's lymphoma (NHL). The human T-cell lymphotropic virus type III/lymphadenopathy associated virus (HTLV-III/LAV) may be responsible for the permissive immune deficient state allowing for opportunistic neoplasia and the aggressive biologic behavior and atypical anatomic distribution these neoplasms exhibit. The clinical features as well as potential etiopathogenetic mechanisms of these malignancies are reviewed.