RESUMO
PURPOSE: In this phase II and pharmacokinetic study, chronic, low-dose, oral etoposide was evaluated for its efficacy in patients with AIDS-related Kaposi's sarcoma who were not previously exposed to cytotoxic therapy. PATIENTS AND METHODS: Of 28 patients accrued for the study, 25 were assessable for toxicity and response. Twenty-four patients were male (homosexual or bisexual cases) and one patient was female (partner of a bisexual male). All patients were human immunodeficiency virus (HIV)-positive, New York University (NYU) disease stage IIB to IVB, and most exhibiting skin and lymph node and/or visceral disease. Median age was 33 years (range, 21 to 50), and median World Health Organization (WHO) performance status was 2 (range, 0 to 3). The patients received a mean number of six treatment courses (range, four to 27). Prior therapy included local/regional irradiation, immunotherapy (interferon-alpha), local resection, and/or cryotherapy. No prior cytotoxic therapy was allowed. Etoposide was administered at a schedule of 25 mg/m2 orally, twice a day for 7 days, every 2 weeks. Plasma concentrations of the drug were measured in six patients by a high-performance liquid chromatography (HPLC) method, after chloroform extraction using teniposide as internal standard. RESULTS: The overall response rate was 32% (two complete and six partial responses), and the median progression-free survival was 8 weeks (range, 4 to 27). Five patients (20%) had stable disease, while 12 cases (48%) did not respond. Patients without a history of opportunistic infections seemed to respond better. The regimen was well tolerated. The main toxic effects consisted of mild to moderate nausea and vomiting in approximately half of the cases, and WHO grodes 3 to 4 leukopenia and thrombocytopenia in eight of 25 (36%) and five of 25 (20%) of cases, respectively. However, only two patients had to discontinue treatment because of prolonged and severe neutropenia. No toxic deaths were documented. The pharmacokinetic analyses revealed the achievement of potentially therapeutic and lowly myelosuppressive plasma etoposide concentrations (2.1 micrograms/mL; range, 1.3 to 2.6) for a significant period of time, ie, for approximately 4.6 hours postdosing. CONCLUSION: At the schedule applied, etoposide shows significant objective antitumor activity in advanced AIDS-related Kaposi's sarcoma, and induces acceptable clinical toxicity. This apparent efficacy of the regimen could be a result of the prolonged maintenance of cytotoxic plasma concentrations of etoposide during each treatment course, and the absence of toxic peak levels of the drug. These results, together with the appreciable bioavailability of oral etoposide, make the regimen feasible for outpatient treatment of patients with advanced AIDS-related Kaposi's sarcoma. Further studies using the above-mentioned approach are warranted.
Assuntos
Síndrome da Imunodeficiência Adquirida/complicações , Antineoplásicos Fitogênicos/uso terapêutico , Etoposídeo/uso terapêutico , Sarcoma de Kaposi/tratamento farmacológico , Adulto , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/farmacocinética , Esquema de Medicação , Etoposídeo/efeitos adversos , Etoposídeo/farmacocinética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Sarcoma de Kaposi/metabolismoRESUMO
AIMS AND BACKGROUND: To evaluate the response rate, toxicity and survival of patients with AIDS-related Kaposi's sarcoma (AIDS-KS) treated in a phase II clinical trial of pentosan polysulpate (PPS), an inhibitor of basic-fibroblast growth factor (b-FGF) which blocks the growth of Kaposi's sarcoma cells both in culture and in animal models. PATIENTS AND METHODS: Between March 1992 and March 1994 16 homosexual males with histopathologically confirmed AIDS-KS were accrued for this phase II clinical trial. PPS was administered at the dose of 25 mg/m2 q6 hrs at day 1, followed by 25 mg/m2 q12 hrs daily by a subcutaneous injection. The number of patients to be included in the trial was calculated according to the two-stage Gehan method. Toxicity was graded according to the NCl Common Toxicity Criteria, while responses were evaluated according to the WHO Criteria adapted for KS lesions. Patients were all homosexual males, median age 35 (27-43) years, performance status (WHO) 1 (0-2), NYU stage II-IV and prior therapy included vincristine and etoposide (3 cases), local irradiation (4 cases) and megestrol acetate (2 cases). Concomitant AZT (zidovudine) was given to 3 patients, while DDI (dideoxyinosine) was administered in one case. RESULTS: A median of 5 (3-11) weeks of therapy was administered to the patients. Pain at the injection site and low grade fever were the only toxicities observed. Drug-related effects on coagulation parameters or thrombocytopenia were not observed in the trial. One objective response (6%) was documented, which lasted for 9 weeks, while stable disease was observed in three patients, lasting for 11, 9 and 5 weeks, respectively. CONCLUSION: This is the first observation of objective antitumor activity with a b-FGF inhibitor in patients with AIDS-KS. Considering it novelty and the lack of significant toxicity, the authors suggest that this experimental approach deserves further evaluation.
Assuntos
Síndrome da Imunodeficiência Adquirida/complicações , Antineoplásicos/uso terapêutico , Fator 2 de Crescimento de Fibroblastos/antagonistas & inibidores , Poliéster Sulfúrico de Pentosana/uso terapêutico , Sarcoma de Kaposi/virologia , Síndrome da Imunodeficiência Adquirida/etiologia , Adulto , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Esquema de Medicação , Homossexualidade Masculina , Humanos , Masculino , Poliéster Sulfúrico de Pentosana/administração & dosagem , Poliéster Sulfúrico de Pentosana/efeitos adversos , Análise de Sobrevida , Resultado do TratamentoRESUMO
O objetivo deste estudo foi avaliar o perfil de toxicidade, índices de respostas objetivas e sobrevida de pacientes portadores de melanoma maligno metastático tratados com a combinação de Interleucina-2 (IL-2)e Interferon-alfa (IFN-alfa) administrados por via subcutânea (SC). Vinte e cinco pacientes com diagnóstico histopatológico de melanoma maligno metastático e doença mensurável foram tratados com IL-2 na dose de 18 milhões de unidades/m2 e IFN-alfa na dose de 3 milhões de unidades/m2 por via SC diariamente nos dias 1-5 e 8-12 de ciclos com 21 dias. Os pacientes foram todos avaliáveis quanto a toxicidade de acordo com o Common Toxicity Criteria do Instituto Nacional do Câncer dos EUA (CTC-NCI), enquanto que as respostas foram codificadas segundo os critérios da OMS. Os pacientes não haviam recebido tratamento químico, rádio ou imunoterápico prévio. Uma mediana de 3 (2-4) ciclos foram administrados. A toxicidade consistiu sobretudo de fadiga, artralgia, mialgias, febre e calafrios e retenção líquida. Não foram observadas toxicidades com risco severo de óbito. Quatro dos 25 pacientes (17 por cento) apresentaram respostas objetivas. Em 2 destes casos foi possível a ressecção completa de massas residuais pós-tratamento imunoterápico, com remissões mantidas por 6 e 24+ meses, respectivamente. Nos outros 2 casos com resposta parcial, progressão clínica foi observada após 7 e 8 meses, respectivamente. Os pacientes que não responderam inicialmente ou apresentaram progressão posterior foram ao óbito após um seguimento mediano de 3 (1-7) meses. Em conclusão, a combinação de IL-2 e IFN-alfa por via SC produziu respostas limitadas em pacientes com melanoma maligno metastático. Ainda que a toxicidade tenha sido manejável, os resultados acima descritos não recomendam esta abordagem para uso clínico de rotina.
Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Interferon-alfa , Interleucina-2 , Melanoma , Neoplasias , Quimioterapia CombinadaRESUMO
Antitumour activity of cytotoxic agents, evaluated in patients with AIDS-related Kaposi's sarcoma (KS), is about 30-80%. However, responses are mostly partial and short. Experience with etoposide is similar. Teniposide has a longer elimination half-life and superior antitumour activity compared with etoposide in some experimental models. Thus a phase II trial was done in 25 patients with AIDS-related KS. Teniposide was given by 60-min infusion at 360 mg/m2 every 3 weeks. 10 (40%) showed a partial response, median duration of 9 (6-20) weeks. The main side-effects were leukopenia, thrombocytopenia, nausea and vomiting, alopecia and mucositis.