Fractionated doses of oral etoposide in the treatment of patients with AIDS-Related Kaposi sarcoma - A clinical and pharmacologic study to improve therapeutic index

The purpose of this study was to examine the antitumor activity, toxic effe cts, and plasma pharmacokinetics of fractionated doses of oral etoposide ai ming at the achievement of prolonged safe and active plasma drug levels in patients with AIDS-related Kaposi sarcoma (KS). This was designed as a phas e II trial in which consecutive patients with progressing AIDS-KS after at least 3 months of active antiretroviral therapy received oral etoposide at the dose of 20 mg/m(2) every 8 hours daily for 7 days every 21 days, with t he study of its plasma pharmacokinetics. Eligible patients were 18 to 60 ye ars old, with a histopathologically confirmed diagnosis of AIDS-related KS, human immunodeficiency virus-positive test, progressing after at least 3 m onths of active antiretroviral therapy, World Health Organization (WHO) per formance status 0 to 3, New York University staging LIA or greater, no acti ve infection except oral candidiasis, normal bone marrow, liver, and renal function, and who signed an informed consent. Objective tumor responses wer e evaluated after at least one full treatment course according to a modifie d WHO criteria, and toxicity was evaluated weekly and graded using the Nati onal Cancer Institute-Common Toxicity Criteria (NCI-CTC) criteria. For the pharmacokinetic study, plasma was obtained from patients during the first d rug administration immediately before and at various time points thereafter . Etoposide was measured after extraction from plasma by a standard high-pe rformance liquid chromatography. Twenty-one patients were accrued for the s tudy, and 18 of them met the eligibility criteria. They were all men, with median age of 36 years old (range: 25-50 years), median WHO performance sta tus 0 (range: 0-3) median CD4+ count (cells/ mm(3)) 67 (range: 8-443), prio r AIDS diagnosis in IO of 18 cases, NYU staging IIA (1 patient), IIB (1), I IIA (7), IIIB (1), IVA (4), and IVB (4) sites of disease: mucocutaneous onl y (5), mucocutaneous/lymph nodes (5), mucocutaneous/lung (5) and mucocutane ous/lymph nodes/lung (2); and prior cytotoxic treatment in two patients. Se venty-two percent of cases presented some form of toxic effect (NCI-CTC). L eukopenia was documented in 50% of cases, anemia occurred in 61%, whereas t hrombocytopenia was documented in 17% of the patients. The main nonhematolo gic toxicities were nausea and vomiting in 17% of cases and alopecia in 44% . The overall objective response rate was 83%, with 2 complete remissions d ocumented (11%). The median duration of responses was 12 weeks (range: 3-45 weeks). The median t(1/2) of etoposide in plasma was 4.11 hours (range: 1. 95-9.64), area under the curve was 13.51 mug/h/ml (range: 7.12-24.42), C-ma x was 2.17 mug/ml (1.40-4.41), t(max) (1.00-2.00), mean residence time 4.62 hours (range: 3.75-5.20 hours), CIt (total clearance) 3.13 l/m(2)/h (range : 1.49-5.20 l/m(2)/h), V-d 13.08 l/m(2) (range: 6.23-19.65 l/m(2)), and the median etoposide plasma concentration time greater than 1 mug/ml was 3.69 hours (range: 1.00-6.80 hours). The use of fractionated oral daily doses of etoposide produced significant antitumor activity with manageable clinical toxicity in the individuals with AIDS-KS included in this trial. This more favorable therapeutic index of etoposide could be due to the achievement o f more sustained plasma levels of the drug within safe but active concentra tions.