Clinical and pharmacokinetic study of oral etoposide in patients with AIDS-related Kaposi's sarcoma with no prior exposure to cytotoxic therapy.

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.