CHRONIC ORAL ETOPOSIDE AND TAMOXIFEN IN THE TREATMENT OF FAR-ADVANCEDHEPATOCELLULAR-CARCINOMA

BACKGROUND. Hepatocellular carcinoma (HCC) is a chemoresistant tumor t hat frequently expresses a high level of p 170 glycoprotein of the mul tidrug-resistance (MDR) gene. Preliminary data suggested that VP-16 sh owed modest activity in HCC. Recently, schedule-dependent cytotoxicity of VP-16 has been demonstrated. In this study, we tested the therapeu tic efficacy of chronic oral VP-16 plus tamoxifen, a potential MDR-rev ersing agent, in patients with far-advanced HCC.METHODS. A prospective single-arm study was conducted in the National Tai wan University Hos pital. To be eligible, patients must have had unresectable and non-emb olizable HCC, objectively measurable tumors, adequate hemogram with ab solute granulocyte count greater than or equal to 2,000/mm(3), and pla telet count greater than or equal to 1 x 10(5)/mm(3), total serum bili rubin less than or equal to 3.0mg/dl, age less than or equal to 75 yea rs, and a Karnofsky performance status of greater than or equal to 50% . The treatment included VP-16 (Bristol-Myers-Squibb, Princeton, NJ), 50 mg/m(2)/day, orally, Days 1 to 21, and tamoxifen (Pharmachemie B.V. , Haarlem, Netherlands), 40 mg/day, orally, Days 1 to 21; repeated eve ry 5 weeks. RESULTS Between December 1990 and December 1993, a total o f 33 patients were enrolled in the study. There were 28 men and 5 wome n, with a median age of 51 years. They received an average of 3.2 (ran ge: 1-10) courses of chemotherapy. ECOG (Eastern Cooperative Oncology Group) Grade 3 and Grade 4 leucopenia developed in 6 patients (18.2%) and 4 (12.1%) patients, respectively. Grade 3 and 4 thrombocytopenia d eveloped in 2 patients (6.1%). Treatment-related death occurred in one patient due to sepsis. Mild gastrointestinal toxicities were common w ith Grade 1 and 2 nausea, Grade 1 and 2 vomiting, Grade 1 and 2 diarrh ea, and Grade 1 and 2 stomatitis, developed in 13 (39.4%), 7 (21.2%), 12 (36.4%), and 16 (48.5%) patients, respectively. Grade 3 and 4 gastr ointestinal toxicities were rare. Deep vein thrombosis occurred in one patient (3.0%). Eight patients (24.2%, 95% confidence interval 11%-42 %) had achieved a partial remission, with a median time-to-progression of 6 months (2-11). Median survivals of the responders and non-respon ders were 8.0 and 3.0 months, respectively (P < 0.05). The median Karn ofsky performance status of the responders improved from 70% to 80%. C ONCLUSIONS. Chronic oral VP-16 and tamoxifen has modest activity and a cceptable toxicity in far-advanced HCC, and is a useful palliative tre atment in about a quarter of such patients. (C) 1996 American Cancer S ociety.