Biochemical modulation of doxorubicin by high-dose tamoxifen in the treatment of advanced hepatocellular carcinoma

BACKGROUND/AIMS: In vitro data have indicated that tamoxifen (>2.5uM) signi ficantly enhances the cytotoxic effect of doxorubicin in hepatocellular car cinoma (HCC) cells. This clinical study was conducted to examine whether ta moxifen, at a dose sufficient to result in a plasma concentration of more t han 2.5uM, may improve the therapeutic efficacy of doxorubicin in patients with advanced HCC. METHODOLOGY: A prospective phase II study was conducted. Eligible patients had unresectable and non-embolizable HCC, objectively measurable tumors, ad equate neogram with absolute granulocyte count >2,000/mm(3) and platelet co unt >1 x 10/mm(3), total serum bilirubin <3.0 mg/dl, age greater than or eq ual to 75 year, and a Karnofsky performance status less than or equal to 50 %. The treatment included oral tamoxifen 40mg/m(2), q.i.d, Day 1 to 7, and intravenous doxorubicin 60mg/m(2), Day 4, repeated every 3 weeks. RESULTS: Between May 1994 and December 1996, a total of 38 patients were en rolled in the study. Thirty-six patients were evaluable for tumor response and treatment-related toxicities. There were 32 men and 4 women, with a med ian age of 49 years. They received an average of 3.8 (range:1-12) courses o f chemotherapy. ECOG (Eastern Cooperative Oncology Group) Grade 304 leucope nia and Grade 3=4 thrombocytopenia developed in 27.2% and 12.5% courses giv en, respectively. Gastrointestinal toxicity was generally mild. Three patie nts developed symptomatic cardiac toxicity. Twelve patients (33.3%, 95% con fidence interval 17-51%) had achieved a partial remission (PR), with a medi an progression-free survival of 7 months. Median survivals of the responder s and nonresponders were 10 and 3 months, respectively (p<0.05). The median Karnofsky performance status of the responders improved from 74.0+/-6.3% t o a post-chemotherapy value of 93.2+/-4.6% (p<0.05). CONCLUSIONS: High dose tamoxifen appears to be an effective biochemical mod ulator of doxorubicin in the treatment of HCC. Prospective randomized phase III studies comparing doxorubicin alone versus doxorubicin plus high-dose tamoxifen are needed.