Cheng A L, Yeh K H, Fine R L, Chuang S E, Yang C H, Wang L H, Chen D S
Department of Internal Medicine, National Taiwan University Hospital, Taipei.
Hepatogastroenterology. 1998 Nov-Dec;45(24):1955-60.
BACKGROUND/AIMS: In vitro data have indicated that tamoxifen (> 2.5 uM) significantly enhances the cytotoxic effect of doxorubicin in hepatocellular carcinoma (HCC) cells. This clinical study was conducted to examine whether tamoxifen, at a dose sufficient to result in a plasma concentration of more than 2.5 uM, may improve the therapeutic efficacy of doxorubicin in patients with advanced HCC.
A prospective phase II study was conducted. Eligible patients had unresectable and non-embolizable HCC, objectively measurable tumors, adequate neogram with absolute granulocyte count > 2,000/mm3 and platelet count > 1 x 10/mm3, total serum bilirubin < 3.0 mg/dl, age > or = 75 year, and a Karnofsky performance status < or = 50%. The treatment included oral tamoxifen 40 mg/m2, q.i.d, Day 1 to 7, and intravenous doxorubicin 60 mg/m2, Day 4, repeated every 3 weeks.
Between May 1994 and December 1996, a total of 38 patients were enrolled in the study. Thirty-six patients were evaluable for tumor response and treatment-related toxicities. There were 32 men and 4 women, with a median age of 49 years. They received an average of 3.8 (range:1-12) courses of chemotherapy. ECOG (Eastern Cooperative Oncology Group) Grade 3-4 leucopenia and Grade 3-4 thrombocytopenia developed in 27.2% and 12.5% courses given, respectively. Gastrointestinal toxicity was generally mild. Three patients developed symptomatic cardiac toxicity. Twelve patients (33.3%, 95% confidence interval 17-51%) had achieved a partial remission (PR), with a median progression-free survival of 7 months. Median survivals of the responders and non-responders were 10 and 3 months, respectively (p<0.05). The median Karnofsky performance status of the responders improved from 74.0+/-6.3% to a post-chemotherapy value of 93.2+/-4.6% (p<0.05)
High dose tamoxifen appears to be an effective biochemical modulator of doxorubicin in the treatment of HCC. Prospective randomized phase III studies comparing doxorubicin alone versus doxorubicin plus high-dose tamoxifen are needed.
背景/目的：体外实验数据表明，他莫昔芬（>2.5μM）可显著增强阿霉素对肝癌（HCC）细胞的细胞毒性作用。本临床研究旨在探讨他莫昔芬在足以使血浆浓度超过2.5μM的剂量下，是否能提高阿霉素对晚期肝癌患者的治疗效果。
进行了一项前瞻性II期研究。符合条件的患者患有无法切除且不可栓塞的肝癌，肿瘤可客观测量，全血细胞计数正常，绝对粒细胞计数>2000/mm³，血小板计数>1×10/mm³，总血清胆红素<3.0mg/dl，年龄≥75岁，卡诺夫斯基功能状态≤50%。治疗方案包括第1至7天口服他莫昔芬40mg/m²，每日4次，第4天静脉注射阿霉素60mg/m²，每3周重复一次。
1994年5月至1996年12月期间，共有38例患者纳入研究。36例患者可评估肿瘤反应和治疗相关毒性。其中男性32例，女性4例，中位年龄49岁。他们平均接受了3.8（范围：1 - 12）个疗程的化疗。在接受的疗程中，分别有27.2%和12.5%出现了美国东部肿瘤协作组（ECOG）3 - 4级白细胞减少和3 - 4级血小板减少。胃肠道毒性一般较轻。3例患者出现有症状的心脏毒性。12例患者（33.3%，95%置信区间17 - 51%）达到部分缓解（PR），中位无进展生存期为7个月。缓解者和未缓解者的中位生存期分别为10个月和3个月（p<0.05）。缓解者的卡诺夫斯基功能状态中位数从74.0±6.3%提高到化疗后的93.2±4.6%（p<0.05）。
高剂量他莫昔芬似乎是阿霉素治疗肝癌的一种有效的生化调节剂。需要进行前瞻性随机III期研究，比较单纯阿霉素与阿霉素加高剂量他莫昔芬的疗效。
