长期口服依托泊苷和他莫昔芬治疗晚期肝细胞癌。

Chronic oral etoposide and tamoxifen in the treatment of far-advanced hepatocellular carcinoma.

作者信息

Cheng A L, Chen Y C, Yeh K H, Chuang S E, Chen B R, Chen D S

机构信息

Department of Internal Medicine, National Taiwan University Hospital, Taipei, Republic of China.

出版信息

Cancer. 1996 Mar 1;77(5):872-7.

PMID:8608477

Abstract

BACKGROUND

Hepatocellular carcinoma (HCC) is a chemoresistant tumor that frequently expresses a high level of p 170 glycoprotein of the multidrug-resistance (MDR) gene. Preliminary data suggested that VP-16 showed modest activity in HCC. Recently, schedule-dependent cytotoxicity of VP-16 has been demonstrated. In this study, we tested the therapeutic efficacy of chronic oral VP-16 plus tamoxifen, a potential MDR-reversing agent, in patients with far-advanced HCC.

METHODS

A prospective single-arm study was conducted in the National Taiwan University Hospital. To be eligible, patients must have had unresectable and non-embolizable HCC, objectively measurable tumors, adequate hemogram with absolute granulocyte count greater than or equal to 2,000/mm3, and platelet count greater than or equal to 1x10 (5)/mm3, total serum bilirubin less than or equal to 3.0 mg/dl, age less than or equal to 75 years, and a Karnofsky performance status of greater then or equal to 50%. The treatment included VP-16 (Bristol-Myers-Squibb, Princeton, NJ), 50 mg/m2/day, orally, Days 1 to 21, and tamoxifen (Pharmachemie B.V. Haarlem, Netherlands), 40 mg/day, orally, Days 1 to 21; repeated every 5 weeks.

RESULTS

Between December 1990 and December 1993, a total of 33 patients were enrolled in the study. There were 28 men and 5 women, with a median age of 51 years. They received an average of 3.2 (range: 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 developed in 2 patients (6.1%). Treatment-related death occurred in one patient due to sepsis. Mild gastrointestinal toxicities were common with Grade 1 and 2 nausea. Grade 1 and 2 vomiting, Grade 1 and 2 diarrhea, 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 gastrointestinal 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-responders were 8.0 and 3.0 months, respectively (P < 0.05). The median Karnofsky performance status of the responders improved from 70% to 80%.

CONCLUSIONS

Chronic oral VP-16 and tamoxifen has modest activity and acceptable toxicity in far-advanced HCC, and is a useful palliative treatment in about a quarter of such patients.

摘要

背景

肝细胞癌（HCC）是一种化疗耐药性肿瘤，常高表达多药耐药（MDR）基因的p170糖蛋白。初步数据表明，VP - 16在HCC中显示出一定活性。最近，已证实VP - 16具有时间依赖性细胞毒性。在本研究中，我们测试了慢性口服VP - 16联合他莫昔芬（一种潜在的MDR逆转剂）对晚期HCC患者的治疗效果。

方法

在台湾大学医院进行了一项前瞻性单臂研究。符合条件的患者必须患有不可切除且不可栓塞的HCC、可客观测量的肿瘤、血常规正常，绝对粒细胞计数大于或等于2000/mm³，血小板计数大于或等于1×10⁵/mm³，总血清胆红素小于或等于3.0mg/dl，年龄小于或等于75岁，卡氏评分大于或等于50%。治疗方案包括VP - 16（百时美施贵宝公司，新泽西州普林斯顿），50mg/m²/天，口服，第1至21天；他莫昔芬（荷兰哈勒姆Pharmachemie B.V.公司），40mg/天，口服，第1至21天；每5周重复一次。

结果

1990年12月至1993年12月，共有33例患者纳入研究。其中男性28例，女性5例，中位年龄51岁。他们平均接受了3.2（范围：1 - 10）个疗程的化疗。6例（18.2%）患者发生3级和4级白细胞减少，4例（12.1%）患者发生3级和4级血小板减少。2例（6.1%）患者发生3级和4级血小板减少。1例患者因败血症发生与治疗相关的死亡。轻度胃肠道毒性常见，1级和2级恶心分别发生在13例（39.4%）、7例（21.2%）、12例（36.4%）和16例（48.5%）患者中。3级和4级胃肠道毒性罕见。1例患者（3.0%）发生深静脉血栓。8例患者（24.2%，95%置信区间11% - 42%）达到部分缓解，中位疾病进展时间为6个月（2 - 11个月）。缓解者和未缓解者的中位生存期分别为8.0个月和3.0个月（P < 0.05）。缓解者的中位卡氏评分从70%提高到80%。