Stuart K, Tessitore J, Rudy J, Clendennin N, Johnston A
Boston Center for Liver Cancer, Beth Israel Deaconess Medical Center, Harvard Medical School, Massachusetts 02215, USA.
Cancer. 1999 Aug 1;86(3):410-4.
Inoperable hepatocellular carcinoma is an incurable malignancy with no accepted standard therapy. Chemotherapy has demonstrated occasional responses and the need is great for a new and effective agent. Therefore the authors conducted this Phase II trial of a novel thymidylate synthase inhibitor, nolatrexed dihydrochloride (designed using structure-based computer modeling), in patients with advanced hepatocellular carcinoma.
Forty-one patients with unresectable or metastatic hepatocellular carcinoma were treated with nolatrexed, which was administered as a 24-hour outpatient intravenous infusion for 5 days at a dose of 795 mg/m2/day as free base (1000 mg/m2/day as salt) during each 21-day cycle. Prophylactic treatment was given for emesis and rash.
Twenty-eight patients received at least 2 courses of treatment and 26 patients were evaluable. Two patients (8%) achieved a partial response and 2 additional patients achieved a minor response that was significant enough to allow surgical resection with curative intent. Fourteen patients (54%) achieved stable disease. The overall median survival was 7 months (10 months among patients who completed 2 cycles) and 1 patient remained free of disease at last follow-up, 37 months after surgery. Toxicity was modest and generally was comprised of stomatitis, nausea, malaise, and rash.
Nolatrexed appears to have modest biologic activity in hepatocellular carcinoma. Due to the lack of alternative treatments, further study of this drug or an oral equivalent may be warranted.
无法手术切除的肝细胞癌是一种无法治愈的恶性肿瘤，尚无公认的标准治疗方法。化疗偶尔显示出疗效，因此对新型有效药物的需求很大。为此，作者开展了一项针对晚期肝细胞癌患者的II期试验，研究一种新型胸苷酸合成酶抑制剂——盐酸诺拉曲塞（基于结构的计算机建模设计）。
41例无法切除或转移性肝细胞癌患者接受诺拉曲塞治疗，在每21天的周期中，以游离碱形式按795mg/m²/天（盐形式为1000mg/m²/天）的剂量进行为期5天的门诊24小时静脉输注。对呕吐和皮疹进行预防性治疗。
28例患者接受了至少2个疗程的治疗，26例患者可进行评估。2例患者（8%）获得部分缓解，另有2例患者获得轻度缓解，程度足以允许进行根治性手术切除。14例患者（54%）病情稳定。总体中位生存期为7个月（完成2个周期的患者为10个月），1例患者在最后一次随访时，即手术后37个月仍无疾病。毒性较轻，一般包括口腔炎、恶心、不适和皮疹。
诺拉曲塞在肝细胞癌中似乎具有一定的生物学活性。由于缺乏其他治疗方法，可能有必要对该药物或其口服等效物进行进一步研究。
