INCIDENCE OF LIVER TOXICITY ASSOCIATED WITH THE USE OF FLUTAMIDE IN PROSTATE-CANCER PATIENTS
INCIDENCE OF LIVER TOXICITY ASSOCIATED WITH THE USE OF FLUTAMIDE IN PROSTATE-CANCER PATIENTS
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DOI：
10.1016/0002-9343(92)90741-s
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发表时间：
1992-05-01
影响因子：
5.9
通讯作者：
LABRIE, F
中科院分区：
文献类型：
--
作者：
GOMEZ, JL;DUPONT, A;LABRIE, F
目的：研究抗雄激素氟他胺联合促黄体生成素释放因子(LHRH)激动剂[D-Trp6，Des-Gly-NH210]LHRH乙胺治疗C、D期前列腺癌患者中氟他胺相关性肝毒性的发生率。方法：分别于治疗后4、8、12周及每3个月进行一次肝功能检查，即测定血清天冬氨酸转氨酶(AST)、丙氨酸氨基转移酶(ALT)、总胆红素、碱性磷酸酶、γ-谷氨酰转肽酶(γ-GT)、凝血酶原和凝血活酶时间。还寻找了肝功能障碍的临床体征和症状。根据在没有其他可能原因的情况下使用抗雄激素与肝损伤之间的时间关系，以及在两名患者中，通过在肝功能正常化一段时间后再次使用假定的致病药物来评估抗雄激素与肝损伤之间的因果联系。结果：只有4名患者(0.36%)的AST和ALT高于正常上限4倍或更多。仅1例血清总胆红素和碱性磷酸酶升高，分别为126mmoL/L和640IU/L。4例患者中仅2例出现肝病临床表现(0.18%)。1例患者进行了活检，组织病理学结果显示为细胞毒性和胆汁淤积的混合型改变。仅停用氟他胺后，肝毒性的所有临床和生物学表现迅速消失。远期随访18、22、31、62个月未见后遗症。剩下的1,087名患者在治疗的前6个月中没有或轻微(低于正常上限的四倍)和一过性的转氨酶水平升高，随后时间间隔恢复正常。结论：尽管到目前为止报道的病例以及我们的大型系列研究表明，氟他胺诱导的肝毒性的发生率非常低，但我们建议在治疗2周和4周时进行连续的血氨基转移酶检测，以发现可能的氟他胺肝损伤的早期迹象，从而避免临床上显著肝毒性的低潜在风险。
PURPOSE: The incidence of flutamide-related liver toxicity was studied in 1,091 consecutive patients treated for stage C or D prostate cancer with the antiandrogen flutamide and the luteinizing hormone-releasing factor (LHRH) agonist [D-Trp6, des-Gly-NH210] LHRH ethylamide.PATIENTS AND METHODS: Liver function tests, namely measurement of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT), total bilirubin, alkaline phosphatase, gamma-glutamyl transpeptidase (gamma-GT), and prothrombin and thromboplastin times, were performed at 4, 8, and 12 weeks and every 3 months thereafter. Clinical signs and symptoms of liver dysfunction were also sought. The causal link between the antiandrogen used and liver injury was assessed on the basis of the temporal relationship with the use of the drug in the absence of other possible causes and, in two patients, through rechallenge of the putative causative drug after a period of normalization of liver function.RESULTS: An increase in AST and ALT at four-fold or more above upper normal limits was observed in only four patients (0.36%). Total serum bilirubin and alkaline phosphatase were elevated in only one patient at 126 mmol/L and 640 IU/L, respectively. Among the four patients, only two developed clinical manifestations of liver disease (0.18%). Biopsy was performed in one patient, and the histopathologic findings showed a mixed pattern of cytotoxic and cholestatic changes. All clinical and biologic manifestations of liver toxicity rapidly disappeared upon discontinuation of flutamide alone. No sequelae were observed in the long-term follow-up at 18, 22, 31, and 62 months. The 1,087 remaining patients experienced no or mild (less than fourfold upper normal limit) and transient elevation in aminotransferase serum levels during the first 6 months of treatment, with normalization at later time intervals.CONCLUSION: Despite the fact that the cases reported so far, along with our large series, indicate that the incidence of flutamide-induced liver toxicity is very low, we recommend serial blood aminotransferase measurements at 2 and 4 weeks of treatment in order to detect early signs of possible flutamide-induced hepatic injury, thus avoiding the low potential risk of clinically significant liver toxicity.