Department of Specialized Surgeries, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
Tokyo Medical and Dental University, Tokyo, Japan.
Clin Colorectal Cancer. 2018 Mar;17(1):e49-e58. doi: 10.1016/j.clcc.2017.09.004. Epub 2017 Sep 28.
Regorafenib (Stivarga) is an oral multikinase inhibitor currently approved for patients with metastatic colorectal cancer or gastrointestinal stromal tumor. Although hepatotoxicity has been a known product profile feature of regorafenib since its initial approval, its clinical features are limited to those found in the clinical trials.
The present study was conducted in 2 analysis sets: a safety analysis set for metastatic colorectal cancer from solicited postmarketing surveillance (PMS) in Japan (n = 1227) and an analysis set for serious hepatic adverse drug reactions (n = 210) from all patients registered for regorafenib use.
The features of liver injury compatible with current product labeling included the second cycle as the most frequently observed time to onset, hepatocellular type as the typical pattern of liver injury, idiosyncratic occurrence as the possible mechanism, and rare fatal outcomes (0.33%; 4 of 1227). In addition to the known features, the present study found unpredictability in the outcome of hepatic events using the onset values of liver chemistry tests and delayed improvement of hepatic parameters after drug withdrawal. Owing to multiple confounding factors in patients with advanced cancer, difficulty remains in the interpretation of exploration for background factors and evaluation using Hy's law in oncology products.
Regorafenib-induced liver injury can be considered idiosyncratic and typically of hepatocellular type, with fatal outcomes rare. Early recognition and timely drug withdrawal are the most important strategies to prevent progression to severe outcomes. At occurrence, careful observation until improvement and monitoring for fulminant hepatic failure are also essential.
瑞戈非尼（Stivarga）是一种口服多激酶抑制剂，目前已被批准用于转移性结直肠癌或胃肠道间质瘤患者。尽管自最初批准以来，瑞戈非尼的肝毒性已被认为是其已知的产品特征之一，但它的临床特征仅限于临床试验中发现的那些。
本研究在两个分析集进行：一个是来自日本的瑞戈非尼上市后监测（PMS）主动报告的转移性结直肠癌安全性分析集（n=1227），另一个是来自所有注册使用瑞戈非尼的患者的严重肝不良药物反应（n=210）的分析集。
与当前产品标签一致的肝损伤特征包括第二周期是最常观察到的发病时间，肝损伤的典型模式为肝细胞型，可能的发病机制为特发性，且结局罕见（0.33%，1227 例中有 4 例）。除了已知特征外，本研究还发现了肝事件结局的不可预测性，表现在肝化学检测的起始值和停药后肝参数的改善延迟。由于晚期癌症患者存在多种混杂因素，因此在解释背景因素和使用 Hy's 法则评估肿瘤产品方面仍然存在困难。
瑞戈非尼引起的肝损伤可被认为是特发性的，且通常为肝细胞型，结局罕见。早期识别和及时停药是预防严重结局进展的最重要策略。在发生肝损伤时，仔细观察直至改善和监测暴发性肝衰竭也至关重要。
