回溯性分析研究Gemcitabine（Gemzar®）作為非小細胞肺癌第一線用藥之肝毒性

Abstract

在非小細胞肺癌（Non-small cell lung cancer）之治療藥物中，gemcitabine（Gemzar&reg;）被使用作為後期（advanced）患者之標準療法用藥之一，和其他細胞毒性（cytotoxic）藥物比較起來，其副作用通常較為輕微。但肝毒性（hepatotoxicity）之發生並不少見（約20~50%），表現多為短暫、無症狀且很快恢復之肝酵素升高，很少會持續惡化；除此之外，近年來，越來越多之案例報告顯示gemcitabine有可能造成嚴重肝毒性，如肝臟靜脈阻塞疾病（hepatic veno-occlusive disease）、致命膽汁鬱積性肝臟衰竭（cholestatic liver failure）及B型肝炎病毒再活化（hepatitis B virus reactivation）。 本研究為回溯性病歷分析設計，以台灣一醫學中心（台大醫院）內，使用gemcitabine作為第一線化療（chemotherapy）之非小細胞肺癌患者為研究族群，統計分析gemcitabine造成肝炎（hepatitis）之發生率、嚴重程度及對治療效果之影響，並找出危險因子；B型肝炎病毒再活化之發生率及治療。對於使用gemcitabine治療失敗後，接受第二線化療之患者，亦統計其使用第二線化療之肝炎發生率，並分析其與gemcitabine肝炎發生與否、第二線用藥處方及肝炎病毒帶原之關連。 研究結果共納入337位研究對象，在大多數患者以單一gemcitabine或gemcitabine併用cisplatin治療下，反應率（response rate）為19%，存活期中位數（median survival）11個月。 Gemcitabine治療後之肝功能檢驗，將近30%屬世界衛生組織（World Health Organization，簡稱WHO）毒性分級（toxicity grades）1及2，4~5%屬毒性分級3及4，其中共有88人（26.1%）符合肝炎發生之定義。而肝炎之發生非gemcitabine劑量累積毒性，且其發生與否對於化學治療後之反應率及存活期並無影響。而若為B型肝炎病毒帶原，則較非帶原者易發生嚴重程度（世界衛生組織毒性分級3及4）之肝炎。 而gemcitabine造成肝炎之預測因子（predictors），在單變數分析（univariate analysis）中，具有顯著性（p<0.05）之危險因子為女性、年齡小、B型肝炎病毒帶原及化療處方不包含類固醇。但以此四危險因子進行多元迴歸（multiple regression），則皆不具有統計上顯著意義。 本研究中唯一符合B型肝炎病毒再活化定義之患者，雖然在肝功能指數異常時即開始以lamivudine治療，但仍於開始化療後72天，因肝腦病變（hepatic encephalopathy）死亡，可能原因為已錯過lamivudine最佳治療時機。 進行第二線化學治療之患者，其肝炎發生率（11.7%）較第一線gemcitabine為低，而化學治療處方及肝炎病毒帶原皆不影響肝炎之發生。且gemcitabine治療是否發生肝炎，與第二線化療是否發生肝炎並無關連，因此，即使在第一線化療無發生肝炎，接受第二線化療之患者仍有必要監測肝功能指數，適時對肝炎之發生作處置，如延後化學治療或更換化療處方，以減低肝臟之損傷。

Gemcitabine (Gemzar&reg;) is one of the standard drugs used in patients with advanced non-small cell lung cancer. Compared with other cytotoxic agents, gemcitabine displayed minimal toxicity. Hepatotoxicity occurred frequently (about 20~50%) and was manifest as a transient, asymptomatic, rapidly reversible elevation of liver enzymes. However, several case reports have revealed that gemcitabine may cause serious hepatotoxicity such as hepatic veno-occlusive disease, cholestatic liver failure and hepatitis B virus reactivation. This retrospective study was conducted to review the use of first-line gemcitabine for non-small cell lung cancer in a tertiary medical center. The aim of this study was to investigate the incidence, severity and risk factors of hepatitis caused by gemcitabine and its influence on treatment outcome; the incidence and treatment of hepatitis B virus reactivation induced by gemcitabine. For those who treated with second-line chemotherapy, this study also sought to find out the risk factors of hepatitis caused by these agents. Three hundreds thirty-seven patients were assessable. Most patients were treated with single gemcitabine or gemcitabine-cisplatin combination. The overall response rate was 19% and the median survival was 11 months. After gemcitabine treatment, WHO grade 1/2 and 3/4 hepatotoxicity was recorded in nearly 30% and 5% of patients, respectively. Among these patients, hepatitis B carriers were more likely to have serious hepatotoxicity (WHO grade 3/4) than non-carriers. The extent of elevation of alanine transaminase in 88 patients (26.1%) was identical to the definition of hepatitis. There was no evidence of dose-cumulative hepatitis and its occurrence was not related to response rate and survival time. In univariate analysis, the predictors of hepatitis were female, young age, hepatitis B carriers and regimen without steroid. Though the only case having hepatitis B virus reactivation was treated with lamivudine immediately after abnormal liver function test, she died of hepatic encephalopathy 72 days following the initiation of gemcitabine treatment. The probable reason was that lamivudine may not be effective in reducing liver injury by this time. It may be more effective in earlier phase of active viral replication. The incidence of hepatitis caused by second-line chemotherapy (11.7%) was much lower than that induced by gemcitabine. There was no specific drug that most likely to cause hepatitis. Also, hepatitis B or C virus infection and the experience of hepatitis in gemcitabine treatment were not predictive of the occurrence of hepatitis.