Li Jingjie, Yuan Zhi, Wang Qun, Fan Weijie, Zhang Guoping
Department of Respiratory Medicine, Renmin Hospital, Fenghua District, Ningbo City, Zhejiang Province, China.
Medicine (Baltimore). 2019 Jan;98(1):e13726. doi: 10.1097/MD.0000000000013726.
Activation of the anaplastic lymphoma kinase (ALK) gene has been found in several human cancers, including non-small-cell lung cancer (NSCLC). Currently, novel drugs targeting ALK gene have been extensively investigated in NSCLC. However, concerns about ALK inhibitors-induced liver toxicities have been increasing.
Eligible prospective clinical studies have been searched in several databases. Primary outcomes of interest were incidence rates of liver toxicities, relative risks (RRs), and 95% confidence intervals (CIs).
Data from 2418 patients (1873 in the experimental arm; 545 in the control arm) were included. The incidences of all-grade alanine transaminase (ALT) and aspartate aminotransferase (AST) elevation were 26.0% (95% CI: 17.4%-37%), and 23.2% (95% CI, 16.7%-31.4%), respectively. The incidences of high-grade ALT and AST elevation were 8.4% (95% CI, 5.1%-13.4% and 7.0% (95% CI: 5.4%-9.0%), respectively. Sub-group analysis according to the ALK inhibitors found that pooled incidence of liver toxicities associated with ceritinib was higher than that of crizotinib and alectinib. In comparison with chemotherapy, ALK inhibitors significantly increased the all-grade and high-grade ALT elevation (RR 2.37, 95% CI, 1.97-2.86; P < .001; RR 7.34, 95% CI, 3.95-13.63; P < .001) and AST elevation (RR 3.27, 95% CI, 2.47-4.34; P < .001; RR 11.54, 95% CI, 4.33-30.7; P < .001), respectively. No publication bias was detected for RR of ALT and AST.
The findings of the present study offer substantial evidence that ALK inhibitors treatment in advanced NSCLC significantly increases the risk of developing all-grade and high-grade liver toxicities in comparison with controls. Clinicians should recognize liver toxicities promptly as early interventions may alleviate future complications.
在包括非小细胞肺癌（NSCLC）在内的多种人类癌症中发现了间变性淋巴瘤激酶（ALK）基因的激活。目前，针对ALK基因的新型药物已在NSCLC中得到广泛研究。然而，对ALK抑制剂引起的肝脏毒性的担忧日益增加。
在多个数据库中检索符合条件的前瞻性临床研究。感兴趣的主要结局是肝脏毒性的发生率、相对风险（RRs）和95%置信区间（CIs）。
纳入了2418例患者的数据（试验组1873例；对照组545例）。所有级别的丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST）升高的发生率分别为26.0%（95%CI：17.4%-37%）和23.2%（95%CI，16.7%-31.4%）。高级别ALT和AST升高的发生率分别为8.4%（95%CI，5.1%-13.4%）和7.0%（95%CI：5.4%-9.0%）。根据ALK抑制剂进行的亚组分析发现，与色瑞替尼相关的肝脏毒性合并发生率高于克唑替尼和阿来替尼。与化疗相比，ALK抑制剂显著增加了所有级别和高级别ALT升高（RR 2.37，95%CI，1.97-2.86；P<0.001；RR 7.34，95%CI，3.95-13.63；P<0.001）以及AST升高（RR 3.27，95%CI，2.47-4.34；P<0.001；RR 11.54，95%CI，4.33-30.7；P<0.001）。未检测到ALT和AST的RR存在发表偏倚。
本研究结果提供了充分的证据，表明与对照组相比，晚期NSCLC患者接受ALK抑制剂治疗显著增加了发生所有级别和高级别肝脏毒性的风险。临床医生应及时识别肝脏毒性，因为早期干预可能减轻未来的并发症。
