探讨索拉非尼序贯瑞戈非尼治疗肝细胞癌(以下简称肝癌)肝移植术后复发的临床疗效与安全性。

回顾性分析青岛大学附属医院2014年2月至2020年9月收治的14例肝癌肝移植术后复发接受索拉非尼序贯瑞戈非尼治疗的患者资料。14例患者经临床确诊为肝癌复发后，予索拉非尼(400 mg/次，2次/d)治疗，当出现疾病进展或患者无法耐受索拉非尼相关不良事件时，序贯口服瑞戈非尼(160 mg/次，1次/d，连续服药21 d后停药7 d，每28天为1个周期)治疗，服药期间辅以对症支持治疗，并进行规律随访，监测甲胎蛋白(AFP)、肝功能和免疫抑制剂血药浓度，定期行超声或CT等影像学检查，同时记录不良事件。非正态分布计量资料用中位数表示，采用Wilcoxon符号秩和检验进行比较。采用Kaplan-Meier法绘制生存曲线。P<0.05为差异有统计学意义。

14例患者中，男性12例，女性2例；中位年龄56.5岁(40.0~65.0岁)。肝移植术后肿瘤复发至开始服用索拉非尼的中位时间间隔为1.0个月(0.1~6.4个月)，索拉非尼中位治疗时间为2.7个月(0.9~9.2个月)，中位肿瘤进展时间(TTP)为4.4个月(0.9~14.1个月)。停用索拉非尼至开始服用瑞戈非尼的中位时间间隔为16.5(1~366 d)，瑞戈非尼的中位治疗时间为9.3个月(1.3~20.4个月)，中位TTP为2.8个月(1.0~9.7个月)，中位总生存期为20.1个月(95%CI 0.7~39.5个月)。索拉非尼治疗前后AFP及肝功能指标差异均无统计学意义(P均>0.05)。瑞戈非尼治疗后AFP较治疗前升高，治疗后血清白蛋白较治疗前降低，差异均有统计学意义(Z＝-2.691和-2.271，P均<0.05)；ALT、AST和总胆红素变化差异均无统计学意义(P均>0.05)。索拉非尼和瑞戈非尼治疗期间出现的不良事件包括：腹泻、乏力、体质量减轻和手足皮肤反应，严重程度分级分别为Ⅰ级10例次和16例次，Ⅱ级10例次和2例次，Ⅲ级均为2例次。其中，2例因严重发生严重腹泻而终止索拉非尼治疗，2例因严重手足皮肤反应分别减少瑞戈非尼剂量和停用，其余患者出现不良反应予对症处理后均可耐受。截至2020年9月，中位随访时间为12.4个月(5.6~34.2个月)，共7例患者死亡，死因均为肝癌复发后肿瘤进展。存活的7例患者中，3例因出现肺部肿瘤进展而停用瑞戈非尼，4例继续应用瑞戈非尼治疗。14例患者接受索拉非尼序贯瑞戈非尼治疗后中位总生存期为14.4个月(95%CI 3.4~25.4个月)，1年和2年累积生存率分别为67.7%和48.4%。

索拉非尼序贯瑞戈非尼治疗肝癌肝移植术后复发具有较好的临床疗效和安全性，但仍需更大样本量的研究支持。

To investigate the clinical efficacy and safety of sorafenib sequential regorafenib in the treatment of recurrence of hepatocellular carcinoma after liver transplantation.

The clinical data of 14 patients with hepatocellular carcinoma who had tumor recurrence after liver transplantation and received sorafenib and regorafenib were collected from the Affiliated Hospital of Qingdao University from February 2014 to September 2020. After the clinical diagnosis of recurrence of liver cancer, sorafenib (400 mg/time, twice a day, oral) was added for treatment. When the disease progressed or the adverse events of sorafenib was not tolerated, sequentially treated with regorafenib (160 mg/time, once a day, oral, continuous medication for 21 days, stop medication for 7 days, every 28 days is a cycle) treatment. The medication was supplemented with symptomatic support treatment, followed up regularly, alpha-fetoprotein (AFP), liver function, immunosuppressive blood concentration, ultrasound or CT and other imaging examinations were monitored, and adverse events were recorded.

Among the 14 patients who finally met the inclusion criteria, 12 were males and 2 were females; the median age was 56.5 (40.0-65.0) years. The median interval from tumor recurrence after liver transplantation to initiation of sorafenib was 1.0 (0.1-6.4) months. The median treatment time for sorafenib was 2.7 (0.9-9.2) months, and the median time to progression (mTTP) was 4.4 (0.9-14.1) months. The median time between cessation of sorafenib and initiation of regorafenib was 16.5 (1-366) d; the median treatment time of regorafenib was 9.3 (1.3-20.4) months, the mTTP was 2.8 (1.0-9.7) months, and the median overall survival (mOS) was 20.1 (95%CI 0.7-39.5) months. There were no significant differences in AFP and liver function indexes before and after sorafenib treatment (all P>0.05). AFP increased and serum albumin decreased after treatment, with statistical significance (all P<0.05). ALT, AST and total bilirubin changes had no statistical difference (all P>0.05). Adverse events during the treatment of sorafenib and regofinib included: diarrhea (9 cases and 10 cases), fatigue (9 cases and 6 cases), decreased body mass (3 cases and 2 cases), and hand-foot skin reactions (1 case and 2 cases), respectively. Among them, sorafenib treatment was terminated in 2 cases due to severe diarrhea, and the dosage of regogafenib was reduced in 1 case, and the treatment of regogafenib was discontinued in 1 case due to hand and foot skin reaction, respectively. The other patients had adverse reactions and were tolerated after symptomatic treatment. By September 2020, the median follow-up time was 12.4 (5.6-34.2) months, and a total of 7 patients died, all due to tumor progression after liver cancer recurrence. Of the 7 patients who survived, 3 were discontinued due to lung tumor progression, and 4 were continued with regofinib. The mOS was 14.4 (95%CI 3.4-25.4) months for 14 patients who received sorafenib sequential regolfinib, and the 1-year and 2-year cumulative survival rates were 67.7% and 48.4%, respectively.

Sorafenib sequential regorafenib for the treatment of tumor recurrence after liver transplantation of hepatocellular carcinoma has good clinical efficacy and safety, but a larger sample size of research support is still needed.