Effect of arsenic trioxide chemotherapy on survival time in liver cancer patients undergoing liver transplantation

Ji JunSong; Chen Ting; Wang Hui; Wang ChenYi; Zhu XinYing; Yin Hao; Fu ZhiRen

doi:10.3969/j.issn.1001-5256.2017.09.023

Issue 9

Sep. 2017

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Article Navigation > Journal of Clinical Hepatology > 2017 > 33(9): 1745-1748

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Effect of arsenic trioxide chemotherapy on survival time in liver cancer patients undergoing liver transplantation

DOI: 10.3969/j.issn.1001-5256.2017.09.023

Department of Liver Transplantation, Zhabei Branch of Changzheng Hospital

Research funding:

Received Date: 2017-03-06
Published Date: 2017-09-20

Abstract

Abstract

Objective To investigate whether arsenic trioxide preventive chemotherapy can prolong the survival time of patients with primary liver cancer undergoing liver transplantation. Methods A retrospective analysis was performed for the clinical data of the patients who underwent liver transplantation in Department of Liver Transplantation in Changzheng Hospital from January to December, 2015, and among these patients, 35 ( observation group) received the chemotherapeutic regimen of epirubicin D1 + 5-fluorouracil ( D1-5) and 35 ( control group) received the chemotherapeutic regimen of arsenic trioxide ( D1-14) . Hematological examinations were performed at the beginning and ending of each cycle of treatment, including routine blood test, hepatic and renal function, and tumor markers, and drug side-effects were observed. Chest CT, liver CT, or MRI was performed at the beginning of every two cycles to record tumor recurrence, survival, and death time. The chi-square test was used for comparison of categorical data between groups, the Kaplan-Meier method was used to plot survival curves, and the log-rank test was used to compare survival curves between groups. Results In the observation group, 3 patients experienced a transient increase in alanine aminotransferase after the last chemotherapy; 30 patients experienced the symptoms of water-sodium retention including mild edema in the face and lower limbs in the late stage of treatment, which were improved after diuretic treatment or at the end of treatment. In the control group, 24 patients experienced varying degrees of gastrointestinal reactions such as poor appetite, nausea, and vomiting, which were improved at the end of chemotherapy. The control group had a 1-year survival rate of 85. 7% ( 30/35) , a 2-year survival rate of 47. 4% ( 18/35) , and a 3-year survival rate of 22. 9% ( 8/35) , and the observation group had a 1-year survival rate of 91. 4% ( 32/35) , a 2-year survival rate of 83. 9% ( 26/31) , and a 3-year survival rate of 57. 1% ( 12/21) . There was no significant difference in 1-year survival rate between the two groups ( χ2= 2. 258, P < 0. 05) , and the observation group had significantly higher 2-and 3-year survival rates than the control group ( χ2= 7. 786 and 6. 720, both P < 0. 05) . Survival curves also showed that the observation group had significantly higher 2-and 3-year survival rates than the control group ( χ2= 6. 573, P < 0. 05) . Conclusion Arsenic trioxide has been used for a long time, and with modern and scientific administration, it can improve the survival time of patients with liver cancer undergoing liver transplantation.
- arsenicals,
- liver neoplasms,
- liver transplantation,
- prognosis

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慢性肝病的共同病理结局是肝纤维化/肝硬化。根据既往是否发生并发症，肝硬化可分为代偿期肝硬化和失代偿期肝硬化，进展至失代偿期肝硬化后，患者死亡风险增加^[1]。失代偿事件中，食管胃底静脉曲张破裂出血(esophageal variceal bleeding, EVB)尤为凶险^[2-3]。预测失代偿事件以采取积极的预防措施，是提高肝硬化患者生存期的关键。血清壳多糖酶3样蛋白1(chitinase-3-like protein 1, CHI3L1)是一种检测纤维化进展的无创指标，可预测ALT正常或轻度升高的患者中、重度肝纤维化^[4]。本研究对CHI3L1预测肝硬化患者出现失代偿事件和代偿期肝硬化患者出现首次失代偿事件风险的临床价值进行回顾性病例对照研究，探索CHI3L1对失代偿事件发生风险的评估价值，以便合理指导治疗，提高肝硬化患者生存期。

1. 资料与方法

1.1 研究对象

收集2019年1月—2021年5月于天津市第二人民医院诊疗的肝硬化患者中，符合纳排标准的患者的人口学特征、临床资料和随访1年内失代偿事件的发生情况。以随访1年内失代偿事件的发生情况进行分组，进行病例对照研究。失代偿事件定义为显性腹水、EVB或显性肝性脑病^[1]。纳入标准：(1)肝硬化诊断符合《肝硬化诊治指南》^[5]；乙型肝炎诊断符合《慢性乙型肝炎防治指南(2019年版)》^[5]；丙型肝炎诊断符合《丙型肝炎防治指南(2019年版)》^[6]；非酒精性脂肪性肝病诊断符合《非酒精性脂肪性肝病防治指南(2018更新版》^[7]；酒精性肝病符合《酒精性肝病防治指南(2018更新版)》^[8]；自身免疫性肝炎诊断符合《自身免疫性肝炎诊断和治疗指南(2021)》^[9]；原发性胆汁性胆管炎诊断符合《原发性胆汁性胆管炎的诊断和治疗指南(2021)》^[10]；(2)随访时间＞1年或随访期间发生终点事件。排除标准：(1)ALT＞2倍正常值上限；(2)合并恶性肿瘤；(3)有严重的肺心肾等系统疾病；(4)接受过降低门静脉高压的预防手段(预防性内镜套扎或硬化剂、经颈静脉肝内门体分流术或口服非选择性β受体阻滞剂)。

1.2 检测方法

血清CHI3L1水平检验采用Microlab STAR IVD ELISA全自动酶联免疫分析仪(瑞士哈美顿博纳图斯有限公司)及CHI3L1酶联免疫法检测试剂盒(杭州普望生物技术有限公司)测定；肝生化指标采用HITACHI全自动生物化学仪-7180及配套试剂(日本东京日立有限公司)测定；血常规采用Sysmex XN-2000血液分析仪及配套试剂(日本希森美康有限公司)测定；凝血指标采用STAGO Compact血凝仪及配套试剂(法国思塔高有限公司)测定。样本测定均由专职人员按照规范流程进行操作。

1.3 统计学方法

采用SPSS 28.0软件对数据进行描述和分析。采用Kolmogorov-Smirnov检验和Shapiro-Wilk检验来检验连续变量是否符合正态分布。符合正态分布的计量资料采用x±s表示，不符合正态分布采用M(P₂₅~P₇₅)，两组间比较采用成组t检验或Mann-Whitney U检验；计数资料两组间比较采用Wilcoxon秩和检验或χ²检验。采用二分类Logistic回归分析各变量与失代偿事件之间的相关性；采用受试者工作特征曲线(ROC曲线)下面积(AUC)来评价各变量对失代偿事件的预测价值，采用约登指数最大值来确定最佳临界值。P＜0.05为差异有统计学意义。

2. 结果

2.1 一般情况

本研究共纳入305例肝硬化患者，其中男176例，女129例；年龄(55.15±11.32)岁；基线时处于代偿期肝硬化患者200例，处于失代偿期肝硬化患者105例。将305例肝硬化患者，以1年内是否发生失代偿事件进行分组，发生失代偿事件组79例，未发生失代偿事件组226例；将200例代偿期肝硬化患者，以1年内是否发生首次失代偿事件进行分组，其中发生首次失代偿事件组43例，未发生首次失代偿事件组157例。两组患者基线人口学特征和临床资料均无缺失。

2.2 基线资料比较

2.2.1 1年内发生与未发生失代偿事件组间比较

发生失代偿事件组的男性占比较高、年龄较大、基线Child-Pugh分级水平较高、基线MELD评分较高、基线Alb水平较低、基线TBil水平较高、基线CHI3L1水平较高、基线INR较高且基线PLT水平较低，差异均有统计学意义(P值均＜0.05)，两组患者的病因、基线ALT水平差异均无统计学意义(表 1)。

表 1 发生与未发生失代偿事件患者基线人口学特征和临床资料的比较

Table 1. Comparison of baseline demographic characteristics and clinical data between decompensation and non-decompensation group

项目	发生失代偿事件组 (n=79)	未发生失代偿事件组 (n=226)	统计值	P值
男性[例(%)]	54(68.4)	122(54.0)	χ²=4.954	0.026
年龄(岁)	58.24±11.57	54.01±11.06	t=-2.308	0.022
病因[例(%)]			χ²=2.248	0.956
乙型肝炎	45(57.0)	115(50.9)
乙型肝炎合并NAFLD	8(10.1)	23(10.2)
丙型肝炎	9(11.4)	22(9.7)
丙型肝炎合并NAFLD	1(1.3)	6(2.7)
酒精性肝病	3(3.8)	8(3.5)
自身免疫性肝炎	2(2.5)	6(2.7)
原发性胆汁性胆管炎	1(1.3)	5(2.2)
其他	10(12.7)	41(18.1)
Child-Pugh分级[例(%)]			Z=-5.434	＜0.001
A级	30(38.0)	169(74.8)
B级	39 (49.4)	37 (16.4)
C级	10(12.7)	20(8.8)
MELD评分	9.53(7.92~12.54)	7.89(6.09~10.73)	U=6 258.500	0.001
ALT(U/L)	19.55(15.10~28.00)	22.00(16.10~29.60)	U=7 822.500	0.102
Alb(g/L)	34.40(29.10~39.90)	41.60(35.08~45.30)	U=5 040.500	＜0.001
TBil(μmol/L)	21.80(14.20~36.40)	17.65(13.30~28.03)	U=7 521.000	0.037
CHI3L1(ng/mL)	243.00(136.00~372.00)	117.50(67.75~205.25)	U=4 720.500	＜0.001
INR	1.20(1.10~1.30)	1.00(1.00~1.20)	U=5 438.000	＜0.001
PLT (×10⁹/L)	77.00(53.00~129.00)	103.50(63.75~163.00)	U=6 700.500	0.001
注：NAFLD，非酒精性脂肪性肝病。

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2.2.2 1年内发生与未发生首次失代偿事件组间比较

发生首次失代偿事件组的基线年龄较大、基线Child-Pugh分级较高、基线MELD评分较高、基线Alb水平较低、基线TBil水平较高、基线CHI3L1水平较高、基线INR较高且基线PLT水平较低，差异均有统计学意义(P值均＜0.001)；两组患者的性别、病因和基线ALT的差异均无统计学意义(表 2)。

表 2 发生与未发生首次失代偿事件患者基线人口学特征和临床资料的比较

Table 2. Comparison of baseline demographic characteristics and clinical data between first-time decompensation and non-first-time decompensation group

项目	发生首次失代偿事件组 (n=43)	未发生首次失代偿事件组 (n=157)	统计值	P值
男性[例(%)]	27(62.8)	90(57.3)	χ²=0.415	0.520
年龄(岁)	56.56±11.41	52.38±10.95	t=2.200	0.029
病因[例(%)]			χ²=4.717	0.680
乙型肝炎	23(53.5)	87(55.4)
乙型肝炎合并NAFLD	3(7.0)	20(12.7)
丙型肝炎	3(7.0)	12(7.6)
丙型肝炎合并NAFLD	1(2.3)	7(4.5)
酒精性肝病	2(4.7)	4(2.5)
自身免疫性肝炎	1(2.3)	4(2.5)
原发性胆汁性胆管炎	0(0.0)	3(1.9)
其他	10(23.3)	20(12.7)
Child-Pugh分级[例(%)]			Z=-5.510	＜0.001
A级	29(67.4)	151(96.2)
B级	14(32.6)	5(3.2)
C级	0(0.0)	1(0.6)
MELD评分	9.39(7.47~12.30)	6.78(5.60~8.87)	U=1 804.000	＜0.001
ALT(U/L)	19.00(15.10~26.30)	22.00(16.00~28.40)	U=2 873.000	0.135
Alb(g/L)	37.30(30.50~44.30)	43.30(39.75~46.30)	U=1 898.000	＜0.001
TBil(μmol/L)	27.53(14.70~35.00)	15.60(12.10~21.25)	U=2 236.500	＜0.001
CHI3L1(ng/mL)	227.98(110.00~314.00)	90.00(58.00~168.50)	U=1 681.500	＜0.001
INR	1.16(1.00~1.30)	1.00(0.90~1.10)	U=1 716.500	＜0.001
PLT(×10⁹/L)	83.26(44.00~100.00)	123.00(85.00~174.50)	U=1 631.000	＜0.001

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2.3 二分类Logistic回归分析

2.3.1 以1年内发生失代偿事件为结局进行二分类Logistic回归分析

单因素回归分析中，患者的年龄、性别、基线Child-Pugh分级、MELD评分、Alb水平、CHI3L1水平、INR和PLT水平是患者1年内发生失代偿事件的影响因素(P值均＜0.05)(表 3)。将以上因素纳入多因素回归分析，结果显示基线Child-Pugh分级(OR=1.722, 95%CI：1.151~2.577，P=0.008)和CHI3L1水平(OR=1.004, 95%CI：1.002~1.006，P＜0.001)均为患者1年内发生失代偿事件的独立影响因素。

表 3 肝硬化患者1年内发生失代偿事件的单因素分析

Table 3. Univariate analysis of factors associated with decompensated events in patients with cirrhosis

变量	OR(95%CI)	P值
年龄	1.035(1.010~1.060)	0.005
性别	0.543(0.316~0.933)	0.027
Child-Pugh分级	2.328(1.608~3.372)	＜0.001
MELD评分	1.111(1.041~1.187)	0.002
ALT	0.983(0.960~1.007)	0.161
Alb	0.898(0.864~0.933)	＜0.001
TBil	1.003(0.994~1.012)	0.508
CHI3L1	1.005(1.003~1.007)	＜0.001
INR	15.077(4.035~56.336)	＜0.001
PLT	0.995(0.991~0.999)	0.026

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2.3.2 以1年内发生首次失代偿事件为结局进行二分类Logistic回归分析

单因素回归分析中，患者的年龄、基线Child-Pugh分级、MELD评分、Alb水平、TBil水平、CHI3L1水平、INR和PLT水平是患者1年内发生首次失代偿事件的影响因素(P值均＜0.05)(表 4)。将以上因素纳入多因素回归分析，结果显示基线Child-Pugh分级(OR=7.184, 95%CI：2.573~ 20.056，P＜0.001)和CHI3L1水平(OR=1.006, 95%CI：1.003~1.008，P＜0.001) 均为患者1年内发生首次失代偿事件的独立影响因素。

表 4 代偿期肝硬化患者1年内发生首次失代偿事件的单因素分析

Table 4. Univariate analysis of factors associated with first decompensated events in patients with compensatory cirrhosis

变量	OR(95%CI)	P值
年龄	1.035(1.003~1.069)	0.031
性别	0.796(0.397~1.594)	0.520
Child-Pugh分级	8.831(3.284~23.746)	＜0.001
MELD评分	1.288(1.146~1.446)	＜0.001
ALT	0.972(0.935~1.010)	0.143
Alb	0.871(0.820~1.924)	＜0.001
TBil	1.027(1.006~1.049)	0.012
CHI3L1	1.006(1.003~1.009)	＜0.001
INR	192.611(17.328~2 140.935)	＜0.001
PLT	0.984(0.976~0.991)	＜0.001

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2.4 预测效能评估

对于肝硬化患者，以1年内失代偿事件的发生情况为状态变量，以CHI3L1为检验变量，绘制ROC曲线。结果显示AUC为0.736(95%CI：0.673~0.798，P＜0.001)，最佳临界值为206.5 ng/mL时，敏感度和特异度分别为62.0%和76.1%(图 1a)。以CHI3L1为检验变量，分别预测1年内腹水、EVB和显性肝性脑病发生风险的AUC(表 5)。

图 1 CHI3L1、Child-Pugh分级和预测模型的ROC曲线

注：a, 失代偿事件；b，首次失代偿事件。

Figure 1. ROC curve of CHI3L1, Child Pugh classification and the model for the prediction

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表 5 血清CHI3L1水平对各失代偿事件的预测价值

Table 5. Predictive value of serum CHI3L1 level for decompensated events in patients with cirrhosis

变量	AUC	95%CI	截断值(ng/mL)	敏感度(%)	特异度(%)	阳性预测值(%)	阴性预测值(%)
腹水	0.726	0.660~0.792	206.5	63.2	74.7	41.7	87.6
EVB	0.824	0.760~0.888	215.5	78.3	76.8	37.5	95.2
显性肝性脑病	0.515	0.394~0.576	102.5	100	61.1	2.1	100

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对于代偿期肝硬化患者，以1年内首次失代偿事件的发生情况为状态变量，以血清CHI3L1水平为检验变量，绘制ROC曲线。结果显示AUC为0.751(95%CI：0.671~0.831，P＜0.001)，最佳临界值为95.5 ng/mL时，敏感度和特异度分别为90.7%和55.4%；以Child-Pugh分级为检验变量，绘制ROC曲线。结果显示AUC为0.643(95%CI：0.538~0.746，P=0.004)。联合Child-Pugh分级和CHI3L1为检验变量建立预测模型，Logit(P)=-4.492+0.006×CHI3L1+1.972×Child-Pugh分级，得到的Logit模型具有统计学意义(χ²=36.855，P＜0.001)；绘制ROC曲线，结果显示AUC为0.809(95%CI：0.737~0.882，P＜0.001)，该模型能够正确分类82.0%的研究对象，约登指数最大时敏感度和特异度分别为72.1%和77.1%(图 1b)。

3. 讨论

CHI3L1是一种含383个氨基酸的单体糖基化蛋白，分子量约40 kD。编码CHI3L1的基因位于人染色体1q32.1的一个8 kb的DNA上。CHI3L1由包括肝巨噬细胞在内的多种类型的细胞以不同模式分泌，与血管生成、炎症反应、组织重塑和纤维化进展等多种病理过程有关，可通过激活TGF-β1、MAPK、ERK和PI3K/AKT等信号通路来发挥作用，但其在疾病进展中确切的作用机制暂未完全明确^[11]。CHI3L1在肝硬化的病程中可通过抑制肝巨噬细胞的凋亡来加剧肝硬化的进程，在肝病领域，现阶段针对CHI3L1的研究主要集中在对肝纤维化/肝硬化程度和对肝癌发生风险的预测^[12]，这一指标还未被用于对肝硬化患者失代偿事件发生风险的预测。本研究尝试使用CHI3L1对代偿期肝硬化患者发生失代偿事件的风险和对代偿期肝硬化患者发生首次失代偿事件的风险进行预测。

肝硬化患者的中位生存期约12年，发生首次失代偿事件后，中位生存期约2年^[13]。为提高肝硬化患者的生存期，需要预测失代偿事件以采取积极的预防措施。笔者团队^[14]联合血小板和使用瞬时弹性成像检查测得的肝硬度数据建立了预测首次失代偿事件发生风险的模型，但是这一模型涉及的瞬时弹性成像检查在很多地区暂未开展，这一模型还未在临床普及应用。本研究发现，将患者血清CHI3L1用于对首次失代偿事件的预测时，AUC为0.751；反映肝脏储备功能的Child-Pugh分级所包含的多项指标是肝硬化患者发生失代偿事件的重要影响因素，将血清CHI3L1与Child-Pugh分级进行联合建立的预测模型，AUC可达0.809，具有一定的临床应用价值，为预测首次失代偿事件提供了新的可选手段。

失代偿事件中，EVB可危及生命。我国的《肝硬化门静脉高压食管胃静脉曲张出血的防治指南》^[15]建议结合胃镜和Child-Pugh分级来判断肝硬化患者EVB的风险，以决定进一步的预防和治疗方案。但胃镜属于侵入性检查，患者接受程度较差，且长期随访困难。作为现阶段临床关注的焦点，很多研究在探索可用于对肝硬化患者发生EVB风险进行预测的模型，但现有的模型存在应用病因范围狭窄和涉及的侵入性检查难以用于随访等诸多问题，仍有必要进行进一步研究^[16-17]。血清学指标相对易获得，本研究使用血清CHI3L1对肝硬化患者发生EVB的风险进行预测时，AUC为0.824, 可用于对肝硬化患者发生EVB风险进行非侵入性的评估，以便针对性地指导肝硬化患者的预防和治疗方案。

综上，本研究纳入了多种病因导致肝硬化的患者共305例，结合患者1年的随访数据，发现血清CHI3L1拥有无创评估肝硬化患者发生首次失代偿事件这一显著影响生存期事件的风险的前景，可作为针对代偿期肝硬化患者预测首次失代偿事件的预测因子。且对于代偿期肝硬化人群发生EVB的风险已具有较好的预测价值，具有较好的临床应用前景。本研究为单中心回顾性研究，由于回顾性和病因构成复杂而存在偏倚问题，需要进一步在外部队列中进行验证。但是本研究所使用的血清学指标方便获得，可重复性强，且避免了影像学检查所存在的主观因素影响。同时作为使用试剂盒即可进行检测的方案，成本较低，易于推广。尤其在瞬时弹性成像检查还未开展的地区，迫切需要一些利于随访的血清学指标^[18]。门静脉高压是肝硬化患者发生失代偿事件的主要驱动因素^[19]，新生血管的生成在门静脉高压的发生和发展中起至关重要的作用^[20]。CHI3L1参与血管生成的病理进程^[10]，考虑其血清学水平可能反映了肝硬化患者门静脉高压的进展程度，进而实现了对患者发生失代偿事件风险的预测效能，但具体机制仍待基础实验和进一步临床研究探索。

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Effect of arsenic trioxide chemotherapy on survival time in liver cancer patients undergoing liver transplantation

DOI: 10.3969/j.issn.1001-5256.2017.09.023