经皮冷冻消融联合无水酒精注射治疗70岁以上老年肝细胞癌患者的效果及安全性分析

罗婧; 吕采红; 杨永平

doi:10.3969/j.issn.1001-5256.2022.02.021

经皮冷冻消融联合无水酒精注射治疗70岁以上老年肝细胞癌患者的效果及安全性分析

DOI: 10.3969/j.issn.1001-5256.2022.02.021

罗婧^{1, 2},
吕采红¹,
杨永平^{1, 2, ,}

1.
北京大学三〇二临床医学院，北京 100039
2.
解放军总医院第五医学中心肝病医学部，北京 100039

基金项目:

国家“十三五”科技重大专项 (2018ZX10725506)

利益冲突声明：本研究不存在研究者、伦理委员会成员、受试者监护人以及与公开研究成果有关的利益冲突。

作者贡献声明：罗婧和吕采红参与了研究数据的获取分析过程；杨永平参与了研究的思路设计。

详细信息

通信作者:
杨永平，yongpingyang@hotmail.com

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出版历程
- 收稿日期: 2021-11-18
- 录用日期: 2021-12-20
- 出版日期: 2022-02-20

Clinical efficacy and safety of percutaneous cryoablation combined with percutaneous ethanol injection in elderly patients with hepatocellular carcinoma aged 70 years or older

Jing LUO^{1, 2},
Caihong LYU¹,
Yongping YANG^{1, 2
, ,}

1.
Peking University 302 Clinical Medical School, Beijing 100039, China
2.
Faculty of Liver Disease, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China

Research funding:

National Science and Technology Major Project during the 13th Five-Year Plan Period (2018ZX10725506)

More Information

Corresponding author: YANG Yongping, yongpingyang@hotmail.com

摘要

摘要: 目的探讨经皮冷冻消融(CRYO)联合无水酒精注射(PEI)对早期老年肝细胞癌患者的疗效和安全性。方法回顾性纳入解放军总医院第五医学中心2014年1月—2018年1月收治的92例老年肝细胞癌患者，其中单一CRYO治疗组46例，CRYO联合PEI(联合治疗)组46例。比较两种治疗方式的效果，不良反应及治疗前后肝功能相关指标的变化，并随访患者肿瘤的复发及生存预后情况。正态分布的计量资料两组间比较用t检验；非正态分布的计量资料两组间比较采用Mann-Whitney U秩和检验。计数资料两组间比较采用χ²检验。两组的生存时间采用Kaplan-Meier方法进行生存分析，并用log-rank检验生存曲线的差异；通过Cox回归法确定影响生存预后的独立危险因素。结果联合治疗组和CRYO组初次消融的有效率分别为89.1%和73.9%，组间差异无统计学意义(P＞0.05)。CRYO组和联合治疗组患者术后总生存率和无瘤生存率间的差异均无统计学意义(P值均＞0.05)，但联合治疗组患者术后第1、2和3年局部肿瘤进展率分别为20%、21%和21%，明显低于CRYO组的30%、46%、46%(χ²=4.187，P＜0.05)。多因素Cox回归分析提示行单一CRYO治疗可能是局部肿瘤进展率的独立危险因素(HR=2.206，95%CI: 1.003~4.850, P=0.049)。在不良反应的发生率上两组间差异没有统计学意义(P＞0.05)，但CRYO组有3例严重不良反应，联合治疗组未出现严重不良反应。结论对于早期老年肝细胞癌患者，CRYO联合PEI治疗较单纯CRYO治疗安全有效，能明显降低局部肿瘤进展率。
- 癌, 肝细胞 /
- 导管消融术 /
- 乙醇 /
- 注射, 病灶内
Abstract: Objective To investigate the clinical efficacy and safety of percutaneous cryoablation combined with percutaneous ethanol injection (PEI) in elderly patients with early-stage hepatocellular carcinoma aged 70 years or older. Methods A retrospective analysis was performed for the clinical data of 92 elderly patients with hepatocellular carcinoma who were admitted to The Fifth Medical Center of Chinese PLA General Hospital from January 2014 to January 2018, among whom 46 underwent cryoablation alone (CRYO group) and 46 underwent cryoablation combined with PEI (combination therapy group). The two groups were compared in terms of clinical outcome, adverse reactions, and changes in liver function parameters after treatment, and the patients were followed up to observe tumor recurrence and survival. The t-test was used for comparison of normally distributed continuous data between two groups, and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups; the chi-square test was used for comparison of categorical data between two groups. The Kaplan-Meier method was used for survival analysis, and the log-rank test was used for comparison of survival curves. The Cox regression analysis was used to identify the independent risk factors for survival and prognosis. Results There was no significant difference in the response rate of initial ablation between the combination therapy group and the CRYO group (89.1% vs 73.9%, P > 0.05). There were no significant differences between the CRYO group and the combination therapy group in overall survival time and tumor-free survival rate after surgery (P > 0.05), and compared with the CRYO group, the combination therapy group had significantly lower 1-, 2-, and 3-year local tumor progression rates (20%/21%/21% vs 30%/46%/46%, χ²=4.187, P < 0.05). The multivariate Cox regression analysis showed that cryoablation alone might be an independent risk factor for local tumor progression(HR=2.206, 95%CI: 1.003-4.850, P=0.049). There was no significant difference in the incidence rate of adverse reactions between the two groups (P > 0.05), but 3 patients in the CRYO group experienced serious adverse reactions, while no patients in the combination therapy group experienced such reactions. Conclusion For elderly patients with early-stage hepatocellular carcinoma, cryoablation combined with PEI is safer and more effective than cryoablation alone and can significantly reduce local tumor progression rate.
- Carcinoma, Hepatocellalar /
- Catheter Ablation /
- Ethanol /
- Injections Intralesional

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图 1 2组患者治疗前后外周血Alb、TBil、ALT、ALP和PLT的变化情况

注: ，基线；，术后1周；，术后3~6个月。

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图 2 两组患者的LTP比较

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图 3 两组患者的OS和TFS比较

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表 1 2组早期老年HCC患者临床特征比较

项目	CRYO组(n=46)	联合治疗组(n=46)	统计值	P值
年龄(岁)	73(70~83)	72(70~81)	U=833.500	0.107
男/女(例)	34/12	34/12	χ²=0.000	1.000
BMI(kg/m²)	22.28±0.51	23.52±0.43	t=1.859	0.066
ECOG PS评分(例)			χ²=2.841	0.092
0	8	15
1	38	31
病因学(例)			χ²=0.066	0.797
HBV	37	36
HCV	9	10
Child-Pugh分级(例)			χ²=0.123	0.726
A级	42	41
B级	4	5
AFP(μg/L)	15.39(5.25~39.90)	17.00(4.63~85.75)	U=1 014.000	0.731
Alb(g/L)	37.00(35.00~40.00)	37.00(33.00~41.00)	U=1 054.500	0.978
TBil(μmol/L)	13.20(9.70~17.30)	13.20(10.50~16.95)	U=1 113.500	0.665
ALT(U/L)	18.00(14.50~44.50)	24.00(16.50~40.00)	U=1 166.500	0.397
AST(U/L)	27.00(22.00~44.00)	35.00(25.00~51.50)	U=1 210.500	0.233
PLT(×10⁹/L)	123.00(79.00~156.50)	114.00(77.50~168.00)	U=1 076.000	0.888
ALP(U/L)	92.00(77.00~105.50)	89.00(75.00~109.50)	U=1 051.000	0.956
GGT(U/L)	38.00(23.50~80.50)	29.00(20.00~49.50)	U=867.500	0.137
肿瘤最大直径(cm)	2.07±0.15	2.20±0.17	t=0.445	0.658
肿瘤数目(例)			χ²=0.522	0.470
单发	33	36
多发	13	10
高危部位肿瘤(例)	36	34	χ²=0.239	0.625
合并基础疾病(例)
肝硬化	21	18	χ²=0.401	0.527
糖尿病	9	9	χ²=0.000	1.000
高血压	21	15	χ²=1.643	0.200
心血管疾病	7	3	χ²=1.795	0.180
既往抗病毒治疗(例)	19	23	χ²=0.701	0.402

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表 2 2组患者的生存预后情况

项目	CRYO组(n=46)	联合治疗组(n=46)	统计值	P值
中位随访期(月)	57(44~60)	67(46~72)	χ²=3.247	0.072
完全消融[例(%)]	34(73.9)	41(89.1)	χ²=3.536	0.060
LTP[例(%)]			χ²=4.187	0.041
1年	14(30)	9(20)
2年	21(46)	10(21)
3年	21(46)	10(21)
TFS[例(%)]			χ²=3.346	0.067
1年	26(58)	27(59)
3年	6(13)	16(34)
5年	2(5)	11(25)
OS[例(%)]			χ²=0.000	0.989
1年	45(97)	42(91)
3年	35(76)	26(68)
5年	25(55)	28(61)

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表 3 影响患者LTP的Cox单因素回归分析

变量	HR(95%CI)	P值
单一治疗方式	2.206(1.003~4.850)	0.049
Child-Pugh B级	0.629(0.149~2.645)	0.399
ECOG PS =1分	1.438(0.654~3.159)	0.245
男性	1.168(0.517~2.640)	0.739
年龄＞75岁	1.052(0.466~2.375)	0.406
BMI＞24 kg/m²	1.081(0.479~2.441)	0.831
HBsAg阳性	1.559(0.634~3.832)	0.282
抗-HCV阳性	1.678(0.584~4.822)	0.980
伴随合并症	1.014(0.489~2.101)	0.778
有门静脉高压	0.835(0.402~1.737)	0.251
规律抗病毒治疗	0.682(0.322~1.445)	0.522
高危部位肿瘤	0.600(0.229~1.574)	0.457
肿瘤直径＞3 cm	0.918(0.350~2.409)	0.906
肿瘤数量＞1个	1.031(0.456~2.329)	0.641
Alb＞35 g/L	0.669(0.304~1.469)	0.863
TBil＞17.1 μmol/L	1.383(0.629~3.038)	0.475
ALT＞40 U/L	1.148(0.508~2.592)	0.441
ALP＞150 U/L	1.314(0.397~4.345)	0.322
AFP＞20 ng/mL	1.237(0.597~2.566)	0.315

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表 4 影响患者TFS和OS的Cox单因素回归分析

变量	TFS		OS
变量	HR(95%CI)	P值	HR(95%CI)	P值
单一治疗方式	1.529(0.958~2.441)	0.067	0.995(0.512~1.934)	0.989
Child-Pugh B级	1.289(0.639~2.603)	0.468	2.603(1.133~5.981)	0.019
ECOG PS =1分	0.617(0.371~1.024)	0.055	0.945(0.461~1.939)	0.878
男性	1.060(0.623~1.802)	0.827	1.082(0.509~2.302)	0.837
年龄＞75岁	1.009(0.618~1.648)	0.970	1.075(0.528~2.189)	0.841
BMI＞24 kg/m²	0.669(0.396~1.130)	0.123	1.767(0.896~3.482)	0.094
HBsAg阳性	1.804(0.986~3.300)	0.056	1.433(0.505~4.063)	0.494
抗-HCV阳性	0.661(0.370~1.182)	0.152	0.653(0.271~1.570)	0.335
伴随合并症	0.846(0.538~1.331)	0.461	0.791(0.407~1.538)	0.486
有门静脉高压	1.376(0.863~2.193)	0.170	1.397(0.722~2.703)	0.316
规律抗病毒治疗	0.920(0.584~1.449)	0.713	1.358(0.703~2.625)	0.358
高危部位肿瘤	0.773(0.450~1.329)	0.341	0.596(0.247~1.437)	0.242
肿瘤直径＞3 cm	1.367(0.785~2.380)	0.258	2.041(0.978~4.260)	0.049 8
肿瘤数量＞1个	1.501(0.904~2.493)	0.107	1.450(0.725~2.904)	0.289
Alb＞35 g/L	1.191(0.754~1.881)	0.445	0.475(0.245~0.921)	0.024
TBil＞17.1 μmol/L	1.405(0.839~2.352)	0.186	1.033(0.497~2.146)	0.931
ALT＞40 U/L	0.855(0.507~1.443)	0.551	0.910(0.427~1.937)	0.805
ALP＞150 U/L	0.900(0.411~1.972)	0.789	1.930(0.733~5.082)	0.173
AFP＞20 ng/mL	1.183(0.750~1.867)	0.462	1.804(0.929~3.504)	0.076

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参考文献(28)

[1]	LI X, LIANG P. Current status and advances in ultrasound-guided thermal ablation for hepatocellular carcinoma[J]. J Clin Hepatol, 2021, 37(3): 510-514. DOI: 10.3969/j.issn.1001-5256.2021.03.004. 李鑫, 梁萍. 超声引导下肝癌热消融治疗的现状与进展[J]. 临床肝胆病杂志, 2021, 37(3): 510-514. DOI: 10.3969/j.issn.1001-5256.2021.03.004.
[2]	TOKUSHIGE K, HASHIMOTO E, HORIE Y, et al. Hepatocellular carcinoma based on cryptogenic liver disease: The most common non-viral hepatocellular carcinoma in patients aged over 80 years[J]. Hepatol Res, 2015, 45(4): 441-447. DOI: 10.1111/hepr.12372.
[3]	MIRICI-CAPPA F, GRAMENZI A, SANTI V, et al. Treatments for hepatocellular carcinoma in elderly patients are as effective as in younger patients: A 20-year multicentre experience[J]. Gut, 2010, 59(3): 387-396. DOI: 10.1136/gut.2009.194217.
[4]	ZHANG YX, ZHANG XH, YU XL, et al. Prognosis of microwave ablation for hepatocellular carcinoma: Does age make a difference?[J]. Int J Hyperthermia, 2020, 37(1): 688-695. DOI: 10.1080/02656736.2020.1778198.
[5]	ZHUO ET, ZHENG YC, FU GH, et al. Clinical effect of transcatheter arterial chemoembolization combined with percutaneous ethanol injection in elderly patients with primary liver cancer[J]. Chin J Gerontol, 2021, 41(14): 2956-2958. DOI: 10.3969/j.issn.1005-9202.2021.14.013. 卓恩挺, 郑扬慈, 符国宏, 等. 肝动脉化疗栓塞术联合无水酒精消融术在老年原发性肝癌中的临床效果[J]. 中国老年学杂志, 2021, 41(14): 2956-2958. DOI: 10.3969/j.issn.1005-9202.2021.14.013.
[6]	LI Z, ZHANG K, LIN SM, et al. Radiofrequency ablation combined with percutaneous ethanol injection for hepatocellular carcinoma: a systematic review and meta-analysis[J]. Int J Hyperthermia, 2017, 33(3): 237-246. DOI: 10.1080/02656736.2016.1237681.
[7]	HUANG H, LIANG P, YU XL, et al. Safety assessment and therapeutic efficacy of percutaneous microwave ablation therapy combined with percutaneous ethanol injection for hepatocellular carcinoma adjacent to the gallbladder[J]. Int J Hyperthermia, 2015, 31(1): 40-47. DOI: 10.3109/02656736.2014.999017.
[8]	WANG XZ, WANG ZX, YANG YP. The value of cryoablation combined with percutaneous ethanol injection in the treatment of liver cancer[J]. Hebei Med J, 2012, 34(15): 2274-2276. DOI: 10.3969/j.issn.1002-7386.2012.15.014. 王新真, 王忠新, 杨永平, 等. 氩氦刀冷冻消融联合无水乙醇注射在肝癌治疗中的价值[J]. 河北医药, 2012, 34(15): 2274-2276. DOI: 10.3969/j.issn.1002-7386.2012.15.014.
[9]	WANG C, WANG H, YANG W, et al. Multicenter randomized controlled trial of percutaneous cryoablation versus radiofrequency ablation in hepatocellular carcinoma[J]. Hepatology, 2015, 61(5): 1579-1590. DOI: 10.1002/hep.27548.
[10]	WANG H, LITTRUP PJ, DUAN Y, et al. Thoracic masses treated with percutaneous cryotherapy: Initial experience with more than 200 procedures[J]. Radiology, 2005, 235(1): 289-298. DOI: 10.1148/radiol.2351030747.
[11]	DINDO D, DEMARTINES N, CLAVIEN PA. Classification of surgical complications: A new proposal with evaluation in a cohort of 6336 patients and results of a survey[J]. Ann Surg, 2004, 240(2): 205-213. DOI: 10.1097/01.sla.0000133083.54934.ae.
[12]	AHMED M, SOLBIATI L, BRACE CL, et al. Image-guided tumor ablation: Standardization of terminology and reporting criteria--a 10-year update[J]. Radiology, 2014, 273(1): 241-260. DOI: 10.1148/radiol.14132958.
[13]	KUDO M. Recent advances in systemic therapy for hepatocellular carcinoma in an aging society: 2020 update[J]. Liver Cancer, 2020, 9(6): 640-662. DOI: 10.1159/000511001.
[14]	European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma[J]. J Hepatol, 2018, 69(1): 182-236. DOI: 10.1016/j.jhep.2018.03.019.
[15]	RHO SY, LEE HW, KIM DY, et al. Current status of therapeutic choice and feasibility for patients with hepatocellular carcinoma aged ≥ 70 years: A nationwide cancer registry analysis[J]. J Hepatocell Carcinoma, 2021, 8: 321-332. DOI: 10.2147/JHC.S306507.
[16]	GALUN D, BOGDANOVIC A, ZIVANOVIC M, et al. Short- and long-term outcomes after hepatectomy in elderly patients with hepatocellular carcinoma: An analysis of 229 cases from a developing country[J]. J Hepatocell Carcinoma, 2021, 8: 155-165. DOI: 10.2147/JHC.S297296.
[17]	KIM JM, CHO BI, KWON CH, et al. Hepatectomy is a reasonable option for older patients with hepatocellular carcinoma[J]. Am J Surg, 2015, 209(2): 391-397. DOI: 10.1016/j.amjsurg.2013.06.010.
[18]	YU B, DING Y, LIAO X, et al. Radiofrequency ablation versus surgical resection in elderly patients with early-stage hepatocellular carcinoma in the era of organ shortage[J]. Saudi J Gastroenterol, 2018, 24(6): 317-325. DOI: 10.4103/sjg.SJG_261_18.
[19]	EI S, HIBI T, TANABE M, et al. Cryoablation provides superior local control of primary hepatocellular carcinomas of > 2 cm compared with radiofrequency ablation and microwave coagulation therapy: An underestimated tool in the toolbox[J]. Ann Surg Oncol, 2015, 22(4): 1294-1300. DOI: 10.1245/s10434-014-4114-7.
[20]	DUNNE RM, SHYN PB, SUNG JC, et al. Percutaneous treatment of hepatocellular carcinoma in patients with cirrhosis: A comparison of the safety of cryoablation and radiofrequency ablation[J]. Eur J Radiol, 2014, 83(4): 632-638. DOI: 10.1016/j.ejrad.2014.01.007.
[21]	SATO M, TATEISHI R, YASUNAGA H, et al. Mortality and morbidity of hepatectomy, radiofrequency ablation, and embolization for hepatocellular carcinoma: A national survey of 54, 145 patients[J]. J Gastroenterol, 2012, 47(10): 1125-1133. DOI: 10.1007/s00535-012-0569-0.
[22]	SHⅡNA S, TATEISHI R, ARANO T, et al. Radiofrequency ablation for hepatocellular carcinoma: 10-year outcome and prognostic factors[J]. Am J Gastroenterol, 2012, 107(4): 569-577; quiz 578. DOI: 10.1038/ajg.2011.425.
[23]	LI Z, ZHANG C, LOU C, et al. Comparison of percutaneous cryosurgery and surgical resection for the treatment of small hepatocellular carcinoma[J]. Oncol Lett, 2013, 6(1): 239-245. DOI: 10.3892/ol.2013.1314.
[24]	ORLACCHIO A, BAZZOCCHI G, PASTORELLI D, et al. Percutaneous cryoablation of small hepatocellular carcinoma with US guidance and CT monitoring: initial experience[J]. Cardiovasc Intervent Radiol, 2008, 31(3): 587-594. DOI: 10.1007/s00270-008-9293-9.
[25]	TAKAHASHI H, MIZUTA T, KAWAZOE S, et al. Efficacy and safety of radiofrequency ablation for elderly hepatocellular carcinoma patients[J]. Hepatol Res, 2010, 40(10): 997-1005. DOI: 10.1111/j.1872-034X.2010.00713.x.
[26]	KAIBORI M, YOSHⅡ K, HASEGAWA K, et al. Treatment optimization for hepatocellular carcinoma in elderly patients in a Japanese Nationwide Cohort[J]. Ann Surg, 2019, 270(1): 121-130. DOI: 10.1097/SLA.0000000000002751.
[27]	HINSHAW JL, LEE FT Jr. Cryoablation for liver cancer[J]. Tech Vasc Interv Radiol, 2007, 10(1): 47-57. DOI: 10.1053/j.tvir.2007.08.005.
[28]	VANDENBROUCKE F, VANDEMEULEBROUCKE J, BULS N, et al. Can tumor coverage evaluated 24 h post-radiofrequency ablation predict local tumor progression of liver metastases?[J]. Int J Comput Assist Radiol Surg, 2018, 13(12): 1981-1989. DOI: 10.1007/s11548-018-1765-z.