Risk Factors for Liver Function Deterioration after Transarterial Chemoembolization Refractoriness in Child-Pugh Class A Hepatocellular Carcinoma Patients

Kang Hyun Park; Jeong Han Kim; Won Hyeok Choe; So Young Kwon; Byung Chul Yoo; Jin Ho Hwang; Sang Woo Park; Young Jun Kim; Hee Sun Park; Mi Hye Yu; Hae Jeong Jeon

doi:10.4166/kjg.2020.75.3.147

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Park, Kim, Choe, Kwon, Yoo, Hwang, Park, Kim, Park, Yu, and Jeon: Risk Factors for Liver Function Deterioration after Transarterial Chemoembolization Refractoriness in Child-Pugh Class A Hepatocellular Carcinoma Patients

Original Article

Korean J Gastroenterol 2020;75(3):147-156.

Published online: 4 October 2020

DOI: https://doi.org/10.4166/kjg.2020.75.3.147

Risk Factors for Liver Function Deterioration after Transarterial Chemoembolization Refractoriness in Child-Pugh Class A Hepatocellular Carcinoma Patients

Kang Hyun Park, Jeong Han Kim

, Won Hyeok Choe, So Young Kwon, Byung Chul Yoo, Jin Ho Hwang¹, Sang Woo Park¹, Young Jun Kim¹, Hee Sun Park¹, Mi Hye Yu¹, Hae Jeong Jeon¹

Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea

¹Department of Radiology, Konkuk University School of Medicine, Seoul, Korea

Correspondence to: Jeong Han Kim, Department of Internal Medicine, Konkuk University School of Medicine, 120-1 Neungdong-ro, Gwangjin-gu, Seoul 05030, Korea. Tel: +82-2-2030-7764, Fax: +82-2-2030-5029, E-mail: 93haan@hanmail.net

Received 22 October 201910 February 2020 Accepted 10 February 2020

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background/Aims

A switch to systemic therapy, such as sorafenib, should be considered for hepatocellular carcinoma (HCC) patients refractory to transarterial chemoembolization (TACE). On the other hand, treatment changes are difficult if the liver function worsens to Child-Pugh B or C. Therefore, predicting the risk factors for non-responsiveness to TACE and deteriorating liver function may be helpful.

Methods

Newly diagnosed Child-Pugh A HCC patients who underwent TACE from January 2012 to June 2018 were included. After 1 year, this study evaluated whether there was a treatment response to TACE and whether the Child-Pugh class had worsened.

Results

Among 121 patients, 65 were refractory and 56 responded to TACE. In multivariable logistic regression analysis, the tumor size, tumor number, and albumin at the time of the diagnosis of HCC were significant prognostic factors for the treatment response to TACE. Among 65 patients who presented TACE-refractoriness, 27 showed liver function deterioration from Child-Pugh class A to class B or C after TACE. In multivariable logistic regression analysis, bilirubin at the diagnosis of HCC was a significant prognostic factor for liver function deterioration. A predictive algorithm based on the regression equations revealed a sensitivity, specificity, positive predictive value, and negative predictive value of 74.1%, 74.5%, 45.5%, and 90.9%, respectively, for TACE-re-fractoriness and liver function deterioration.

Conclusions

The prognostic model incorporating the tumor size, tumor number, albumin, and bilirubin at the diagnosis of HCC may help identify patients who show a poor response to TACE and aggravation of liver function after TACE, who may benefit from early switching into systemic therapy before liver function aggravation.

Keywords: Carcinoma, hepatocellular, Chemoembolization, therapeutic

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Fig. 1.

Patient flow diagram. HCC, hepatocellular carcinoma; TACE, transarterial chemoembolization; RFA, radiofrequency ablation.

Fig. 2.

ROC curves and equations of the multivariable logistic regression of TACE refractoriness. AUC, area under the curve; HCC, hepatocellular carcinoma; Alb, albumin; ROC, receiver operating characteristic; TACE, transarterial chemoembolization.

Fig. 3.

Total bilirubin ROC curves of the univariable logistic regression of liver function deterioration. AUC, area under the curve; ROC, receiver operating characteristic.

Fig. 4.

Prediction of patients with reduced liver function without a response after TACE using the regression formula. HCC, hepatocellular carcinoma; TACE, transarterial chemoembolization.

Table 1.

Baseline Characteristics of All the Patients (n=121) with HCC and Child-Pugh Class A Liver Function First Treated by TACE and Comparisons of the Patients according to the TACE Response

Variable	Total	With TACE response (n=56)	Without TACE response (n=65)	p-value
Age (years)	65.1 (58.0-74.0)	66.6 (68.0-72.8)	63.9 (55.5-76.0)	0.336
Male	84 (69.4)	37 (66.1)	47 (72.3)	0.458
Diabetes mellitus	45 (37.2)	20 (35.7)	25 (38.5)	0.755
BMI (kg/m²)	23.2 (20.7-26.1)	23.8 (21.0-26.3)	23.1 (20.6-26.0)	0.222
Alcohol (g/day)	1.8 (0.0-54.0)	27.6 (0.0-54.0)	32.4 (0.0-54.0)	0.929
Etiology of HCC				0.527
HBV	65 (53.7)	30 (53.6)	35 (53.8)
HCV	23 (19)	9 (16.1)	14 (21.5)
Alcohol	23 (19)	12 (21.4)	11 (16.9)
Other	10 (8.3)	5 (8.9)	5 (7.7)
Final follow-up state				<0.001
Died	25 (20.7)	5 (8.9)	20 (30.8)
Ongoing follow-up	61 (50.4)	42 (75.0)	19 (29.2)
Lost to follow-up	35 (28.9)	9 (16.1)	26 (40.0)
Tumor size (cm)	2.5 (1.6-5.3)	2.9 (1.5-3.6)	4.7 (2.0-6.4)	0.006
Number of tumors	2.0 (1.0-3.0)	1.7 (1.0-2.0)	2.9 (1.0-5.0)	<0.001
Portal vein thrombosis	8 (6.6)	1 (1.8)	7 (10.8)	0.067
Liver cirrhosis	113 (93.4)	53 (94.6)	60 (92.3)	0.724
Platelet (×10³/µL)	130.0 (86.0-166.0)	137.3 (97.5-159.3)	125.0 (76.0-168.5)	0.229
Albumin (g/dL)	3.8 (3.4-4.1)	3.9 (3.6-4.3)	3.62 (3.3-4.0)	0.003
Total bilirubin (mg/dL)	0.9 (0.6-1.2)	0.9 (0.9-1.2)	1.0 (0.6-1.3)	0.682
AST (U/L)	50 (33.5-67.0)	55.8 (30.0-66.8)	62.6 (36.5-68.5)	0.231
ALT (U/L)	34 (22.0-45.0)	32.3 (21.0-44.0)	41.5 (22.0-48.0)	0.437
BUN (mg/dL)	14.5 (12.5-17.6)	15.0 (12.6-17.0)	15.5 (12.5-18.0)	0.457
Creatinine (mg/dL)	0.9 (0.7-1.0)	0.9 (0.7-1.0)	0.9 (0.7-1.0)	0.843
Na (mmol/L)	139.0 (136.0-141.0)	138.9 (137.0-140.8)	138.1 (136.0-141.0)	0.427
Prothrombin time (INR)	1.1 (1.0-1.2)	1.1 (1.0-1.1)	1.1 (1.0-1.2)	0.052
AFP (ng/mL)	14.1 (5.7-102.1)	201.5 (4.3-44.1)	14,799.6 (8.8-384.8)	0.004
PIVKA II (mAU/mL)	54.8 (21.5-313.0)	357.6 (19.6-168.2)	5,216.2 (24.0-721.0)	0.036
MELD score	8.0 (7.0-9.0)	8.1 (7.0-9.0)	8.6 (7.0-10.0)	0.010
Modified UICC				0.023
Stage I	22 (18.2)	15 (26.8)	7 (10.8)
Stage II	43 (35.5)	22 (39.3)	21 (32.3)
Stage III	38 (31.4)	16 (28.6)	22 (33.8)
Stage IV	18 (14.8)	3 (5.4)	15 (23)
BCLC stage				0.030
Very early stage (0)	8 (6.6)	13 (23.2)	6 (9.2)
Early stage (A)	14 (11.6)	16 (28.6)	13 (20)
Intermediate stage (B)	25 (20.7)	15 (26.8)	25 (38.5)
Advanced stage (C)	72 (59.5)	10 (23)	21 (32.3)
Terminal sate (D)	2 (1.7)	2 (3.6)	0 (0)
Child-Pugh				0.031
Score 5	74 (61.2)	40 (71.4)	34 (52.3)
Score 6	47 (38.8)	16 (28.6)	31 (47.7)

Values are presented as median (interquartile range) or n (%).

HCC, hepatocellular carcinoma; TACE, transarterial chemoembolization; BMI, body mass index; HBV, hepatitis B virus; HCV, hepatitis C virus; AST, aspartate transaminase; ALT, alanine transaminase; BUN, blood urea nitrogen; Na, sodium; INR, international normalized ratio; AFP, alpha-fetoprotein; PIVKA II, protein induced by vitamin K absence-II; MELD, model for end-stage liver disease; UICC, Union for International Cancer Control; BCLC, Barcelona Clinic Liver Cancer.

Table 2.

Prognostic Factor Analysis for the TACE Refractoriness by Logistic Regression

Characteristic	Univariable OR (95% CI)	p-value	Multivariable OR (95% CI)	p-value
Age (years)	0.977 (0.945-1.010)	0.169
Male	0.746 (0.343-1.619)	0.458
BMI (kg/m²)	0.936 (0.843-1.040)	0.221
Portal vein thrombosis	0.151 (0.018-1.265)	0.081
Tumor size (cm)	1.238 (1.067-1.437)	0.005	1.204 (1.018-1.424)	0.030
Number of tumors	1.642 (1.235-2.184)	0.001	1.503 (1.117-2.023)	0.007
Albumin (g/dL)	0.321 (0.142-0.686)	0.004	0.287 (0.120-0.685)	0.005
Platelet (×10³/μ L)	0.996 (0.990-1.003)	0.244
Na (mmol/L)	0.933 (0.838-1.040)	0.209
Prothrombin time (INR)	23.864 (0.870-654.732)	0.060
AFP (ng/mL)	1.000 (1.000-1.001)	0.232
PIVKA II (mAU/mL)	1.000 (1.000-1.000)	0.245

TACE, transarterial chemoembolization; OR, odds ratio; CI, confidence interval; BMI, body mass index; Na, sodium; INR, international normalized ratio; AFP, alpha-fetoprotein; PIVKA II, protein induced by vitamin K absence-II.

Table 3.

Baseline Clinical and Tumor Characteristics according to Liver Function Deterioration after TACE among the Patients Who Showed TACE Refractoriness

Variable	Remained in Child-Pugh class A (n=38)	Worsened to Child-Pugh class B or C (n=27)	p-value
Age (years)	65.2 (57.5-75.3)	62.0 (49.0-76.0)	0.351
Male	29 (76.3)	18 (66.7)	0.392
Diabetes mellitus	16 (42.1)	9 (33.3)	0.474
BMI (kg/m²)	23.5 (20.8-26.5)	22.5 (19.8-25.3)	0.242
Alcohol (g/day)	25.1 (0.0-43.2)	42.6 (0.0-72.0)	0.136
Tumor size (cm)	4.4 (2.1-5.6)	5.2 (1.6-9.4)	0.920
Number of tumors	2.8 (1.0-6.0)	2.9 (1.0-4.0)	0.632
Portal vein thrombosis	4 (10.5)	3 (11.1)	1.000
Liver cirrhosis	34 (89.5)	26 (96.3)	0.393
Platelet (×10³/μ L)	126.1 (76.8-161.3)	123.4 (73.0-179.0)	0.859
Albumin (g/dL)	3.7 (3.4-4.0)	3.5 (3.1-4.0)	0.207
Total bilirubin (mg/dL)	0.8 (0.5-1.0)	1.2 (0.9-1.4)	<0.001
AST (U/L)	58.0 (35.8-60.0)	69.1 (38.0-86.0)	0.082
ALT (U/L)	38.8 (22.0-42.3)	45.2 (26.0-59.0)	0.196
BUN (mg/dL)	16.1 (13.3-17.9)	14.7 (11.1-18.1)	0.214
Creatinine (mg/dL)	0.9 (0.8-1.0)	0.8 (0.6-1.0)	0.285
Na (mmol/L)	137.7 (136.0-140.0)	138.7 (136.0-141.0)	0.260
Prothrombin time (INR)	1.1 (1.0-1.2)	1.2 (1.0-1.3)	0.024
AFP (ng/mL)	19,298.5 (8.9-231.0)	8,467.9 (7.3-963.4)	0.331
PIVKA II (mAU/mL)	867.1 (23.5-403.3)	11,337.3 (24.0-2147.0)	0.372
MELD score	8.1 (7.0-9.0)	9.2 (8.0-11.0)	0.023
Modified UICC			0.628
Stage I	3 (7.9)	4 (14.8)
Stage II	12 (31.6)	9 (33.3)
Stage III	15 (39.5)	7 (25.9)
Stage IV	8 (21.1)	7 (25.9)
BCLC stage			0.948
Very early stage (0)	1 (2.6)	1 (3.7)
Early stage (A)	2 (5.3)	1 (3.7)
Intermediate stage (B)	9 (23.7)	5 (18.5)
Advanced stage (C)	26 (68.4)	20 (74.1)
Terminal sate (D)	0 (0)	0 (0)
Child-Pugh			0.038
Score 5	24 (63.2)	10 (37.0)
Score 6	14 (36.8)	17 (63.0)

Values are presented as median (interquartile range) or n (%).

TACE, transarterial chemoembolization; BMI, body mass index; AST, aspartate transaminase; ALT, alanine transaminase; BUN, blood urea nitrogen; Na, sodium; INR, international normalized ratio; AFP, alpha-fetoprotein; PIVKA II, protein induced by vitamin K absence-II; MELD, model for end-stage liver disease; UICC, Union for International Cancer Control; BCLC, Barcelona Clinic Liver Cancer.

Table 4.

Prognostic Factor Analysis for Liver Function Deterioration after TACE by Logistic Regression

Characteristic	Univariable OR (95% CI)	p-value	Multivariable OR (95% CI)	p-value
Age (years)	0.980 (0.942-1.019)	0.313
Male	1.611 (0.539-4.817)	0.393
BMI (kg/m²)	0.916 (0.791-1.060)	0.239
Alcohol (g/day)	1.008 (0.997-1.020)	0.145
Albumin (g/dL)	0.515 (0.184-1.438)	0.205
Total bilirubin (mg/dL)	10.441 (2.511-43.410)	0.001	10.441 (2.511-43.410)	0.001
BUN (mg/dL)	0.926 (0.820-1.045)	0.213
Prothrombin time (INR)	115.984 (1.728-7,786.880)	0.027
PIVKA II (mAU/mL)	1.000 (1.000-1.000)	0.177

TACE, transarterial chemoembolization; OR, odds ratio; CI, confidence interval; BMI, body mass index; BUN, blood urea nitrogen; INR, international normalized ratio; PIVKA II, protein induced by vitamin K absence-II.

Table 5.

Calculation of the Prediction of Patients with Reduced Liver Function without a Response after TACE Using the Regression Formula

	No response and liver function deteriorated to Child-Pugh class B or C
	Positive (n=27)	Negative (n=94)
Calculation using regression formula
Positive (n=44)	True positive (n=20)	False positive (n=24)
Negative (n=77)	False negative (n=7)	True negative (n=70)

Sensitivity=74.1%, specificity=74.5%, positive predictive value=45.5%, negative predictive value=90.9%. TACE, transarterial chemoembolization.

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ORCID iDs: Jeong Han Kim
https://orcid.org/0000-0002-8383-8524
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