Prognosis of patients with hepatocellular carcinoma and portal vein tumor thrombus treated with combination of transarterial chemoembolization and palliative thermal ablation

Figures & data

Figure 1. Flowchart of the patients selection. TACE: transarterial chemoembolization; P-ablation: palliative ablation; PSM: propensity score matching.

Table 1. Demographic and clinical characteristics of patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT), before and after propensity score matching (PSM), by type of treatment (TACE + P-ablation vs. TACE), January 2012 to December 2017.

Characteristics	Before PSM			After PSM After PSM
	TACE + P-ablation N (%)	TACE N (%)	p	TACE + P-ablation N (%)	TACE N (%)	p
Total patients	86 (100)	142 (100)	–	63 (100)	63 (100)	–
Sex
Male	81 (94.2)	127 (89.4)	.22	58 (92.1)	56 (88.9)	.54
Female	5 (5.8)	15 (10.6)		5 (7.9)	7 (11.1)	–
Age, years
<60	57 (66.3)	109 (76.8)	.09	44 (69.8)	35 (55.6)	.10
≥60	29 (33.7)	33 (33.2)		19 (30.2)	28 (44.4)	–
Albumin–bilirubin (ALBI) grade^a
1	62 (72.1)	60 (42.3)	<.001	44 (69.8)	35 (55.6)	.10
2	24 (27.9)	80 (56.3)	–	19 (30.2)	28 (44.4)	–
3	0 (0.0)	2 (1.4)	–	0 (0.0)	0 (0.0)	–
Child–Pugh grade^b
A	74 (86)	107 (73.4)	.053	54 (85.7)	50 (79.4)	.29
B	12 (14)	35 (26.6)		9 (14.3)	13 (20.6)
ECOG score
0	38 (44.2)	55 (38.7)	.19	27 (42.9)	24 (38.1)	.43
1	48 (53.8)	87 (61.3)	–	36 (56.1)	39 (61.9)	–
Alpha-fetoprotein, ng/mL
<400	37 (43.0)	59 (41.5)	.83	28 (44.4)	28 (44.4)	1.00
≥400	49 (57.0)	83 (58.5)		35 (55.6)	35 (55.6)	–
Alanine transaminase, IU/L
≤40	35 (40.7)	49 (34.5)	.35	25 (39.7)	20 (31.7)	0.35
>40	51 (59.3)	93 (65.5)	–	38 (60.3)	43 (68.3)	–
Aspartate aminotransferase, IU/L
≤40	23 (26.7)	19 (13.4)	.01	13 (20.6)	13 (20.6)	1.00
>40	63 (73.3)	123 (86.6)		50 (79.4)	50 (79.4)
Hepatitis^c	72 (83.7)	110 (77.5)	.25	51 (81)	49 (77.8)	.66
Portal hypertension^d	18 (20.9)	39 (27.5)	.27	10 (15.9)	16 (25.4)	.19
Comorbidity^e	11 (12.8)	12 (8.5)	.29	7 (11.1)	3 (4.8)	.19
Cirrhosis^f	43 (50.0)	59 (41.5)	.21	29 (40.6)	25 (39.7)	.47
Characteristics	Before PSM			After PSM fter PSM
	TACE + P-ablation mean ± SD	TACE mean ± SD	p	TACE + P-ablation mean ± SD	TACE mean ± SD	p
Neutrophil count, × 10^9/L	5.46 ± 2.15	5.37 ± 2.43	.65	4.55 ± 2.22	5.15 ± 2.23	.15
Platelet count, × 10^9/L	189.24 ± 95.75	192.94 ± 95.45	.78	196.78 ± 100.24	194.67 ± 108.12	.91
Hemoglobin, g/L	137.18 ± 19.8	135.83 ± 18.93	.61	135.39 ± 19.77	137.19 ± 19.67	.61
Prothrombin time (PT), s	12.81 ± 1.45	12.64 ± 1.06	.70	12.29 ± 1.09	12.64 ± 1.61	.15

^aALBI grade based on score calculated from serum albumin and bilirubin levels, used to identify different mortality risk subsets of patients: Grade 1 (lowest mortality risk) for ALBI score ≤ −2.60, Grade 2 (intermediate mortality risk) for ALBI score > −2.60 and ≤ −1.39) and grade 3 (highest mortality risk) for ALBI score > −1.39 (34).

^bChild–Pugh grade based on five clinical measures of liver disease (PT or INR, ascites, bilirubin, albumin and encephalopathy), each scored from 1 to 3 based on severity, with maximum total score 15: Grade A = scores 5–6, Grade B = scores 7–9.

^cHepatitis defined as a history of chronic HBV infection and/or positive hepatitis C virus RNA test.

^dPortal hypertension defined as esophageal varices and/or splenomegaly on imaging studies combined with a decreased platelet count [≤100 × 10⁹/L]).

^eComorbidity defined as hypertension, diabetes, coronary disease and/or severe anemia.

^fBased on imaging showing scarring or diminished size of right or left lobe of liver, compensatory enlargement of caudate lobe of liver and splenomegaly.

TACE: transarterial chemoembolization; P-ablation: palliative thermal ablation; MWA: microwave ablation; RFA: radiofrequency ablation.

Table 2. Tumor- and treatment-related characteristics of patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT), before and after propensity score matching (PSM), by type of treatment (TACE + P-ablation vs. TACE), January 2012 to December 2017.

Characteristics	Before PSM			After PSM
	TACE + P-ablation N (%)	TACE N (%)	p	TACE + P-ablation N (%)	TACE N (%)	p
Total patients	86 (100)	142 (100)	–	63 (100)	63 (100)	–
HCC tumors
1	37 (43.0)	36 (25.4)	<.001	27 (42.9)	27 (42.9)	.96
2–3	20 (23.2)	12 (8.4)	–	8 (12.7)	9 (14.3)	–
> 3	29 (33.8)	94 (66.2)		28 (44.4)	27 (42.8)
Maximum HCC tumor size, cm
< 10	58 (67.4)	76 (53.5)	.04	37 (58.7)	40 (63.5)	.58
≥ 10	28 (32.6)	66 (46.5)	–	26 (41.3)	23 (36.5)	–
Portal vein tumor thrombus (PVTT) type^a
I	15 (17.4)	15 (10.6)	.29	9 (14.3)	9 (14.3)	.63
II	38 (44.2)	73 (51.4)	–	29 (46.0)	24 (38.1)	–
III	33 (38.4)	54 (38.0)	–	25 (39.7)	20 (31.7)	–
TACE treatments
1	32 (37.2)	80 (56.3)	<.001	29 (46.0)	38 (60.3)	.44
2–3	22 (25.6)	45 (31.7)		18 (28.6)	17 (27.0)	–
> 3	32 (37.2)	17 (12.0)		16 (25.4)	8 (12.7)	–
P-ablation treatments^b
1	52 (60.4)	–	–	37 (58.7)	–	–
2–3	17 (19.8)	–	–	14 (22.2)	–	–
> 3	17 (19.8)	–	–	12 (19.1)	–	–

^aPVTT type based on level of thrombus extension into portal vein: type I, tumor thrombus involving segmental branches of portal vein or above; type II, tumor thrombus involving right/left portal vein; type III, tumor thrombus involving main portal vein; and type IV, tumor thrombus involving superior mesenteric vein [31].

^bPalliative (P-)ablation included microwave ablation (MWA) and/or radiofrequency ablation (RFA).

TACE: transarterial chemoembolization.

Figure 2. Kaplan–Meier curves for progression-free survival (PFS) in 228 patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT), before propensity score matching (PSM), January 2012 to December 2017: (A) The PFS rates of the group of 86 patients who had transarterial chemoembolization (TACE) + palliative (P)-ablation (microwave ablation [MWA] and/or radiofrequency ablation [RFA]) were significantly higher than for the group of 142 patients who had only TACE (p < .001); (B) Of the group of 86 patients who had both TACE and P-ablation, for patients received more times of ablation had better PFS. Patients received more than 3 times of ablation had the best PFS. The OS rates were in good correlation with the times of P-ablation treatments (p = .03).

Table 3. Overall survival (OS) and progression-free survival (PFS) rates in patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT), before and after propensity score matching (PSM), by type of treatment (TACE + P-ablation vs. TACE), January 2012 to December 2017.

Survival variables	Before PSM			After PSM
	TACE + P-ablation (n = 86) %	TACE (n = 142) %	p	TACE + P-ablation (n = 63) %	TACE (n = 63) %	p
3-month OS	98.8	88.0	<.001	98.4	93.7	.04
6-month OS	70.9	57.0	0.02	74.6	63.5	.04
9-month OS	54.7	31.7	<.001	52.4	35.8	.03
12-month OS	46.5	23.1	<.001	41.3	26.1	.03
18-month OS	31.0	10.0	<.001	28.1	12.2	.01
2-month PFS	76.7	56.2	<.001	74.6	61.6	.09
4-month PFS	50.0	22.8	<.001	47.6	25.9	.005
6-month PFS	32.6	15.6	.002	30.2	17.8	.04

TACE: transarterial chemoembolization; P-ablation: palliative thermal ablation; MWA: microwave ablation; RFA: radiofrequency ablation.

Table 4. Multivariate analyses of impact of clinical, tumor-related and treatment-related characteristics^a on progression-free survival (PFS) in 228 patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT), before and after propensity score matching (PSM), by type of treatment (TACE + P-ablation vs. TACE), January 2012 to December 2017.

Characteristics	Variables	Before PSM		After PSM
		HR (95% CI)	p	HR (95% CI)	p
Albumin–bilirubin (ALBI) grade^b	2–3 vs. 1	1.38 (1.03–1.85)	.033	–	–
HCC tumors^c
	1	Reference [1]	–	Reference [1]	–
	2–3	1.13 (0.73–1.75)	.588	0.92 (0.50–1.67)	.777
	>3	1.40 (0.99–1.96)	.053	1.81 (1.20–2.73)	.005
Portal vein tumor thrombus (PVTT) type^d
	I	–	–	–	–
	II	1.74 (1.12–2.7)	.014	2.69 (1.44–5.03)	.002
	III	2.00 (1.24–3.23)	.005	2.27 (1.20–2.73)	.011
Treatment type	TACE vs. TACE + P-ablation	1.56 (1.13–2.16)	.007	1.88 (1.27–2.80)	.002
TACE treatments
	1	1.81 (1.26–2.60)	.001	1.75 (1.08–2.85)	.024
	2–3	1.71 (1.16–2.52)	.007	1.10 (0.64–1.88)	.071
	>3	Reference [1]	–	Reference [1]	–

^aOnly those characteristics (listed in Tables 1 and 2) with p values less than .05 in the univariate analysis were subjected to the multivariate Cox regression model and are included here in this Table.

^bALBI grade based on score calculated from serum albumin and bilirubin levels, used to identify different mortality risk subsets of patients: Grade 1 (lowest mortality risk) for ALBI score ≤−2.60, Grade 2 (intermediate mortality risk) for ALBI score >−2.60 and ≤−1.39), and grade 3 (highest mortality risk) for ALBI score >−1.39 [33].

^cALBI grade after PSM was applied did not have p value less than .05 in univariate analysis, so was not subjected to multivariate analysis.

^dPVTT type based on level of thrombus extension into portal vein: type I, tumor thrombus involving segmental branches of portal vein or above; type II, tumor thrombus involving right/left portal vein; type III, tumor thrombus involving main portal vein; and type IV, tumor thrombus involving superior mesenteric vein [31].

TACE: transarterial chemoembolization; P-ablation: palliative thermal ablation; MWA: microwave ablation; RFA: radiofrequency ablation; HR: hazard ratio; CI: confidence interval.

Figure 3. Kaplan–Meier curves for overall survival (OS) in 228 patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT), before propensity score matching (PSM), January 2012 to December 2017: (A) The OS rates of the group of 86 patients who had transarterial chemoembolization (TACE) + palliative (P)-ablation (microwave ablation [MWA] and/or radiofrequency ablation [RFA]) were significantly higher than for the group of 142 patients who had only TACE (p < .001); (B) Of the group of 86 patients who had both TACE and P-ablation, for patients received more times of ablation had better OS. Patients received more than 3 times of ablation had the best OS. The OS rates were in good correlation with the times of P-ablation treatments (p = .025).

Table 5. Median overall survival (OS) in patients with different type of portal vein tumor thrombus (PVTT)^a, before and after propensity score matching (PSM), by type of treatment (TACE + P-ablation vs. TACE), January 2012 to December 2017.

Type of PVTT	Before matching		After matching (1:1)
	TACE + P-ablation	TACE	TACE + P-ablation	TACE
	(Median, 95% CI)	(Median, 95% CI)	(Median, 95% CI)	(Median, 95% CI)
I	16.47 (12.65–28.88)	10.6 (3.84–16.29)	17.1 (7.24–27.96)	10.07 (4.23–15.9)
II	10.57 (8.28–14.86)	6.4 (5.8–6.98)	11.27 (8.2–13.95)	7.63 (5.35–9.9)
III	7.57 (6.03–9.11)	5.27 (3.74–7.6)	7.53 (6.12–8.95)	6.8 (4.7–8.9)

^aPVTT type based on level of thrombus extension into portal vein: type I, tumor thrombus involving segmental branches of portal vein or above; type II, tumor thrombus involving right/left portal vein; type III, tumor thrombus involving main portal vein; and type IV, tumor thrombus involving superior mesenteric vein [31].

Table 6. Multivariate analyses of impact of clinical, tumor-related and treatment-related characteristics^a on overall survival (OS) in 228 patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT), before and after propensity score matching (PSM), by type of treatment (TACE + P-ablation vs. TACE), January 2012 to December 2017.

Characteristics	Variables	Before PSM		After PSM
		HR (95% CI)	p	HR (95% CI)	p
Albumin–bilirubin (ALBI) grade^b	2–3 vs. 1	0.82 (0.61–1.09)	.17	1.30 (0.87–1.92)	.20
HCC tumors^c
	1	0.88 (0.65–1.19)	.41	–	–
	2–3	0.93 (0.74–1.16)	.50	–	–
	> 3	Reference [1]	–	–	–
Portal vein tumor thrombus (PVTT) type^d
	I	Reference [1]	–	Reference [1]-	–
	II	1.86 (1.2–2.88)	.006	1.54 (0.86–2.76)	.14
	III	1.76 (1.13–2.74)	.01	2.31 (1.40–3.80)	.001
Treatment type	TACE vs. TACE + P-ablation	1.40 (1.01–1.96)	.04	1.56 (1.04–2.23)	.03
TACE treatments
	1	2.69 (1.79–4.03)	<.001	2.31 (1.40–3.80)	.001
	2–3	2.02 (1.32–3.09)	.001	1.54 (0.86–2.76)	.14
	> 3	Reference [1]	–	Reference [1]	–

^aOnly those characteristics (listed in Tables 1 and 2) with p values less than .05 in the univariate analysis were subjected to the multivariate Cox regression model and are included here in this Table.

^bALBI grade based on score calculated from serum albumin and bilirubin levels, used to identify different mortality risk subsets of patients: Grade 1 (lowest mortality risk) for ALBI score ≤ −2.60, Grade 2 (intermediate mortality risk) for ALBI score > −2.60 and ≤ −1.39) and grade 3 (highest mortality risk) for ALBI score > −1.39 [33].

^cHCC tumors after PSM was applied did not have p value less than .05 in univariate analysis, so were not subjected to multivariate analysis.

^dPVTT type based on level of thrombus extension into portal vein: type I, tumor thrombus involving segmental branches of portal vein or above; type II, tumor thrombus involving right/left portal vein; type III, tumor thrombus involving main portal vein; and type IV, tumor thrombus involving superior mesenteric vein [31].

TACE: transarterial chemoembolization; P-ablation: palliative thermal ablation; MWA: microwave ablation; RFA: radiofrequency ablation; HR: hazard ratio; CI: confidence interval.

Figure 4. Kaplan–Meier curves for (A) progression-free survival (PFS) and (B) overall survival (OS) in 59 patients with tumor size no more than 7 cm and portal vein tumor thrombus (PVTT), January 2012 to December 2017. PFS and OS rates for the group of 26 patients who had transarterial chemoembolization (TACE) + palliative (P)-ablation (microwave ablation [MWA] and/or radiofrequency ablation [RFA]) were significantly higher than for the group of 33 patients who had only TACE (p = .048 and p = .001, respectively).

Figure 5. Kaplan–Meier curves for (A) progression-free survival (PFS) and overall survival (OS) (B) in 126 patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT), after propensity score matching (PSM), January 2012 to December 2017. PSM was used to create clinically comparable cohorts and to correct for potential biases, with patients matched 1:1 using the nearest neighbor method with a caliber of 0.05. OS and PFS rates for the group of patients who had transarterial chemoembolization (TACE) + palliative (P)-ablation (microwave ablation [MWA] and/or radiofrequency ablation [RFA]) were significantly higher than for the group of patients who had only TACE (p = .001 and p < .001, respectively).

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