Radiological response and inflammation scores predict tumour recurrence in patients treated with transarterial chemoembolization before liver transplantation

Table 1 Clinical, radiological and laboratory characteristics of the study population at the initial evaluation n (%)

Variable	All treated patients (n = 70)
Demographics and indications
Age at LT (yr) [median (IQRs)]	57 (51-62)
Male gender	62 (88.6)
Biochemical MELD Score [median (IQRs)]	11 (7-15)
Child-Pugh class A/B/C	29 (41.4)/27 (38.6)/14 (20.0)
Virus B-related cirrhosis	15 (21.4)
Virus C-related cirrhosis	41 (58.6)
Pre-TACE radiological evaluation
Type of imaging technique (CT/MR)	49 (70.0)/21 (30)
Exceeding Milan criteria	22 (31.4)
Exceeding UCSF criteria	12 (17.1)
Number of nodules [median (IQRs)]	1 (1-2)
Single/multiple	40 (57.1)/30 (42.9)
Sum of nodule diameters (cm) [median (IQRs)]	3.35 (2.1-5.4)
Sum of nodule diameters > 5 cm	22 (31.4)
Diameter of the largest nodule (cm) [median (IQRs)]	2.6 (2.0-3.4)
Diameter of the largest nodule > 5 cm	7 (10.0)
Pre-TACE laboratory evaluation
1AFP (ng/mL) [median (IQRs)]	12.5 (5.8-52.0)
AFP > 400 ng/mL	5 (8.1)
2NLR [median (IQRs)]	2.0 (1.4-3.1)
NLR > 4	13 (20.3)
3PLR [median (IQRs)]	67.2 (44.6-84.0)
PLR > 150	2 (3.1)
AST/ALT (U/L) [median (IQRs)]	69 (43.7-108.7)/56 (34.0-88.2)
WBC (× 103/mmc) [median (IQRs)]	4.7 (3.7-5.8)
Characteristics of TACE and time-intervals between procedures
Number of treatments [median (IQRs)]	2 (1-2)
Repeated TACE	37 (52.9)
Type of TACE (DEB/conventional)	54 (77.1)/16 (22.9)
Interval of last imaging-LT (mo) [median (IQRs)]	1.4 (0.7-2.7)
Interval of last TACE-LT (mo) [median (IQRs)]	3.9 (2.1-7.4)
Interval of first TACE-LT (mo) [median (IQRs)]	6.9 (3.7-11.0)

¹The AFP value was missing in 8 patients;

²TACE NLR was missing in 6 patients;

³PLR was missing in 6 patients. LT: Liver transplantation; IQR: Interquartile range; MELD: Model for End-Stage Liver Disease; TACE: Transarterial chemoembolization, CT: Computed tomography; MR: Magnetic resonance, USCF: University of California San Francisco; AFP: Alpha-fetoprotein; NLR: Neutrophil-to-lymphocyte ratio; PLR: Platelet-to-lymphocyte ratio; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; WBC: White blood cell; DEB: Doxorubicin-eluting bead.

Table 2 Radiological and laboratory characteristics of the study population after transarterial chemoembolization procedures and tumour histopathological data n (%)

Variable	All treated patients (n = 70)
Pre-LT radiological evaluation
mRECIST overall response
Complete/partial response	24 (34.3)/26 (37.1)
Stable/progressive disease	10 (14.3)/10 (14.3)
EASL overall response
Complete/partial response	24 (34.3/25 (35.7)
Stable/progressive disease	11 (15.7)/10 (14.3)
Number of enhancing nodules [median (IQRs)]	1 (0.0-2.0)
None/single/multiple	24 (34.3)/22 (31.4)/24 (34.3)
Sum of enhancing diameters (cm) [median (IQRs)]	1.4 (0.0-3.3)
Sum of enhancing diameters > 5 cm	8 (11.4)
Diameter of the largest enhancing nodule (cm) [median (IQRs)]	1.3 (0.0-2.1)
Diameter of the largest enhancing nodule > 5 cm	1 (1.4)
Pre-LT laboratory evaluation
1AFP (ng/mL) [median (IQRs)]	13.5 (5.3-65.0)
AFP > 400 ng/mL	6 (9.1)
2AFP increase > 15 ng/mL per month	6 (10.2)
NLR [median (IQRs)]	2.6 (1.8-3.8)
NLR > 4	15 (21.4)
3NLR increase > 0.24	16 (29.6)
PLR [median (IQRs)]	62.9 (49.7-85.9)
PLR > 150	5 (7.1)
3PLR increase > 3.04	16 (29.6)
AST/ALT (UI/L) [median (IQRs)]	68 (43-100)/49 (32-76)
WBC (× 103/mmc) [median (IQRs)]	4.7 (3.7-5.8)
Tumour histopathological characteristics
Number of viable nodules [median(IQRs)]	1 (1-3)
Number of viable nodules > 3	11 (15.7)
Tumour differentiation (4Gx/G1-G2/G3-G4)	14 (20.0)/48 (68.6)/8 (11.4)
Microvascular invasion	8 (11.4)
Exceeding Milan criteria	12 (17.1)
Exceeding UCSF criteria	11 (15.7)
% of necrosis on cumulative tumour area (100/99-50/< 50)	14 (20.0)/28 (40.0)/28 (40.0)

¹The AFP value was missing in 4 patients;

²The AFP progression value was missing in 11 patients due to the lack of pre-TACE or pre-LT value;

³NLR and PLR modification was missing in 6 patients due to the lack of pre-TACE values;

⁴Tumour grading was not available in 14 patients with complete histological necrosis at the explant examination. LT: Liver transplantation; mRECIST: Modified Response Evaluation Criteria in Solid Tumours; EASL: European Association for the Study of the Liver; IQR: Interquartile range; AFP: Alpha-fetoprotein; NLR: Neutrophil-to-lymphocyte ratio; PLR: Platelet-to-lymphocyte ratio; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; WBC: White blood cell; USCF: University of California San Francisco.

Table 3 Correlation analysis between histological necrosis and radiological response according to modified Response Evaluation Criteria in Solid Tumours and European Association for the Study of the Liver criteria n (%)

	Overall response				Target lesion response
	Patients (n)	% of necrosis on CTA			Patients (n)	% of necrosis on CTA1
		100	50-99	< 50		100	50-99	< 50
mRECIST
Complete response	24	13 (54.2)	8 (33.3)	3 (12.5)	29	16 (55.2)	8 (27.6)	5 (17.2)
Partial response	26	1 (3.8)	19 (73.1)	6 (23.1)	25	2 (8.0)	16 (64.0)	7 (28.0)
Stable/progressive disease	20	0 (0.0)	1 (5.0)	19 (95.0)	16	0 (0.0)	0 (0.0)	16 (100.0)
EASL
Complete response	24	13 (54.2)	8 (33.3)	3 (12.5)	29	16 (55.2)	8 (27.6)	5 (17.2)
Partial response	25	1 (4.0)	17 (68.0)	7 (28.0)	25	1 (4.0)	15 (60.0)	9 (36.0)
Stable/progressive disease	21	0 (0.0)	3 (14.3)	18 (85.7)	16	1 (6.3)	1 (6.3)	14 (87.5)

¹For radio-histological correlation of the target lesion response, the percentage of necrosis on CTA was re-calculated considering only nodules ≥ 1 cm in diameter. CTA: Cumulative Tumour Area; mRECIST: Modified Response Evaluation Criteria in Solid Tumours; EASL: European Association for the Study of the Liver.

Table 4 Univariate and multivariate analysis of the preoperative risk factors related to tumour recurrence

Risk factors	Univariate analysis			Multivariate analysis
	3-yr RFS rate (%)	HR (95%CI)	Log-rank P value	Exp(b) (95%CI)	P value
Pre-TACE radiological and laboratory evaluation
Exceeding Milan criteria	77.7 vs 91.2	3.41 (0.78-14.92)	0.074
Exceeding UCSF criteria	60.6 vs 92.8	5.06 (0.78-32.74)	0.011	4.69 (1.14-19.30)	0.033
Multiple nodules	77.2 vs 93.4	4.33 (1.06-17.72)	0.049	1.77 (0.27-11.48)	0.550
AFP > 400 ng/mL	80.0 vs 85.3	1.96 (0.13-30.81)	0.520
NLR > 4	100 vs 80.4	NA	0.185
PLR > 150	50.0 vs 88.6	5.98 (0.06-573.48)	0.059
Pre-LT radiological and laboratory evaluation
mRECIST non response	71.2 vs 94.3	6.96 (1.54-31.50)	0.006	9.19 (1.65-51.30)	0.012
EASL non response	76.8 vs 91.6	3.67 (0.82-16.34)	0.056
AFP > 400 ng/mL	83.3 vs 89.0	4.74 (0.29-77.77)	0.034	1.43 (0.23-9.10)	0.703
AFP increase > 15 ng/mL per month	41.7 vs 87.7	3.89 (0.30-50.72)	0.072
NLR > 4	80.8 vs 87.9	1.54 (0.25-9.41)	0.594
NLR increase > 0.24/mo	83.3 vs 100	NA	0.114
PLR > 150	50.0 vs 89.1	5.32 (0.28-101.01)	0.022	5.95 (1.04-33.95)	0.046
PLR increase > 3.04	80.8 vs 88.7	1.48 (0.24-9.04)	0.636

RFS: Recurrence-free survival; HR: Hazard ratio; TACE: Transarterial chemoembolization; USCF: University of California San Francisco; AFP: Alpha-fetoprotein; NLR: Neutrophil-to-lymphocyte ratio; PLR: Platelet-to-lymphocyte ratio; LT: Liver transplantation; mRECIST: Modified Response Evaluation Criteria in Solid Tumours; EASL: European Association for the Study of the Liver.