Prolonged post-ablation fever may predict one-year tumor recurrence in hepatocellular carcinoma after radiofrequency ablation

Figures & data

Figure 1. Flowchart of patient recruitment. Abbreviations: HCC: Hepatocellular carcinoma; RFA: Radiofrequency ablation; LTP: local tumor progression; IHM: intrahepatic distant metastasis; EHM: extrahepatic metastasis.

Table 1. Comparisons of baseline features of the patients with prolonged post-ablation fever (PAF) and others.

Variables	Overall (N = 135)	Prolonged PAF (N = 22)	Others (N = 113)	p Value
Age (years)^a	67.0 ± 11.0	67.0 ± 8.8	67.0 ± 11.5	0.9941
Gender (male, %)	96 (71.1)	13 (59.0)	83 (73.5)	0.1740
HCC treatment naïve (n, %)	83 (61.4)	13 (59.0)	70 (61.9)	0.8021
NBNC/HBV/HCV, n (%)	18/57/60 (13.3/42.2/44.4)	5/9/8 (22.7/40.9/36.3)	13/48/52 (11.5/42.5/46)	0.3436
TNM stage I/II, n (%)	103/32 (76.3/23.7)	12/10 (54.5/44.5)	91/22 (80.5/19.5)	0.0087
CTP A/B, n (%)	124/11 (91.9/8.1)	19/3 (86.4/13.6)	105/8 (92.9/7.1)	0.3037
BCLC stage 0 + A/B + C (%)	108/27 (80.0/20.0)	15/7 (68.2/31.8)	93/20 (82.3/17.7)	0.1298
Total bilirubin (mg/dL)	0.7 (0.2-3.7)	0.7 (0.2-2)	0.8 (0.3-3.7)	0.5199
AST (U/L)	40 (12–405)	39 (22–150)	40 (12–405)	0.9952
ALT (U/L)	31 (10–192)	30 (12–140)	31 (10–192)	0.7521
Albumin (g/dL)	3.8 (2.3–4.7)	3.7 (3–4.7)	3.8 (2.3–4.7)	0.9976
AFP (ng/mL)	10.4 (1.9–37257)	49.2 (1.9–37257)	9 (2–33163)	0.1589
Platelet (1000/μL)	103 (23–436)	108 (38–436)	103 (23–362)	0.8024
Pretreatment NLR	1.7 (0.3–11.7)	1.8 (0.3–11.7)	1.7 (0.5–9.5)	0.6006
Increased NLR fold > 2, n (%)	48 (35.6)	13 (59.1)	35 (30.9)	0.0117
FIB4 > 3.25, n (%)	96 (71.1)	16 (72.7)	80 (70.8)	0.8550
APRI > 2, n (%)	39 (28.9)	7 (31.8)	32 (28.3)	0.7404
ALBI grade 1/2/3, n (%)	57/75/3 (42.2/55.6/2.2)	9/13/0 (40.9/59.1/0)	48/62/3 (42.5/54.9/2.7)	0.7211
Target lesion size (cm)	2.2 (0.6-5.2)	2.7 (0.7-5.2)	2.1 (0.6-5.2)	0.1378
Tumor size > 3cm, n (%)	31 (22.9)	9 (40.9)	22 (19.5)	0.0287
Tumor number 1/2/≥3, n (%)	102/28/5 (75.6/20.7/3.7)	14/6/2 (63.6/27.3/9.1)	88/22/3 (77.9/19.5/2.7)	0.2128
Ablation volume (cm^3)	44.1 (4.2-329.1)	74.9 (9.5-221.8)	43.2 (4.2-321.9)	0.0749
Ablation duration (minute)	18 (5-60)	23 (6-42)	18 (5-60)	0.4447
Ablation power (watt)	120 (30-200)	140 (30-200)	120 (60-200)	0.4253
Edmondson-Steiner grade I + II/III, n (%)	104/18 (85.3/14.7)	19/2 (90.5/9.5)	85/16 (84.2/15.8)	0.4576
Recurrence free duration (months)	14.5 (0.9–77.4)	7.7 (1.3–56.5)	15.3 (0.9–77.4)	0.0290
Follow-up duration (months)	52 (3.8–78.4)	52.6 (3.8–73)	51 (4.3–78.4)	0.9810

^aDemonstrated as mean ± standard deviation (SD).

AFP: alpha-fetoprotein; ALBI: albumin-bilirubin index; ALT: alanine aminotransferase; APRI: AST to platelet ratio index; AST: aspartate aminotransferase; BCLC: Barcelona Clinic Liver Cancer; CTP: Child–Turcotte–Pugh; HBV: hepatitis B virus; HCC: hepatocellular carcinoma; HCV: hepatitis C virus; NBNC: non-B non-C; FIB-4: fibrosis-4; NLR: Neutrophil-to-lymphocyte ratio; PAF: post-ablation fever.

Table 2. Logistic regression for predictors of prolonged post-ablation fever.

Variables		Crude OR (95%CI)	p Value	Adjusted OR (95%CI)	p Value
TNM stage	I	Referent		Referent
	II	3.447 (1.32–9.0)	0.0115	3.185 (1.173–8.64)	0.0231
Tumor size	≤3cm	Referent		Referent
	>3cm	2.864 (1.087–7.547)	0.0334	2.337 (0.84–6.52)	0.1051
Increased NLR fold	≤2	Referent		Referent
	>2	3.219 (1.259–8.213)	0.0147	2.68 (1.008–7.17)	0.0483

NLR: Neutrophil-to-lymphocyte ratio;.

Figure 2. Kaplan–Meier curve showing cumulative recurrence rate for all patients. Of all the 135 patients, prolonged PAF had higher 1-year tumor recurrence rate comparing to those without prolonged PAF (median time-to-recurrence interval: 19.6 vs. 40.5 months, 1-year cumulative tumor recurrence rate: 72.7% vs. 37.1%, Log rank test, p = 0.002).

Table 3. Comparisons of baseline features of the patients with early recurrence and nonrecurrence.

Variables	Overall (N = 135)	Early recurrence (LTP + IHM + EHM)		p Value
		Yes (N = 58)	No (N = 77)
Age (years)^a	67.0 ± 11.0	66.7 ± 10.2	67.2 ± 11.6	0.7953
Gender (male,%)	96 (71.1)	44 (75.8)	52 (67.5)	0.2905
HCC treatment naïve (n,%)	83 (61.4)	28 (48.2)	55 (71.5)	0.0062
NBNC/HBV/HCV, n (%)	18/57/60 (13.3/42.2/44.4)	7/30/21 (12.1/51.7/36.2)	11/27/39 (14.3/35/50.7)	0.1460
TNM stage I/II, n (%)	103/32 (76.3/23.7)	41/17 (70.7/29.3)	62/15 (80.5/19.4)	0.1837
CTP A/B, n (%)	124/11 (91.9/8.1)	53/5 (91.4/8.6)	71/6 (92.2/7.7)	0.8617
BCLC stage 0 + A/B + C (%)	108/27 (80/20)	44/14 (75.9/24.1)	64/13 (83.1/16.8)	0.2969
Total bilirubin (mg/dL)	0.7 (0.2–3.7)	0.7 (0.2–2)	0.8 (0.3–3.7)	0.6567
AST (U/L)	40 (12–405)	40.5 (19–175)	40 (12–405)	0.4418
ALT (U/L)	31 (10–192)	32 (10–187)	30 (10–192)	0.3995
Albumin (g/dL)	3.8 (2.3–4.7)	3.8 (2.3–4.7)	3.8 (2.4–4.7)	0.9168
AFP > 20 (ng/mL), n (%)	54 (40)	32 (55.1)	22 (28.5)	0.0018
Platelet (1000/μL)	103 (23–436)	118 (23–436)	100 (31–322)	0.2397
Pretreatment NLR	1.7 (0.3–11.7)	1.5 (0.3–11.7)	1.8 (0.5–9.5)	0.1498
Increased NLR fold >2, n (%)	48 (35.6)	22 (38)	26 (33.8)	0.6168
FIB-4 > 3.25, n (%)	96 (71.1)	40 (69.0)	56 (72.7)	0.6331
APRI > 2, n (%)	39 (28.9)	18 (31.0)	21 (27.2)	0.6331
ALBI grade 1/2/3, n (%)	57/75/3 (42.2/55.6/2.2)	25/32/1 (43.1/55.1/1.7)	32/43/2 (41.5/55.8/2.6)	0.9348
Target lesion size (cm)	2.2 (0.6–5.2)	2.3 (0.7–4.7)	2.1 (0.6–5.2)	0.5543
Tumor size > 3cm, n (%)	31 (22.9)	15 (25.9)	16 (20.8)	0.4870
Tumor number 1/2/≥3, n (%)	102/28/5 (75.6/20.7/3.7)	41/14/3 (70.7/24.1/5.2)	61/14/2 (79.2/18.2/2.6)	0.4779
Ablation volume (cm^3)	44.1 (4.2–329.1)	44.1 (9.5–231)	43.2 (4.2–321.9)	0.9203
Ablation duration (minute)	18 (5–60)	18 (5–57)	18 (9–60)	0.3611
Ablation power (watt)	120 (30–200)	120 (30–200)	140 (60–200)	0.3844
Edmondson-Steiner grade I + II/III, n (%)	104/18 (85.3/14.7)	40/10 (80/20)	64/8 (88.9/11.1)	0.1733
Prolonged PAF, n (%)	22 (16.3)	16 (27.5)	6 (7.8)	0.0021
Recurrence free duration (months)	14.5 (0.9–77.4)	5 (0.9–11.2)	23.8 (5.3–77.4)	<0.001
Follow up duration (months)	52 (3.8–78.4)	29.8 (3.8–76.6)	58 (5.3–78.4)	<0.001

^aDemonstrated as mean ± standard deviation (SD).

AFP: alpha-fetoprotein; ALBI: albumin-bilirubin index; ALT: alanine aminotransferase; APRI: AST-to-platelet ratio index; AST: aspartate aminotransferase; BCLC: Barcelona Clinic Liver Cancer; CTP: Child–Turcotte–Pugh; EHM: extra-hepatic metastasis; HBV: hepatitis B virus; HCC: hepatocellular carcinoma; HCV: hepatitis C virus; LR: local recurrence; NBNC: non-B non-C; FIB-4: fibrosis-4; NLR: Neutrophil-to-lymphocyte ratio; PAF: post-ablation fever.

Table 4. Cox’s proportional hazards model for predictors of progression free survival (PFS).

Variables	Univariate			Multivariate
	HR	95%CI	p-value	HR	95%CI	P-value
Age (years)	0.998	0.975–1.021	0.8439
Male vs. female	0.715	0.392–1.304	0.2736
HCC recurrent history vs. no	2.005	1.197–3.361	0.0082	1.792	1.064-3.019	0.0284
Virus infection vs. NBNC	1.159	0.526–2.554	0.7147
TNM stage II vs. I	1.548	0.879–2.727	0.1299
CTP B vs. A	1.169	0.467–2.927	0.7382
BCLC stage B + C vs. 0 + A	1.388	0.761–2.533	0.2854
Total bilirubin (mg/dL)	0.855	0.502–1.455	0.5632
AST (U/L)	1.001	0.997–1.006	0.5131
ALT (U/L)	1.004	0.998–1.010	0.1724
Albumin (g/dL)	0.986	0.608–1.598	0.9542
AFP > 20 (ng/mL)	2.203	1.311–3.702	0.0028	1.868	1.098-3.176	0.0211
Platelet (1000/μL)	1.003	0.999–1.007	0.0946
Pretreatment NLR	0.904	0.724–1.128	0.3722
Increased NLR fold >2	1.099	0.646–1.867	0.7285
FIB-4 > 3.25	0.870	0.499–1.517	0.6230
APRI > 2	1.164	0.667–2.030	0.5932
ALBI grade 2 vs. 1	1.004	0.598–1.684	0.9885
ALBI grade 3 vs. 1	0.670	0.093–4.837	0.6910
Target lesion size (cm)	0.968	0.739–1.268	0.8134
Tumor number > 1	1.427	0.811–2.513	0.2177
Ablation volume (cm^3)	1.000	0.995–1.005	0.9838
Ablation duration (minute)	0.991	0.965–1.018	0.5028
Ablation power (watt)	0.997	0.990–1.003	0.3415
Edmondson-Steiner grade III vs. I + II	1.792	0.906–3.545	0.0936
Prolonged PAF vs. no	2.450	1.373–4.370	0.0024	2.092	1.162–3.764	0.0138

AFP: alpha-fetoprotein; ALBI: albumin-bilirubin index; ALT: alanine aminotransferase; APRI: AST-to-platelet ratio index; AST: aspartate aminotransferase; BCLC: Barcelona Clinic Liver Cancer; CTP: Child–Turcotte–Pugh; HBV: hepatitis B virus; HCC: hepatocellular carcinoma; HCV: hepatitis C virus; NBNC: non-B non-C; FIB-4: fibrosis-4; NLR: Neutrophil-to-lymphocyte ratio; PAF: post-ablation fever.

Figure 3. Kaplan–Meier curve showing cumulative recurrence rate for different TNM stages. (A) In TNM stage I (N = 103), the patients with prolonged PAF had a trend to have a higher early recurrence rate (prolonged PAF vs. without: 63.6% vs. 36.2%, Log rank p = 0.097). (B) As for TNM stage II (N = 32), patients with prolonged PAF had significantly higher early recurrence rate (prolonged PAF vs. without: 81.8% vs. 40.9%, Log rank p = 0.040).

Figure 4. Kaplan–Meier curve showing cumulative recurrence rate for HCC treatment-naïve and single tumor patients. Of the subgroup of 64 patients with HCC treatment-naïve and single tumor, prolonged PAF had higher 1-year tumor recurrence rate comparing to those without prolonged PAF (median time-to-recurrence interval: 6.4 vs. 20.8 months, 1-year cumulative tumor recurrence rate: 66.6% vs. 27.2%, Log rank test, p = 0.008).