Pre/Post-Treatment Dynamic of Inflammatory Markers Has Prognostic Value in Patients with Small Hepatocellular Carcinoma Managed by Stereotactic Body Radiation Therapy

Figures & data

Table 1 Patient and Tumor Characteristics

Characteristics	Patients (n=60)	Percentage (%)
No. of men	49	81.7
No. of women	11	18.3
Mean age (y)	61.0 ± 12.8
Median tumor size (cm)	2.3 (1.5–3.0)
Gross tumor volume (cm^3)	16.0 (5.2–43.2)
Biologically effective dose (Gy)	96.0 (86.4–100.0)
Pre-treatment red blood cell (x10^12/L)	4.58 ± 0.53
Pre-treatment neutrophil count (x10^9/L)	3.5 (2.7–4.2)
Pre-treatment platelet count (x10^9/L)	120.5 ± 59.9
Pre-treatment lymphocyte count (x10^9/L)	1.35 ± 0.55
Post-treatment neutrophil count (x10^9/L)	3.0 (2.4–4.1)
Post-treatment platelet count (x10^9/L)	111.0 ± 57.5
Post-treatment lymphocyte count (x10^9/L)	0.69 ± 0.30
Child-Pugh classification A	60	100
Type of chronic hepatitis	44	73.3
Hepatitis B	43	71.7
Hepatitis C	1	1.7
Previous treatments	45	75.0
Surgery treatment	19	31.7
TACE or RFA or PEI	31	51.7
No. of lesions
1	57	95.0
2	3	5.0
SBRT-related toxicity
Grade 2	2	3.3
Grade 3	1	1.7

Notes: Unless otherwise noted, data were numbers with percentages, or medians, with interquartile ranges in parentheses, except for age, pre-treatment red blood cell, pre- and post- treatment lymphocyte count and platelet count, which were presented as mean ± standard deviation.

Abbreviations: TACE, transarterial chemoembolization; RFA, radiofrequency ablation; PEI, percutaneous ethanol injection; SBRT, stereotactic body radiation therapy.

Table 2 Factors Associated with Patient Outcomes at the Univariate Level

Variables	Progression-Free Survival		Overall Survival
HR (95% CI)	p value	HR (95% CI)	p value
Age (≥60)	0.58 (0.32–1.07)	0.080	0.77 (0.33–1.82)	0.555
Gender (female)	1.00 (0.44–2.26)	0.998	1.31 (0.38–4.48)	0.666
Presence of hepatitis (n=44)	2.51 (1.15–5.48)	0.021	1.92 (0.64–5.74)	0.040
Presence of previous treatments (n=45)	1.67 (0.79–3.53)	0.183	2.46 (0.16–4.72)	0.155
Tumor size (≥1.5cm)	2.44 (1.12–5.33)	0.025	1.13 (0.91–4.80)	0.042
Pre-treatment red blood cell (≥4.5x10^12/L)	0.27 (0.12–0.60)	0.001	0.52 (0.19–1.39)	0.046
Pre-treatment AFP (≥20.0 ng/mL)	1.01 (0.48–1.68)	0.049	1.13 (0.54–2.81)	0.031
Gross tumor volume (≥29.3cm^3)	1.49 (0.78–2.83)	0.226	1.99 (1.23–2.71)	0.070
Biologically effective dose (≥96.0 Gy)	0.63 (0.28–1.44)	0.269	0.92 (0.31–2.73)	0.870
Pre-treatment NLR (≥3.5)	1.22 (0.51–1.93)	0.450	0.95 (0.38–3.14)	0.110
Pre-treatment PLR (≥78.8)	1.73 (0.84–3.57)	0.136	1.17 (0.47–2.93)	0.733
Post-treatment NLR (≥6.5)	2.36 (1.20–4.65)	0.013	3.70 (1.53–8.93)	0.002
Post-treatment PLR (≥263.0)	2.25 (1.12–4.53)	0.024	3.21 (1.27–8.11)	0.009
Change in NLR (≥2.7-fold)	2.74 (1.28–5.87)	0.009	2.83 (1.12–7.17)	0.028
Change in PLR (≥2.5-fold)	1.63 (0.73–3.63)	0.236	2.86 (1.12–7.28)	0.028

Abbreviations: AFP, alpha-fetoprotein; NLR, neutrophil-to-lymphocyte ratio; PLR, platelet-to-lymphocyte; HR, hazard ratio; CI, confidence interval.

Table 3 Multivariate Analysis of Post-Treatment NLR and PLR for Patient Outcomes

Variables	Progression-Free Survival		Overall Survival
HR (95% CI)	p value	HR (95% CI)	p value
Presence of hepatitis	3.26 (1.01–10.22)	0.043	3.83 (0.71–10.76)	0.048
Tumor size (≥1.5cm)	1.11 (0.28–4.44)	0.878	1.45 (0.27–7.14)	0.768
Pre-treatment AFP (≥20.0 ng/mL)	1.41 (0.44–4.53)	0.560	2.02 (0.37–11.05)	0.418
Pre-treatment RBC (≥4.5x10^12/L)	0.18 (0.05–0.66)	0.010	0.12 (0.02–1.01)	0.050
Post-treatment NLR (≥6.5)	1.02 (0.38–2.75)	0.962	2.17 (0.25–6.05)	0.339
Post-treatment PLR (≥263.0)	3.70 (1.07–12.76)	0.038	3.23 (1.01–9.11)	0.043

Abbreviations: NLR, neutrophil-to-lymphocyte ratio; PLR, platelet-to-lymphocyte ratio; AFP, alpha-fetoprotein; RBC, red blood cell; HR, hazard ratio; CI, confidence interval.

Table 4 Multivariate Analysis of Change in NLR for Patient Outcomes

Variables	Progression-Free Survival		Overall Survival
HR (95% CI)	p value	HR (95% CI)	p value
Presence of hepatitis	5.08 (1.43–12.98)	0.012	3.79 (1.14–10.38)	0.114
Tumor size (≥1.5cm)	1.02 (0.35–3.55)	0.820	1.01 (0.12–3.93)	0.784
Pre-treatment RBC count (≥4.5x10^12/L)	0.25 (0.07–0.88)	0.031	0.11 (0.02–0.64)	0.014
Pre-treatment AFP (≥20.0 ng/mL)	2.05 (0.67–6.23)	0.208	4.12 (0.77–10.07)	0.098
Change in NLR (≥2.7-fold)	1.54 (0.61–3.87)	0.360	3.43 (1.14–10.38)	0.029

Abbreviations: NLR, neutrophil-to-lymphocyte ratio; RBC, red blood cell; AFP, alpha-fetoprotein; HR, hazard ratio; CI, confidence interval.

Table 5 Median PFS After SBRT According to Different Levels of Post-Treatment NLR and PLR

PFS	Value of Post-Treatment NLR			Value of Post-Treatment PLR
<6.5 (n=15)	≥6.5 (n=42)	p value	<263.0 (n=11)	≥263.0 (n =46)	p value
Median (range)	22.0 (3.2–66.9)	15.2 (1.8–46.7)	0.027	23.6 (4.7–66.9)	17.0 (1.8–50.6)	0.046

Abbreviations: PFS, progression-free survival; SBRT, stereotactic body radiation therapy; NLR, neutrophil-to-lymphocyte ratio; PLR, platelet-to-lymphocyte ratio; CI, confidence interval.

Figure 1 (A–D) Kaplan-Meier survival curves for prognosis according to different levels of post-treatment neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR): (A, B) post-PLR <263.0 and post-NLR <6.5 predicted better progression-free survival with log rank test p-value of p=0.02 and p=0.01, respectively; (C, D): post-PLR <263.0 and post-NLR<6.5 predicted better overall survival with log rank test p-value of p=0.009 and p=0.002, respectively.