Dynamic Changes in Neutrophil-to-Lymphocyte Ratio are Associated with Survival and Liver Toxicity Following Stereotactic Body Radiotherapy for Hepatocellular Carcinoma

Figures & data

Table 1 Patient and Treatment Characteristics (n=93)

Characteristics
Male, no. (%)	72 (77.4)
Age, median (IQR), years	65 (55–74)
Viral hepatitis, no. (%)
HBV	52 (55.9)
HCV	26 (28.0)
Both	5 (5.4)
None	10 (10.8)
Total GTV, median (IQR), cm^3	131.4 (43.1–314.2)
PTV, median (IQR), cc	182.2 (70.8–452.5)
Multiple tumors, no. (%)	64 (68.8)
Macrovascular invasion, no. (%)	34 (36.6)
Extrahepatic spread, no. (%)	25 (26.9)
ECOG performance status, no. (%)
0–1	72 (77.4)
≥2	21 (22.6)
AFP level, no. (%)
<400 ng/mL	53 (57.0)
≥400 ng/mL	40 (43.0)
Total bilirubin, median (IQR), mg/dL	0.8 (0.6–1.4)
Albumin, median (IQR), g/dL	3.6 (3.2–3.9)
CTP class, no. (%)
A	65 (69.9)
B	28 (30.1)
BCLC stage, no. (%)
0–A	14 (15.1)
B	14 (15.1)
C	62 (66.7)
D	3 (3.2)
SBRT dose, median (range), Gy	45 (25–60)
Fraction number, median (range)	5 (4–6)
BED, median (IQR), Gy	85.5 (70.4–100.0)
Prior liver-directed therapy^†, no. (%)
Liver resection	24 (25.8)
RFA	13 (14.0)
TACE	49 (52.7)
Prior treatment number^†, no (%)
0	39 (41.9)
1–3	37 (39.8)
>3	17 (18.3)

Note: ^†More than one may apply.

Abbreviations: AFP, α-fetoprotein; BCLC, Barcelona Clinic Liver Cancer; BED, biologically effective dose; CTP, Child–Turcotte–Pugh liver function scale; ECOG, Eastern Cooperative Oncology Group; GTV, gross tumor volume; HBV, hepatitis B virus; HCV, hepatitis C virus; IQR, interquartile range; PTV, planning target volume; RFA, radiofrequency ablation; SBRT, stereotactic body radiotherapy; TACE, trans-arterial chemoembolization.

Table 2 Dynamic Changes of Complete Blood Counts and Immune Parameters Pre- and Post-SBRT

Parameter	Pre-SBRT	Post-SBRT	% Change	P^#
Leukocyte count, × 10^9/L	5.8 ± 2.8	4.5 ± 2.5	−27.5 (−72.0 to 139.3)	<0.001
	5.4 (1.1–14.9)	3.9 (0.6–14.6)
Neutrophil count, × 10^9/L	3.8 ± 2.3	3.2 ± 2.2	−22.7 (−70.2 to 258.6)	<0.001
	3.3 (0.5–12.9)	2.6 (0.3–12.5)
Lymphocyte count, × 10^9/L	1.2 ± 0.6	0.7 ± 0.4	−42.3 (−90.3 to 167.5)	<0.001
	1.1 (0.3–3.1)	0.6 (0.1–2.2)
Hemoglobin, g/dL	12.1 ± 2.0	11.9 ± 1.9	−0.9 (−35.2 to 28.7)	0.203
	11.9 (6.7–17.4)	12.3 (6.9–15.4)
Platelet count, × 10^9/L	145.6 ± 85.4	102.4 ± 64.6	−27.4 (−83.2 to 105.9)	<0.001
	124 (24–479)	87 (28–383)
NLR	3.6 ± 2.5	5.9 ± 5.3	47.6 (−81.9 to 894.3)	<0.001
	2.8 (0.9–13.3)	4.3 (0.9–28.7)
PLR	132 ± 79	190 ± 180	30.2 (−72.9 to 740.7)	0.003
	111 (31–422)	143 (44–1061)

Notes: Data are presented as mean ± standard deviation and median (range); ^#The difference between pre- and post-SBRT immune parameters were evaluated using the Wilcoxon signed-rank test.

Abbreviations: NLR, neutrophil-to-lymphocyte ratio; PLR, platelet-to-lymphocyte ratio; SBRT, stereotactic body radiotherapy.

Table 3 Prognostic Factors on Overall Survival by Cox Proportional-Hazards Model

	UVA		MVA in NLR Model		MVA in PLR Model
	HR (95% CI)	P	HR (95% CI)	P	HR (95% CI)	P
Age >65 years	0.79 (0.50–1.24)	0.304
Female vs male	1.47 (0.87–2.48)	0.151
Underlying liver disease
HBV vs no	0.79 (0.50–1.25)	0.309
HCV vs no	1.00 (0.62–1.62)	0.987
CTP class B vs A	2.07 (1.28–3.33)	0.003	2.35 (1.27–4.37)	0.007	2.48 (1.38–4.44)	0.002
Total GTV (per 10 cc increase)	1.002 (0.996–1.008)	0.566
Multiple tumors	1.81 (1.09–3.03)	0.023	1.99 (1.08–3.68)	0.028	1.71 (0.93–3.15)	0.083
Macrovascular invasion	2.20 (1.36–3.55)	0.001	1.51 (0.87–2.62)	0.143	1.92 (1.13–3.26)	0.016
Extrahepatic spread	3.35 (1.92–5.85)	<0.001	1.68 (0.91–3.08)	0.097	1.61 (0.85–3.04)	0.141
Performance status ≥2	2.01 (1.17–3.46)	0.012	0.77 (0.40–1.50)	0.443	1.14 (0.61–2.15)	0.676
AFP level ≥400 ng/mL	1.67 (1.06–2.65)	0.029	1.72 (1.00–2.95)	0.051	1.59 (0.94–2.69)	0.081
BED ≥85.5 Gy	1.16 (0.73–1.83)	0.527
Prior treatment no.
0	Reference	0.552
1–3	1.30 (0.78–2.16)	0.311
>3	1.29 (0.68–2.46)	0.431
Pre-RT Hgb (per 1 g/dL increase)	0.91 (0.82–1.00)	0.057	0.97 (0.87–1.09)	0.629	1.01 (0.91–1.13)	0.860
ASL	2.33 (1.44–3.76)	0.001	1.01 (0.54–1.90)	0.971	1.67 (0.99–2.84)	0.056
Pre-RT NLR (per 1-unit increase)	1.20 (1.10–1.30)	<0.001	1.24 (1.12–1.38)	<0.001
Delta-NLR (per 1-unit increase)	1.11 (1.05–1.18)	0.001	1.10 (1.02–1.18)	0.011
Pre-RT PLR (per 10-unit increase)	1.02 (1.00–1.05)	0.070			1.00 (0.97–1.04)	0.813
Delta-PLR (per 10-unit increase)	1.01 (0.99–1.02)	0.401

Abbreviations: AFP, α-fetoprotein; ASL, acute severe lymphopenia; BED, biologically effective dose; CI, confidence interval; CTP, Child–Turcotte–Pugh liver function scale; GTV, gross tumor volume; HBV, hepatitis B virus; HCV, hepatitis C virus; Hgb, hemoglobin; HR, hazard ratio; MVA, multivariable analysis; NLR, neutrophil-to-lymphocyte ratio; OS, overall survival; PLR, platelet-to-lymphocyte ratio; RT, radiotherapy; UVA, univariable analysis.

Figure 1 Survival groups based on pre-SBRT NLR and dNLR. Kaplan–Meier curve of overall survival (A) according to pre-SBRT NLR and subgroup comparisons among the (B) pre-SBRT NLR <2.4 cohort and (C) the pre-SBRT NLR ≥2.4 cohort using the dNLR cut-off of 1.3.

Figure 2 Box–whisker plot of peri-SBRT NLR changes in patients categorized according to (A) CTP class and (B) development of liver toxicity. Note only 90 patients were evaluable for liver toxicity. Extreme outliers and mild outliers were marked with an asterisk (*) and a circle (O) on the box–whisker plot, respectively.

Figure 3 Waterfall plot of HCC patients ranked according to dNLR after SBRT. Patients with dNLR ≥1.9 were more likely to present with liver toxicity than those with dNLR <1.9.