Inflammation-Based Scores Predict Responses to PD-1 Inhibitor Treatment in Intrahepatic Cholangiocarcinoma

Figures & data

Table 1 Baseline Characteristics of the Enrolled Patients

Variables	N = 73
Age, y	57 (31–75)
Gender (male/female)	49/24 (67.1/32.9)
Hepatitis (yes /no)	36/37 (49.3/50.7)
ALT, U/L, (>/≤50)	27.6 (6.5–133.8)
AST, U/L, (>/≤40)	35.1 (14.5–207.7)
ALB, g/L, (>/≤35)	41.7 (25.9–50.1)
TBIL, umol/L, (>/≤17.1)	11.2 (2.6–45.3)
CA19-9U/mL, (>/≤100)	61.6 (1.2–35,704)
Largest tumour size, cm	8.2 (3.6–17.2)
Tumor number (>1/1)	50/23 (68.5/31.5)
Macrovascular invasion (yes/no)	33/40 (45.2/54.8)
Lymph node metastasis (yes/no)	48/25 (65.8/34.2)
TNM stage (III–IV /II)	50/23 (68.5/31.6)
CRP (1/0)	38/35 (52.4/47.9)
PLR (1/0)	18/55 (24.7/75.3)
NLR (1/0)	37/36 (50.7/49.3)
LCR (1/0)	40/33 (54.8/45.2)
LMR (1/0)	22/51 (30.1/69.9)
SII (1/0)	24/49 (32.9/67.1)
CAR (1/0)	39/34 (53.4/46.6)
PNI (1/0)	36/37 (49.3/50.7)
GPS (2/1/0)	7/40/26 (9.6/54.8/35.6)
PI (2/1/0)	12/38/23 (16.4/52.1/31.5)

Note: Values are presented as the median (range) or n (%).

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALB, albumin; TBIL, total bilirubin; TNM, tumour-node-metastasis; CRP, C-reactive protein; PLR, platelet-to-lymphocyte ratio; NLR, neutrophil-to-lymphocyte ratio; LCR, lymphocyte-to-C-reactive protein ratio; LMR, lymphocyte-to-monocyte ratio; SII, systemic immune-inflammation index; CAR, C-reactive protein-to-albumin ratio; PNI, prognostic nutritional index; GPS, Glasgow Prognostic Score; PI, prognostic index.

Table 2 Systemic Inflammation-Based Prognostic Scores

Scoring System	Score
C-reactive protein (CRP)
CRP≤12.75	0
CRP >12.75	1
Platelet-to-lymphocyte ratio (PLR)
Platelet count (×109/L): lymphocyte count (×109/L) ≤ 222.52	0
Platelet count (×109/L): lymphocyte count (×109/L) > 222.52	1
Neutrophil-to-lymphocyte ratio (NLR)
Neutrophil count (×109/L): lymphocyte count (×109/L) ≤ 3.56	0
Neutrophil count (×109/L): lymphocyte count (×109/L) > 3.56	1
Lymphocyte-to-C-reactive protein ratio (LCR)
10^4×lymphocyte count (×109/L): CRP (mg/L) > 1166.91	0
10^4×lymphocyte count (×109/L): CRP (mg/L) ≤ 1166.91	1
Lymphocyte-to-monocyte ratio (LMR)
Lymphocyte count (×109/L): monocyte count (×109/L) ≤ 2.15	0
Lymphocyte count (×109/L): monocyte count (×109/L) > 2.15	1
Systemic Immune-inflammation Index (SII)
Platelet count (×109/L) × neutrophil count (×109/L)/lymphocyte count (×109/L) ≤ 1271.81	0
Platelet count (×109/L) × neutrophil count (×109/L)/lymphocyte count (×109/L) > 1271.81	1
CRP-to-albumin ratio (CAR)
CRP (mg/L): albumin (g/L) ≤ 0.3	0
CRP (mg/L): albumin (g/L) > 0.3	1
Glasgow Prognostic Score (GPS)
CRP ≤10 mg/L and albumin ≥ 35 g/L	0
CRP ≤10 mg/L and albumin < 35 g/L	1
CRP >10 mg/L and albumin ≥ 35 g/L	1
CRP >10 mg/L and albumin < 35 g/L	2
Prognostic Index (PI)
CRP ≤10 mg/L and WBC count ≤10 × 109/L	0
CRP ≤10 mg/L and WBC count >10 × 109/L	1
CRP >10 mg/L and WBC count ≤10 × 109/L	1
CRP >10 mg/L and WBC count >10 × 109/L	2
Prognostic Nutritional Index (PNI)
Albumin (g/L) + 5 × lymphocyte count (×109/L) > 49	0
Albumin (g/L) + 5 × lymphocyte count (×109/L) ≤ 49	1

Abbreviation: WBC, white blood cell.

Table 3 Univariate and Multivariate Cox Regression Analyses of Risk Factors for Overall Survival

Variables	Univariate			Multivariate
	HR	95% CI	P	HR	95% CI	P
Age, y (≤/>50)	0.418	0.220–0.795	0.008
Gender (male/female)	1.287	0.648–2.554	0.471
Hepatitis (yes /no)	1.217	0.649–2.283	0.541
ALT, U/L, (>/≤50)	2.090	0.969–4.507	0.060
AST, U/L, (>/≤40)	1.289	0.689–2.413	0.427
ALB, g/L, (>/≤35)	0.417	0.171–1.015	0.054
TBIL, umol/L, (>/≤17.1)	1.379	0.601–3.163	0.448
CA19-9U/mL, (>/≤100)	1.426	0.762–2.668	0.268
Largest tumour size (>/≤10 cm)	1.15	0.615–2.152	0.662
Tumor number (>1/1)	1.546	0.783–3.053	0.209
Macrovascular invasion (yes/no)	1.233	0.661–2.300	0.509
Lymph node metastasis (yes/no)	3.316	1.521–7.229	0.003	3.112	1.372–7.056	0.007
TNM stage (III–IV /II)	3.311	1.460–7.510	0.004
CRP (1/0)	8.405	3.549–19.906	<0.001	6.032	2.467–14.752	<0.001
PLR (1/0)	3.618	1.772–7.387	<0.001	2.433	1.151–5.145	0.020
NLR (1/0)	2.530	1.324–4.838	0.005
LCR (1/0)	5.695	2.622–12.368	<0.001
LMR (1/0)	2.336	1.209–4.512	0.012
SII (1/0)	3.751	1.895–7.426	<0.001
CAR (1/0)	6.731	2.968–15.265	<0.001
PNI (1/0)	3.777	1.834–7.779	<0.001
GPS
0	Reference	Reference	Reference
1	3.564	1.625–7.815	0.002
2	6.350	2.009–20.069	0.002
PI
0	Reference	Reference	Reference
1	4.485	1.817–11.070	0.001
2	9.148	3.072–27.238	<0.001

Note: P-value < 0.05 is statistically significant in both univariate and multivariate analyses.

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALB, albumin; TBIL, total bilirubin; TNM, tumour-node-metastasis; CRP, C-reactive protein; PLR, platelet-to-lymphocyte ratio; NLR, neutrophil-to-lymphocyte ratio; LCR, lymphocyte-to-C-reactive protein ratio; LMR, lymphocyte-to-monocyte ratio; SII, systemic immune-inflammation index; CAR, C-reactive protein-to-albumin ratio; PNI, prognostic nutritional index; GPS, Glasgow Prognostic Score; PI, prognostic index.

Figure 1 Kaplan–Meier curves of the overall survival of ICC patients after PD-1 inhibitors therapy. (A) CRP, (B) PLA, (C) NLR, (D) LCR, (E) LMR, (F) SII, (G) CAR, (H) PNI, (I) GPS and (J) PI.

Table 4 AUROC for the Comparison of Different Inflammatory-Based Scores

Scores	6-Month AUROC	12-Month AUROC	18-Month AUROC	24-Month AUROC
CRP	0.778(68.42–87.11)	0.84(72.65–95.42)	0.87(79.01–94.96)	0.843(75.64–92.96)
PLR	0.703(58.92–81.71)	0.618(50.38–73.29)	0.674(59.36–75.42)	0.661(58.38–73.88)
NLR	0.679(56.27–79.61)	0.656(49.85–81.41)	0.704(53.13–87.73)	0.667(47.01–86.34)
LCR	0.799(71.37–88.38)	0.776(63.67–91.49)	0.853(77.12–93.48)	0.827(74.03–91.45)
LMR	0.642(52.04–76.35)	0.611(46.94–75.24)	0.707(62.32–79.17)	0.692(61.00–77.47)
SII	0.711(59.45–82.76)	0.681(56.10–80.12)	0.729(64.42–81.45)	0.713(62.88–79.65)
CAR	0.778(68.42–87.11)	0.824(70.83–93.98)	0.855(77.40–93.69)	0.83(74.26–91.67)
GPS	0.718(61.30–82.28)	0.811(68.02–94.15)	0.834(68.35–98.50)	0.789(61.06–96.77)
PI	0.761(66.73–85.55)	0.815(69.10–93.99)	0.798(63.15–96.51)	0.738(64.46–89.67)
PNI	0.678(56.10–79.52)	0.774(65.41–89.33)	0.811(72.63–89.58)	0.788(70.10–87.59)

Note: Values are presented as the AUROC (95% confidence interval).

Abbreviations: AUROC, area under the receiver operating characteristic curve; CRP, C-reactive protein; PLR, platelet-to-lymphocyte ratio; NLR, neutrophil-to-lymphocyte ratio; LCR, lymphocyte-to-C-reactive protein ratio; LMR, lymphocyte-to-monocyte ratio; SII, systemic immune-inflammation index; CAR, C-reactive protein-to-albumin ratio; PNI, prognostic nutritional index; GPS, Glasgow Prognostic Score; PI, prognostic index.

Figure 2 Time-dependent AUC plot for survival prediction of inflammation-based scores.

Table 5 Baseline Characteristics of the Patients Grouped by CRP Score

Variables	CRP≤12.75	CRP>12.75	P
	N=35	N=38
Age, y	57 (36–77)	56.5 (31–76	0.629
Gender (male/female)	19/16 (54.3/45.7)	30/8 (78.9/21.1)	0.025
Hepatitis (yes /no)	18/17 (51.4/48.6)	18/20 (50/45.9)	0.729
ALT, U/L, (>/≤50)	25.7 (6.7–133.8)	28.5 (6.5–95.4)	0.834
AST, U/L, (>/≤40)	35 (14.5–207.7)	35.85 (17.6–168.6)	0.604
ALB, g/L, (>/≤35)	44.5 (33.4–50.1)	39.05 (25.9–47.1)	<0.001
TBIL, umol/L, (>/≤17.1)	12.6 (2.6–45.3)	10.85 (4.4–44.4)	0.711
CA19-9U/mL, (>/≤100)	40.15 (1.2–35,704)	217.75(1.54–9475)	0.068
Largest tumour size, cm	8.1 (3.6–17.2)	8.6 (5.5–15.8)	0.32
Tumor number (>1/1)	24/11 (68.6/31.4)	26/12 (68.4/31.6)	0.989
Macrovascular invasion (yes/no)	18/17 (51.4/48.6)	15/23 (39.5/60.5)	0.305
Lymph node metastasis (yes/no)	19/16 (54.3/45.7)	48/25 (65.8/34.2)	0.048
TNM stage (III–IV /II)	20/15 (57.1/42.9)	30/8 (78.9/21.1)	0.045
Best tumor response
CR	0(0)	0(0)
PR	8(22.9)	2(5.3)
SD	19(54.3)	18(47.4)
PD	8(22.9)	18(47.4)
ORR	8(22.9)	2(5.3)	0.023
DCR	27(77.1)	20(52.6)	0.002

Notes: Values are presented as the median (range) or n (%). P-value < 0.05 is statistically significant.

Abbreviations: CRP, C-reactive protein; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALB, albumin; TBIL, total bilirubin; TNM, tumour-node-metastasis; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; ORR, objective response rate; DCR, disease control rate.