The Predictive Role of Inflammatory Biomarkers for Treatment Response and Progression-Free Survival in Patients with Hepatocellular Carcinoma Receiving Hepatic Arterial Infusion Chemotherapy with FOLFOX Regimen: A Preliminary Study

Figures & data

Table 1 Baseline Characteristics of the 124 Patients

Gender (male vs female)	109 versus 15 (87.9 versus 12.1)
Age (y), mean ± SD (<60 vs≥60)	51.93±11.95 (92 versus 32)
Maximum tumor size (>100mm or ≤100mm)	82 versus 42 (66.1 versus 33.9)
BCLC stage (B vs C)	15 versus 109 (12.1 versus 87.9)
Tumor number (N) (1 vs >1)	39 versus 85 (31.5 versus 68.5)
Extrahepatic metastasis (YES/NO)	17 versus 107(13.7 versus 86.3)
PVTT type (0/I/II/III/IV)	16/26/46/33/3
Cause of disease (HBV vs others^●)	117 versus 7 (94.4 versus 5.6)
Child-Pugh class (A vs B)	102 versus 22 (82.3 versus 17.7)
DCP (mAU/mL) (≤1000 vs >1000)	22 versus 102 (17.7 versus 82.3)
ALB (g/L) (≤35 vs >35)	29 versus 95 (23.4 versus 76.6)
AST (U/L) (≤40 vs >40)	10 versus 114 (8.1 versus 91.9)
ALT (U/L) (≤40 vs >40)	24 versus 100 (19.4 versus 80.6)
TBIL (μmol/L) (≤20 vs >20)	60 versus 64 (48.4 versus 51.6)
PT(s) (≤13 vs >13)	59 versus 65 (47.6 versus 52.4)
AFP (ng/mL) (≤20 vs 20~200 vs ≥200)	14/18/92
mALBI grade (1/2a/2b/3)	35/45/41/3
PLR (low vs high score)	88 versus 36 (71.0 versus 29.0)
MLR (low vs high score)	92 versus 32 (74.2 versus 25.8)
SII (low vs high score)	77 versus 47 (62.1 versus 37.9)
PNI (low vs high score)	78 versus 46 (62.9 versus 37.1)

Note: ^●3 cases of unknown causes and 4 cases of HCV infection.

Abbreviations: SD, Standard deviation; BCLC, Barcelona Clinic Liver Cancer; PVTT, portal vein tumor thrombus; HBV, Hepatitis B virus; AST, aspartate aminotransferase; ALT, alanine aminotransferase; AFP, Alpha-fetoprotein; ALB, Albumin; PT, Prothrombin time; DCP, des-γ-carboxy prothrombin; TBIL, Total bilirubin; mALBI grade, modified Albumin-bilirubin grade; PLR, platelet-lymphocyte ratio; MLR, monocyte-lymphocyte ratio; SII, systemic immune inflammation index; PNI, prognostic nutritional index.

Figure 1 Diagnostic value of inflammatory biomarkers for the HAIC non-response according to ROC curves.

Abbreviations: ROC, receiver operating characteristic; MLR, monocyte-lymphocyte ratio; SII, systemic immune inflammation index; PNI, prognostic nutritional index; PLR, platelet-lymphocyte ratio.

Table 2 Univariate and Multivariate Analyses for Evaluation of HAIC Response

Variables	Univariate Analysis		Multivariate Analysis
	P	HR (95% CI)	P	HR (95% CI)
Gender (male vs female)	0.068	2.803(0.928–8.467)
Age (<60vs≥60)	0.227	0.604(0.267–1.367)
Maximum size (>100mm vs ≤100mm)	0.719	0.868(0.401–1.878)
BCLC stage (B vs C)	0.698	0.798(0.255–2.496)
HBV vs others	0.216	3.887(0.453–33.347)
Extrahepatic metastasis (YES/NO)	0.197	2.184(0.667–7.145)
PVTT type (0/I/II/III/IV)	0.886	1.026(0.722–1.458)
Child-Pugh class (A vs B)	0.517	1.382(0.518–3.688)
Tumor number (1 vs >1)	0.628	1.212(0.558–2.633)
DCP (≤ 1000 vs >1000)	0.517	0.723(0.271–1.930)
AST (≤40 vs >40)	0.415	1.714(0.469–6.269)
ALT (≤40 vs >40)	0.177	1.857(0.755–4.566)
TBIL (≤20 vs >20)	0.116	1.800(0.864–3.748)
ALB (≤35 vs >35)	0.034*	2.910(1.086–7.801)
PT (≤13 vs >13)	0.813	1.091(0.528–2.256)
AFP (≤20/20~200/≥200)	0.695	0.897(0.520–1.546)
mALBI grade (1/2a/2b/3)	0.002*	2.135(1.327–3.434)	0.032*	2.027(1.513–3.328)
PLR (low vs high)	0.024*	2.786(1.143–6.792)
MLR (low vs high)	0.001*	8.861(2.521–31.149)	0.002*	7.250(2.011–26.136)
SII (low vs high)	0.011*	2.874(1.278–6.461)
PNI (low vs high)	<0.001*	0.243(0.112–0.527)	0.003*	0.296(0.131–0.670)

Note: *P-value indicates statistically significant.

Abbreviations: BCLC, Barcelona Clinic Liver Cancer; PVTT, portal vein tumor thrombus; HBV, Hepatitis B virus; AST, aspartate aminotransferase; ALT, alanine aminotransferase; AFP, Alpha-fetoprotein; ALB, Albumin; PT, Prothrombin time; DCP, des-γ-carboxy prothrombin; TBIL, Total bilirubin; mALBI grade, modified Albumin-bilirubin grade; PLR, platelet-lymphocyte ratio; MLR, monocyte-lymphocyte ratio; SII, systemic immune inflammation index; PNI, prognostic nutritional index.

Figure 2 Nomogram to predict non-response of HCC receiving HAIC.

Abbreviations: MLR, monocyte-lymphocyte ratio; PNI, prognostic nutritional index; mALBI grade, modified Albumin-bilirubin grade; HAIC, hepatic arterial infusion chemotherapy.

Table 3 Association Between Inflammatory Markers and Clinical Data

Characteristics	Total Patients (N, 124)	MLR		P	PNI		P
		Low (N, 92)	High (N, 32)		Low (N, 78)	High (N, 46)
Gender
Male	109	80	29	0.584	67	42	0.372
Female	15	12	3		11	4
Age (y)
<60	92	67	25	0.555	55	37	0.223
≥60	32	25	7		23	9
Maximum tumor size
>100mm	82	58	24	0.218	52	30	0.869
≤100mm	42	34	8		26	16
BCLC stage
B	15	13	2	0.239	11	4	0.372
C	109	79	30		67	42
Tumor number(n)
1	39	28	11	0.679	22	17	0.311
>1	85	64	21		56	29
Extrahepatic metastasis
YES	17	11	6	0.336	10	7	0.708
NO	107	81	26		68	39
PVTT
None	16	14	2	0.588	12	4	0.308
I	26	20	6		12	14
II	46	31	15		29	17
III	33	25	8		23	10
IV	3	2	1		2	1
HBV	117	86	31	0.473	72	45	0.198
Others	7	6	1		6	1
Child-Pugh class
A	102	79	23	0.074	58	44	0.003*
B	22	13	9		20	2
DCP (mAU/mL)
≤1000	22	16	6	0.862	16	6	0.293
>1000	102	76	26		62	40
ALT (U/L)
≤40	24	20	4	0.255	13	11	0.324
>40	100	72	28		65	35
AST (U/L)
≤40	10	8	2	0.662	3	7	0.025*
>40	114	84	30		75	39
ALB (g/L)
≤35	29	16	13	0.007*	29	0	< 0.001*
>35	95	76	19		49	46
TBIL (μmol/L)
≤20	60	48	12	0.153	38	22	0.924
>20	64	44	20		40	24
PT(s)
≤13	59	49	10	0.032*	32	27	0.057
>13	65	43	22		46	19
AFP (ng/mL)
≤20	14	9	5	0.629	10	4	0.653
20~200	18	13	5		10	8
≥200	92	70	22		58	34
mALBI grade
1	35	29	6	0.012*	6	29	< 0.001*
2a	45	37	8		30	15
2b	41	23	18		39	2
3	3	3	0		3	0

Note: *P-value indicates statistically significant.

Abbreviations: BCLC, Barcelona Clinic Liver Cancer; PVTT, portal vein tumor thrombus; HBV, Hepatitis B virus; AST, aspartate aminotransferase; ALT, alanine aminotransferase; AFP, Alpha-fetoprotein; ALB, Albumin; PT, Prothrombin time; DCP, des-γ-carboxy prothrombin; TBIL, Total bilirubin; mALBI grade, modified Albumin-bilirubin grade; MLR, monocyte-lymphocyte ratio; PNI, prognostic nutritional index.

Table 4 Cox Regression Analysis for PFS of HCC Patients

Variables	PFS
	Univariate Analysis		Multivariate Analysis
	P	HR (95% CI)	P	HR (95% CI)
Gender (male vs female)	0.187	1.634(0.788–3.388)
Age (<60/≥60)	0.049*	0.590(0.349–0.998)
Maximum size (>100mm vs ≤100mm)	0.530	1.158(0.732–1.832)
BCLC stage (B vs C)	0.478	1.285(0.643–2.566)
HBV vs others	0.904	0.940(0.344–2.571)
Extrahepatic metastasis (YES/NO)	0.556	1.202(0.652–2.215)
PVTT (0/I/II/III/IV)	0.524	1.068(0.873–1.306)
Child-Pugh class (A vs B)	0.937	1.022(0.593–1.761)
Tumor number (1 vs >1)	0.158	1.420(0.873–2.308)
DCP (≤1000 vs >1000)	0.529	1.197(0.684–2.092)
AST (≤40 vs >40)	0.918	0.960(0.442–2.083)
ALT (≤40 vs >40)	0.418	1.267(0.714–2.249)
TBIL (≤20 vs >20)	0.634	1.109(0.724–1.700)
ALB (≤35 vs >35)	0.486	1.186(0.734–1.914)
PT (≤13 vs >13)	0.498	1.161(0.754–1.790)
AFP (≤20/20~200/≥200)	0.812	1.040(0.755–1.431)
mALBI grade (1/2a/2b/3)	0.607	1.066(0.835–1.362)
PLR (low vs high)	0.074	1.511(0.960–2.378)
MLR (low vs high)	0.017*	1.746(1.106–2.758)	0.021*	1.714(1.086–2.704)
SII (low vs high)	0.064	1.504(0.976–2.315)
PNI (low vs high)	0.835	0.954(0.615–1.481)

Note: *P-value indicates statistically significant.

Abbreviations: BCLC, Barcelona Clinic Liver Cancer; PVTT, portal vein tumor thrombus; HBV, Hepatitis B virus; AST, aspartate aminotransferase; ALT, alanine aminotransferase; AFP, Alpha-fetoprotein; ALB, Albumin; PT, Prothrombin time; DCP, des-γ-carboxy prothrombin; TBIL, Total bilirubin; mALBI grade, modified Albumin-bilirubin grade; PLR, platelet-lymphocyte ratio; MLR, monocyte-lymphocyte ratio; SII, systemic immune inflammation index; PNI, prognostic nutritional index.

Figure 3 Kaplan-Meier curve of progression-free survival (PFS) of patients with HCC after HAIC according to MLR, PLR, SII, PNI. (A) MLR, (B) PLR, (C) SII, (D) PNI.

Abbreviations: MLR, monocyte-lymphocyte ratio; PLR, platelet-lymphocyte ratio; SII, systemic immune inflammation index; PNI, prognostic nutritional index.