Clinical significance of systemic immune-inflammation index (SII) and C-reactive protein-to-albumin ratio (CAR) in patients with esophageal cancer: a meta-analysis

Figures & data

Figure 1 Flow diagram of included studies for this meta-analysis.

Figure 2 Quality assessment of 12 cohort studies included in the meta-analysis according to predefined eight items.

Table 1 Main characteristics of all included studies

	Study/ Year	Pathological type	Country	Study type	Included period	No. of sample	Age (years)	Outcomes	Follow-up	Cutoff value	Cut-off selection	Treatment methods	Stage	MVA
SII	Geng Y, 2016^Citation14	ESCC	China	R	2002–2012	916	median: 60	OS	≥5 years	307	X-tile software	With-surgery	Non-metastatic	Yes
	Feng JF, 2017^Citation16	ESCC	China	R	2005 −2008	298	NA	CSS	≥5 years	410	Cutoff Finder	With-surgery	Non-metastatic	Yes
	Wang L, 2017^Citation19	ESCC	China	R	2012.1–2012.12	280	mean: 64.1	OS	<5 years	560	ROC analysis	With-surgery	Mixed	Yes
	Ishibashi Y, 2018^Citation20	ESCC/EAC/Others	Japan	R	2009–2014	143	mean: 70.6	OS	≥5 years	650	ROC analysis	With-surgery	Mixed	Yes
	Zhang H, 2018^Citation21	ESCC	China	R	2005 −2013	655	median: 61	OS	≥5 years	387.65	ROC analysis	With-surgery	Non-metastatic	Yes
CAR	Wei XL, 2015^Citation22	ESCC	China	R	2006–2010	423	median: 58	OS	≥5 years	0.095	ROC analysis	Mixed	Mixed	Yes
	Xu XL, 2015^Citation23	ESCC	China	R	2000–2010	468	median: 58	OS	≥5 years	0.5	ROC analysis	With-surgery	Non-metastatic	Yes
	Otowa Y, 2017^Citation24	ESCC	Japan	R	2007–2014	149	mean: 66.9	OS	≥5 years	0.03	ROC analysis	With-surgery	Non-metastatic	Yes
	Jomrich G, 2017^Citation25	ESCC/EAC	Austria	R	2003–2014	283	mean: 63	OS	≥5 years	0.95	NA	With-surgery	Mixed	Yes
	Ishibashi Y, 2018^Citation20	ESCC/EAC/Others	Japan	R	2009–2014	143	mean: 70.6	OS	≥5 years	0.3	ROC analysis	With-surgery	Mixed	Yes
	Kunizaki M, 2018^Citation26	ESCC	Japan	R	2007–2014	116	mean: 66	OS	≥5 years	0.042	ROC analysis	Mixed	Mixed	Yes
	Yu X, 2018^Citation27	ESCC	China	R	2005–2012	160	median: 59	OS	≥5 years	0.023	ROC analysis	With-surgery	Non-metastatic	Yes

Abbreviations: R, retrospective; ESCC, esophageal squamous cell carcinoma; EAC, esophageal carcinoma; OS, overall survival; CSS, cancer-specific survival; MVA, multivariate analysis. ROC, receiver operating characteristic curve; NA, not available.

Figure 3 Meta-analysis of the correlation between SII and OS.

Abbreviations: OS, overall survival; SII, systemic immune-inflammation index; HR, hazard ratio; 95%CI, 95% confidence interval.

Table 2 Subgroup analysis of the correlation between SII and OS

Subgroup factor	No. of studies	Pooled HR (95% CI)	P-value	Heterogeneity
				I^2 (%)	Phet
Pathological type
ESCC	4	1.34(1.14–1.53)	<0.001	35.1	0.202
Mixed	1	1.64(0.74–3.96)	NS	-	-
Cut-off value
≥462	2	2.23(1.26–3.21)	<0.001	0.0	0.367
<462	3	1.30(1.11–1.50)	<0.001	0.0	0.735
Follow-ups
≥5 years	4	1.31(1.11–1.50)	<0.001	0.0	0.853
<5 years	1	2.58(1.62–4.09)	<0.001	-
Clinical stage
Non-metastatic	3	1.30(1.11–1.50)	<0.001	0.0	0.735
Mixed	2	2.23(1.26–3.21)	<0.001	0.0	0.367

Abbreviations: ESCC, esophageal squamous cell carcinoma; HR, hazard ratio; 95%CI, 95% confidence interval; NS: not significant.

Figure 4 Meta-analysis of the relationship between SII and clinical pathology in EC patients: A) histological grade; B) infiltration depth; C) lymph node metastasis; D) clinical stage.

Abbreviations: SII, systemic immune-inflammation index; EC, esophageal cancer; OR, odds ratio; 95%CI, 95% confidence interval.

Figure 5 Meta-analysis of the correlation between CAR and OS.

Abbreviations: OS, overall survival; CAR, C-reactive protein-to-albumin ratio; HR, hazard ratio; 95%CI, 95% confidence interval.

Table 3 Subgroup analysis of the correlation between CAR and OS

Subgroup factor	No. of studies	Pooled HR(95% CI)	P-value	Heterogeneity
				I^2 (%)	Phet
Pathological type
ESCC	5	1.64(1.30–1.98)	<0.001	47.8	0.104
Mixed	2	1.43(0.73–2.12)	NS	27.5	0.240
Cut-off value
≥0.277	3	1.92(1.42–2.42)	<0.001	62.3	0.070
<0.277	4	1.41(1.02–1.80)	<0.001	0.0	0.668
Treatments
With-surgery	5	1.78(1.33–2.23)	<0.001	43.6	0.131
Mixed	2	1.45(1.03–1.86)	<0.001	9.7	0.293
Clinical stage
Non-metastatic	3	2.04(1.44–2.64)	<0.001	50.0	0.135
Mixed	4	1.44(1.09–1.80)	<0.001	0.0	0.477

Abbreviations: ESCC, esophageal squamous cell carcinoma; HR, hazard ratio; 95%CI, 95% confidence interval; NS: not significant.

Figure 6 Meta-analysis of the relationship between CAR and clinical pathology in EC patients: (A) histological grade; (B) infiltration depth; (C) lymph node metastasis; (D) clinical stage.

Abbreviations: CAR, C-reactive protein-to-albumin ratio; EC, esophageal cancer; OR, odds ratio; 95%CI, 95% confidence interval.

Figure 7 Publication bias assessment for OS with SII (A) and CAR (B).

Abbreviations: OS, overall survival; SII, systemic immune-inflammation index; CAR, C-reactive protein-to-albumin ratio.

Figure 8 Sensitivity analysis for OS in SII (A) and CAR (B).

Abbreviations: OS, overall survival; SII, systemic immune-inflammation index; CAR, C-reactive protein-to-albumin ratio.

Figure S1 Risk of bias assessment for SII.

Abbreviations: SII, systemic immune-inflammation index.

Figure S2 Risk of bias assessment for CAR.

Abbreviations: CAR, C-reactive protein-to-albumin ratio.

Table S1 Relevant data of clinicopathologic characteristics for SII and CAR in EC patients

SII					CAR
histological grade					histological grade
	Poorly/undifferentiated		Well/Moderate			Poorly/undifferentiated		Well/Moderate
Study	High SII	Low SII	High SII	Low SII	Study	High CAR	Low CAR	High CAR	Low CAR
Geng Y, 2016^Citation14	306	114	357	139	Wei XL, 2015^Citation22	66	93	81	183
Feng JF, 2017^Citation16	43	15	174	66	Xu XL, 2015^Citation23	23	62	64	318
Wang L, 2017^Citation19	46	81	67	86	Ishibashi Y, 2018^Citation20	13	7	62	61
Ishibashi Y, 2018^Citation20	12	8	58	65	Yu X, 2018^Citation27	21	31	64	44
Zhang H, 2018^Citation21	77	37	328	213
infiltration depth					infiltration depth
	T 3-4		T0-2			T 3-4		T1-2
Study	High SII	Low SII	High SII	Low SII	Study	High CAR	Low CAR	High CAR	Low CAR
Geng Y, 2016^Citation14	377	106	286	147	Wei XL, 2015^Citation22	88	174	27	87
Wang L, 2017^Citation19	75	70	38	97	Xu XL, 2015^Citation23	74	286	11	82
Ishibashi Y, 2018^Citation20	52	31	18	42	Ishibashi Y, 2018^Citation20	57	26	18	42
Zhang H, 2018^Citation21	328	173	77	77	Kunizaki M, 2018^Citation26	34	29	17	36
lymph node metastasis					lymph node metastasis
Study	LNM +	LNM -	LNM +	LNM -		High CAR		Low CAR
Geng Y, 2016^Citation14	341	322	103	150	Study	LNM +	LNM -	LNM +	LNM -
Wang L, 2017^Citation19	65	48	58	109	Wei XL, 2015^Citation22	54	49	104	154
Ishibashi Y, 2018^Citation20	42	28	41	32	Xu XL, 2015^Citation23	69	18	228	153
Zhang H, 2018^Citation21	184	221	105	145	Ishibashi Y, 2018^Citation20	46	29	37	31
clinical stage					clinical stage
	III-IV		0-II			III-IV		I-II
Study	High SII	Low SII	High SII	Low SII	Study	High CAR	Low CAR	High CAR	Low CAR
Geng Y, 2016^Citation14	271	82	392	171	Wei XL, 2015^Citation22	97	104	50	172
Feng JF, 2017^Citation16	107	18	110	63	Xu XL, 2015^Citation23	66	197	21	184
Wang L, 2017^Citation19	55	46	58	121	Ishibashi Y, 2018^Citation20	47	30	28	38
Ishibashi Y, 2018^Citation20	43	34	27	39	Kunizaki M, 2018^Citation26	36	29	15	36
Zhang H, 2018^Citation21	253	117	152	133

Abbreviations: SII, systemic immune-inflammation index; CAR, C-reactive protein-to-albumin ratio; EC, esophageal cancer; LNM, lymph node metastasis.

Table S2 Study quality of all included cohort studies in the meta-analysis

	Study [Reference]*	Hypothesis and/or objective(s) stated	Tumor stage clearly described	Clear description of eligibility criteria	Patients with inflammatory disease or coagulation disorders excluded	Predictors and outcome(s) clearly predefined	Confounders considered in multivariate analysis	Follow-up period reported and long enough for outcomes to occur	Bias and limitations considered	Quality score (0 − 8)
SII	Geng Y, 2016^Citation14	yes	yes	yes	no	no	yes	yes	yes	6
	Feng JF, 2017^Citation16	yes	yes	yes	yes	no	yes	yes	yes	7
	Wang L, 2017^Citation19	yes	yes	yes	yes	yes	yes	no	yes	7
	Ishibashi Y, 2018^Citation20	yes	yes	no	no	yes	yes	yes	yes	6
	Zhang H, 2018^Citation21	yes	yes	yes	yes	yes	yes	yes	yes	8
CAR	Wei XL, 2015^Citation22	yes	yes	yes	yes	yes	yes	yes	yes	8
	Xu XL, 2015^Citation23	yes	yes	yes	yes	yes	yes	yes	yes	8
	Otowa Y, 2017^Citation24	yes	yes	yes	no	yes	yes	yes	yes	7
	Jomrich G, 2017^Citation25	yes	yes	yes	yes	yes	yes	yes	yes	8
	Ishibashi Y, 2018^Citation20	yes	yes	no	no	yes	yes	yes	yes	6
	Kunizaki M, 2018^Citation26	yes	yes	no	no	no	yes	yes	yes	5
	Yu X, 2018^Citation27	yes	yes	yes	yes	yes	yes	yes	yes	8

Abbreviations: SII, systemic immune-inflammation index; CAR, C-reactive protein-to-albumin ratio.

Geng Y, Shao Y, Zhu D, et al. Systemic immune-inflammation index predicts prognosis of patients with esophageal squamous cell carcinoma: a propensity score-matched analysis. Sci Rep. 2016;6:39482. doi:10.1038/srep3948228000729

 PubMed Web of Science ®Google Scholar

Feng JF, Chen S, Yang X. Systemic immune-inflammation index (SII) is a useful prognostic indicator for patients with squamous cell carcinoma of the esophagus. Medicine (Baltimore). 2017;96(4):e5886. doi:10.1097/MD.000000000000588628121932

 PubMed Web of Science ®Google Scholar

Wang L, Wang C, Wang J, et al. A novel systemic immune-inflammation index predicts survival and quality of life of patients aftercurative resection for esophageal squamous cell carcinoma. J Cancer Res Clin Oncol. 2017;143(10):2077–2086. doi:10.1007/s00432-017-2451-128601935

 PubMed Web of Science ®Google Scholar

Ishibashi Y, Tsujimoto H, Hiraki S, et al. Prognostic value of preoperative systemic immunoinflammatory measures in patients with esophageal cancer. Ann Surg Oncol. 2018;25(11):3288–3299. doi:10.1245/s10434-018-6651-y30019304

 PubMed Web of Science ®Google Scholar

Zhang H, Shang X, Ren P, et al. The predictive value of a preoperative systemic immune‐inflammation index and prognostic nutritional index in patients with esophageal squamous cell carcinoma. J Cell Physiol. 2018. doi:10.1002/jcp.27052 [ [Epub ahead of print]].

 Web of Science ®Google Scholar

Wei XL, Wang FH, Zhang DS, et al. A novel inflammation-based prognostic score in esophageal squamous cell carcinoma: the C-reactive protein/albumin ratio. BMC Cancer. 2015;15:350. doi:10.1186/s12885-015-1584-325934640

 PubMed Web of Science ®Google Scholar

Xu XL, Yu HQ, Hu W, et al. A novel inflammation-based prognostic score, the C-Reactive Protein/Albumin Ratio predicts the prognosis of patients with operable esophageal squamous cell carcinoma. PLoS One. 2015;10(9):e0138657. doi:10.1371/journal.pone.013865726390126

 PubMed Web of Science ®Google Scholar

Otowa Y, Nakamura T, Yamamoto M, et al. C-reactive protein to albumin ratio is a prognostic factor for patients with cStage II/III esophageal squamous cell cancer. Dis Esophagus. 2017;30(12):1–5. doi:10.1093/dote/dox107

 PubMed Web of Science ®Google Scholar

Jomrich G, Paireder M, Gleiss A, et al. Comparison of inflammation-based prognostic scores in a cohort of patients with resectable esophageal cancer. Gastroenterol Res Pract. 2017;2017:1678584. doi:10.1155/2017/167858428740506

 PubMed Web of Science ®Google Scholar

Kunizaki M, Tominaga T, Wakata K, et al. Clinical significance of the C-reactive protein-to-albumin ratio for the prognosis of patients with esophageal squamous cell carcinoma. Mol Clin Oncol. 2018;8(2):370–374. doi:10.3892/mco.2017.152729435305

 PubMed Web of Science ®Google Scholar

Yu X, Wen Y, Lin Y, et al. The value of preoperative glasgow prognostic score and the C-Reactive protein to albumin ratio as prognostic factors for long-term survival in pathological T1N0 esophageal squamous cell carcinoma. J Cancer. 2018;9(5):807–815. doi:10.7150/jca.2275529581759

 PubMed Web of Science ®Google Scholar