Prognostic and clinicopathological significance of Systemic Immune-Inflammation Index in cancer patients receiving immune checkpoint inhibitors: a meta-analysis

Figures & data

Figure 1. Flowchart representation of the steps of the literature search and selection in this meta-analysis.

Table 1. Basic characteristics of included studies in the current meta-analysis.

Study	Year	Country	Sample size	Study design	Gender (M/F)	Cancer type	Age Median (range) year	Study centre	TNM stage	ICIs type	Study period	SII cut-off value	Outcome	Follow-up Median (range) (months)	Survival analysis	NOS score
Bauckneht, M. et al. [11]	2021	Italy	45	Prospective	29/16	NSCLC	70.6(50.3–81.5)	Multicentre	IV	Nivolumab	2015–2020	197.2	OS	9.43	Univariate	8
Chang, L. et al. [15]	2022	China	69	Retrospective	67/2	Esophageal cancer	60(44–78)	Single centre	III–IV	Camrelizumab/ Sintilimab/ Toripalimab	2017–2020	837	OS, PFS	1–30	Multivariate	8
Chen, Y. et al. [16]	2021	China	139	Retrospective	103/36	Gastric cancer	60	Single centre	III–IV	Anti-PD-1/PD-L1	2015–2019	665.3	OS, PFS	23.8	Multivariate	7
De Giorgi, U. et al. [17]	2019	Italy	313	Prospective	235/78	RCC	65(40–84)	Multicentre	IV	Nivolumab	2015–2016	1375	OS	1–24	Multivariate	9
Du, F. et al. [18]	2021	China	60	Retrospective	41/19	BTC	61(28–83)	Multicentre	IV	Anti-PD-1	2016–2019	720	OS, PFS	1–28	Univariate	8
Ekinci, F. et al. [19]	2022	Turkey	168	Retrospective	119/49	Mixed	<65 y: 101 ≥65 y: 67	Multicentre	IV	Nivolumab/ Atezolizumab/ Pembrolizumab/ Ipilimumab	2016–2020	1156	OS	91	Multivariate	8
Fornarini, G. et al. [20]	2021	Italy	267	Prospective	221/46	Urothelial carcinoma	69	Multicentre	III–IV	Atezolizumab	2016–2020	1375	OS, PFS	9.5	Multivariate	9
Huang, R. et al. [21]	2022	China	110	Retrospective	100/10	HCC	54.5(31–84)	Single centre	III–IV	Anti-PD-1	2019–2020	970	OS, PFS	1–20	Multivariate	7
Iinuma, K. et al. [22]	2021	Japan	43	Retrospective	31/12	RCC	69	Multicentre	IV	Nivolumab +  Ipilimumab	2018–2021	561.7	PFS	14	Univariate	8
Kauffmann et al. [23]	2021	Germany	29	Prospective	24/5	NSCLC	64.1	Single centre	IV	Nivolumab/ Pembrolizumab	2016–2019	1217	PFS	1–46	Univariate	8
Lee, J. H. et al. [24]	2022	Korea	266	Retrospective	135/131	Melanoma	60	Single centre	IV	Nivolumab/ Pembrolizumab	2015–2021	850	OS, PFS	13.9	Multivariate	7
Liu, J. et al. [25]	2019	China	44	Retrospective	33/11	NSCLC	60(43–74)	Single centre	III–IV	Nivolumab	2016–2018	603.5	OS, PFS	6.9	Multivariate	8
Qu, Z. et al. [26]	2022	China	106	Retrospective	72/34	Gastric cancer	>65 y: 27 ≤65 y: 77	Single centre	IV	Anti-PD-1	2019–2021	1140.9	OS, PFS	17.5	Univariate	8
Shang, J. et al. [27]	2021	China	122	Retrospective	87/35	Pancreatic cancer	56(33–85)	Single centre	III–IV	Nivolumab/ Pembrolizumab/ Atezolimab/ Ipilimumab/ Sintilimab	2015–2019	566	OS, PFS	1–80	Multivariate	7
Stühler, V. et al. [28]	2022	Germany	49	Retrospective	35/14	RCC	64.6(39.9–83.5)	Single centre	IV	Nivolumab +  Ipilimumab	2012–2018	788	OS, PFS	9.53(0.33–45.9)	Multivariate	8
Wu, X. et al. [29]	2021	China	119	Retrospective	102/17	Esophageal cancer	61(42–78)	Single centre	III–IV	Anti-PD-1	2018–2020	829	PFS	1–21	Univariate	7
Xiong, Q. et al. [30]	2021	China	41	Retrospective	36/5	SCLC	61(42–80)	Single centre	I–IV	Anti-PD-1/PD-L1	2015–2018	730	PFS	1–8	Univariate	8

Note: NSCLC: non-small cell lung cancer; RCC: renal cell carcinoma; BTC: biliary tract cancer; HCC: hepatocellular carcinoma; SCLC: small cell lung cancer; OS: overall survival; PFS: progression-free survival; NOS: Newcastle-Ottawa Scale; SII: Systemic Immune-Inflammation Index.

Table 2. The details of NOS scale for included studies in this meta-analysis.

		Selection（0–4 point）				Comparability (0–2 point)	Outcome (0–3 point)
Study	Year	Representativeness of the exposed cohort	Selection of the non exposed cohort	Ascertainment of exposure	Demonstration that outcome of interest was not present at start of study	Comparability of cohorts on the basis of the design or analysis	Assessment of outcome	Was follow-up long enough for outcomes to occur	Adequacy of follow up of cohorts	Total score
Bauckneht, M. et al. [11]	2021	★	★	★	★	★★	★	⋆	★	8
Chang, L. et al. [15]	2022	★	★	⋆	★	★★	★	★	★	8
Chen, Y. et al. [16]	2021	★	★	★	★	★⋆	★	⋆	★	7
De Giorgi, U. et al. [17]	2019	★	★	★	★	★★	★	★	★	9
Du, F. et al. [18]	2021	★	★	⋆	★	★★	★	★	★	8
Ekinci, F. et al. [19]	2022	★	★	★	★	★⋆	★	★	★	8
Fornarini, G. et al. [20]	2021	★	★	★	★	★★	★	★	★	9
Huang, R. et al. [21]	2022	★	★	⋆	★	★⋆	★	★	★	7
Iinuma, K. et al. [22]	2021	★	★	★	★	★⋆	★	★	★	8
Kauffmann et al. [23]	2021	★	★	★	★	★★	★	⋆	★	8
Lee, J. H. et al. [24]	2022	★	★	★	★	★★	★	★	⋆	7
Liu, J. et al. [25]	2019	★	★	★	★	★★	★	⋆	★	8
Qu, Z. et al. [26]	2022	★	★	★	★	★⋆	★	★	★	8
Shang, J. et al. [27]	2021	★	★	⋆	★	★★	★	⋆	★	7
Stühler, V. et al. [28]	2022	★	★	★	★	★⋆	★	★	★	8
Wu, X. et al. [29]	2021	★	★	★	★	★⋆	★	★	⋆	7
Xiong, Q. et al. [30]	2021	★	★	⋆	★	★★	★	★	★	8

Note: NOS: Newcastle-Ottawa Scale. A ★ represents 1 point, a ⋆ represents 0 point.

Figure 2. Forest plot of HR for the relationship between SII and overall survival in cancer patients receiving ICIs.

Figure 3. Forest plot of HR for the association between SII and progression-free survival in cancer patients receiving ICIs.

Table 3. The prognostic value of SII for OS in cancer patients treated with ICIs.

Subgroups	No. of studies	No. of patients	Effects model	HR (95%CI)	p	Heterogeneity I^2 (%) Ph
Overall	13	1,758	Random	2.62(1.76–3.90)	<.001	88.5	<0.001
Study design
Prospective	3	625	Fixed	2.66(2.09–3.39)	<.001	0	0.702
Retrospective	10	1,133	Random	2.62(1.64–4.18)	<.001	82.7	<0.001
Sample size
<100	5	267	Fixed	2.53(1.80–3.56)	<.001	0	0.413
≥100	8	1,491	Random	2.46(1.50–4.03)	<.001	91.0	<0.001
Study centre
Single centre	8	905	Random	2.76(1.56–4.86)	<.001	82.0	<0.001
Multicentre	5	853	Fixed	2.58(2.09–3.19)	<.001	0	0.841
TNM stage
III–IV	6	751	Fixed	2.60(2.01–3.36)	<.001	32.8	0.190
IV	7	1007	Random	2.18(1.30–3.65)	.003	88.9	<0.001
ICIs type
Anti-PD-1	8	1117	Random	2.45(1.47–4.09)	.001	89.0	<0.001
Anti-PD-1/PD-L1	1	41	–	1.99(1.23–3.22)	.005	–	–
Anti-PD-1/PD-L1 + Anti-CTLA-4	2	290	Fixed	3.24(1.81–5.78)	<.001	35.4	0.213
Anti-PD-1 + Anti-CTLA-4	1	43	–	6.91(0.87–55.05)	.068	–	–
Anti-PD-L1	1	267	–	2.45(1.67–3.59)	<.001	–	–
Cut-off value of SII
<800	6	459	Fixed	2.42(1.79–3.26)	<.001	28.1	0.224
≥800	7	1299	Random	2.35(1.39–3.96)	.001	91.5	<0.001
Country
Asian	9	1084	Random	2.51(1.57–4.02)	<.001	83.7	<0.001
Non-Asian	4	674	Fixed	2.69(2.12–3.43)	<.001	0	0.680
Survival analysis
Univariate	3	211	Fixed	2.15(1.48–3.11)	<.001	0	0.910
Multivariate	10	1547	Random	2.85(1.75–4.64)	<.001	90.2	<0.001
Cancer type
NSCLC	2	89	Random	3.61(1.20–10.87)	.023	57.6	0.125
Esophageal cancer	1	69	–	2.49(1.24–4.97)	.010	–	–
Gastric cancer	2	245	Fixed	1.98(1.31–2.99)	.001	0	0.964
RCC	2	362	Fixed	3.07(2.14–4.40)	<.001	0	0.436
BTC	1	60	–	2.05(1.14–3.68)	.016	–	–
Mixed	1	168	–	2.79(1.49–5.21)	.001	–	–
Urothelial carcinoma	1	267	–	2.45(1.67–3.59)	<.001	–	–
HCC	1	110	–	5.56(1.78–17.38)	.003	–	–
Melanoma	1	266	–	1.08(1.05–1.11)	<.001	–	–
Pancreatic cancer	1	122	–	8.06(1.71–37.93)	.008	–	–

Note: SII: Systemic Immune-Inflammation Index; OS: overall survival; ICIs: immune checkpoint inhibitors; NSCLC: non-small cell lung cancer; RCC: renal cell carcinoma; BTC: biliary tract cancer; HCC: hepatocellular carcinoma.

Figure 4. Results of the analysis of publication bias. (A) OS, Begg’s test, p = .583; (B) PFS, Begg’s test, p = .956.

Table 4. The prognostic value of SII for PFS in cancer patients treated with ICIs.

Subgroups	No. of studies	No. of patients	Effects model	HR (95%CI)	p	Heterogeneity I^2 (%) Ph
Overall	14	1464	Random	2.09(1.48–2.95)	<.001	80.2	<0.001
Study design
Prospective	2	296	Random	2.36(1.33–4.20)	.004	54.6	0.138
Retrospective	12	1168	Random	2.02(1.37–2.98)	<.001	75.7	<0.001
Sample size
<100	7	335	Fixed	2.78(1.96–3.93)	<.001	23.0	0.254
≥100	7	1129	Random	1.68(1.15–2.44)	.007	80.8	<0.001
Study centre
Single centre	11	1094	Random	2.02(21.34–3.03)	.001	77.4	<0.001
Multicentre	3	370	Fixed	2.04(1.55–2.70)	<.001	27.0	0.254
TNM stage
III–IV	7	870	Random	2.06(1.40–3.03)	<.001	55.8	0.035
IV	6	553	Random	2.32(1.25–4.30)	.007	82.8	<0.001
I–IV	1	41	–	0.38(0.04–3.48)	.392	–	–
ICIs type
Anti-PD-1	8	983	Random	2.15(1.30–3.55)	.003	82.0	<0.001
Anti-PD-1/PD-L1	2		Fixed	1.31(0.87–1.96)	.201	19.6	0.265
Anti-PD-1/PD-L1 + Anti-CTLA-4	1	122	–	2.84(1.03–7.82)	.043	–	–
Anti-PD-1 + Anti-CTLA-4	2	92	Fixed	4.44(1.83–10.78)	.001	0	0.365
Anti-PD-L1	1	267	–	1.91(1.39–2.63)	<.001	–	–
Cut-off value of SII
<800	7	498	Random	2.40(1.47–3.93)	<.001	51.5	0.054
≥800	7	966	Random	1.87(1.20–2.93)	.006	83.7	<0.001
Country
Asian	11	1119	Random	1.92(1.30–2.83)	.001	74.8	<0.001
Non-Asian	3	345	Fixed	2.19(1.66–2.91)	<.001	39.2	0.193
Survival analysis
Univariate	6	398	Fixed	2.01(1.44–2.81)	<.001	48.7	0.083
Multivariate	8	1066	Random	2.13(1.38–3.28)	.001	84.1	<0.001
Cancer type
NSCLC	2	73	Fixed	3.84(2.13–6.93)	<.001	0	0.744
Esophageal cancer	2	188	Fixed	1.27(0.71–2.26)	.425	0	0.545
Gastric cancer	2	245	Fixed	1.46(1.01–2.12)	.042	0	0.525
RCC	2	92	Fixed	4.44(1.83–10.78)	.001	0	0.365
BTC	1	60	–	2.24(1.25–4.02)	.007	–	–
Urothelial carcinoma	1	267	–	1.91(1.39–2.63)	<.001	–	–
HCC	1	110	–	7.11(2.37–21.31)	<.001	–	–
Melanoma	1	266	–	1.04(0.97–1.11)	.254	–	–
Pancreatic cancer	1	122	–	2.84(1.03–7.82)	.043	–	–
SCLC	1	41	–	0.38(0.04–3.48)	.392	–	–

Note: SII: Systemic Immune-Inflammation Index; PFS: progression-free survival; ICIs: immune checkpoint inhibitors; NSCLC: non-small cell lung cancer; RCC: renal cell carcinoma; BTC: biliary tract cancer; HCC: hepatocellular carcinoma; SCLC: small cell lung cancer.

Table 5. The correlation between SII and clinicopathological variables in cancer patients undergoing ICIs treatment.

Variables	No. of studies	No. of patients	Effects model	OR (95%CI)	p	Heterogeneity I^2 (%) Ph
Gender (male vs female)	3	323	Fixed	1.01(0.59–1.73)	.959	0	0.529
Age (years) (≥65 vs <65)	2	274	Random	1.08(0.39–2.98)	.881	57.4	0.126
No. of metastasis sites (≥3 vs <3)	3	323	Fixed	1.49(0.90–2.46)	.119	46.8	0.152
LN metastasis (presence vs absence)	3	468	Fixed	1.41(0.92–2.17)	.117	0	0.747

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Data availability statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.