Neutrophil-to-lymphocyte ratio as a prognostic factor for survival in patients with colorectal liver metastases: A systematic review

Table 1 Patient demographics, neutrophil to lymphocyte ratio cut-off value, follow-up time and time of sample acquisition for patients after hepatectomy

Ref.	Number of patients	Sex	Mean age (years)	NLR threshold	Follow up (mo), mean (range)	Sample acquisition
Erstad et al[13]	151	84 M, 67 F	58	5	41.3 ± 36.7 (2-186)	Within 6 mo prior to surgery and prior to chemotherapy
Halazun et al[14]	440	289 M, 151 F	64 (32-88)	5	24 (11-97)	1 d prior to surgery
Kishi et al[15]	290	Resection group 132 M, 68 F; non resection group 61 M, 29 F	Resection, 57; non resection, 56	5	28 (2-102)	Resection group: Before chemotherapy and before resection
Neal et al[16]	302	192 M, 110 F	64.8 (26-85)	5	29.5 (4-96)	Prior to surgery
Hand et al[17]	322	205 M, 117 F	252 p < 70 yr; 70 p > 70 yr	5	41	On admission; the night prior to or on the morning of surgery
Peng et al[18]	150	97 M, 53 F	58 (20-82)	4.63	36 (2-126)	Within 7 d prior to surgery
Kim et al[19]	83	62 M, 21 F	59.5	1.94	NS	Within 1 wk prior to surgery
Mao et al[20]	183	123 M, 60 F	67 p > 60 yr	2.3	36.3	Within 10 d before chemotherapy and surgery
Neofytou et al[21]	140	88 M, 52 F	78% < 70 yr	2.4	33 (1-103)	Within 10 d prior to surgery
Giakoustidis et al[22]	169	104 Μ, 65 F	135 p < 70 yr, 34 p > 40 yr	2.5	34.6	10 d prior to surgery - after preoperative chemotherapy
Dupré et al[23]	343	236 M, 107 F	65.8 ± 10.9	2.5, 2.6 and 7.261	49	Within 1 wk prior to surgery
Hamada et al[24]	29	20 M, 9 F	63 ± 11.6 (41-83)	4.1	51 (2-97)	NS
Zeman et al[25]	130	70 M, 60 F	60 (33-82)	5	39.3	NS

¹Cut-off values that reached statistical significance.

M: Male; F: Female; p: Patients; NS: Not stated.

Table 2 Survival and disease characteristics

Ref.	Median Survival	5-year OS	5-year DFS	Extrahepatic Disease	Primary Tumor	Chemotherapy
Erstad et al[13]	3.1 yr, NLR > 5; 6.3 yr NLR < 5	28.7%, NLR > 5; 59.6%, NLR < 5	NS	Νο	Previous resection of rectum or colon	Neoadjuvant
Halazun et al[14]	NS	22%, NLR > 5; 43%, NLR < 5	12%, NLR > 5; 42%, NLR < 5	No disseminated or unresectable EHD	Previously resected	Neoadjuvant
Kishi et al[15]	34 mo, NLR > 5; 45 mo, NLR < 5	26%, NLR > 5; 36%, NLR < 5	NS	No	Previously resected	Neoadjuvant, n = 200; Without resection, n = 90
Neal et al[16]	27.8 mo, NLR > 5; 39.8 mo, NLR < 5	18.5% NLR > 5; 30.6% NLR < 5	22.3%, NLR > 5; 35.2%, NLR < 52	NS	Rectum n = 149, Colon n = 153	Adjuvant, n = 126
Hand et al[17]	59 mo	Chemotherapy group, 50.8%; No chemotherapy group, 42.5%	NS	NS	No	Neoadjuvant, n = 202
Peng et al[18]	NS	18.8%, NLR > 4.63; 46.7%, NLR < 4.63	NS	No	58% colon, 42% rectum	Neoadjuvant, n = 59
Kim et al[19]	NS	NS	NS	No	NS	Neoadjuvant, n = 24
Mao et al[20]	31.1 mo NLR > 2.3 43.1 mo NLR < 2.3	NS	NS	No	Colon n = 104	Neoadjuvant, n = 183
Neofytou et al[21]	55 mo, NLR > 2.4; Not reached, NLR < 2.4	42%, NLR > 2.4; 69%, NLR < 2.4	Total 27%. 14%, NLR > 2.4; 40%, NLR < 2.4	Νο	Resection prior to hepatectomy in 81%	Neoadjuvant
Giakoustidis et al[22]	75 mo	51%, NLR > 2.5; 74% NLR < 2.5	NS	No	Synchronous resection, n = 26; ‘liver first’, n = 7	Neoadjuvant, n = 169
Dupré et al[23]	50.3, NLR < 2.5; 38.4, NLR > 2.5; 44.8, NLR < 7.26; 25.4, NLR > 7.26	NS	11.6, NLR < 2.5; 9.7, NLR > 2.5; 10.3, NLR < 7.26; 6.3, NLR > 7.261	Resectable EHD in 36 patients	Synchronous, n = 169; Right colon, n = 73; Left colon, n = 126; Rectum, n = 142; Multiple, n = 2	Neoadjuvant, n = 198
Hamada et al[24]	NS	NS	NS	Yes, n = 5	NS	Adjuvant, n = 15
Zeman et al[25]	Resection group, 56 mo	46.6%, resection group; 9.5%, RFA group	30.5%, resection group, 21 mo median	No	Rectum n = 60, colon n = 70	Adjuvant, n = 25

¹PFS: Progression-Free Survival.

²CSS: Cancer-Specific Survival.

OS: Overall survival; DFS: Disease-free survival; NLR: Neutrophil to lymphocyte ratio; NS: Not stated; EHD: Extra-hepatic disease.

Table 3 Univariate and multivariate analysis results after hepatectomy

Ref.	Univariate analysis	Multivariate analysis
Erstad et al[13]	NLR > 5 was significantly associated with reduced OS (P = 0.001)	NLR > 5 associated with reduced OS (P = 0.032)
Halazun et al[14]	NLR > 5 was associated with reduced OS (P < 0.0001); NLR > 5 was the sole positive predictor of recurrence (P < 0.0001)	NLR > 5 was associated with reduced OS (P < 0.0001)
Kishi et al[15]	NLR > 5 predicted worse survival (P = 0.011)	NLR > 5 predicted worse survival using variables available before surgery (P = 0.016) and after surgery (P = 0.048)
Neal et al[16]	NLR > 5 was significantly associated with worse OS (P = 0.001) and CSS (P < 0.001) following metastasectomy	NLR > 3 was associated with shorter survival (P < 0.001); NLR > 3 was associated with adverse outcomes regarding CSS (P < 0.001)
Hand et al[17]	Following index hepatectomy, patients with NLR > 5 had a median survival of 55 mo vs 70 mo when NLR < 5 (P = 0.027); Following neoadjuvant chemotherapy, no association between NLR and survival was demonstrated (P = 0.93); NLR > 5 had no impact on prognosis following repeat hepatectomy	There is an independent association between elevated preoperative neutrophil count and shortened overall survival (P = 0.001); no such association was found for NLR
Peng et al[18]	Patients with NLR > 4.63 were more likely to present multiple hepatic metastases than those with low NLR (68.8% vs 40.3%, P = 0.030); 5-year RFS and OS for high NLR were significantly inferior to those for low NLR (RFS: 12.5% vs 38.5%, P = 0.015; OS: 18.8% vs 46.7%, P = 0.004)	NLR was not identified as an independent inflammatory factor for better RFS
Kim et al[19]	NLR > 1.94 was a prognostic factor for poor OS (P = 0.035) and DFS; High NLR was associated with recurrence (P = 0.031)	NLR > 1.94 was an independent prognostic factor for OS (P = 0.01) and prognostic factor for poor DFS; High NLR was associated with recurrence (P = 0.006)
Mao et al[20]	Pre- and post-chemotherapy NLR > 2.3 was associated with decreased OS (P = 0.012)	NLR > 2.3 was a significant predictor both for worse OS (P < 0.001) and for RFS (P = 0.017)
Neofytou et al[21]	NLR > 2.4 was associated with decreased DFS (P = 0.033) and OS (P = 0.007)	No significant correlation was found between NLR and OS/DFS
Giakoustidis et al[22]	NLR > 2.5 was associated with decreased OS (P = 0.009) and decreased DFS (P = 0.09)	High NLR remained a significant prognostic factor for poor OS (P = 0.012)
Dupré et al[23]	NLR of 2.5 was an independent prognostic factor for OS and PFS	High NLR was significantly associated with decreased OS (P < 0.002)
Hamada et al[24]	NLR > 4.1 was significantly correlated with better CSS (P = 0.026)	Only univariate analysis was performed
Zeman et al[25]	NLR > 5 was significantly associated with DFS (P = 0.044); OS was significantly affected by the preoperative number of leukocytes (P = 0.0014) and neutrophils (P = 0.0036) but not by the NLR.	NLR > 5 was significantly associated with DFS (P = 0.03); Leukocyte number was significantly associated with OS (P = 0.0014); no effect of NLR was demonstrated on OS

NLR: Neutrophil to lymphocyte ratio; OS: Overall survival; CSS: Cancer-specific survival; RFS: Recurrence-free survival; DFS: Disease-free survival.

Table 4 Patient demographics, NLR cut-off value, follow up and time of sample acquisition for patients treated with radio-frequency ablation, radioembolization or solely chemotherapy

Ref.	Number of patients and procedure	Sex	Mean age (yr)	NLR threshold	Follow up (mo)	Sample acquisition
Tohme et al[29]	104 RE	69 M, 35 F	60.8 ± 12.2, NLR > 5, 66.4 ± 12.2, NLR < 5	5	100 patients died during follow up	Same day before RE
Chang et al[26]	98 RFA	56 M, 42 F	62 (28-92)	2.5	35.2 ± 21.89	1 d before RFA - 1 mo after RFA
Zhang et al[27]	92 RFA	51 M, 41 F	59 (43-78)	5	27.1 ± 9.8 (range 5-62)	Preoperatively as part of the routine workup. 1-3 d before RFA
Weiner et al[28]	131 RE	84 M, 47 F	59	5	117 deaths during follow up	NS
Kishi et al[15]	90 chemotherapy	61 M, 29 F	56	5	28 (2-102)
Wu et al[31]	55 chemotherapy	35 M, 20 F	59	4	Complete clinical records (no exact mention)	Preoperatively and before 2nd cycle of chemotherapy
Philips et al[30]	71	-	-	5	-	-

RE: Radioembolization; RFA: Radiofrequency ablation; M: Male; F: Female; NLR: Neutrophil to lymphocyte ratio; NS: Not stated.

Table 5 Survival and disease characteristics of patients that were treated with radio-frequency ablation, radioembolization or solely chemotherapy

Ref.	Median Survival	5-year OS	5-year DFS	Extrahepatic disease	Primary tumor	Chemotherapy
Tohme et al[29]	5.6 m high NLR 10.6 m low NLR	-	-	40 (less than 10% of tumor burden)	Some patients had undergone CRC resection (number not mentioned)	All patients
Chang et al[26]	-	-	(Preoperative NLR) 11.1% high NLR 22.6% low NLR (NLR increase after RFA 8.6%) (No postoperative NLR increase 22.2%)	No	All patients had undergone CRC resection	No mention
Zhang et al[27]	-	18,4% high NLR 41.7% low NLR	9.5% high NLR 26.7% low NLR	No	All patients had undergone CRC resection	If necessary after primary tumor resection (number not mentioned)
Weiner et al[28]	7.9 m high NLR 13 low NLR	-	-	59	79% had undergone primary CRC resection	All patients
Kishi et al[15]	11 m high NLR 21 m low NLR	0% high NLR 14% low NLR	-	No	All patients had undergone CRC resection	All patients
Wu et al[31]	24 m high NLR 56 m low NLR	-	-	No	All patients had undergone CRC resection	All patients
Philips et al[30]	14.7 m high NLR 31.9 m low NLR	-	-	Liver dominant disease	Not mentioned	All patients

RFA: Radio-frequency ablation; RE: Radioembolization; OS: Overall survival; DFS: Disease-free survival; NLR: Neutrophil to lymphocyte ratio; CRC: Colorectal cancer.

Table 6 Univariate and multivariate analysis outcomes for patients treated with radio-frequency ablation, radioembolization or solely chemotherapy

Ref.	Univariate analysis	Multivariate analysis
Tohme et al[29]	High NLR associated with decreased OS P < 0.001	High NLR associated with decreased OS (HR = 1.927, 95%CI: 1.202-3.089, P = 0.006)
Chang et al[26]	Preoperative high NLR and postoperative increase in NLR were associated with decreased DFS (P = 0.044 and P = 0.022, respectively)	Only postoperative NLR increase was associated with decreased DFS (P = 0.029)
Zhang et al[27]	High NLR associated with decreased OS (P = 0.007) and DFS (P = 0.007)	High NLR associated with decreased OS (P = 0.039, HR = 3.59, 95%CI: 1.54-9.67) and DFS (P = 0.022, HR = 3.19, 95%CI: 1.87-8.24).
Weiner et al[28]	High NLR associated with decreased OS (HR = 2.18, 95%CI: 1.45-3.28, P = 0.0002)	High NLR associated with decreased OS (HR = 2.22, 95%CI: 1.46-3.38, P = 0.0002)
Kishi et al[15]	High NLR associated with decreased OS (HR = 3.1, 95%CI: 1.7-5.9, P < 0.001)	High NLR associated with decreased OS (HR = 2.9, 95%CI: 1.5-5.5, P = 0.001).
Wu et al[31]	High NLR (HR = 3.182, 95%CI: 1.277-7.933, P = 0.013) associated with decreased OS and DFS (HR = 2.284, 95%CI: 1.156-4.498, P = 0.017). Patients with normalization of NLR had better DFS than those with high NLR that did not decrease (P = 0.002).	No association between NLR and survival
Philips et al[30]	High NLR associated with decreased OS P = 0.067 (statistically significant)	No association between NLR and survival

CI: Confidence interval; RFA: Radio-frequency ablation; RE: Radioembolization; OS: Overall survival; DFS: Disease-free survival; NLR: Neutrophil to lymphocyte ratio.