Baseline characteristics of patients
The median age of 209 patients was 60 (range 29–90) years. We observed liver-only metastases in 133 patients (63.3%), lung-only metastases in 79 patients (37.6%), liver-lung metastases in 12 patients (5.7%), and extra-regional lymph nodes metastases in 23 patients (11.0%). As for primary tumor, 28 (13.4%) patients had left-sided CRC, 179 (85.6%) had right-sided CRC. The N2 stage CRC was in 52 (24.9%) patients, the T4 stage CRC was in 103 (49.3%) patients (Table 1).
Table 1
Baseline characteristics of patients.
Characteristics | Total patients n (%) |
Age (years) (median, range) | 60 (29–90) |
Gender | |
Male | 137 (65.6%) |
Female | 72 (34.4%) |
BMI (kg/m2) (median, range) | |
≤ 18.5 | 16 (7.6) |
18.5–23.9 | 87 (41.4) |
23.9–27 | 72 (34.3) |
> 28 | 34 (16.7) |
Timing of metastasis | |
Synchronous | 117 (55.7) |
Metachronous | 92 (44.3) |
Liver-only metastases | 133 (63.3) |
Lung-only metastases | 79 (37.6) |
Liver-lung metastases | 12 (5.7) |
Extra-regional lymph nodes metastases | 23 (11) |
No. of involving sites | |
1 | 90 (42.9) |
≥ 2 | 119 (57.1) |
Clinical T stage | |
T2 | 17 (8.1) |
T3 | 68 (32.5) |
T4 | 103 (49.3) |
Unknown | 21 (10.1) |
Clinical N stage | |
N0 | 63 (30.1) |
N1 | 69 (33.0) |
N2 | 52 (24.9) |
Unknown | 25 (12.0) |
Primary tumor location | |
Left | 179 (85.6) |
Right | 28 (13.4) |
Unknown | 2 (1) |
WBC | |
༜4 | 25 (12.0) |
4–10 | 171 (81.8) |
> 10 | 13 (6.2) |
LMR (median, range) | 3.50 (0.44–69.30) |
NLR (median, range) | 2.36 (0.17–27.74) |
PLR (median, range) | 163.19 (0.00-475.86) |
CA199(ng/ml) | |
0–40 | 120 (57.4) |
> 40 | 63 (30.2) |
Unknown | 26 (12.4) |
CEA (ng/ml) | |
0–5 | 74 (35.4) |
> 5 | 120 (57.4) |
Unknown | 15 (7.2) |
Fibrinogen(G/L) | |
<2 | 2 (1.0) |
2–4 | 140 (67.0) |
> 4 | 56 (26.7) |
Unknown | 11 (5.3) |
Treatment | |
Primary tumor resection | 185 (88.1) |
Lung resection | 20 (9.5) |
Liver resection | 43 (20.5) |
Interventional therapy | 45 (21.5) |
Radiotherapy | 37 (17.7) |
Chemotherapy | 175 (83.7) |
Targeted therapy | 71 (34) |
Cut-off Values Of Inflammatory Markers
According to the maximum sum of specificity and sensitivity, we calculated the Youden index and obtained optimal cut-off values for NLR, LMR, and PLR were 3.57,3,97, and 208, respectively. CEA > 5 (ng/ml), CA19-9 > 40 (ng/ml), fibrinogen > 3.41 (G/L), and WBC > 10 (10^9/L) were classified into elevated-level groups based on the normal range.
Relationships Between Lmr, Nlr, And Plr And Patients’ Characteristics
We observed that 131(62.7%) patients were in the LMR-low group, 78 (37.3%) patients were in the LMR-high group, higher CEA level (P = 0.020) and CA-199 level (P = 0.019) were detected in the LMR-low group compared with the LMR-high group. 162 (77.5%) patients had decreased NLR which was significantly related with lower WBC (P < 0.001), fibrinogen (P = 0.016), and higher N-stage (P = 0.031). The Males were more common in the elevated-NLR group than the low-NLR group (P = 0.005). Compared with the low-PLR group, patients in the high-PLR group significantly presented higher WBC (P = 0.038). Other clinical-related characteristics including age, BMI, the timing of metastasis, distribution of metastatic organs, number of involved sites, T stage, primary tumor location, treatments were comparable in different subgroups (all P > 0.05). More details were showed in Supplement Table 1.
Relationships Between Lmr, Nlr, Plr And Survival Outcomes
The median follow-up was 32 (range 2–91) months. 142 (67.9%) patients were alive on the last follow-up, the cumulative 3-year and 5-year OS rates were 72.2% and 67.9%, respectively.149 (71.2%) patients had evidence of cancer progression, the cumulative 3-year and 5-year PFS rates were 31.1% and 29.2%, respectively. Patients in the PLR-high group showed poorer OS (P = 0.0003) and PFS (P = 0.0310) than the PLR-low group, whereas low LMR only was associated with prolonged PFS (P = 0.0434). Compared with the NLR-low group, the OS for the NLR-high group was significantly improved (P = 0.0420). Figure.1 provided the relationships between LMR, NLR, PLR and survival outcomes.
Predictive accuracy of a nomogram based on pretreatment inflammatory markers and clinical pathology characteristics
The univariate analysis showed that extra-regional lymph nodes metastases (HR, 2.006, 95% CI,1.704–3.748, P = 0.029), more involving sites (HR, 1.797, 95% CI: 1.803–3.748, P = 0.023), advanced N stage (HR, 4.195, 95% CI: 1.972–8.924, P = 0.002), increased NLR (HR, 1.709, 95% CI: 1.012–2.886, P = 0.045) and the high-level fibrinogen (HR, 2.777, 95%CI: 1.593–4.840, P < 0.01) were associated with shorter OS. Primary tumor resection (HR, 0.501, 95%CI: 0.261–0.960, P = 0.037), lung resection (HR, 0.242, 95%CI: 0.059–0.987, P = 0.048), and reduced PLR (HR, 2.448, 95%CI: 1.448–4.028, P < 0.001) were found statistically significant for longer OS. In addition, advanced N stage (HR, 2.083, 95%CI: 1.353–3.206, P = 0.001) presented worse PFS (Supplement Table 2).
Table 2
Multivariate Cox analysis of factors associated with survival.
Characteristics | OS | PFS |
| 3-year (%) | Univariate | Multivariate | 3-year (%) | Univariate | Multivariate |
| HR (95%CI) | P | HR (95%CI) | P | HR (95%CI) | P | HR (95%CI) | P |
Extra-regional lymph nodes metastases | | | | | | | | | | |
No | 68.7 | Reference | | Reference | | 26.7 | Reference | | | |
Yes | 51.5 | 2.006 (1.704–3.748) | 0.029 | 2.472 (1.247–4.903) | 0.010 | 17.4 | 1.613 (0.994–2.617) | 0.053 | | |
Clinical N stage | | | 0.002 | | 0.001 | | | 0.001 | | 0.007 |
N0 | 83.6 | Reference | | Reference | | 31.9 | Reference | | Reference | |
N1 | 66.2 | 2.504 (1.164–5.387) | 0.019 | 2.834 (1.256–6.396) | 0.012 | 21.3 | 1.342 (0.888–2.028) | 0.163 | 1.342 (0.888–2.028) | 0.163 |
N2 | 48.3 | 4.195 (1.972–8.924) | ༜0.01 | 4.602 (2.055–10.305) | ༜0.01 | 17.4 | 2.083 (1.353–3.206) | 0.001 | 2.100 (1.364–3.231) | 0.001 |
Fibrinogen (G/L) | | | | | | | | | | |
≤ 3.41 | 80.2 | Reference | | Reference | | 27.6 | Reference | | | |
> 3.41 | 55.1 | 2.777 (1.593–4.840) | ༜0.01 | 2.254 (1.246–4.078) | 0.007 | 24.9 | 1.008 (0.720–1.409) | 0.965 | | |
Primary tumor resection | | | | | | | | | | |
No | 42.8 | Reference | | Reference | | 28.5 | Reference | | | |
Yes | 69.1 | 0.501 (0.261–0.960) | 0.037 | 0.367 (0.148–0.908) | 0.030 | 24.9 | 1.385 (0.798–2.404) | 0.246 | | |
PLR | | | | | | | | | | |
≤ 208.48 | 72.3 | Reference | | | | 28.8 | Reference | | Reference | |
> 208.48 | 49.7 | 2.448 (1.448–4.028) | ༜0.01 | 2.396 (1.391–4.126) | 0.002 | 13.4 | 1.414 (0.985–2.031) | 0.061 | 1.371(0.953–1.972) | 0.09 |
The multivariate analysis further revealed that extra-regional lymph nodes metastases (HR, 2.472, 95%CI: 1.247–4.903, P = 0.010), early clinical N stage (HR, 4.602, 95%CI: 2.055–10.305, P = 0.001), the low-level fibrinogen (HR, 2.254, 95%CI: 1.246–4.078, P = 0.007), primary tumor resection (HR, 0.367, 95%CI: 0.148–0.908, P = 0.03), and decreased PLR (HR, 2.396, 95%CI: 1.391–4.126, P = 0.002) were related with good OS. Regarding PFS, advanced N stage (HR, 2.100, 95%CI: 1.364–3.231, P = 0.007) independently predicted poor PFS (Table 2).
Based on the multivariate analysis, all statistically significant factors were identified to build the nomogram, including PLR, extra-regional lymph nodes metastases, clinical N stage, fibrinogen, and primary tumor resection (Figure. 2). The C-index of the nomogram is 0.721 for 3-year OS (Figure. 3a) and 5-year OS (Figure. 3b), and the AUC of ROC in the nomogram was 0.772 (Figure. 4). The calibration and ROC curves showed no significant performance discrimination between predicted probability and real survival.