Clinicopathological characteristics
The median age of all 157 patients was 58.00 (IQR: 51.50-64.00) years and most patients (55.4%) was male. The proportion of patients with positive serum hepatitis B surface antigen (HBsAg) was 21.7%. The proportion of patients with lesions in the central liver was 49.7%. The median diameter of the largest ICC lesion was 5.5 (IQR 3.8-7.0) cm, and 54.8% of patients had a lesion larger than 5 cm. A total of 19.1% of patients had multiple tumors and 26.8% of the patients had LNM. Ninety one patients(58.0%) were observed with poorly differentiated tumors.
The preoperative clinical laboratory tests were as follows: tumor markers: preoperative CA19-9 > 27 U/mL (52.4%), preoperative CEA > 5 ng/mL (22.3%); liver function markers: ALB ≥ 40 g/L (79.0%), TBIL > 21 µmol/L (11.5%), AST > 40 U/L (9.6%), and ALT > 50 U/L (8.9%). The median RDW-SD level was 41.1 fl (IQR 39.7-43.3). The median RDW-CV level was 12.4% (IQR 12.0-13.1). A total of 58.6% of the patients have postoperative complications. Seventy-nine patients had an operation time ≥ 230 min, and 49.0% patients had blood loss ≥ 300 mL. Ten patients (6.4%) received preoperative therapy and 66 patients (42.0%) received postoperative therapy. The detailed clinicopathologic parameters of patients are in Table 1.
Relationships among RDW-SD, RDW-CV, SCC and clinicopathological characteristics
X-tile software was used to determine 40.2 fl and 12.6% as the optimal cut-off values for RDW-SD and RDW-CV, respectively. Based on RDW-SD levels, 157 patients were classified into a low RDW-SD (≤ 40.2, n = 53) group and high RDW-SD (> 40.2, n = 104) group. Based on RDW-CV levels, 157 patients were classified into a low RDW-CV (≤ 12.6, n = 94) group and high RDW-CV (> 12.6, n = 63) group. Based on the RDW-SD combined with RDW-CV (SCC), 46 patients were classified into the SCC = 0 group, 55 patients were classified into the SCC = 1 group, and 56 patients were classified into the SCC=2 group.
The high RDW-SD group had more patients with an ASA status of 1-2 (P = 0.027) and operation time < 230 min (P = 0.027) than the low RDW-SD group. The high RDW-CV group had more patients with non-liver cirrhosis (P = 0.020), T1-T2 stage disease (P = 0.005) and TBIL ≤ 21 µmol/L (P = 0.015). The patients with SCC = 0 was associated with an age < 60 years (P = 0.029)(Table 1).
Prognostic value of RDW-SD, RDW-CV and SCC for survival
The median follow-up time was 33.00 months. The median OS and median PFS were 28.00 months (95% CI: 12.9–43.1) and 10.00 months (95% CI: 7.2–12.8), respectively. One hundred and nine patients (69.4%) underwent recurrence, and 73 patients (46.5%) died. The 1-, 3- and 5-year progression-free survival rates were 41.8%, 29.5%, and 20.9%, respectively. The 1-, 3- and 5-year survival rates were 72.9%, 46.0% and 41.1%, respectively.
Kaplan-Meier curve analysis revealed that patients with RDW-SD > 40.2 were significantly associated with better OS (P = 0.004, median OS: 68.0 months versus 17.0 months) and better PFS (P = 0.047, median PFS: 11.0 months versus 7.0) than those with low RDW-SD values (Figure 1). Patients with RDW-CV > 12.6 were significantly associated with better OS (P = 0.030, median OS: not reached versus 22.0 months) and had an equivalent PFS (P = 0.579, median PFS: 11.0 months versus 10.0) than those with low RDW-CV values (Figure 2). Compared with patients with SCC = 0 or SCC = 1, patients with SCC = 2 were significantly associated with better OS (P < 0.001, median OS: did not reach versus 33.0 months versus 16, respectively), but all three SCC values had an equivalent PFS (P = 0.247, median PFS: 11.0 months versus 12.0 months versus 7.0 months, respectively) (Figure 3).
OS analysis
In the univariate analysis, T3-T4 stage (P < 0.001), lymph node metastasis (P < 0.001), noncentral tumor (P = 0.027), poor differentiation (P = 0.044), preoperative CEA > 5 ng/mL (P = 0.001), RDW-SD ≤ 40.2 fl (P = 0.004), RDW-CV≤12.6% (P = 0.030), ALB < 40 g/L (P = 0.048), operation time ≥ 230 min (P = 0.015), blood loss ≥ 300 ml (P = 0.030) and decreased SCC score (P = 0.007) were all associated with shorter OS (Table 2). The RDW-SD level and RDW-CV level exhibited collinearity (P < 0.001). To prevent colinearity, RDW-SD was included in the multivariate analysis of model 1, and RDW-CV was included in the multivariate analysis of model 2. In the multivariate analysis of model 1, RDW-SD > 40.2 fl (HR = 0.446, 95% CI: 0.262-0.760, P = 0.003), central tumor (HR = 0.367, 95% CI: 0.210-0.641, P < 0.001), and adjuvant therapy (HR = 0.423, 95% CI: 0.232-0.774, P = 0.005) were significantly associated with favorable OS. In the multivariate analysis of model 2, RDW-CV > 12.6% (HR = 0.425, 95% CI: 0.230-0.783, P = 0.006), central tumor (HR = 0.307, 95% CI: 0.171-0.552, P < 0.001), and adjuvant therapy (HR = 0.481, 95% CI: 0.264-0.876, P = 0.017) were significantly associated with favorable OS. Because the SCC score was based on RDW-SD and RDW-CV, the multivariate analysis of the prognostic value of the SCC score included factors with a P < 0.1 in the univariate analysis, excluding RDW-SD and RDW-CV. The multivariate analysis showed that compared with SCC = 0, SCC = 1 (HR = 0.296, 95% CI: 0.153-0.571, P < 0.001) and SCC = 2 (HR = 0.270, 95% CI: 0.133-0.549, P < 0.001) were associated with favorable OS.
PFS analysis
In the univariate analysis, RDW-SD ≤ 40.2 fl (P = 0.047), T3-T4 stage (P = 0.017), lymph node metastasis (P < 0.001), multiple tumors (P = 0.018), preoperative CEA > 5 ng/mL (P < 0.001), ALT > 50 U/L (P = 0.019) and blood loss ≥300 mL (P = 0.008) were associated with worse PFS. RDW-CV (P = 0.579) and SCC score (P = 0.247) were not associated with PFS. The multivariate analysis showed that RDW-SD level was not an independent prognostic factor (Table 3).