Nomograms incorporated serum direct bilirubin level for predicting prognosis in stages II and III colorectal cancer after radical resection

Abstract

An elevated serum bilirubin has been reported to be associated with a reduced risk of some cancer; however, the prognostic significance of serum bilirubin in colorectal cancer wasn't fully understood. The purpose of this study was to evaluate whether serum bilirubin could predict the prognosis of patients in stages II and III colorectal cancer. A retrospective cohort of 986 patients with colorectal cancer who received surgical resection between January 2005 and December 2010 was included in the study. Levels for serum bilirubin were obtained from medical records. Survival analysis was used to evaluate the predictive value of bilirubin. Serum direct bilirubin (DBIL) was validated as a significant prognostic factor by univariate cox regression test for both overall survival (OS) and disease free survival (DFS) (P < 0.05). X-tile program identified 3.6 as optimal cutoff values for DBIL in terms of OS and DFS. Patients were then divided into DBIL high (DBIL ≥ 3.60 μmol/l) and low group (DBIL < 3.60 μmol/l) according to the optimal cutoff. High DBIL had higher percentage of lymph node metastasis and lymphovascular invasion as compared with low DBIL levels (P < 0.05). Multivariate cox regression analyses confirmed that high DBIL level was an independently prognostic factor for both OS (HR: 1.337, 95% CI: 1.022-1.748, P = 0.034) and DFS (HR: 1.312, 95% CI: 1.049-1.643, P = 0.018). In addition, nomograms on OS and DFS were established according to all significant factors, and c-indexes were 0.715 (95% CI: 0.683-0.748) and 0.704 (95% CI: 0.678-0.730), respectively. Nomograms based on OS and DFS can be recommended as practical models to evaluate prognosis for CRC patients.

Keywords: colorectal cancer; direct bilirubin; surgery; survival analysis.

Figure 1. X-tile analyses of 5-year OS and DFS were performed using patients’ data to determine the optimal cut-off value for DBIL

The sample of CRC patients was equally divided into training and validation sets. X-tile plots of training sets are shown in the left panels, with plots of matched validation sets shown in the smaller inset. The optimal cut-off values highlighted by the black circles in left panels are shown in histograms of the entire cohort (middle panels), and Kaplan-Meier plots are displayed in right panels. P values were determined by using the cut-off values defined in training sets and applying them to validation sets. The optimal cut-off value for DBIL in terms of OS and DFS happens to be 3.6 μmol/l.

Figure 2. Nomograms conveyed the results of prognostic models using clinicopathological characteristics and pretreatment inflammatory biomarkers to predict OS (A) and DFS (B) of patients with CRC

Nomograms can be interpreted by summing up the points assigned to each variable, which is indicated at the top of scale. The total points can be converted to predicted 5-year probability of death and recurrence or metastasis for a patient in the lowest scale. The Harrell’s c-indexes for OS and DFS prediction were 0.715 (95% CI: 0.683–0.748) and 0.704 (95% CI: 0.678–0.730), respectively. Calibration curves for 5-year OS (C) and 5-year DFS (D) using nomograms with clinicopathological characteristics and pretreatment inflammatory biomarkers are shown. The x-axis is nomogram-predicted probability of survival and y-axis is actual survival. The reference line is 45 degree and indicates perfect calibration.