Intertwined leukocyte balances in tumours and peripheral blood as robust predictors of right and left colorectal cancer survival

ARTICLE HIGHLIGHTS

Research background

Colorectal cancer (CRC) points to 9.4% of cancer deaths worldwide, ranking second after lung cancer. Despite the wide variety of factors tested to predict their outcome, most patients with similar variables show big differences in survival. Moreover, right-sided CRC (RCRC) and left-sided CRC (LCRC) patients exhibit large differences in outcome after surgical intervention as assessed by preoperative blood leukocyte ratios [today, the most extended parameters used to assess a patient’s overall survival (OS) and recurrence-free survival (RFS) after surgery]. However, few efforts have been made to link tumour infiltrated leukocyte ratios to patient outcomes.

Research motivation

To determine whether both RCRC and LCRC patient outcomes could be accurately predicted based on the counting of infiltrated leukocytes in tumour and peritumoural tissues.

Research objectives

The aim of this study was to find stronger indexes than circulating (blood) leukocyte ratios to predict RCRC and LCRC patient outcomes.

Research methods

A prospective study was performed with CRC patients who had undergone surgical intervention to resect the tumours. Leukocyte concentrations in peripheral blood, tumour, and non-neoplastic peritumoural tissues were determined. Ratios of these parameters were evaluated as predictors for OS and RFS using Spearman correlations, Cox univariate and multivariate proportional hazards regression followed by the calculation of the receiver-operating characteristic and area under the curve (AUC) and the determination of Youden’s optimal cutoff values for those variables that significantly correlated with either RCRC or LCRC patient outcomes. Clinician-friendly nomograms were developed to predict OS and RFS from the prediction indexes. The accuracy of the model was evaluated using calibration and validation analyses.

Research results

We obtained six robust predictors of worse OS in RCRC: CD8⁺ lymphocyte content in peritumour (CD8_pt, AUC = 0.585, cutoff < 8.250, P = 0.0077), total lymphocyte content in peritumour (CD4CD8_pt, AUC = 0.550, cutoff < 10.160, P = 0.0188), lymphocyte-to-monocyte ratio in peritumour (LMR_pt, AUC = 0.807, cutoff < 3.185, P = 0.0028), CD8⁺ LMR in peritumour (CD8MR_pt, AUC = 0.757, cutoff < 1.650, P = 0.0007), the ratio of blood LMR to LMR in peritumour (LMR_b/LMR_pt, AUC = 0.672, cutoff > 0.985, P = 0.0244), and the ratio of blood LMR to CD8⁺ LMR in peritumour (LMR_b/CD8MR_pt, AUC = 0.601, cutoff > 1.485, P = 0.0101). In addition, three robust predictors of worse RFS in RCRC were found: LMR_pt (AUC = 0.737, cutoff < 3.185, P = 0.0046), LMR_b/LMR_pt (AUC = 0.678, cutoff > 0.985, P = 0.0155), and LMR_b/CD8MR_pt (AUC = 0.615, cutoff > 1.485, P = 0.0141). Furthermore, the ratio of blood LMR to CD4⁺ LMR in peritumour (LMR_b/CD4MR_pt, AUC = 0.786, cutoff > 10.570, P = 0.0416) was found to robustly predict poorer OS in LCRC patients. The developed nomograms to predict OS and RFS of RCRC patients showed C-indexes of 0.600 (95% confidence interval: 0.561-0.639) and 0.605 (95% confidence interval: 0.579-0.631), respectively.

Research conclusions

Easily obtainable variables at preoperative consultation, defining the status of leukocyte balances between peripheral blood and peritumoural tissue, have been shown to render indexes that accurately predict OS and RFS of CRC patients after surgical ablation of the tumours.

Research perspectives

We hope these indexes could be implemented in the first line of prognosis, making it easier to predict the outcome of patients after surgery depending on the tumour location and leukocyte distribution in both peripheral blood and biopsies of the peritumoural region.