Prognostic and diagnostic role of peri-operative inflammatory markers in colorectal cancer

Background and objectives: The relationship between chronic inflammation and tumorigenesis has been largely investigated, and tumor-promoting inflammation proposed as an ‘enabling characteristic’ for tumor development. Also, it is increasingly recognized that the outcome of oncological patients depends not only on the intrinsic characteristics of the tumour, but also on the host immune-response and its ability to recognize and destroy tumour cells before escape. The aim of this study was to evaluate if changes in circulating immune cells occurs before the diagnosis of colorectal cancer (CRC), and to assess their relationship with survival outcomes. Moreover, we investigated if peri-operative inflammation influences long-term outcomes. Materials and methods: Consecutive patients undergoing surgery for CRC at a single center were assessed for inclusion. The longitudinal changes in immune cell profile were evaluated in patients undergoing surgery for all stages (2005-2020) with a minimum follow-up of 24 months. For each patient a complete blood count (Pre-CBC) dated at least 24 months before surgery was retrieved. All parameters of Pre-CBC were tested for potential associations with survival after surgery. To evaluate the role of peri-operative inflammation, the analysis was restricted to patients submitted to elective minimally invasive potentially curative (R0-1) surgery for stage I-III CRC (2005-2022). Patients were categorized in a high-CRP (H-CRP) and low-CRP (L-CRP) group according to the highest value of post-operative CRP. Peri-operative outcomes, long-term survival and recurrence rates were compared between the two groups. Results: Pre-CBC was available for 334 patients. Pre-Leukocyte (Pre-Leu), Pre-Neutrophils (Pre-Neut), and Pre-neutrophils-to-lymphocyte ratio (Pre-NLR) showed an increasing trend approaching the date of diagnosis, while Pre-Lymphocyte (Pre-Lymph) tended to decrease. On multivariate Cox regression analysis, Pre-Leu, Pre-Neut, Pre-Lymph and Pre-NLR resulted independent prognostic factors for OS and CSS, with pathological stage and age. Higher Pre-Leu, Pre-Neut, and Pre-NLR and lower Pre-Lymph were associated with worse CSS, and the effect was more evident when blood samples were closer to surgery. Considering peri-operative inflammation, 436 patients with stage I-III CRC were included in the analysis. According to ROC analysis for recurrence, the optimum cut-off for postoperative CRP was 151.5 mg/L (AUC = 0.599). Patients who developed a recurrence showed a higher CRPmax compared to patients without recurrence (170.8 versus 136.8 mg/L, p = 0.019). OS (p < 0.001), RFS (p = 0.005), and CSS (p = 0.001) were significantly worse in patients in the H-CRP group. When conducting subgroup analysis for stage, the results were confirmed only in stage III CRC. Considering pT, no differences in OS, RFS and CSS were found in patients with early pT, while the difference remained statistically significant for pT3 and pT4. On multivariate analysis, H-CRP proved to be an independent risk factor for recurrence (p = 0.007), together with rectal location of the tumor (p < 0.001), presence of lympho-vascular invasion (p = 0.027), and stage III (p = 0.007). Conclusions: Changes in circulating immune cells could be detected as early as 24 months before the diagnosis of CRC, and this may represent an important window of opportunity for early diagnosis. Moreover, we demonstrated a significant association between early changes in circulating immune cells, OS, and CSS, reinforcing the body of evidence that suggests a bidirectional relationship between the tumor and the immune system. Our study also highlighted the potential role of surgical stress as tumor-promoting inflammation identifying post-operative CRP peak as a negative prognostic factor for OS, CSS, and RFS.