High-Grade Inflammation Attenuates Chemosensitivity and Confers to Poor Survival of Surgical Stage III CRC Patients

Abstract

Background: Heterogeneous clinical and molecular characteristics are reported in colorectal cancer (CRC) with different tumor laterality. However, the outcome of left- and right-sided patients with stage I–III CRC and the role of chronic inflammation in survival differences between them remain unclear.Method: A prospective study including 1,181 surgical patients with stage I–III CRC was carried out to investigate the involvement of circulating fibrinogen-to-pre-albumin (Alb) ratio (FPR) and primary tumor sidedness in the clinical outcome of those patients. We further investigated the effect of FPR on adjuvant chemotherapy response and recurrence in stage III patients.Results: Our study showed that the right tumor location was significantly associated with poor recurrence-free survival (RFS) (p = 0.04, adjusted HR = 1.41, 95% CI = 1.02–1.94) and overall survival (OS) (p = 0.04, adjusted HR = 1.55, 95% CI = 1.01–2.38) only in the stage III disease. In these patients, T4 stage distribution (83.39 vs. 70.94%, p < 0.01) within right-sided cases was significantly higher than left-sided patients. Moreover, preoperative FPR within right-sidedness (p < 0.01), T4 stage (p < 0.05), and large cancer bulk (≥5 cm) (p < 0.05) subgroups was significantly elevated compared to their counterparts, and it was gradually rising following the increased cancer bulk (p trend < 0.01). High-FPR distribution (52.30 vs. 27.00%, p < 0.01) within right-sided patients with the stage III disease was significantly higher than that in the left-sided cases. RFS (plog−rank < 0.01) and OS (plog−rank < 0.01) of the high-FPR patients were extremely inferior to the low-FPR cases, and the significant associations were observed when they were adjusted by other confounders including primary tumor location (p < 0.01, adjusted HR = 1.96, 95% CI = 1.42–2.70 for RFS; p < 0.01, adjusted HR = 2.44, 95% CI = 1.59–3.75 for OS). Additionally, RFS of adjuvant chemotherapy-treated high-FPR patients was superior to the patients without chemotherapy (plog−rank = 0.01) but was inferior to the low-FPR patients undergoing the treatment, especially in the 5-FU- and XELOX-treated subgroup.Conclusion: These findings indicate that chronic high-grade inflammation weakens chemotherapy efficacy and contributes to the poor prognosis of stage III surgical CRC patients.

Prognostic Factors Influencing Survival in Stage II and Stage III Colorectal Cancer Patients

“…These findings are concordant with the results of Dienstmann et al who investigated stage II-III CRC patients and showed a significant decrease in survival rates in stage III CRC patients, which was accompanied by lymph node metastasis [ 15 ]. Furthermore, Ying et al, in their study of 1,181 stage I-III CRC patients, showed that persistent high inflammation levels reduce the effectiveness of chemotherapy and play a role in the unfavorable outlook for individuals with stage III surgical CRC [ 16 ].…”

Recent Advances in Fibrinogen Research in Colorectal Cancer

“…Therefore, FPR can be used as an indicator to differentiate eligible patients for chemotherapy and predict chemotherapy efficacy [35]. A prospective study of 1181 patients undergoing surgery for stage I-III CRC showed that patients with high FPR had a lower survival rate after chemotherapy than patients with low FPR on the same course of treatment, but better than those who did not undergo chemotherapy after surgical resection, and concluded that chronic high-intensity inflammation could reduce the sensitivity of chemotherapy and lead to a poor prognosis for patients with stage III CRC, providing a basis for targeted anti-inflammatory therapy combined with adjuvant chemotherapy, provide new ideas for the clinical application of targeted anti-inflammatory therapy in patients with high FPR [36].…”