Reconsidering the TNM stage in non-metastatic colorectal cancer according to the survival paradox

There was a survival paradox in the AJCC TNM staging manual for colorectal cancer (CRC) - some patients at later stages have a better prognosis than those at earlier stages. We aimed to reveal the main causes of this phenomena.

We conducted a retrospective study using data on 73,804 non-metastatic colorectal cancer cases obtained from the SEER database and 1192 stage IIB/C and IIIA colorectal cancer cases obtained from the local database of Zhejiang Cancer Hospital, all of whom were patients who had undergone surgery between 2010 and 2019.The primary endpoint was overall survival. Overall survival was assessed using Kaplan-Meier curves and cox regression analysis, and prognosis for each stage under similar conditions was explored using propensity matching analysis.

The subgroups with survival paradoxes are between stage IIB/C and IIIA, between stage IIA and IIIA, and between T4N0 (stage IIB/C) and T3N1 (stage IIIB) in the SEER database. Multivariate Cox regression analysis showed that stage IIB/C vs stage IIIA: hazard ratio (HR)=0.63 (95% confidence interval (95% CI)：0.56∼0.71) p＜0.001; stage IIA vs stage IIIA:HR=1.18 (95%CI：1.07∼1.31) p=0.001; stage T4N0 vs stage T3N1：HR=0.96 (95%CI：0.90∼1.03) p=0.249. Among patients without chemotherapy, stage IIA survival is better than stage IIIA and the prognosis of T4N0 stage is better than that of T3N1 stage，but chemotherapy is followed by the opposite. After PSM analysis, it was shown that stage IIB/C vs stage IIIA：HR=0.70 (95%CI：0.60∼0.81) p＜0.001;stage IIA vs stage IIIA：HR=1.20 (95%CI：1.04∼1.37) p=0.012;stage T4N0 vs stage T3N1：HR=0.93(95%CI：0.86∼1.01) p=0.102. In the data of Zhejiang Cancer Hospital, the survival paradox between stage IIB/C and stage IIIA was verified (HR=0.59(0.42∼0.83) p=0.002), and chemotherapy and microsatellite instability status were not the main factors contributing to it.

In non-metastatic colorectal cancer, the survival paradox exists not only between stages IIB/C and IIIA, but also between stages IIA and IIIA, and between stages T4N0 and T3N1. The causes of the survival paradox are multifactorial, but the main cause is chemotherapy and the imbalance between the weight of T and N scores. Therefore, it is of great significance to accurately screen colorectal cancer patients requiring chemotherapy in stage II and continuously improve the TNM staging system for the survival and prognosis of colorectal cancer patients.

The authors.

This work was supported by Zhejiang University of Chinese Medicine Graduate Research Fund Project (Y202248750) and the Medical Health Science and Technology Project of Zhejiang Province (2021KY104).

All authors have declared no conflicts of interest.