College of American Pathologists Tumor Regression Grading System for Long-Term Outcome and Adjuvant Chemotherapy in Patients with Locally Advanced Rectal Cancer: Result from a Multicentre, Observational, Cohort Study

Background: NCCN's Rectal Cancer Guideline Panel recommends the American Joint Committee on Cancer and the College of American Pathologists tumor regression grading (AJCC/CAP TRG) system to evaluate pathologic response to neoadjuvant chemoradiotherapy (nCRT) for locally advanced rectal cancer (LARC). Yet, the clinical significance of AJCC/CAP TRG system has not been fully defined. Methods: This was a retrospectively designed, multicentre and prospectively maintained cohort study. Of which, LARC cases from one institution formed discovery cohort to determine the relationship between AJCC/CAP TRG system and overall survival (OS), disease free survival (DFS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS), as well as the risk of disease progression (death, disease relapse, local recurrence, and distant metastasis). Moreover, patients from other institutions formed the validation cohort. Kaplan-Meier survival functions were computed and the hazard ratios calculated, with the Cox regression hazards model. Findings: The discovery cohort (940 cases) found and validation cohort (2156 cases) further confirmed that the inferior AJCC/CAP TRG categories were closely correlated with an unfavorable OS, DFS, LRFS and DMFS, as well as a higher risk of disease progression (all P < 0·05). Significantly, the pairwise comparison revealed that any 2 of the 4 TRG categories had a distinguished survival (OS, DFS, LRFS and DMFS) ratio and risk of disease progression. In contrast, the similar findings were not observed at the ypT and ypN stage categories patients, as some two consecutive ypT and ypN categories patients had the comparable survival (OS, DFS, LRFS and DMFS) ratio and risk of disease progression. Importantly, after the propensity score matching, Kaplan-Meier analysis showed that the AJCC/CAP TRG0 category patients treated with or without adjuvant chemotherapy had a similar OS, DFS, LRFS and DMFS. Conversely, for the AJCC/CAP TRG1-3 categories cases, adjuvant chemotherapy treatment significantly improved the 3-year OS (90·2% vs. 84·6%, P < 0·001). Receiver operating characteristic and multivariate analysis demonstrated AJCC/CAP TRG system was an independent prognostic surrogate in discovery cohort and validation cohort (all P < 0·05). Interpretation: Based on one of the largest dataset, AJCC/CAP TRG system, a useful prognostic surrogate, appears ideal for further strategizing therapy after nCRT for LARC. Funding: National Natural Science Foundation of China, International Center for Genetic Engineering and Biotechnology grant. Declaration of Interest: All authors declare no competing interests. Ethical Approval: The Clinical Ethics Review Committee at the Sixth Affiliated Hospital of Sun Yat-sen University approved this study.