College of American Pathologists Tumor Regression Grading System for Long-Term Outcome in Patients with Locally Advanced Rectal Cancer
Authors: Chen Hai-Yang , Feng Li-Li , Li Ming , Ju Huai-Qiang , Ding Yi , Lan Mei , Song Shu-Mei , Han Wei-Dong , Yu Li , Wei Ming-Biao , Pang Xiao-Lin , He Fang , Liu Shuai , Zheng Jian , Ma Yan , Lin Chu-Yang , Lan Ping , Huang Mei-Jin , Zou Yi-Feng , Yang Zu-Li , Wang Ting , Lang Jin-Yi , Orangio Guy R. , Poylin Vitaliy , Ajani Jaffer A , Wang Wei-Hu , Wan Xiang-Bo 
Published: February 2021

Abstract

Background
The National Comprehensive Cancer Network's Rectal Cancer Guideline Panel recommends American Joint Committee of Cancer and College of American Pathologists (AJCC/CAP) tumor regression grading (TRG) system to evaluate pathologic response to neoadjuvant chemoradiotherapy for locally advanced rectal cancer (LARC). Yet, the clinical significance of the AJCC/CAP TRG system has not been fully defined.

Materials and Methods
This was a multicenter, retrospectively recruited, and prospectively maintained cohort study. Patients with LARC from one institution formed the discovery set, and cases from external independent institutions formed a validation set to verify the findings from discovery set. Overall survival (OS), disease-free survival (DFS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were assessed by Kaplan-Meier analysis, log-rank test, and Cox regression model.

Results
The discovery set (940 cases) found, and the validation set (2,156 cases) further confirmed, that inferior AJCC/CAP TRG categories were closely /ccorrelated with unfavorable survival (OS, DFS, LRFS, and DMFS) and higher risk of disease progression (death, accumulative relapse, local recurrence, and distant metastasis) (all p &lt; .05). Significantly, pairwise comparison revealed that any two of four TRG categories had the distinguished survival and risk of disease progression. After propensity score matching, AJCC/CAP TRG0 category (pathological complete response) patients treated with or without adjuvant chemotherapy displayed similar survival of OS, DFS, LRFS, and DMFS (all p &gt; .05). For AJCC/CAP TRG1–3 cases, adjuvant chemotherapy treatment significantly improved 3-year OS (90.2% vs. 84.6%, p &lt; .001). Multivariate analysis demonstrated the AJCC/CAP TRG system was an independent prognostic surrogate.

Conclusion
AJCC/CAP TRG system, an accurate prognostic surrogate, appears ideal for further strategizing adjuvant chemotherapy for LARC.

Implications for Practice
The National Comprehensive Cancer Network recommends the American Joint Committee of Cancer and College of American Pathologists (AJCC/CAP) tumor regression grading (TRG) four-category system to evaluate the pathologic response to neoadjuvant treatment for patients with locally advanced rectal cancer; however, the clinical significance of the AJCC/CAP TRG system has not yet been clearly addressed. This study found, for the first time, that any two of four AJCC/CAP TRG categories had the distinguished long-term survival outcome. Importantly, adjuvant chemotherapy may improve the 3-year overall survival for AJCC/CAP TRG1–3 category patients but not for AJCC/CAP TRG0 category patients. Thus, AJCC/CAP TRG system, an accurate surrogate of long-term survival outcome, is useful in guiding adjuvant chemotherapy management for rectal cancer.