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 < .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 > .05). For AJCC/CAP TRG1–3 cases, adjuvant chemotherapy treatment significantly improved 3‐year OS (90.2% vs. 84.6%, p < .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.

Neoadjuvant chemoradiotherapy (nCRT) followed by total mesorectal excision and adjuvant chemotherapy is the standard regimen for patients with locally advanced rectal cancer (LARC). However, whether and to which extent neoadjuvant radiotherapy could be removed from nCRT for patients with LARC is still unclear. This was a multicenter, retrospectively recruited, prospectively maintained cohort study. A propensity score matching model was employed to minimize potential confounding factors between subgroup patients treated with neoadjuvant chemotherapy (nCT) or nCRT. Overall survival (OS), disease‐free survival (DFS), local recurrence‐free survival (LRFS), and distant metastasis‐free survival (DMFS) were assessed between subgroup patients by Kaplan‐Meier analysis, log‐rank test, and Cox regression model. In total, 3233 consecutive patients, consist of 571 nCT and 2662 nCRT‐treated cases, were included. After propensity score matching (1:4), 565 nCT‐treated patients were matched to 1852 nCRT‐treated patients. Compared with nCT, nCRT treatment indeed decreased 3‐y local recurrence (10.0% vs 6.6%, P = .026), but had no impact on OS, DFS and DMFS (all P > .05) for LARC. Stratified analysis further confirmed that nCRT treatment was associated with higher 3‐y LRFS and 3‐y DFS than nCT treatment for baseline high‐risk subgroup (cT4, cN+, and cIII stage) patients (all P < .05). Conversely, for the baseline low‐risk subgroup patients (cT3, cN0, and cII stage), nCRT and nCT treatment had similar 3‐y OS, LRFS, DFS, and DMFS (all P > .05). The administration of neoadjuvant radiotherapy for LARC patients might be determined by baseline risk classification, the high‐risk individuals could be delivered while low‐risk patients might be omitted.