Patient Risk Subgroups Predict Benefit of Adjuvant Chemotherapy in Stage II Rectal Cancer Patients Following Neoadjuvant Chemoradiation and Total Mesorectal Excision

Background: The benefit of adjuvant chemotherapy (AC) is unclear in stage II (cT3-T4 N0) rectal adenocarcinoma (RAC) after neoadjuvant chemoradiation (NCRT) and total mesorectal excision (TME). We aim to identify pathologic factors that influence overall survival (OS) and stratify patients into risk profiles to assess the AC benefit within each profile.

Patients and methods: The National Cancer Database for rectal cancer was utilized to identify patients with stage II RAC who completed NCRT and TME. Cox multivariable analysis was used to identify pathologic predictors of 5-year OS, which were then used to construct a nomogram and stratify patients into low-, intermediate-, and high-risk subgroups. Propensity score matching was applied for the receipt of AC within each risk stratum, and Kaplan-Meier analysis was used to measure 5-year OS.

Results: We identified 3570 patients who met the inclusion criteria. Inadequate lymphadenectomy (<12), poor differentiation, involved distal margin, involved circumferential margin, perineural invasion, and absence of T-downstaging after NCRT were identified as unfavorable predictors of 5-year OS and were used to construct the nomogram. Kaplan-Meier analysis of the matched patients demonstrated the absolute 5-year survival benefits for each risk stratum as follows: 4% for low-risk patients (hazard ratio (HR) = 0.869; [0.651-1.021]; P = .062), 26% for intermediate-risk patients (HR, 0.249; [0.133-0.468]; P < .001), and 10% in high-risk patients (HR = 0.633 [0.427-0.940]; P = .024).

Conclusions: The survival benefit of AC for clinical stage II RAC following NCRT and TME is most pronounced among intermediate- and high-risk patients as determined by our nomogram. Risk-adaptive AC may be appropriate for selected patients by integrating standard reported pathologic elements into the treatment plan.