RESIDUAL NODAL DISEASE AFTER TOTAL NEOADJUVANT THERAPY AND SURGICAL RESECTION FOR RECTAL CANCER: PROGNOSTIC IMPLICATIONS BEYOND PRIMARY TUMOR RESPONSE

Abstract

Background: Total neoadjuvant therapy (TNT) improves major and complete primary tumour response in locally advanced rectal cancer but regression of the rectal wall does not necessarily equate with eradication of regional nodal disease. Goal: To review and synthesize the literature on RPND after neoadjuvant therapy and surgical resection in a critical manner with an emphasis on the prognostic information not provided by the response of the primary tumor. Methods: A focused narrative review was conducted in the databases of PubMed/MEDLINE, Scopus, Web of Science and Google Scholar. Searches were updated on 19 September 2026 and included terms for rectal cancer, total neoadjuvant therapy, neoadjuvant chemoradiotherapy, ypT0, ypN, lymph-node metastasis, nodal regression, magnetic resonance imaging, watch-and-wait, tumour deposits and circulating tumour DNA. Randomized trials of TNT, systematic reviews, guidelines, and cohort studies reporting post-treatment nodal status or oncologic outcomes were prioritized. Historical chemoradiotherapy cohorts were included when they were relevant to the study of ypT0N positive disease, but were separately analyzed from modern TNT era data. Results: A meta analysis estimated residual nodal metastasis in around 4.6% of patients who achieved complete response (CR) to neoadjuvant chemoradiotherapy (nCRT) [6]. There were 44 patients with ypT0N1–2 disease in the 2025 cohort of 457 ypT0 patients; the 5-year disease-free survival rate was 84.8% for ypT0N0 and 68.4% for ypT0N1–2, with residual nodal disease independently predicting disease-free survival (adjusted hazard ratio 2.285, 95% CI 1.246–4.192); the overall survival was not significantly different (93.9% vs 88.8%) [12]. A 2025 pathologic study revealed that 29 of 503 patients had ypT0N-positive disease (5.8%), and that histologic regression of the lymph node (LR) was an independent predictor of occult nodal metastasis (odds ratio 4.11, 95% confidence interval 1.71–9.52) [23]. Restaging MRI is still not entirely accurate to rule out microscopic residual nodal disease [15]. Conclusions: In addition to primary-tumour regression, residual nodal disease seems to offer a poor prognosticator of recurrence and disease-free survival. But optimal management in the 21st century after TNT and the effect size after TNT are still unknown as a lot of evidence is retrospective or from before the era of TNT. The postoperative risk assessment should therefore take into account ypN status together with ypT category, margins, tumor deposits, lymphovascular invasion, perineural invasion and other features of residual disease; and molecular residual-disease strategies are investigational.