Predictors of Survival for Locally Advanced Rectal Cancer Patients With Poor Response to Neoadjuvant Chemoradiotherapy Publisher Pubmed



Kolahdouzan K ; Abyaneh R ; Barootchi E ; Zamani P ; Naseri S ; Mostakhdemin Hoseini S ; Nouranifar A ; Javid H ; Saraee E ; Ghalehtaki R
Source: Radiation Oncology Published:2026

Abstract

Background: Patients with locally advanced rectal cancer (LARC) who respond poorly to neoadjuvant chemoradiotherapy (nCRT) represent a high-risk subgroup with inferior survival, but specific prognostic factors for this group are unclear. This study aimed to identify independent predictors of survival outcomes exclusively in poor responders. Methods: This retrospective study included patients with LARC who exhibited a poor pathological response (ypT3-4 and/or ypN+) to nCRT between 2008 and 2024. The primary endpoint was overall survival (OS). Secondary endpoints were disease-free survival (DFS), locoregional recurrence-free survival (LRRFS), and distant metastasis-free survival (DMFS). Prognostic factors were analyzed using univariate and multivariate Cox proportional hazards models, with a significance threshold of p < 0.05. Results: Among 295 poor responders (mean age 55.48 ± 12.51 years, 63.4% male), 89.8% had ≥ypT3 and 38.6% had ypN+ disease after nCRT. The median follow-up time was 42 months. The median OS was 67.4 months (95% CI: 57.9–98.2), with an estimated 3-year OS rate of 74.7%. In univariate analysis for OS, significant predictors were: age (HR 1.021, p = 0.013), distance from AV (HR 0.93, p = 0.025), lymph node (LN) ratio (HR 3.36, p = 0.002), ypN2 status (HR 2.08, p = 0.015), involved surgical margin (HR 2.59, p = 0.002), and TRG 2–3 vs. 0–1 (HR 2.24, p = 0.031). Based on multivariate analysis, independent predictors for OS were age (HR 1.044, p = 0.002), involved margin (HR 6.18, p < 0.001), ypN2 status (HR 3.02, p = 0.012), and a higher number of dissected LNs (HR 0.92, p = 0.010). In multivariate analysis, surgical margin, ypN2 status, and number of dissected LNs remained independent predictors for DFS, LRRFS, and DMFS. Additionally, the presence of PNI was a predictor of worse DFS, and advanced age predicted poorer DFS and DMFS. Conclusions: In LARC patients who respond poorly to nCRT, survival is dominantly determined by surgical outcomes and the burden of resistant disease. Specifically, an involved resection margin, ypN2 status, and a low LN count are independent predictors of worse survival across all endpoints. These findings indicate that the quality of surgical resection is a critical modifiable factor for this high-risk group. Therefore, management should prioritize these patients for intensified adjuvant systemic therapy. Future efforts should develop preoperative tools to identify such high-risk patients earlier, enabling more aggressive neoadjuvant treatment. © The Author(s) 2026.