Total Neoadjuvant Therapy Outcomes and Watch-and-Wait Feasibility in Locally Advanced Rectal Cancer: A Single-Institution Retrospective Cohort Study

Background/Objectives: Total neoadjuvant therapy (TNT), integrating systemic chemotherapy and radiotherapy before surgery or surveillance, has become a standard approach for locally advanced rectal cancer (LARC). However, optimal sequencing strategies and long-term outcomes of watch-and-wait (W&W) following sandwich TNT remain insufficiently characterized. We evaluated oncologic outcomes and treatment response in patients treated with an institutional sandwich TNT protocol. Methods: We conducted a retrospective cohort study of consecutive patients with LARC treated with sandwich TNT (induction chemotherapy followed by hypofrac-tionated intensity-modulated radiotherapy with simultaneous integrated boost [IMRT-SIB] chemoradiotherapy and consolidation chemotherapy) at the Institute of Oncology Ljubljana between 2016 and 2023. The primary endpoint was an overall complete response (CR; pathological [pCR] and clinical [cCR]). Secondary endpoints included tumor regression grade (TRG), major pathological response (MPR), R0 resec-tion rate, organ preservation, overall survival (OS), and disease-free survival (DFS). Results: Among 205 patients (median age 61 years), overall CR was 29.5% (pCR 19.3% and cCR 10.2%). Major pathological response (TRG 3–4) occurred in 37.6%. R0 resec-tion was achieved in 94.5%. In the W&W cohort (n=21), local regrowth occurred in 33.3% (95% CI 14.6–57.0%) over a median follow-up of 4.96 years. Surgery-free sur-vival at 5 years was 73.1% (95% CI 55.0–97.2%). Estimated five-year OS was 81.1% (95% CI 75.5–87.2%) and 5-year DFS was 75.2% (95% CI 69.0–82.0%). In multivariable analysis, non-R0 resection (HR 6.06), MRI circumferential resection margin positivity (HR 3.11), and extramural vascular invasion positivity (HR 1.97) remained independ-ent predictors of DFS. Conclusions: Sandwich TNT yields meaningful tumor response and durable survival in MRI-defined high-risk LARC. Structured W&W offers organ preservation with acceptable oncologic control under intensive surveillance.