Tailoring Rectal Cancer Treatment: Total Neoadjuvant Therapy and the Shift Towards Organ Preservation

Locally advanced rectal cancer (LARC) remains a significant clinical challenge due to the risks of distant metastasis and treatment-related functional morbidity. Although total mesorectal excision (TME) combined with neoadjuvant chemoradiotherapy (CRT) has achieved excellent locoregional control, limitations in systemic disease control and quality-of-life outcomes have driven the evolution of treatment strategies beyond surgery-centred approaches. Total neoadjuvant therapy (TNT) integrates systemic chemotherapy and radiotherapy entirely within the preoperative phase to improve treatment compliance, enhance tumour regression, and provide earlier control of micrometastatic disease. This strategy has enabled selective organ preservation through nonoperative management (NOM) and watch-and-wait (WW) approaches in patients achieving a clinical complete response. Evidence from landmark trials such as RAPIDO, PRODIGE-23, OPRA, STELLAR, and the recently reported NO-CUT study supports the oncologic efficacy of TNT, while underscoring the importance of appropriate patient selection, treatment sequencing, and structured surveillance. Beyond summarising trial outcomes, this review provides a practical, clinician-oriented framework for contemporary rectal cancer management. We emphasise MRI-based risk stratification to guide selection for TNT, discuss evidence-based sequencing when organ preservation is intended, outline standardised criteria for response assessment, and translate available data into a pragmatic surveillance protocol, with attention to real-world feasibility and resource-limited settings. The review also critically appraises emerging technologies, including adaptive and MR-guided radiotherapy, dose-escalation strategies, circulating tumour DNA, and evolving molecular biomarkers, highlighting their potential roles and current limitations. Overall, this review contextualises TNT within modern rectal cancer care, balancing oncologic safety, functional preservation, and practical implementation.