Paradigm Shift in the Management of Locally Advanced Rectal Cancer: Role of PreoperativeRadiotherapy and Total Neoadjuvant Therapy

Abstract

Rectal cancer ranks among the most common malignancies globally, with significant challenges in local recurrence and systemic failure despite advances in treatment. Historically, surgeryalone was associated with recurrence rates as high as 20–50%, but the integration of preoperative radiotherapy has markedly improved outcomes by reducing recurrence and enablingsphincter preservation. Evidence from landmark trials, including the Swedish, Dutch, and German CAO/ARO/AIO-94 studies, established preoperative radiotherapy and chemoradiotherapyas standards of care. Comparative analyses of short-course radiotherapy (SCRT) and long-course chemoradiotherapy (LC-CRT) demonstrate comparable long-term outcomes, though LC-CRT may be preferable in advanced, distal tumors, while SCRT offers a pragmatic option for smaller, proximal lesions. Persistent systemic failures prompted the adoption of totalneoadjuvant therapy (TNT), shifting chemotherapy to the preoperative setting. Trials such as PRODIGE 23 and RAPIDO have confirmed TNT’s ability to improve compliance, pathologicalcomplete response rates, disease-free survival, and distant metastasis control compared to conventional strategies. Both induction- and consolidation-based TNT regimens have shownefficacy, particularly in high-risk locally advanced rectal cancer (LARC) patients. While organ preservation strategies such as watch-and-wait are being investigated, current evidencesupports TNT combined with total mesorectal excision as a robust paradigm shift in LARC management, offering improved oncological outcomes and patient adherence.