Advances in the management of locally advanced rectal cancer: A shift toward a patient-centred approach to balance outcomes and quality of life

Abstract

The treatment of locally advanced rectal cancer (LARC) has undergone a significant evolution in recent years, shifting toward more selective strategies that balance oncological outcomes with quality of life (QoL) preservation. Total neoadjuvant treatment (TNT) has improved local control and reduced distant metastases, but its long-term toxicities have sparked growing interest in treatment de-escalation strategies aimed at minimizing adverse effects while maintaining efficacy. This review focuses on the therapeutic advancements for LARC, analysing both established standards and emerging innovations. We discuss the increasing adoption of organ-preserving approaches, particularly the Watch-and-Wait (WW) strategy for patients achieving a clinical complete response (cCR), and potentially the selective omission of radiotherapy in well-defined cases. Additionally, we explore and examine less invasive surgical techniques that preserve function without compromising cure rates. Beyond standard treatment approaches, we highlight the role of immunotherapy, particularly its breakthrough efficacy in LARC with deficient mismatch repair/microsatellite instability (dMMR/MSI), leading to the concept of immune-ablation: achieving complete tumor regression while sparing patients from chemotherapy, radiotherapy, and surgery. Ongoing research is investigating immunotherapy's potential role also in proficient mismatch repair/microsatellite stable (pMMR/MSS) LARC. Finally, we discuss emerging predictive biomarkers, such as circulating tumor DNA (ctDNA) and radiomics, which might refine patient selection and guide treatment individualization. The future of LARC management lies in a precision-driven approach, where survival is optimized without compromising QoL. By embracing innovation and personalizing care, we are entering a new era where cure remains paramount, but never at the expense of the patient's well-being.

Keywords: Immunotherapy; Locally advanced rectal cancer; Organ preservation; Total neoadjuvant treatment; Treatment de-escalation; Watch-and-wait.