Clinical advancements in total neoadjuvant therapy for locally advanced rectal cancer: a narrative review

Background and Objective: Total neoadjuvant therapy (TNT), which integrates systemic chemotherapy and chemoradiotherapy before surgery, has been shown to improve pathological complete response (pCR) rates and treatment compliance compared to traditional postoperative strategies in locally advanced rectal cancer (LARC). Landmark phase II and III trials have explored various TNT approaches, differing in chemotherapy regimens, radiotherapy (RT) schedules, and surgical timing. However, due to substantial heterogeneity across these studies, it remains challenging to define a single, optimal TNT strategy suitable for all patients. Our aim is to analyze the current evidence to tailor TNT strategies. Methods: We conducted a comprehensive literature review using the PubMed database, applying the advanced search tool with filters set for studies published between 2015 and 2025. The search strategy included a combination of free-text terms and MeSH keywords related to “rectal cancer”, “locally advanced”, and “total neoadjuvant therapy”. Key Content and Findings: This review summarizes the clinical evidence supporting TNT in LARC, highlights key trials shaping current practice, and discusses emerging strategies such as organ preservation, immunotherapy, and biomarker-driven approaches. We analyzed both phase II and III trials validating the role of TNT, exploring the advantages and limitations of each strategy. We also evaluated the feasibility of treatment de-escalation, particularly for low-risk patients and those with microsatellite instability (MSI) or deficient mismatch repair (dMMR). Moreover, we emphasized the predictive value of pCR in identifying candidates for organ preservation strategies aimed at reducing the long-term toxicities associated with surgery and RT. Finally, based on the available evidence, we proposed a clinical algorithm to guide treatment decision-making in clinical practice. Conclusions: Further refinement of TNT strategies is necessary, especially in tailoring treatment intensity, identifying candidates for RT omission, and selecting patients suitable for non-operative management (NOM). Circulating tumor DNA (ctDNA) is emerging as a promising biomarker for real-time assessment of minimal residual disease (MRD), potentially enabling personalized treatment adjustments. However, its routine clinical application requires validation in prospective trials.