Total Neoadjuvant Therapy and Organ Preservation in Locally Advanced Rectal Cancer: A State-of-the-Art Systematic Review and Critical Appraisal

Evidence indicates that the management of locally advanced rectal cancer (LARC) has shifted from a surgery-centric model to a response-adaptive paradigm centered on total neoadjuvant therapy (TNT). This state-of-the-art review synthesizes contemporary evidence from 45 publications across 30 trials, critically evaluating TNT's efficacy, toxicity, impact on organ preservation (OP), and predictive biomarkers. We confirm that TNT (RAPIDO, PRODIGE 23, STELLAR) improves disease-free survival and reduces distant metastases versus standard chemoradiotherapy. The TNTCRT trial further demonstrated that long-course radiotherapy-based TNT with CAPOX significantly improves 3-year DFS (77.0% vs. 67.9%; HR 0.623) and pCR rates (27.5% vs. 9.9%). However, we critically examine trade-offs, including the increased locoregional recurrence risk observed in RAPIDO, which suggests that the choice between short-course radiotherapy (SCRT) and long-course chemoradiotherapy (LCRT) within TNT requires individualization. The Polish II trial long-term results showed no sustained OS benefit for SCRT with consolidation chemotherapy versus chemoradiation, with 8-year OS of 49% in both groups. While the integration of immune checkpoint inhibitors (UNION, STELLAR II, SPRING-01, PRECAM) has shown promising increases in pCR rates (approximately 40-60%) in MSS disease, we emphasize that these results remain hypothesis-generating and require confirmation in phase III trials before routine adoption. The SPRING-01 trial reported a pCR rate of 59.2% with SCRT plus sintilimab and CAPOX versus 32.7% without immunotherapy (p=0.015). Organ preservation is a durable outcome in expert centers (OPRA: 54% 5-year TME-free survival), but these results may not be immediately generalizable. The MONT-R trial demonstrated that adding oxaliplatin to nCRT enhanced tumor regression (CAP 0-1: 58.6% vs. 46.8%) but did not improve 3-year DFS or OS. A three-tier clinical response system (CCR/NCR/ICR) powerfully predicts OP success. The CINTS-R trial is evaluating ctDNA-guided precision neoadjuvant therapy, with interim analysis confirming feasibility and safety of risk-adapted TNT. Predictive factors for pCR include low CEA and small tumor size, while lateral pelvic lymph node involvement remains a negative prognostic factor. The GRECCAR 4 trial demonstrated that response-adapted strategies (good responders proceeding directly to surgery without additional CRT) are feasible. We conclude that while TNT is a preferred strategy for high-risk LARC, its application requires nuanced decision-making that balances systemic benefits against local control risks, acknowledges the investigational nature of emerging therapies, and considers the substantial infrastructure required for safe organ preservation.