Personalized Radiotherapy and Treatment Strategies for Locally Advanced Rectal Cancer: Early Outcomes of a Tailor-Made Total Neoadjuvant Therapy Protocol

Background/Objectives: The uniform application of total neoadjuvant therapy (TNT) for locally advanced rectal cancer (LARC) risks overtreatment and surgical complications. We evaluated a novel tailor-made therapy that personalizes radiotherapy and chemotherapy to balance oncological safety with organ preservation. Methods: We retrospectively analyzed 38 patients with cStage II–III LARC treated between 2023 and 2025. Patients were stratified by sphincter preservation feasibility and high systemic risk (cN2, extramural vascular invasion, lateral lymph node enlargement). Group A (sphincter-preserving, n = 20) received induction chemotherapy; long-course chemoradiotherapy (LCCRT) was omitted in favorable responders but added if MRF-positive or to aim for non-operative management (NOM) in exceptional responders. Group B (non-sphincter-preserving, low systemic risk, n = 8) received LCCRT plus consolidation chemotherapy. Group C (non-sphincter-preserving, high systemic risk, n = 10) received short-course radiotherapy plus consolidation chemotherapy. Results: Over a median observation period of 20 months (range, 6–37), NOM was initiated in 7 patients (18% overall; Group A: 10%, Group B: 50%, Group C: 10%), with one local regrowth observed to date, resulting in 6 of 7 patients (85.7%) successfully maintaining NOM. Preoperative radiotherapy was safely omitted in 32% of the total cohort, and notably in 60% of patients in Group A. Surgery was performed in 28 patients (74%), achieving an R0 resection rate of 100% across all groups. Distant metastasis recurrence during preoperative treatment occurred in 5 patients (13%). Risk-stratified, tailor-made therapy for LARC facilitates the highly customized application or omission of radiotherapy. Conclusions: Risk-stratified, tailor-made therapy facilitates the safe omission or targeted application of radiotherapy in LARC. This personalized approach prevents overtreatment, maintains complete surgical curability, and achieves successful organ preservation in appropriately selected patients.