Total neoadjuvant therapy for organ preservation in rectal cancer: Interpreting heterogeneous trial evidence

Total neoadjuvant therapy (TNT) in locally advanced rectal cancer (LARC) aims to improve disease control and increase opportunities for organ preservation. However, interpretation and comparison of outcomes across TNT trials remain challenging due to heterogeneity in study design, treatment sequencing, and the timing and methodology of response assessment. This narrative review examines key prospective clinical trials evaluating TNT strategies in rectal cancer, focusing on factors that influence organ preservation outcomes. Rather than critically appraising individual trials, the review highlights how differences in radiotherapy regimens, chemotherapy sequencing, inclusion criteria, response assessment strategies, and clinical endpoints contribute to heterogeneity across studies. These methodological differences complicate interpretation and limit direct comparison of reported response and organ-preservation rates when translating TNT strategies into clinical practice. Future progress will depend on improved methodological standardization and patient-centered trial design. Harmonized definitions of clinical complete response (cCR) and sustained cCR, standardized timing and methodology of response assessment, and integration of patient-reported outcomes are required to enable meaningful comparison between TNT strategies. Aligning oncologic safety with functional preservation and quality of life represents the next critical step in advancing individualized rectal cancer care.