Total neoadjuvant therapy for rectal cancer: where are we now, where do we go?

Total neoadjuvant therapy (TNT) refers to the addition of an entire course of preoperative systemic therapy to short-course radiotherapy (SCRT; 5 × 5 Gy) or chemoradiation (CRT), either as induction chemotherapy before CRT or as consolidation therapy after SCRT/CRT, followed by total mesorectal excision (TME) surgery. Randomized trials have demonstrated improved pathological complete response rates and a significant improvement in disease-free survival with TNT compared to neoadjuvant CRT plus surgery with or without adjuvant chemotherapy. TNT is increasingly considered the preferred treatment strategy, especially for patients with MRI-defined high-risk rectal cancer. (such as cT4, cN2, Magnetic Resonance Circumferential Resection Margins Positive (mrCRM+), Extramural Vascular Invasion Positive (EMVI+), lateral lymph node involvement). Key questions remain, including the optimal RT regimen (SCRT vs. CRT), the sequence of treatment components (induction vs. consolidation therapy), the number of chemotherapy cycles, RT-dose escalation strategies, the need of adjuvant chemotherapy after TNT and surgery, and the role of immunotherapy in both mismatch repair-deficient and mismatch repair-proficient (dMMR/pMMR) disease. Due to the higher rates of clinical complete response achieved with TNT, organ-preserving ("watch-and-wait") strategies are increasingly favored and continue to be refined in ongoing clinical trials (e.g., ACO/ARO/AIO 18.1, JANUS, ENSEMBLE, TRESOR, and STELLAR II).