Abstract
Total neoadjuvant therapy (TNT) has emerged as a transformative approach in the management
of locally advanced rectal cancer, shifting radiation and chemotherapy to the preoperative
setting to optimize local and distant disease control. Landmark trials have demonstrated
improved compliance, tumor downstaging, and disease-free survival with TNT, increasing
options for nonoperative strategies such as watch-and-wait. This paradigm allows patients
who achieve a clinical complete response (cCR) to avoid surgery and its associated
morbidity, including ostomy formation and low anterior resection syndrome (LARS).
The Organ Preservation in Patients with Rectal Adenocarcinoma (OPRA) trial and other
prospective studies have validated the oncologic safety of watch-and-wait, showing
comparable disease-free and overall survival to traditional approaches, with salvage
surgery effective in cases of regrowth. However, not all patients are ideal candidates
for TNT and watch-and-wait protocols. Tumor location, anatomy, comorbidities, and
patient preferences influence treatment selection. For mid-to-upper rectal tumors,
TNT may be over-treatment, as suggested in the Preoperative Treatment of Locally Advanced
Rectal Cancer (PROSPECT) Trial, which supports selective use of chemoradiation. This
is an important option for patients wishing to preserve fertility. Additionally, predicting
cCR and regrowth remain challenging, and intensive surveillance is required. This
article reviews the evolution of TNT and watch-and-wait strategies, highlighting key
trials such as OPRA, the Rectal Cancer and Preoperative Induction Therapy followed
by Dedicated Operation (RAPIDO) Trial, the Partenariat de Recherche en Oncologie Digestive
23 (PRODIGE 23) Trial, the Organ Preservation after TNT for Locally Advanced Rectal
Cancer (CAO/ARO/AIO-16) Trial, and PROSPECT. We examine the oncologic safety, organ
preservation rates, and quality-of-life implications of nonoperative management, including
the risks of LARS and ostomy formation. With multiple validated strategies, surgeons
must balance oncologic outcomes with quality of life for each individual patient.
Ongoing trials continue to refine these approaches, aiming to optimize tumor downstaging,
integrate immunotherapy, and expand organ-preserving options.
Keywords rectal cancer - total mesorectal excision - total neoadjuvant therapy - nonoperative
management - watch-and-wait
