In this trial short-course radiotherapy followed by chemotherapy and surgery for locally advanced rectal cancer was compared to standard long-course chemoradiotherapy followed by surgery. The experimental treatment was significantly associated with locoregional failure and a greater risk of mesorectal breach during surgery. Other oncologic outcomes were instead favorable to the experimental group. The stated primary endpoint, disease-related treatment failure, and distant metastasis rates were significantly decreased after total neoadjuvant treatment, while overall survival was similar. The authors recognized that the proposed total neoadjuvant treatment schedule should be revised.