Disruptive Analysis of Total Neoadjuvant Therapy in Locally Advanced Rectal Cancer: Clinical and Therapeutic Distinctions Between Low- and Mid-Rectal Cancers

Abstract

Total neoadjuvant therapy (TNT) has become a cornerstone in the treatment of locally advanced rectal cancer, improving systemic control and increasing the potential for organ preservation. However, current trials and guidelines continue to treat rectal cancer as a homogeneous entity, overlooking the significant anatomic and therapeutic differences between mid- and low-rectal tumors. This uniform approach fails to reflect the impact of tumor location on both oncologic outcomes and functional consequences. Low-rectal cancers—defined as tumors located < 1 cm from the anal ring—pose distinct anatomic and functional challenges. These include more complex lymphatic drainage, higher risks of positive margins, and greater impact on continence. By contrast, mid-rectal tumors are generally more amenable to standard resection with preserved function and may benefit from treatment deintensification, particularly regarding radiotherapy. Drawing on data from over 80 studies and clinical trials, this review argues that mid- and low-rectal cancers should be considered distinct clinical entities requiring tailored treatment strategies. We examine evidence supporting radiotherapy de-escalation for mid-rectal tumors and intensified TNT for low-rectal tumors when organ and sphincter preservation is essential. Adopting a location-specific, patient-centered approach can better align treatment intensity with oncologic risk and individual functional priorities, ultimately improving both outcomes and quality of life.