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

This publication is a narrative review examining how tumor location within the rectum should influence the use and intensity of total neoadjuvant therapy (TNT) in locally advanced rectal cancer.

Key points:

• The authors argue that rectal cancer is currently approached too uniformly in trials and guidelines, despite important anatomic and functional differences between mid- and low-rectal tumors.

• Low-rectal cancers (defined here as <1 cm from the anal ring):
• Have more complex lymphatic drainage and a higher risk of positive margins.
• Carry greater risk of functional impairment, particularly continence.
• Often require more aggressive, intensified TNT when sphincter and organ preservation are major goals.

• Mid-rectal cancers:
• Are generally more amenable to standard resection with better preservation of function.
• May be appropriate candidates for treatment deintensification, especially radiotherapy de-escalation, without compromising oncologic control.

• The review synthesizes data from more than 80 studies and clinical trials to:
• Support a risk-adapted, location-specific strategy.
• Highlight where radiotherapy can potentially be reduced in mid-rectal disease.
• Support more intensive TNT strategies in low-rectal tumors when organ preservation is prioritized.

• The overarching conclusion is that mid- and low-rectal cancers should be treated as distinct clinical entities. A patient-centered, location-specific approach to TNT could better match treatment intensity to oncologic risk and functional priorities, with the goal of improving both disease outcomes and quality of life.