Tardo.

Top Line: There have now been lots of studies suggesting total neoadjuvant therapy is the best sequencing of treatment for locally-advanced rectal cancer.

The Study: If you recall, RAPIDO was a large randomized trial demonstrating an improvement in disease-free survival with this approach due to a lower rate of distant progression. The unfortunate thing about the design was the TNT arm received short-course radiation while the control arm received standard long-course radiation with concurrent capecitabine. And this was among specifically “high-risk” patients with cT4a/4b tumor, mesorectal fascia involvement, extramural vascular invasion, N2 disease, or lateral node involvement. In other words, if you’re ever going to use standard-course radiation, it would be for this group. We now have long-term reporting of locoregional failure at 5 years, and it was 50% more likely among those in the TNT/short-course arm (12%) than in the control arm (8%). While this included patients who never underwent resection, they also looked only at patients who received an R0/R1 resection, and post-op recurrence was 10% in the TNT arm versus 6% in the control arm. Despite this increase in locoregional failure, the  overall improvement in distant mets and disease-free survival with TNT remained after 5 years.

TBL: TNT improves disease-free survival for high risk rectal cancer, but in the RAPIDO trial, TNT using short-course RT increases the risk of locoregional failure compared to standard long-course chemoRT.  TNT with standard-course radiation followed by chemo then surgery is likely the treatment strategy to afford the best local and distant control for high-risk locally-advanced rectal cancer. | Dijkstra, Ann Surg 2023