Does the Gain of Total Neoadjuvant Therapy Outweigh the Harm in Rectal Cancer? Importance of the ATRESS (neoAdjuvant Therapy-RElated Shortening of Survival) Phenomenon: A Systematic Review

SIMPLE SUMMARY: Total neoadjuvant therapy (TNT) refers to delivering both (chemo)radiation and chemotherapy before surgery, aiming to reduce incidence of distant metastases. Indeed, in two randomised trials, TNT reduced distant metastases incidence compared with neoadjuvant chemoradiation, but without improvement of overall survival (OS), and at the expense of severe toxicity. We aimed to evaluate whether TNT results in long-term OS or quality of life (QoL) benefit. Systematic review of randomised trials comparing TNT with neoadjuvant (chemo)radiation identified six trials. Follow-ups were too short to resolve whether TNT improves long-term OS. The ATRESS phenomenon (i.e., reduction in post-metastatic survival) could explain a discrepancy between reduction of distant metastases and the absence of OS improvement after TNT in one trial. QoL analysis performed based on one trial’s data, showed that QoL might not have been improved with TNT if all patients are being considered for radical resection. ABSTRACT: Background: We aimed to evaluate whether total neoadjuvant therapy (TNT) results in long-term overall survival (OS) or quality of life (QoL) benefit compared with chemoradiation if all patients are being considered for radical resection, and whether the ATRESS phenomenon (i.e., reduction in post-metastatic survival) impacts OS after TNT. Methods: Systematic review of randomised trials comparing TNT with neoadjuvant (chemo)radiation. Results: Six trials were identified. Follow-ups were too short to resolve whether TNT improves long-term OS. QoL analysis in one trial showed worse long-term neurotoxicity-related QoL (any neurotoxicity: 14% vs. 3%), higher rate of grade III+ acute toxicity (48% vs. 25%), longer duration of neoadjuvant treatment (19 vs. 6 weeks) and higher rate of locoregional failure (10% vs. 7%) in TNT vs. chemoradiation. This should be weighed against an absolute 8% reduction in the incidence of distant metastases (DM) after TNT. ATRESS could explain a discrepancy between reduction of DM and the absence of OS improvement after TNT in one trial. Conclusion: In the light of unproven OS benefit, the gain of TNT (reduction of DM) does not seem to outweigh the harm (excess of toxicity). ATRESS can be a reason for the absence of the OS benefit despite the reduction in DM.