Association of total neoadjuvant therapy sequencing with surgical intervention and overall survival in locally advanced rectal cancer: An NCDB analysis.

e15630 Background: Pooled analyses of the CAO/ARO/AIO-12 and OPRA trials in locally advanced rectal cancer (LARC) suggest that chemoradiotherapy followed by consolidation chemotherapy (CRT-CNCT) achieves higher pathological complete response (pCR) rates compared to induction chemotherapy followed by chemoradiotherapy (INCT-CRT). However, no significant differences in long-term outcomes such as overall survival (OS) or disease-free survival (DFS), nor an increased toxicity was observed. Objective: This study evaluates the association of Total Neoadjuvant Therapy (TNT) sequencing with overall survival (OS) and surgical intervention (SI) using data from the National Cancer Database (NCDB). Methods: Using NCDB, A total of 2,836 patients with LARC treated with TNT between 2016 to 2021 were included. SI evaluated were sphincter-preserving surgery (SPS), abdominal perineal resection (APR), and no surgery. Multivariable logistic regression assessed the association between TNT sequencing and odds of SI. OS was analyzed using Kaplan-Meier (KM) survival curves, log-rank tests, and Cox proportional hazards models, both for the entire cohort and stratified by SI. Demographic and clinical variables, including age, race, gender, socioeconomic factors, stage, and grade, were adjusted. Sensitivity analyses included patients receiving long-course radiation only. Results: Of 2,836 eligible patients, 2,352 underwent INCT-CRT (Group A) and 511 underwent CRT-CNCT (Group B). Among them, 135 were Stage II and 2,701 were Stage III. Long-course radiation was received by 2,535 patients, while 301 received short-course radiation. SI were SPS (54.9%), APR (21.8%), and no surgery (23.1%), with similar distribution between groups ( p=0.409) Logistic regression revealed that Group A patients had 38% higher odds of undergoing rectal surgery (APR or SPS) compared to no surgery (odds ratio [OR]: 1.38; 95% confidence interval [CI]: 1.07–1.79). Among patients who underwent surgery, no significant difference was observed between Group A and Group B in the likelihood of receiving APR versus SPS(P=0.405). KM survival curves demonstrated better OS for Group A patients overall and for those receiving SPS (p<0.05). Cox regression revealed a 41% lower risk of death for Group A patients undergoing SPS compared to Group B (hazard ratio [HR]: 0.59; 95% CI: 0.394–0.88). No significant survival differences were observed for APR or no surgery. Sensitivity analyses restricted to long-course radiation patients supported these findings. Conclusions: INCT-CRT was associated with improved OS in LARC patients, particularly among those undergoing SPS. These results emphasize the importance of TNT sequencing in optimizing surgical and survival outcomes. Further research is needed to clarify the role of TNT sequencing in surgical decision-making for LARC.