Pathologic response in relation to total neoadjuvant therapy sequence, completion, and extra consolidation chemotherapy in locally advanced rectal cancer.

Abstract

e15648 Background: Total neoadjuvant therapy (TNT) is widely used in locally advanced rectal cancer (LARC); however, the effect of TNT sequencing, treatment completion, and additional consolidation chemotherapy on pathologic response remains unclear. We evaluated the association between different TNT delivery patterns and pathologic complete response (pCR) and modified Ryan tumor regression grade (TRG). Methods: We retrospectively analyzed 161 patients with LARC treated with chemoradiotherapy (CRT)-based TNT followed by surgery. TNT delivery was categorized using three complementary classification schemes: (1) six predefined sequence/completion patterns (TNT1) including complete CRT-chemotherapy (CT), complete CT-CRT, additive CT-CRT-CT while awaiting surgery, incomplete CRT-CT, incomplete CT-CRT, and incomplete additive CT-CRT-CT; (2) ordinary (complete CRT-CT or CT-CRT) versus aberrant (any incomplete and/or additive patterns) (TNT2); and (3) extra consolidation chemotherapy (additive complete CT-CRT-CT), incomplete chemotherapy (failure to complete planned systemic therapy), and ordinary (TNT3). Continuous variables were compared using non-parametric tests and categorical variables using chi-square or Fisher’s exact tests. Multivariable logistic regression models were constructed for pCR. Results: Median age was 63 years. pCR was achieved in 22 patients (13.7%). Modified Ryan TRG distribution was TRG0 13.7%, TRG1 24.2%, TRG2 50.9%, and TRG3 11.2%. pCR rates did not differ significantly across TNT1 (p = 0.613), TNT2 (p = 0.271), or TNT3 (p = 0.378). Modified Ryan TRG distributions were comparable among all TNT grouping strategies (TNT1 p = 0.953, TNT2 p = 0.712, TNT3 p = 0.682). Significant differences across TNT groupings were observed for selected baseline and treatment-related variables, including locoregional lymph node involvement (TNT1 p = 0.023), neoadjuvant chemotherapy regimen (TNT1 p = 0.002), total neoadjuvant chemotherapy cycles (TNT1 p < 0.001; TNT2 p = 0.007; TNT3 p < 0.001), and carcinoembryonic antigen (CEA) after TNT (TNT1 p = 0.031; TNT2 p = 0.030; TNT3 p = 0.027). Across three multivariable models adjusted for clinical T4 status and locoregional lymph node involvement, TNT1, TNT2, and TNT3 classifications were not independently associated with pCR. Conclusions: In this real-world cohort, TNT sequence was not associated with differences in pCR or modified Ryan tumor regression, and extra consolidation chemotherapy did not improve pCR rates. These findings suggest that TNT sequence and intensification do not translate into superior pathologic response. De-escalation and sequencing modifications based on patient clinical status may be feasible, which should be evaluated in future prospective studies to better define the optimal TNT strategy.