Pathological lymph node response after immunotherapy-based total neoadjuvant therapy supports local excision for organ preservation in locally advanced rectal cancer: a propensity-score weighted analysis.

Background: The immunotherapy-based total neoadjuvant therapy (iTNT) has improved response rates in locally advanced rectal cancer (LARC); however, a majority of patients do not achieve clinical complete response (cCR) and still require total mesorectal excision. High rates of ypT0-1 and particularly ypN0 in non-cCR patients suggest organ preservation Methods: We included 1568 LARC patients with pathological outcomes after neoadjuvant therapy in three cohorts: 238 received fluorouracil-based chemoradiotherapy (CRT); 1256 received total neoadjuvant therapy (TNT); and 74 received iTNT from the prospective TORCH trial (NCT04518280). Baseline characteristics among three cohorts were balanced using the stabilized inverse probability of treatment weighting (IPTW) method. Results: After IPTW adjustment, the overall rates of positive lymph nodes after neoadjuvant therapy (ypN+) were 44.1%, 34.0%, and 13.4% in the CRT, TNT, and iTNT cohorts, respectively. Notably, pathologic complete response of lymph nodes was achieved in both ypT0 and ypT1 tumors following iTNT. In contrast, the ypN+ rates for ypT0 and ypT1 tumors remained high at 16.8% and 26.4% with CRT and 11.2% and 19.2% with TNT. Univariate regression analysis identified that ypT2-4, positive ypMRF, and positive ypEMVI were associated with higher ypN+ risk, rather than baseline clinical characteristics. Conclusions: iTNT markedly improved lymph node regression in ypT0-1 tumors compared to CRT or TNT. LE, guided by tumor response but not by baseline clinical stages, may be considered for organ preservation in near-cCR patients with LARC following iTNT.