Prognosis and risk factors for pathological non-response to neoadjuvant chemoimmunotherapy in locally advanced...

Neoadjuvant chemotherapy combined with immunotherapy (NACI) is promising for treating locally advanced esophageal squamous cell carcinoma (LA-ESCC), yet a subset of patients exhibit a pathological non-response (pNR). The prognosis and risk factors for pNR to NACI remain unclear.

We retrospectively analyzed 253 patients with LA-ESCC who received NACI followed by surgery between 2020 and 2023. The immune checkpoint inhibitors (ICIs), which included pembrolizumab (200 mg), camrelizumab (200 mg), tislelizumab (200 mg), sintilimab (200 mg), nivolumab (200 mg), and toripalimab (200 mg), were administered intravenously once every three weeks. Patients with >50% residual viable tumor cells (Becker TRG3) were classified as having a pNR, while the others were classified as having a pathological response (pR). Survival and recurrence patterns were compared between the two groups. Risk factors associated with pNR and prognosis were identified.

The pNR rate was 39.5% (100/253). Compared with the pR group, the pNR group had significantly worse 3-year overall survival (OS) (58.2% vs. 75.8%, P = 0.001) and disease-free survival (DFS) (46.1% vs. 65.5%, P = 0.001), with higher rates of locoregional (13.0% vs. 4.6%, P = 0.015) and distant recurrence (19.0% vs. 7.8%, P = 0.008). Multivariate analysis confirmed that pNR was an independent risk factor for poor OS (HR 1.926; 95% CI 1.250-2.970; P = 0.003) and DFS (HR 1.899; 95% CI 1.300-2.775; P = 0.001). Lymphovascular invasion (LVI) and perineural invasion (PNI) were independent risk factors for pNR (both P<0.001). Within the pNR subgroup, the PNI and ypN2/N3 stage were independent prognostic factors for poor survival (all P<0.05).

pNR to NACI strongly predicts worse outcomes in LA-ESCC patients. LVI and PNI are key risk factors, with PNI or advanced ypN stage further defining a high-risk pNR subgroup warranting aggressive postoperative management and surveillance.