# Efficacy and safety of sequential immunotherapy following concurrent radiotherapy with S-1 in older patients with esophageal squamous cell carcinoma: an inverse probability weighting analysis

## TL;DR

Adding immunotherapy after radiotherapy and chemotherapy may improve outcomes for older patients with esophageal cancer, but requires monitoring for side effects.

## Contribution

This study evaluates the safety and efficacy of sequential immunotherapy after CCRT in older ESCC patients using IPTW analysis.

## Key findings

- Sequential ICIs after CCRT significantly improved progression-free survival in older ESCC patients.
- Immunotherapy increased risks of pneumonitis and hypothyroidism but reduced neutropenia and vomiting.
- Age ≥75, ECOG score 2, T4, and N3 stages were identified as adverse prognostic factors.

## Abstract

To evaluate the efficacy and safety of sequential immune checkpoint inhibitors (ICIs) following concurrent chemoradiotherapy (CCRT) in older (≥70 years) patients with locally advanced esophageal squamous cell carcinoma (ESCC).

A total of 193 older patients (≥70 years) with locally advanced ESCC treated between January 2022 and December 2023 were retrospectively analyzed and divided into two groups: the CCRT group (radiotherapy with concurrent S-1, n=108) and the CCRT+ICIs group (sequential ICIs after CCRT, n=85). Baseline imbalances were adjusted via inverse probability of treatment weighting (IPTW). The primary endpoints were overall survival (OS) and progression-free survival (PFS), whereas the secondary endpoints included safety and prognostic factors.

After IPTW adjustment, OS in the CCRT+ICIs group tended to improve compared with that in the CCRT alone group (HR = 0.70, 95% CI: 0.48–1.04, p=0.071), although the difference was not statistically significant. In contrast, PFS was significantly improved in the CCRT+ICIs group (HR = 0.59, 95% CI: 0.42–0.84, p=0.003). Multivariate analysis identified age ≥75 years (OS: HR = 1.893; PFS: HR = 2.097), ECOG score =2 (OS: HR = 3.310; PFS: HR = 2.188), T4 stage (OS: HR = 2.221; PFS: HR = 2.080), and N3 stage (OS: HR = 3.841; PFS: HR = 2.920) as independent adverse prognostic factors. Immunotherapy-specific toxicities, including hypothyroidism and pneumonitis, occurred more frequently in the CCRT+ICIs group, which is consistent with the toxicity profile of ICIs, whereas neutropenia and vomiting were less common. A lower incidence of vomiting was also observed in the CCRT+ICIs group, although the difference did not reach statistical significance (p=0.053).

Sequential ICI therapy after CCRT significantly improved PFS and reduced mortality risk in older ESCC patients, though close monitoring is warranted for pneumonitis and skin-related toxicities. The reduced incidence of neutropenia suggests a hematologic safety advantage of the sequential strategy. Patients aged ≥75 years, with an Eastern Cooperative Oncology Group (ECOG) score of 2, or with N3 disease constitute high-risk subgroups and warrant individualized treatment approaches.