Upfront surgery versus neoadjuvant chemoimmunotherapy versus neoadjuvant chemoradiotherapy for esophageal squamous cell carcinoma in elderly patients: a multicenter cohort study

Purpose The optimal treatment strategy for elderly patients (aged ≥65 years) with operable locally advanced esophageal squamous cell carcinoma (ESCC) remains controversial. This study aimed to compare the survival outcomes of upfront surgery (US), neoadjuvant chemoimmunotherapy (nCIT), and neoadjuvant chemoradiotherapy (nCRT) in this population. Methods This multicenter, retrospective cohort study analyzed patients aged ≥65 years with pathologically confirmed, operable locally advanced ESCC at five Chinese medical centers between January 2020 and December 2024. Patients received either US, nCIT, or nCRT. The primary endpoint was progression-free survival (PFS). Inverse probability of treatment weighting (IPTW) was the primary analytical method, and overlap weighting (OW) was used for sensitivity analysis. P values for the three pairwise comparisons were adjusted using the Bonferroni method. Results A total of 1693 patients were included: the US (n=824), nCIT (n=581), and nCRT (n=288) groups. Surgery was not performed in 4.8% (28/581) of patients in the nCIT group and 5.2% (15/288) in the nCRT group. Median follow-up was 37.9 months (IQR, 26.2-55.2). After IPTW, the nCRT group was associated with more favorable PFS than the nCIT group (HR, 0.60; 95% CI, 0.44-0.82; Padj=.001) and the US group (HR, 0.62; 95% CI, 0.47-0.83; P adj =.001). Similarly, nCRT was associated with longer OS than nCIT (HR = 0.56, 95% CI 0.37-0.83; P adj =0.004) and US (HR = 0.59, 95% CI 0.42-0.84; P adj =0.004). The 3-year PFS rates were 63.5% (nCRT), 51.5% (nCIT), and 48.5% (US); the corresponding 3-year OS rates were 74.9%, 62.1%, and 60.3%. Results of the OW sensitivity analysis were consistent with those of the IPTW analysis. Conclusions In this retrospective, weighted cohort of elderly patients with operable locally advanced ESCC, nCRT was associated with improved PFS and OS compared with nCIT and US. However, because treatment-related toxicity data were not uniformly available, the tolerability of nCRT in this population should be interpreted with caution, and prospective validation is warranted.