Abstract:

Objective To investigate the correlation between dynamic changes in serum soluble programmed death-1 （sPD-1） during neoadjuvant camrelizumab combined with chemotherapy and pathological response in patients with esophageal squamous cell carcinoma （ESCC）， and to evaluate the feasibility of sPD-1 as a predictive indicator of therapeutic efficacy. Methods A total of 125 patients with locally advanced ESCC who received neoadjuvant treatment with camrelizumab combined with albumin paclitaxel and cisplatin at Affiliated Huai′an No.1 People's Hospital of Nanjing Medical University from January 2019 to December 2021 were selected as the research subjects. Serum sPD-1 levels were measured at baseline， after the first cycle， after the second cycle， and before surgery. Patients were divided into the decreasing group （n=45） and non-decreasing group （n=80） based on early sPD-1 reduction （≥30% vs. <30%）. Correlations between sPD-1 dynamic changes and pathological complete response （pCR）， major pathological response （MPR）， and event-free survival （EFS） were analyzed using generalized estimating equation （GEE） models. Logistic regression model was used to identify the influencing factors of patients' pathological response； Kaplan-Meier curves were plotted to assess EFS in patients from the decreasing and non-decreasing groups， and the log-rank test was conducted； the Cox proportional hazards regression model was used to evaluate the influencing factors of patients' EFS. Results All 125 patients completed neoadjuvant therapy and surgery， with an R0 resection rate of 100% and no perioperative deaths. The baseline sPD-1 levels in the decreasing and non-decreasing groups were 5.9 （4.5， 7.3） and 5.7 （4.3， 7.6） ng/ml， respectively， with no statistically significant difference （Z=0.52， P=0.472）. Following the first treatment cycle， sPD-1 levels decreased to 3.1 （2.4， 4.0） ng/ml in the decreasing group and 4.8 （3.7， 6.5） ng/ml in the non-decreasing group， with a statistically significant difference （Z=19.26， P<0.001）. After the second treatment cycle， levels were 2.8 （2.2， 3.7） and 4.5 （3.4， 6.0） ng/ml， respectively， with a statistically significant difference （Z=22.13， P<0.001）. Before surgery， sPD-1 levels were 2.6 （2.0， 3.5） and 4.2 （3.3， 5.7） ng/ml，with a statistically significant difference （Z=21.84， P<0.001）. GEE analysis revealed that both the main effects of time （χ²=112.40， P<0.001） and group （χ²=7.63， P=0.006） were significant， and a significant interaction effect between time and group was observed （χ²=9.18， P=0.027）. After the first treatment cycle， the pCR rate for patients in decreasing group was 42.2% （19/45）， significantly higher than the 19.5% （16/80） in the non-decreasing group （χ²=7.59， P=0.006）. The MPR rate in the decreasing group was 68.9% （31/45）， significantly higher than that in the non-decreasing group， which was 48.1% （38/80） （χ²=5.35， P=0.021）. The survival analysis showed that the median EFS in the decreasing group was 34 months， longer than that of 28 months in the non-decreasing group （χ²=8.33， P=0.004）. Multivariate analysis indicated that an early reduction in sPD-1 of ≥30% （OR=2.34， 95%CI： 1.18-4.63， P=0.015） and baseline sPD-1 levels （OR=0.89， 95%CI： 0.80-0.98， P=0.023） were independent influencing factors of pCR in patients with locally advanced ESCC. Furthermore， early sPD-1 reduction ≥30% （HR=0.44， 95%CI： 0.23-0.85， P=0.014） and baseline sPD-1 （HR=1.09， 95%CI： 1.02-1.18， P=0.021） were identified as independent influencing factors for EFS in patients with locally advanced ESCC. The total incidence of adverse events was 52.0% （65/125）， mainly consisting of bone marrow suppression and mild to moderate immune-related reactions； the incidence of grade ≥3 adverse events was 9.6% （12/125）， with no treatment-related deaths. Conclusions Both baseline sPD-1 levels and early dynamic decline during neoadjuvant camrelizumab plus chemotherapy are significantly associated with pathological response and EFS in patients with locally advanced ESCC. Serum sPD-1， as a simple and dynamically monitorable peripheral blood marker， is expected to become a predictive tool for the efficacy of neoadjuvant immunotherapy.

Key words: Esophageal squamous cell carcinoma, Neoadjuvant chemotherapy, Camrelizumab, Programmed cell death-1, Pathological response