A meta-analysis based on propensity analysis studies comparing neoadjuvant immunochemotherapy and neoadjuvant chemoradiotherapy for esophageal squamous cell carcinoma

Abstract

Background

To systematically compare the efficacy and safety of neoadjuvant immunochemotherapy (NICT) and neoadjuvant chemoradiotherapy (NCRT) in the treatment of resectable esophageal squamous cell carcinoma (ESCC).

Methods

Databases were searched to collect clinical studies comparing NICT and NCRT for ESCC based on propensity score analysis. Primary outcomes included overall survival (OS), disease-free survival (DFS), pathological response rate, local recurrence and distant relapse rate. Secondary outcomes included the number of lymph nodes dissected, R0 resection rate, and postoperative complication rates.

Results

11 studies involving 4,684 patients were included. The NICT group showed significantly better OS and DFS than the NCRT group (HR = 0.61, 95% CI: 0.52–0.72; HR = 0.62, 95% CI: 0.53–0.72). The pathological complete response (pCR) rate and major pathological response (MPR) rate were lower in the NICT group (RR = 0.67, 95% CI: 0.56–0.81; RR = 0.75, 95% CI: 0.65–0.86). However, there was no significant difference in the local recurrence rate between NICT and NCRT group (RR = 0.93, 95%CI 0.51–1.72, I² = 58%), and NICT group had a greater advantage in the distant relapse rate (RR = 0.51, 95%CI 0.40–0.65, I² = 0). The number of lymph nodes dissected was significantly higher in the NICT group (MD = 6.68, 95% CI: 4.00–9.36). No significant differences were observed in R0 resection rate or major postoperative complication rates between the two groups.

Conclusions

NICT demonstrated superior survival benefits compared to NCRT in the treatment of ESCC, despite its lower pCR and MPR rate. The safety of the two treatment methods were comparable.

Supplementary Information

The online version contains supplementary material available at 10.1007/s12672-025-03607-8.

Introduction

Esophageal cancer is one of the most common malignant tumors worldwide, with squamous cell carcinoma and adenocarcinoma being the two predominant histological types [1]. Notably, esophageal squamous cell carcinoma (ESCC) shows particularly high incidence in Asian countries, while esophageal adenocarcinoma is more prevalent in Western populations. This distinct geographical distribution pattern is closely associated with differential exposure to risk factors such as dietary habits, tobacco use, and alcohol consumption. According to the 2020 Global Cancer Statistics, esophageal cancer ranks as the 10th most commonly diagnosed cancer and the 6th leading cause of cancer-related mortality globally, posing a significant threat to public health [2].

The clinical presentation of esophageal cancer is often insidious, with nonspecific early symptoms leading to frequent diagnoses at locally advanced or metastatic stages. While surgical resection remains the cornerstone of treatment, monotherapy with surgery yields suboptimal outcomes, characterized by persistently high rates of local recurrence and distant metastasis. In recent years, the adoption of multidisciplinary treatment approaches has established neoadjuvant therapy as an increasingly vital component in the management of resectable esophageal cancer [3, 4].

Although conventional neoadjuvant chemoradiotherapy (NCRT) can improve pathological complete response (pCR) rates, its impact on long-term survival remains limited, with 5-year overall survival rates plateauing around 50% [5–7]. The rapid advancement of cancer immunotherapy has recently introduced neoadjuvant immunochemotherapy (NICT) as a promising therapeutic strategy for esophageal cancer. Immune checkpoint inhibitors have revolutionized treatment paradigms by reactivating host antitumor immunity, potentially generating durable therapeutic effects [8]. Emerging evidence suggests that NICT demonstrates both favorable safety profiles and encouraging efficacy in ESCC, with potential long-term survival benefits [9–11]. However, large-scale randomized controlled trials directly comparing the efficacy and safety between NICT and conventional NCRT are still lacking.

This study aims to systematically compare the efficacy and safety profiles of NICT versus NCRT in ESCC treatment through meta-analysis. We will focus on evaluating differences in both therapeutic outcomes and safety parameters between these two approaches. By synthesizing existing clinical evidence, our findings will provide crucial references for selecting optimal neoadjuvant strategies in ESCC and offer valuable insights for future research directions.

Materials and methods

Search strategy

This study adhered to the PRISMA guidelines [12]. PubMed, Embase, and the Cochrane Library were searched for clinical studies comparing NICT and NCRT for ESCC patients. The search strategy combined Medical Subject Headings (MeSH) terms and free-text words, including “esophageal squamous cell carcinoma,” “esophageal cancer,” “esophageal carcinoma,” “neoadjuvant immunochemotherapy,” “neoadjuvant chemoradiotherapy,” “neoadjuvant immunotherapy combined with chemotherapy,” and “neoadjuvant immunotherapy.” All literature searches were performed by two independent authors and then cross-checked.

Inclusion and exclusion criteria

Inclusion criteria: (1) Patients with pathologically confirmed resectable ESCC; (2) Comparison of NICT and NCRT in terms of efficacy and/or safety; (3) Reporting of at least one clinical outcome; (4) Study design of randomized controlled trials or propensity analysis studies. Exclusion criteria: (1) Non-English publications; (2) Duplicate or incomplete data; (3) Case reports or review articles. References of relevant studies and review articles were manually screened to supplement the electronic search. The selection process is illustrated in Fig. 1. For studies with the same set of data published repeatedly, the literature with the most complete data will be selected.

Fig. 1.

Detailed flowchart of inclusion and exclusion criteria for the literature search

Literature quality assessment

Two researchers independently screened the titles and abstracts of the literature. After excluding studies that clearly did not meet the inclusion criteria, they reviewed the full texts of potentially eligible studies to determine whether they satisfied the inclusion criteria. Cross-checking was then performed, and any disagreements were resolved by a third researcher, who made the final decision on study inclusion. The quality of the included studies was assessed using the Newcastle-Ottawa Scale to identify potential quality defects. The Newcastle-Ottawa Scale (NOS) consists of 8 methodological quality assessment items with a total possible score of 8 points [13]. Studies were categorized based on their scores as follows: low qualit (0–3 points); moderate quality (4–6 points); high quality (7–8 points).

Data extraction and statistical analysis

Data extraction was performed independently by two researchers, including study characteristics, patient demographics, treatment regimens, and outcome measures (OS, DFS, pCR, major pathological response (MPR), local recurrence, distant relapse, number of lymph nodes dissected, R0 resection rate, anastomotic leakage, chylothorax, recurrent laryngeal nerve injury, pulmonary complication and cardiac complication). Statistical analyses were conducted using RevMan software. Time-survival variable was expressed as hazard ratio (HR) with 95% confidence intervals (CI), dichotomous variable as risk ratio (RR) with 95% CI, and continuous variable as mean difference (MD) with 95% CI. Heterogeneity was evaluated using the I² statistic, with I²>50% indicating significant heterogeneity. A random-effects model was applied regardless of whether I² was > 50% or ≤ 50%. Sensitivity analysis was further performed to assess the robustness of the meta-analysis and determine the source of heterogeneity. Publication bias was assessed using Egger’s test and funnel plots. All P values were two-sided, and a significance level of 0.05 was considered statistically significant.

Results

Literature retrieval results and quality assessment

A total of 4,000 records were identified, and 11 studies involving 4,684 patients were ultimately included [10, 11, 14–22]. All studies were observational and employed propensity analysis, with three using inverse probability of treatment weighting and eight using propensity score matching (Table 1). The overall quality of the included studies was high, with Newcastle-Ottawa Scale scores ranging from 7 to 8 (Supplementary Table 1).

Table 1.

Study characteristics and patient demographics

Study	Study type	RT	CT	ICIs	Before PSM / IPTW		After PSM / IPTW
					N1	N2	N1	N2
Hong 2022	Single-center PSM	40–56 Gy	TP/PF	Sintilimab Pembrolizumab Toripalimab Camrelizumab	52	35	32	32
Zhao 2023	Single-center PSM	40–50.4 Gy	TP/PF	Sintilimab Pembrolizumab Toripalimab Camrelizumab	81	200	55	110
Duan 2024	Single-center PSM	40–41.4 Gy	TP/PF	Sintilimab Pembrolizumab Toripalimab Camrelizumab Tislelizumab Durvalumab	78	136	66	66
Xu 2022	Single-center IPTW	32.4–50.4 Gy	TP/PF	Pembrolizumab Camrelizumab	314	154	465.6	469.9
Wang 2024	Single-center PSM	36–45 Gy	TP/PF	Sintilimab Pembrolizumab Toripalimab Camrelizumab	162	328	144	216
Tian 2024	Multi-center IPTW	40 Gy	TP	Pembrolizumab Camrelizumab	148	172	148	174
Yang 2025	Single-center PSM	40–41.4 Gy	TP/PF	Sintilimab Pembrolizumab Toripalimab Camrelizumab Tislelizumab Nivolumab	182	143	124	124
Yu 2024	Single-center IPTW	40.0–50.4 Gy	TP	Sintilimab Pembrolizumab Toripalimab Camrelizumab	81	121	207.3	195.3
Guo 2025	Multi-center PSM	40–41.4 Gy	TP/PF	Sintilimab Pembrolizumab Toripalimab Camrelizumab Tislelizumab Nivolumab	724	704	532	532
Shi 2025	Single-center PSM	40–41.4 Gy	TP/PF	Sintilimab Camrelizumab Tislelizumab	220	252	175	175
Shao 2025	Single-center PSM	36–50 Gy	TP	Durvalumab Pembrolizumab Toripalimab Sintilimab Camrelizumab Nivolumab	88	309	75	75

RT radiotherapy, CT chemotherapy, ICI Immune checkpoint inhibitor, TP platinum-based drugs and paclitaxel, PF platinum-based drugs and fluorouracil, PSM propensity score matching, IPTW inverse probability of treatment weighting.

Primary outcomes

Seven studies separately provided OS and DFS data. Eleven and ten studies separately reported pCR and MPR data. Four studies reported data related to local recurrence and distant relapse within two years.

The NICT group exhibited significantly better OS (HR = 0.61, 95% CI 0.52–0.72, I² = 0%) and DFS (HR = 0.68, 95% CI 0.54–0.85, I² = 53%) than the NCRT group (Fig. 2). The pCR rate (RR = 0.67, 95% CI 0.56–0.81, I² = 66%) and MPR rate (RR = 0.75, 95% CI 0.65–0.86, I² = 80%) were lower in the NICT group (Fig. 3). However, there was no significant difference in the local recurrence rate between NICT and NCRT group (RR = 0.93, 95%CI 0.51–1.72, I² = 58%), and NICT group had a greater advantage in the distant relapse rate (RR = 0.51, 95%CI 0.40–0.65, I² = 0) (Fig. 3).

Fig. 2.

Meta-analyses of OS (a), DFS (b)

Fig. 3.

Meta-analyses of pCR (a) and MPR (b), local recurrence (c), distant relapse (d)

We performed a subgroup analysis based on different radiation doses (40–41.4 Gy and other radiation doses). The meta-analysis demonstrated that NICT was associated with significantly superior OS compared to NCRT, regardless of radiation dose (HR = 0.57, 95%CI 0.47–0.70, I² = 0; HR = 0.70, 95%CI 0.51–0.97, I² = 17%). In the subgroup receiving 40–41.4 Gy, NICT also showed significantly improved DFS over NCRT (HR = 0.59, 95% CI 0.50–0.70, I² = 0); in subgroups with other radiation doses, the advantage of NICT in DFS was not statistically significant (HR = 0.84, 95% CI 0.55–1.27, I² = 59%) (Supplementary Fig. 1).

Secondary outcomes

Nine studies provided lymph node dissection data, while seven studies provided R0 resection rate data. Regarding major postoperative complications: nine studies contained data on esophagogastric anastomotic leakage, four studies reported chylothorax incidence, and seven studies documented recurrent laryngeal nerve injury. Additionally, six studies each provided data on pulmonary complication and cardiac complication.

The number of lymph nodes dissected was significantly higher in the NICT group (MD = 6.68, 95% CI 4.00–9.36, I² = 92%) (Fig. 4). No significant differences were observed in R0 resection rate (RR = 1.00, 95% CI 0.98–1.01, I² = 23%) or major postoperative complication rates, including anastomotic leakage (RR = 0.81, 95% CI 0.54–1.20, I² = 54%), chylothorax (RR = 0.94, 95% CI 0.40–2.21, I² = 0), recurrent laryngeal nerve injury (RR = 1.02, 95% CI 0.66–1.56, I² = 22%), pulmonary complication (RR = 0.97, 95% CI 0.85–1.10, I² = 0), and cardiac complication (RR = 0.99, 95% CI 0.68–1.44, I² = 33%) (Figs. 4 and 5).

Fig. 4.

Meta-analyses of the number of lymph nodes dissected (a) and R0 resection rate (b)

Fig. 5.

Meta-analysis of DFS after omitting the study of Zhao et al

Publication bias and sensitivity analysis

Egger’s funnel plots indicated no significant publication bias (Supplementary Fig. 2). Significant heterogeneity was observed when comparing DFS, pCR, MPR, the number of lymph nodes dissected and anastomotic leakage. Sensitivity analysis using the leave-one-out method indicated that the between-group heterogeneity did not alter the significance of the meta-analysis (Supplementary Fig. 3). The largest sensitivity in the comparison of DFS originated from the study by Zhao et al., and after omitting this study, the heterogeneity stabilized at I² = 0% (HR = 0.62, 95% CI 0.53–0.72) (Fig. 6).

Fig. 6.

Meta-analysis of DFS after omitting the study of Zhao et al

Discussion

Surgery combined with neoadjuvant therapy has been proven to be an effective treatment strategy for ESCC. This meta-analysis systematically compared the antitumor efficacy and safety of NICT and NCRT in patients with locally advanced ESCC. The findings of this study are clinically significant.

This meta-analysis indicates that NICT provides superior survival benefits compared to NCRT in the treatment of ESCC. Furthermore, regardless of the radiation dose used in NCRT, the NICT group demonstrated significantly better OS than the NCRT group. No significant difference was observed in local recurrence rates between NICT and NCRT; however, NICT showed a clear advantage in reducing distant relapse. Furthermore, our study revealed higher rates of pCR and MPR in the NCRT group than in the NICT group. This suggests that although NCRT achieved better tumor response, this advantage did not translate into improvements in recurrence, metastasis, or survival outcomes. Although the pCR and MPR rates of NICT are relatively low, NICT can reduce distant relapse and is associated with a better survival prognosis.

Whether pathological response can serve as a surrogate endpoint for survival in esophageal cancer within clinical research remains a subject of ongoing debate. A meta-analysis of 40 studies involving 55,344 esophageal cancer patients indicated that although pCR is associated with improved survival, it is not always an independent prognostic factor [23]. Similar findings have been reported in other malignancies such as breast cancer and non-small cell lung cancer [24, 25]. Yost KE et al. performed an integrated analysis of 79,046 tumor cells from matched tissue samples of basal cell carcinoma and squamous cell carcinoma patients before and after anti-PD-1 therapy, using paired single-cell RNA sequencing and T-cell receptor sequencing [26]. Their results demonstrated that PD-1 blockade facilitates the replacement of exhausted T cells with new T-cell clones, thereby maintaining long-term immune surveillance. Consequently, these memory T cells can persist long after surgery and rapidly initiate immune responses upon tumor recurrence, ultimately improving DFS and OS. This suggests that the immune system can sustain anti-tumor activity even without a significant reduction isn initial tumor burden. A study demonstrated that NICT significantly upregulates PD-L1 Tumor Proportion Score (TPS), PD-L1 Combined Positive Score (CPS), and the levels of CD3⁺ T cells and CD8⁺ T cells. The combination strategy of chemotherapy and immunotherapy may more effectively activate anti-tumor immune responses within the tumor microenvironment (TME) [27]. Researchers have already developed prognostic models for predicting NICT efficacy in ESCC patients. They found that NICT may exert anti-tumor effects by enriching immune cells and reinvigorating exhausted T cells, with tumor-infiltrating CD3+, PD-L1+, and CD3 + PD-L1 + cells being closely associated with treatment efficacy [28].

In esophageal cancer surgery, lymph node dissection is of critical importance, as pathological staging largely depends on the status of lymph node metastasis [29, 30]. Notably, in our study, the number of lymph nodes dissected was significantly higher in the NICT group compared to the NCRT group. On one hand, this phenomenon may reflect the modulating effect of immunotherapy on the regional lymph node microenvironment, enabling surgeons to identify and remove more lymph nodes, thereby improving the radicality of surgery. On the other hand, with advances in clinical research, the concept of radical resection has gained increasing emphasis. Three-field lymph node dissection has been more widely adopted in recent years, particularly in high-volume surgical centers, which may also contribute to the higher number of lymph nodes removed in the NICT group. Recent studies have elucidated the frequency and distribution patterns of lymph node metastasis in patients with locally advanced esophageal squamous cell carcinoma after NICT, providing valuable guidance for determining the extent of surgical lymph node dissection [19, 31].

Due to limitations in the included studies, we were unable to extract and analyze data on adverse events related to immune checkpoint inhibitors. Previous research has shown that the incidence of immune-related adverse events (irAEs) is generally acceptable, with some studies even reporting that patients who experience irAEs tend to have better prognoses compared to those who do not [32–34]. Therefore, the key focus in using immune checkpoint inhibitors lies in identifying and managing patients who develop grade ≥ 3 irAEs [35]. In some studies, identified risk factors associated with an increased incidence of irAEs include the presence of thymic tumors, specific human leukocyte antigen (HLA) genotypes, elevated body mass index (BMI), and baseline deviations from normal ranges in certain cytokine levels—such as interleukin (IL)-6 and IL-17 [36–44]. The administration of corticosteroids, both intravenously and orally, has been proven effective in preventing and treating irAEs [45].

Our study analyzed the incidence of major postoperative complications, including anastomotic leakage, chylothorax, recurrent laryngeal nerve injury, pulmonary complication, and cardiac complication. The results indicated that, compared to NCRT, NICT did not increase the incidence of major postoperative complications. In addition, among the literature included in our study, 4 reported data on short-term mortality of patients within 30 days after surgery, with no events occurring in the NICT group. A multicenter retrospective cohort study similarly reported no elevated risk of anastomotic leakage or pulmonary complications with NICT [46]. This indicates that NICT does not increase surgical or postoperative risks. These findings are of great significance for clinical decision-making, as the safety of treatment is always an important factor to consider when choosing a treatment plan.

Limitations

This study has several limitations. First, all included studies were retrospective, and although propensity analysis was applied, residual confounding may still exist. Second, since all the studies included in this meta-analysis were conducted in Asian populations and specifically focused on squamous cell carcinoma, the applicability of the research results to Western countries where adenocarcinoma is predominant is limited. Therefore, the results should be interpreted with caution. Furthermore, the use of different chemotherapy drugs, radiation doses and immune checkpoint inhibitors may lead to heterogeneity in the outcomes. In the studies we included, a wide variety of immune checkpoint inhibitors were used, and we were unable to discuss them separately. Additionally, it must be acknowledged that our analysis is derived from data available in the 11 included studies, and the impact of neoadjuvant therapies on survival is multifaceted. For instance, our study did not capture information on long-term radiation-related complications, such as strictures, cardiotoxicity, and pulmonary toxicity, or non-cancer deaths. These late toxicities are particularly relevant in elderly patients or those with pre-existing cardiovascular or respiratory conditions. The inability to quantitatively synthesize these outcomes constitutes a significant limitation. Finally, some patients received adjuvant therapy after surgery, and in certain cases, the adjuvant regimen differed from the neoadjuvant approach. However, we were unable to stratify these patients separately. This is understandable, as treatment plans must ultimately be tailored to individual clinical circumstances.

Conclusion

This meta-analysis highlights the superior survival benefits of NICT over NCRT in ESCC treatment, despite a lower pCR rate. NICT facilitates more extensive lymph node dissection without increasing postoperative complications. These findings support the use of NICT as a viable neoadjuvant strategy for ESCC.

Author contributions

(1) Study concept and design: J.S., B.Z, (2) Analysis and interpretation of data: Z.J., J.N.Z., J.Z, (3) Drafting of the manuscript: Z.J., J.N.Z., J.Z, (4) Critical revision of the manuscript for important intellectual content: J.S., B.Z, (5) All authors reviewed the manuscript.

Funding

None.

Data availability

All data generated or analysed during this study are included in this published article.

Declarations

Ethical approval and consent to participate

Not required.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.