Efficacy and safety of neoadjuvant immunotherapy combined with chemotherapy for resectable esophageal cancer: a systematic review and meta-analysis

Introduction

Malignant esophageal cancer is one of the most common tumors, with a large number of new cases reported annually worldwide. This ranks as the sixth most common cause of cancer-related death (1). In Asia, the incidence of esophageal squamous cell carcinoma (ESCC) remains high, with over 90% of patients being pathologically classified as having this type of carcinoma (2,3). However, due to the lack of distinct early signs, many individuals are typically diagnosed when the disease is advanced, significantly impacting long-term survival prospects (4,5). These statistics underscore the significant threat that esophageal cancer poses to human health.

Based on the results of the CROSS study, preoperative neoadjuvant chemotherapy and radiation therapy have been accepted as the recommended treatment for individuals with advanced locally diagnosed ESCC (6). On the other hand, neoadjuvant chemotherapy may significantly increase toxic side effects and postoperative mortality, according to some research (7). A Japanese study, JCOG9907, demonstrated that radiotherapy did not significantly enhance the effectiveness of neoadjuvant chemotherapy (8), and neither treatment approach significantly improved long-term patient survival (9,10). Hence, there is an urgent need to develop a new treatment plan that will enhance patient survival, decrease the occurrence of surgical complications, and improve safety.

Immunotherapy aims to boost the immune response against tumors by inhibiting the interaction between tumor cell surface ligands and T lymphocyte surface receptors. This approach has had a transformative effect on the treatment of several types of cancer, including ESCC. Based on the results of the KEYNOTE-590 trial, immunotherapies may be recommended as palliative treatment for patients with advanced esophageal cancer (11). Immune checkpoint inhibitors have been shown in preclinical trials to provide benefits as preoperative treatment. Immunotherapies may promote the development and growth of new antigen-specific T cells inside tumors, which might result in anti-tumor immune responses (12). Numerous studies have examined the effectiveness and side effects of neoadjuvant immunotherapy, including nivolumab (13), pembrolizumab (14), camrelizumab (15-17), sintilimab (18,19), and toripalimab (20-22). Overall, the utilization of neoadjuvant combined immunotherapy results in higher rates of major pathological response (MPR) and pathological complete response (pCR). However, neoadjuvant immunochemotherapy (NICT) represents a novel treatment approach. It is still unknown whether NICT treatment will complicate surgery, increase risk, or lead to post-surgery complications. In order to treat ESCC, this research aims to investigate the safety and therapeutic effectiveness of esophagectomy following NICT. The aim of this study was to investigate the efficacy and safety of NICT in the treatment of locally advanced resectable esophageal cancer. We present this article in accordance with the PRISMA reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-198/rc).

Methods

Under the ID CRD42023485797, the study protocol was uploaded to the International Prospective Register of Systematic Reviews database.

Search strategy and trial selection

We conducted a search for articles on the clinical effectiveness of immunotherapy for neoadjuvant treatment of resectable ESCC published before November 2023 in China Biomedical Literature Database (CBM), Embase, Cochrane, China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP), PubMed, WanFang and Web of Science. The search keywords included “esophageal cancer”, “neoadjuvant therapy”, “immunotherapy”, “PD-1”, “PD-L1”, and others.

Inclusion criteria: (I) pathological stage II–IVa; (II) experimental group: NICT; (III) control group: neoadjuvant chemotherapy; (IV) outcome: MPR, pCR, adverse reaction rate, short-term efficacy, R0 resection rate, surgical complications, 30-day, 90-day, and 1-year overall survival (OS).

Exclusion criteria: (I) serious information missing on outcome measures; (II) no more than 10 patients enrolled; (III) single-arm trials; and (IV) duplicate publications, case reports, reviews, expert opinions, and reviews.

Data collection

Using the aforementioned search method, two reviewers independently evaluated titles and abstracts to obtain the following data: (I) baseline data for each study; (II) endpoint data, including MPR, pCR, disease control rate (DCR), objective response rate (ORR), surgical complications, R0 resection rate, and Treatment Related Adverse Events (TRAE) incidence; and (III) study characteristics. To ensure that no data were missing or incorrectly classified, each research was examined more than once. A third researcher was consulted to resolve any disputes.

Assessing publication bias and study quality

The quality of the literature was assessed using the Newcastle-Ottawa Quality Assessment Scale (NOS), which comprises eight items. The assessment encompasses aspects such as study population selection, comparability, and outcome evaluation. A total score of 9 is assigned, with articles scoring 6 or higher considered to be of high quality. In the event of disagreement during the assessment, a final decision will be reached through thorough discussion or by consulting a third investigator.

Outcome measures

Adverse events were assessed according to the standard Criteria Guidelines for Adverse Events, Version 4.0 (23), while tumor node metastasis classification (TNM) staging corresponded to the American Joint Committee on Cancer (AJCC), Version 8 (24). After neoadjuvant treatment and surgical removal, pCR was defined as the absence of residual cancer cells in the completely excised cancer material, while MPR was characterized by the presence of fewer than 10% residual tumor cells.

Statistical analysis

Stata 17.0 was utilized for the meta-analysis, and the odds ratio (OR) was used as the pooled analysis measure for binary variables. A significant criterion of P≤0.05 was utilized to determine if there was a difference between the two groups. The I² statistic was employed to measure heterogeneity: If I² was less than 50%, we considered heterogeneity absent and used a fixed-effects model. If I² was 50% or greater, we considered heterogeneity present and used a random-effects model.

Results

Basic information included in literature

After an initial review, a full-text review, a review of the titles and abstracts, and a final review, a total of thirteen research findings were identified in the literature. Please refer to Figure 1 for the search flow. Table 1 presents details about the authors, publication dates, and the number of cases for the 13 studies included in the study characteristics table (25-37).

Figure 1 Literature screening flowchart.

Literature quality evaluation

All 13 articles represent retrospective studies. The NOS scores of all 13 articles are ≥6, indicating a quality that is above average but below excellent. Please refer to Table 1 for details.

Evaluation of efficacy outcomes

The study evaluated the efficacy of neoadjuvant immunotherapy by assessing pCR, MPR, DCR, ORR, and R0 resection rate.

Among the six studies (25-28,30,36) with available pCR data, patients in the NICT group had a significantly higher rate of pCR compared to the chemotherapy group [OR =5.72, 95% confidence interval (CI): 3.40–9.63]. Subgroup analysis by immunotherapy group and surgical method revealed that the McKeown procedure led to a higher pCR rate compared to other surgical procedures. Furthermore, carrelizumab showed a significant advantage over other immunotherapy drugs (OR =6.68; 95% CI: 3.37–13.24), as depicted in Figures 2,3.

Figure 2 The forest plot of pCR (drug type). NICT, neoadjuvant immunochemotherapy; NCT, neoadjuvant chemotherapy; CI, confidence interval; OR, odds ratio; pCR, pathological complete response.

Figure 3 The forest plot of pCR (surgical methods). NICT, neoadjuvant immunochemotherapy; NCT, neoadjuvant chemotherapy; CI, confidence interval; OR, odds ratio; pCR, pathological complete response.

Among the three studies (27,29,30) with available MPR data, individuals in the combination group exhibited better response rates than those in the chemotherapy group (OR =3.70, 95% CI: 2.32–5.91) when it came to severe diseases. Subgroup analyses of the immunotherapy revealed significant differences between the carrelizumab study arms (OR =4.60, 95% CI: 2.73–7.75). As seen in Figure 4.

Figure 4 The forest plot of MPR. NICT, neoadjuvant immunochemotherapy; NCT, neoadjuvant chemotherapy; CI, confidence interval; OR, odds ratio; MPR, major pathologic response.

Patients in the immunotherapy group exhibited a higher rate of ORR compared to those in the control group (OR =2.22; 95% CI: 1.44–3.40, P<0.001), as reported in seven studies (26,31-36) that documented ORR, as shown in Figure 5, the subgroup analysis of immunotherapy revealed statistically significant differences between the pembrolizumab trial groups. In all seven of these studies (26,31-36), there was no significant difference in the DCR between the NCT and NICT groups. The subgroup analysis is illustrated in Figure 6, showing a significant difference between the carrelizumab trial groups.

Figure 5 The forest plot of ORR. NICT, neoadjuvant immunochemotherapy; NCT, neoadjuvant chemotherapy; CI, confidence interval; OR, odds ratio; ORR, objective response rate.

Figure 6 The forest plot of DCR. NICT, neoadjuvant immunochemotherapy; NCT, neoadjuvant chemotherapy; CI, confidence interval; OR, odds ratio; DCR, disease control rate.

R0 resection rates were reported in all seven trials (26-28,31,32,35,36). Patients who received NICT had higher R0 resection rates compared to those who underwent NCT alone, as indicated by a review. The groups that received immunotherapy with pembrolizumab (OR =2.77, 95% CI: 1.40–5.48, P=0.003) and sintilimab (OR =5.25, 95% CI: 1.27–21.66, P=0.02) demonstrated significantly higher R0 resection rates than the control group. Based on the surgical technique, the R0 resection rate was significantly increased by left thoracoesophageal resection and esophagogastric (or colon or jejunal) chest/neck anastomosis, or thoracoscopic three incision esophagectomy for esophageal cancer, as demonstrated in Figures 7,8.

Figure 7 The forest plot of R0 resection rates (drug type). NICT, neoadjuvant immunochemotherapy; NCT, neoadjuvant chemotherapy; CI, confidence interval; OR, odds ratio.

Figure 8 The forest plot of R0 resection rates (surgical methods). NICT, neoadjuvant immunochemotherapy; NCT, neoadjuvant chemotherapy; CI, confidence interval; OR, odds ratio.

Adverse reactions and postoperative complications

Eleven trials (26,27,29-37) reporting the incidence of myelosuppression did not find a significant difference between the NICT and NCT groups. The five studies (25-28,36) that reported the incidence of pneumonia did not show any differences between the two groups. Statistically significant differences were found between the carrelizumab study arms (OR =10.15, 95% CI: 2.70–38.15, P=0.001) in seven studies (26,27,29,30,35-37) that investigated the incidence of rash following NCT. The findings revealed that the immunotherapy group had a higher incidence of rash compared to the NCT group (OR =4.69, 95% CI: 1.42–15.49) (Figure 9). Ten studies (25,27,29-32,34-37) reported the incidence of vomiting after neoadjuvant chemotherapy, and there was no statistically significant difference between NICT and NCT (Figure 10). Five studies (25,28-30,36) reported rates of cardiac events, and a meta-analysis showed no difference between the two groups (Figure 11). Two studies (25,28) reported the incidence of postoperative pleural effusion, and a meta-analysis revealed a higher occurrence in patients undergoing NICT. According to Figure 12, individuals with NCT had a 3.99-fold higher risk of experiencing this event compared to those who received combined immunizations.

Figure 9 The forest plot of Rash. NICT, neoadjuvant immunochemotherapy; NCT, neoadjuvant chemotherapy; CI, confidence interval; OR, odds ratio.

Figure 10 The forest plot of vomit. NICT, neoadjuvant immunochemotherapy; NCT, neoadjuvant chemotherapy; CI, confidence interval; OR, odds ratio.

Figure 11 The forest plot of cardiac events. NICT, neoadjuvant immunochemotherapy; NCT, neoadjuvant chemotherapy; CI, confidence interval; OR, odds ratio.

Figure 12 The forest plot of postoperative pleural effusion. NICT, neoadjuvant immunochemotherapy; NCT, neoadjuvant chemotherapy; CI, confidence interval; OR, odds ratio.

Survival

In three studies (25,28,29), there was no difference in 30-day survival between the two groups. According to two studies (28,29), there was no statistically significant difference in the 90-day survival rates in either of the groups. Two studies (26,29) also showed that the immunotherapy group outlived the chemotherapy group by 1 year (OR =10.08, 95% CI: 4.32–23.56, P<0.001) (Figure 13).

Figure 13 The forest plot of survival rate. NICT, neoadjuvant immunochemotherapy; NCT, neoadjuvant chemotherapy; CI, confidence interval; OR, odds ratio.

Assessment of publication bias

The ORR, R0 resection rate, and bone marrow suppression were selected as criteria for evaluation. The funnel plot was generated using STATA 17.0 software for analysis. As shown in Figure 14, the funnel plot displayed a generally uniform distribution overall but was slightly asymmetric, indicating the potential presence of publication bias in the included articles. This bias may be associated with an inadequate sample size or low article quality (Figure 14).

Figure 14 The funnel plot of ORR, R0 resection rate, and bone marrow suppression: assessment of publication bias. ORR, objective response rate.

Sensitivity analysis

Sensitivity analysis was conducted on the pCR of six studies (25-28,30,36). The reliability of the analysis’s conclusions was demonstrated by the lack of any significant differences between the findings before and after conducting a sensitivity analysis (Figure 15).

Figure 15 Sensitivity analysis based on pCR. pCR, pathological complete response; CI, confidence interval.

Discussion

Immunotherapy has advanced rapidly in recent years for patients with ESCC. With studies such as ESCORT, ATTRACTION-3, and KEYNOTE-181, immunotherapy was established as a second-line treatment option in 2019 (38-40). Furthermore, in the same year, the Food and Drug Administration (FDA) approved pembrolizumab for the treatment of programmed death-ligand 1 (PD-L1)-positive (Combined Positive Score ≥10) ESCC that had relapsed, progressed locally, or metastasized (41). Furthermore, as evidenced by the latest phase III research studies KEYNOTE-590 and Checkmate 649 (11,42), individuals with advanced esophageal cancer may benefit from initial treatment with pembrolizumab or nivolumab alongside chemotherapy. These investigations demonstrate the efficacy of immunosuppressants. The National Cancer Center of Japan initiated the JCOG 1804E phase 1 study (clinical trial number NCT03914443) in 2019 to evaluate the effectiveness of preoperative nivolumab in combination with chemotherapy for the treatment of advanced localized esophageal cancer. These clinical trials are advancing immunotherapy research in the field of neoadjuvant therapy for ESCC. At the 2020 ESMO conference, Liu et al. (43) presented the NICE investigation of neoadjuvant camrelizumab in combination with chemotherapy for advanced locally advanced ESCC. All 11 patients in the NICT trial underwent successful operations and achieved R0 resection. Additionally, the pCR rates were 45.4%, a rate comparable to the results of the CROSS study (44).

The study results showed that the immunotherapy group had higher rates of pCR, MPR, ORR, and R0 resection compared to the chemotherapy group. Subgroup analysis of the pCR rate revealed differences among the study groups based on different surgical methods and immune drugs, with the carrelizumab study group showing superior efficacy. The McKeown surgical technique may enhance effectiveness and reduce the incidence of postoperative complications, according to a previous study (45). As a result, it was believed that the types of immunotherapies and surgical techniques had an impact on the pCR rate after neoadjuvant immunotherapy. The analysis of MPR by the immunopharmaceuticals subgroup for the primary pathological response rate revealed statistical differences in MPR between the carrelizumab study groups, further emphasizing the clinical efficacy of immunotherapy. The results of the subgroup analysis of DCR and ORR revealed statistical differences between the pembrolizumab and carrelizumab study groups, respectively. This indicates that there is still a disparity in short-term efficacy among different immune drugs, which may be associated with the programmed cell death protein 1 (PD-1)/PD-L1 levels of patients (46). Subgroup analysis of the R0 resection rate revealed that patients in the pembrolizumab arm who received neoadjuvant immunotherapy were superior to those who received neoadjuvant chemotherapy, indicating a significant improvement in the R0 resection rate with pembrolizumab. It was also found that performing a left thoracic esophagectomy and creating an esophagogastric, esophagocolonic, or esophagojejunal thoracic/collateral anastomosis could result in a higher R0 resection rate, indicating that different surgical methods have a certain influence. The aforementioned factors influence the impact of neoadjuvant immunotherapy on the rates of surgical resection.

In terms of adverse reactions and postoperative complications following neoadjuvant immunotherapy, patients in the NICT group did not experience an increased incidence of bone marrow suppression, pneumonia, vomiting, or cardiac adverse events, indicating a favorable safety profile. However, compared to the control group, the NICT group experienced a significantly higher occurrence of rash. Subgroup analysis revealed statistical differences between the carrelizumab study arms (OR =10.15, 95% CI: 2.70–38.15, P=0.001). This finding suggests that increased use of immunotherapy during neoadjuvant therapy may elevate the likelihood of skin-related adverse events. The examples documented by Shu et al. (47) are consistent with the findings of this study. As a result, when immunotherapy is used in clinical practice, it is necessary to be vigilant for the occurrence of skin adverse events. The study also found that neoadjuvant immunotherapy increased the occurrence of postoperative pleural effusion, which may be associated with the surgical approach.

The survival analysis indicated that there was no difference in the survival rates at 30 and 90 days between the two groups. On the other hand, the group that received neoadjuvant immunotherapy exhibited a significantly higher 1-year survival rate (OR =10.08, 95% CI: 4.32–23.56, P<0.001) compared to the group that received neoadjuvant chemotherapy. This suggests that receiving neoadjuvant therapy in combination with immunization may enhance the long-term survival rate of individuals with advanced locally diagnosed ESCC.

This study has limitations. Firstly, several of the clinical studies included in this meta-analysis are still awaiting completion of their objectives. Analyzing the impact of neoadjuvant treatment on survival parameters such as OS and PFS was not feasible; additional data are required to obtain reliable findings. Furthermore, bias may have resulted from the limited number of included studies, insufficient sample size, absence of randomized controlled trials (RCTs), and reliance on single study types, despite a comprehensive search of previous research. Therefore, to further confirm the findings of this study, additional high-quality research and subsequent network meta-analyses are necessary. Furthermore, there is still uncertainty about the therapeutic effectiveness of different immunotherapy drugs when combined with various surgical techniques. The present study’s limitations also underscore the obstacles that need to be addressed before the implementation of neoadjuvant immunotherapy. Future research will be able to improve control over adverse responses and surgical complications, as well as enhancing patient outcomes and quality of life, by elucidating the underlying causes of each issue.

Conclusions

Neoadjuvant immunotherapy has shown promising efficacy in patients with locally advanced ESCC; however, it is linked to a higher occurrence of adverse events. Therefore, its use in clinical practice should be carefully considered.

Acknowledgments

Funding: This study was supported by Scientific Research Project of Higher Education Department of Anhui Province (No. 2023AH050834).

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-198/rc

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-198/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-198/coif). All authors report that this study was supported by Scientific Research Project of Higher Education Department of Anhui Province (No. 2023AH050834). The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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