Assessment of efficacy, safety and survival of tislelizumab as neoadjuvant therapy for locally advanced esophageal squamous cell carcinoma: a real-world data study

Introduction

According to the latest statistics, esophageal cancer results in approximately 511,000 new diagnoses and 445,000 deaths each year, currently ranking 11th in global incidence and 7th in mortality (1). Approximately 85% of cases worldwide are esophageal squamous cell carcinomas (ESCC) (2). While surgery remains the cornerstone of treatment for ESCC, most patients are diagnosed at an advanced or middle stage, and surgery alone is associated with poor outcomes. Based on the CROSS (3) and NEOCRTEC5010 (4) studies, several regions in Western Europe have adopted neoadjuvant chemoradiotherapy (nCRT) followed by surgery as the standard treatment for locally advanced, resectable esophageal cancer and gastroesophageal junction cancer. A 10-year follow-up study by Eyck et al. (5) demonstrated that, compared to surgery alone, preoperative chemoradiotherapy plus surgery significantly improved overall survival (OS), cause-specific mortality, cumulative esophageal cancer mortality, and recurrence rates. However, there was no significant improvement in long-term survival when compared to preoperative neoadjuvant chemotherapy (nCT) (6). Additionally, nCRT is associated with greater toxicity and increased surgical complexity, suggesting that surgery following nCT may be more effective and less complicated for patients with locally advanced ESCC (7). Therefore, based on the findings of the JCOG9907 study (8), nCT is preferred as a treatment option in East Asian regions, such as China and Japan.

In recent years, immunotherapeutic agents, particularly immune checkpoint inhibitors (ICIs), have made significant advancements in cancer treatment (9). Among these agents, programmed cell death protein 1 (PD-1) (10) acts as a T-cell immune checkpoint, modulating immune responses by binding to programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-L2). Antibody therapies that inhibit the PD-1/PD-L1 pathway have demonstrated durable efficacy in a range of advanced cancers. In ESCC, multiple phase III clinical trials, including KEYNOTE-590 (11), CheckMate-649 (12), ESCORT-1st (13), JUPITER-06 (14), and ORIENT-15 (15), have confirmed the efficacy and safety of neoadjuvant immunochemotherapy (nICT) in the treatment of ESCC. Tislelizumab is an anti-PD-1 immunoglobulin G4 (IgG4) monoclonal antibody that, due to its unique binding epitope and kinetics, maximizes the inhibition of PD-1 binding to PD-L1. This mechanism reduces the binding to macrophage FcγR, decreases antibody-dependent phagocytosis, and minimizes the development of drug resistance (16,17). Its dissociation rate is significantly lower than that of pembrolizumab and nivolumab (18). A phase II trial (19) indicated that the 12-month overall survival (OS) rate for patients treated with tislelizumab in combination with chemotherapy was 50% [95% confidence interval (CI): 23–72%], demonstrating a significant improvement in patient survival. Despite the breakthroughs made by tislelizumab in the treatment of ESCC, there remains a lack of comprehensive reporting on its actual efficacy, safety, and long-term prognosis.

This study aims to provide robust and precise evidence to support the clinical application of tislelizumab in the neoadjuvant therapy of ESCC through a retrospective analysis of real-world data. The goal is to optimize treatment regimens, enhance patient prognosis, and promote advancements in treatment strategies for ESCC. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2099/rc).

Methods

Study design

This was a retrospective, single-center, real-world cohort study designed to evaluate the efficacy and safety of tislelizumab combined with chemotherapy as neoadjuvant therapy in patients with surgically resectable ESCC. Data were collected from the electronic medical records of the First Affiliated Hospital of Fujian Medical University between August 2022 and April 2024. This study was approved by the Ethics Committee of Fujian Medical University (No. [2021]300) and was conducted in accordance with the principles outlined in the Declaration of Helsinki and its subsequent amendments. Individual consent for this retrospective analysis was waived.

Participants

From August 2022 to April 2024, patients diagnosed with locally advanced (Stage IIA–IVA) ESCC, as confirmed by pathology, were admitted to the First Affiliated Hospital of Fujian Medical University. After assessment by thoracic surgeons and medical oncologists, they completed neoadjuvant therapy followed by surgical resection.

Patients were enrolled in the study if the following inclusion criteria were satisfied: (I) patients confirmed to have ESCC through endoscopic examination of pathological tissues; (II) all patients were evaluated by experienced thoracic surgeons and found to have indications for preoperative neoadjuvant therapy; (III) complete data on patient treatment status, clinicopathological characteristics, and postoperative complications were available.

The following exclusion criteria were applied: (I) patients who did not undergo surgical treatment after neoadjuvant therapy; (II) patients who did not receive tislelizumab during neoadjuvant therapy; (III) patients with immune deficiency disorders, those undergoing progressive systemic immunosuppressive therapy (prednisone >10 mg/day or other immunosuppressive drugs), individuals with infectious diseases, clinically significant concurrent cancers, intolerance to gastric tube reconstruction, or allergies to paclitaxel albumin-bound and carboplatin; (IV) patients unwilling to undergo long-term follow-up; (V) patients with mental illness; (VI) patients with incomplete clinical data.

Therapy protocol

Pretreatment staging

All admitted patients underwent comprehensive evaluations, which included electronic gastroduodenoscopy with pathological biopsy, esophageal digital radiography, and both plain and enhanced chest computed tomography (CT) scans. Distant examinations were performed, such as whole-body bone scintigraphy, abdominal ultrasound, cranial magnetic resonance imaging (MRI) or CT, neck lymph node (LN) ultrasound, and positron emission tomography-computed tomography (PET-CT). Following assessment by qualified physicians, preoperative neoadjuvant therapy was deemed feasible.

Neoadjuvant therapy

According to the Chinese Society of Clinical Oncology (CSCO) Guidelines for Esophageal Cancer, the treatment regimen included an intravenous infusion of albumin-bound paclitaxel at 135 mg/m² on day 1, cisplatin at 75 mg/m² on day 1, and tislelizumab at 200 mg on day 2. This regimen was administered every 3 weeks as a cycle, with patients receiving a total of 2 cycles of treatment. Throughout the treatment period, symptomatic therapies such as hormone therapy, gastric and liver protection, and anti-allergic measures were provided, along with close monitoring for the occurrence of adverse reactions in the patients.

Surgery

Before surgery, the patients underwent further examinations, including esophagography, chest CT scan and PET-CT, to assess the response to treatment. Radical esophagectomy for esophageal cancer is typically conducted within 4–6 weeks after completing neoadjuvant chemotherapy. The decision to utilize minimally invasive or open surgery was based on the patient’s specific condition. All procedures were performed by chief physicians at the First Affiliated Hospital of Fujian Medical University, each of whom has experience with over 100 esophageal cancer surgeries. Postoperative complications, including hematological toxicity, anastomotic leakage, pleural effusion, and lung infections, were documented in the case report forms for up to 90 days post-surgery.

Follow-up

Follow-up visits were scheduled every 3 months during the first year after the end of treatment, every 6 months in the second year, and then annually at the end of each subsequent year until 5 years post-treatment.

Endpoints

The primary endpoints of this study were the rate of pathological complete response (pCR) and the assessment of the safety of neoadjuvant therapy.

The secondary endpoints included the R0 resection rate, tumor regression grade (TRG), objective response rate (ORR), postoperative complications, OS, and disease-free survival (DFS) rate.

Evaluation criteria

pCR were defined as the absence of any intact tumor cell residue in the surgically resected specimen. Additionally, if a patient was diagnosed with carcinoma in situ following surgical treatment, this was also regarded as achieving pCR. Safety was evaluated based on treatment-related adverse events, immune-related adverse events, and postoperative complications. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (CTCAE 5.0). R0 resection refers to the complete removal of the tumor, with no cancer cells detected in the surgical margin tissue.

TRG was assessed according to the Becker criteria (20). TRG 1a = no residual tumor (complete tumor regression), TRG 1b = residual tumor less than 10% of the tumor bed (near-complete tumor regression), TRG 2 = residual tumor accounting for 10% to 50% of the tumor bed (partial tumor regression), and TRG 3 = residual tumor accounting for more than 50% of the tumor bed. The objective response rate (ORR) was calculated according to the Response Evaluation Criteria in Solid Tumours 1.1 (RECIST 1.1) guidelines: complete response (CR) was declared when all lesions (including scars) were assessed radiologically or endoscopically. Partial response (PR) was indicated when the size of target lesions decreased by ≥30% (LN short diameter >15 mm). Stable disease (SD) is declared when the change in target lesions is within ±20%, and progressive disease (PD) is declared when lesions increases by 20%. Perioperative complications referred to any complications, whether directly or indirectly related to the surgery, that occurred from the day of the procedure up to 30 days postoperatively.

Statistical analysis

Statistical analysis was performed using SPSS 26.0. Count data were expressed as percentages and described using frequency and rate. Survival curves were plotted using the Kaplan-Meier method. Two-sided P value <0.05 was considered to indicate statistical significance.

Results

Baseline demographic and clinical characteristics

The patient flowchart is presented in Figure 1. This study included a total of 59 patients who visited our hospital between August 2022 and April 2024, underwent two cycles of nICT treatment, and 4 patients did not meet surgical criteria due to disease progression and 5 patients declined surgery for personal reasons, finally, 50 patients (85%) completed surgical intervention.

Figure 1 Patient selection diagram. CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.

As shown in Table 1, the majority of patients were male (46/59, 78%), with only 13 female patients. Ages ranged from 39 to 75 years, with 65 years serving as the cutoff. More than half of the patients (37/59, 63%) were aged <65 years, while the total number of patients aged 65 and older was 22 (37%). Despite the high proportion of males, smoking history (14/59, 24%) and alcohol consumption history (3/59, 5%) were not statistically significant. Six patients were diagnosed with diabetes (6/59, 10%), 10 with hypertension (10/59, 17%), and 11 patients (11/59, 19%) had a history of surgery at other sites before the operation. Forty (68%) tumors were located in the middle third of the esophagus, while 15 (25%) patients had tumors in the lower third, and only 4 (7%) tumors were found in the upper third of the esophagus.

Safety and feasibility

As shown in Table 2, during the nICT period, the most common treatment-related adverse events (trAEs) were anemia (33/59, 56%), lymphocytopenia (29/59, 49%), anorexia (15/59, 25%), thrombocytopenia (8/59, 14%), elevated transaminases (4/59, 7%), and leukopenia (3/59, 5%). Immune-related adverse events (irAEs) primarily included rash (1/59, 2%), hypothyroidism (3/59, 5%), and pneumonia (1/59, 2%). Most treatment-related AEs were grade 1 or 2, while all immune-related AEs were grade 1. The incidence of grade ≥3 AEs was 10% (6/59). No patients experienced serious adverse events (grade ≥4), pneumonia, or esophageal bleeding, and no surgeries were delayed due to adverse reactions.

Among these (in Figure 1), a total of 8% (5/59) patients experienced CR, 47% (28/59) patients experienced PR, 37% (22/59) patients had SD, and only 6% (4/59) patients exhibited PD. The overall response rate (ORR) was 56%, while the disease control rate (DCR) was 93%.

Fifty (85%) patients underwent radical esophagectomy within 4–6 weeks after nICT. As shown in Table 3, among these patients, 39 (78%) underwent minimally invasive surgery, while 11 (22%) underwent open surgery. The average operative duration was 338.26 minutes, with a minimum of 180 minutes and a maximum of 485 minutes. The average intraoperative blood loss was 152.8 milliliters, and the average number of LN stations dissected was 30. During the surgery, 31 patients (31/50, 62%) exhibited no adhesions, 11 patients (11/50, 22%) presented with mild adhesions, and 8 patients (8/50, 16%) had significant adhesions that increased the surgical difficulty. One patient experienced a rupture of a pulmonary bulla during the operation and was treated with a retained closed chest drainage tube, ultimately recovering without complications. No intraoperative deaths were reported. Pathologic staging showed 6 patients were classified as stage IIB, 7 as stage IIIA, 40 as stage IIIB and 6 as stage IVA. Postoperative pTNM staging revealed that 11 patients were in stage 0, 1 in stage IA, 3 in stage IB, 8 in stage IIA, 5 in stage IIB, 5 in stage IIIA, and 17 in stage IIIB. Among these patients, 32 (64%) experienced downstaging.

The summary of postoperative complications is presented in Table 4. The most prevalent postoperative complications included lung infection (13/50, 26%), pleural effusion (11/50, 22%), arrhythmia (5/50, 10%), and anastomotic leakage (3/50, 6%). Additional complications included one case (2%) of postoperative anastomotic bleeding and two cases (4%) that required transfer to the intensive care unit (ICU) for further treatment due to the severity of illness. Among these patients, one recovered and was discharged, while another chose to be discharged voluntarily after family members declined to continue treatment. No complications, such as recurrent laryngeal nerve paralysis, anastomotic stenosis, or postoperative chylothorax, occurred, and no patients required reoperation due to surgical complications.

Efficacy

As shown in Table 5, all 50 patients who underwent surgery achieved an R0 resection (50/50, 100%). Eleven patients (22%) attained a pCR in the primary tumor (ypT0N0M0). Based on radiological assessment after neoadjuvant therapy, tumor size reduction was observed in 48 patients.

Based on the postoperative pathological tumor regression grading assessment (Becker grading), 22% were classified as TRG1a (no residual tumor cells), 6% as TRG1b (residual tumor cells <10%), 32% as TRG2 (residual tumor cells 10–50%), and 40% as TRG3 (residual tumor cells >50%). The waterfall plot offers a more intuitive visualization of the distribution of pathological responses in the primary tumor. (as shown in Figure 2).

Figure 2 Waterfall plot of pathological tumor regression in the per-protocol population (n=50), with each bar representing an individual patient. Purple: TRG Grade 3; blue: TRG Grade 2; green: TRG Grade 1b. TRG, tumor regression grade.

Follow-up

We conducted regular follow-ups for all post-operative patients. At the time of analysis, no patients were lost to follow-up. A total of 5 patients (10%) died, all due to tumor-related causes. No cases of recurrence were observed. Only 9 patients (18%) experienced distant metastasis.

In the entire patient cohort, the median disease-free survival (DFS) and median OS have not yet been reached (Figure 3A,3B). The 1-year OS rate was 93.9%, while the 1-year DFS rate was 73.5%. In post hoc analyses of survival (Figure 3C,3D), we found that patients who achieved pCR had significant improvements in DFS (P=0.043; 95% CI: 15.81–19.45), but not in OS (P=0.34; 95% CI: 17.72–20.59) compared to those who did not achieve pCR.

Figure 3 Survival curves. (A) OS of all patients (N=50); (B) DFS curve of all patients (N=50). (C) OS curves of the pCR group (n=11) and the non-pCR group (n=39). (D) Disease-free survival curves of the pCR group (n=11) and the non-pCR group (n=39). DFS, disease-free survival; OS, overall survival; pCR, pathological complete response.

Discussion

This study employed a retrospective analysis to investigate the efficacy, safety, and prognostic performance of tislelizumab in patients with resectable ESCC. By examining real-world data, the study aims to provide a more practical, precise, and reliable evidence base for the clinical application of tislelizumab as a neoadjuvant therapy for ESCC.

In recent years, pCR has garnered significant attention as a critical indicator for evaluating the efficacy of neoadjuvant therapy in pathology. We observed that among patients with ESCC who underwent nCT alone as the sole treatment modality, the pCR rate was only 4.7% (21), 6.4% (5), and 9% (22). In our study, 50 patients received two cycles of neoadjuvant chemotherapy combined with tislelizumab and successfully completed surgery, of which 11 patients (22%) achieved pCR postoperatively. The pCR rate in our study was significantly higher than those in studies where only nCT was administered. This suggests that the use of tislelizumab in nICT can significantly improve pCR rates among patients. Our study’s data are comparable to those from a real-world study conducted by Yang et al. (pCR rate of 25.5%) (23), but are relatively lower than those from studies such as TD-NICE (pCR rate of 50%) (24), NIC-ESCCC2019 (pCR rate of 31.4%) (25), and SIN-NCE (pCR rate of 35.3%) (26). A comprehensive analysis of the differences among these studies indicates that the patients in our study were diagnosed at a relatively advanced stage of cancer at diagnosis (78% were at stage IIIB/IVA). In the field of lung cancer, scholars have noted that increasing the number of preoperative neoadjuvant therapy cycles may enhance the pCR rate (27). However, various reports suggest that while immunotherapy is effective in combating cancer, it may also provoke significant tissue reactions, leading to fibrosis in the surgical area (28,29). In our practice, we observed that increasing the number of immunotherapy administrations resulted in tissue edema and heightened adhesions in the surgical area, rendering some patients intolerant to surgical intervention. Consequently, our patients received only two cycles of neoadjuvant therapy before surgery, which may be one of the reasons for the relatively lower pCR rate in our data. Currently, there is no established optimal number of neoadjuvant therapy cycles. However, two local studies on ESCC, ESONICT-1 (30) and ESONICT-2 (31), reported pCR rates of 22% and 16.7%, respectively, which are comparable to our findings. This coincidence leads us to consider whether there is a correlation with specific lifestyle habits, genetic traits, or other regional factors among local patients, which merits further investigation.

We conducted regular follow-ups with our postoperative patients and calculated the 1-year OS rate at 93.9% and the 1-year disease-free survival (DFS) rate at 73.5%. Studies by Zhang et al. (32), Yin et al. (33), and Guo et al. (34) have reported the prognoses of patients undergoing surgery following neoadjuvant immunotherapy combined with chemotherapy (nICT), with 1-year OS rates of 90.8%, 92.8%, and 89.4%, respectively, and 1-year DFS rates of 68.3%, 86.4%, and 68.2%, respectively. Our study results are comparable to those of previous studies, suggesting that tislelizumab may enhance postoperative survival outcomes for patients. However, our data have a relatively short follow-up period, and additional follow-up results are necessary to confirm the long-term prognosis of tislelizumab. Previous studies have demonstrated that achieving a pCR after neoadjuvant therapy in patients with ESCC significantly reduces the risk of recurrence and prolongs both OS and DFS (35,36). We analyzed the relationship between patients achieving pCR postoperatively and DFS, and the results indicated a significant correlation between pCR and prolonged DFS (P<0.05). None of the patients who achieved pCR had experienced recurrence, metastasis, or death as of the data cutoff date. We analyzed the possible reasons why the P value did not reach significance: First, the number of pCR patients in this study was relatively small (n=11), which may have limited the statistical power; Second, the median follow-up time has not yet been reached, potentially obscuring OS differences; Third, we used the Kaplan-Meier method for survival analysis, which may lack sensitivity for subgroup analyses with small sample sizes.

In terms of safety assessment, this study demonstrated that tislelizumab combined with chemotherapy has an acceptable safety profile in patients with surgically resected ESCC. The proportion of treatment-related adverse events (trAEs) recorded in this study that reached grades 3–4 was 10%. Furthermore, all immune-related adverse events (irAEs) were classified as grades 1–2, and there were no instances in which surgery was delayed or suspended due to adverse events. Compared to the nCRT regimens NEOCRTEC5010 (36) (61.5%) and PALACE-1 (37) (65%), nICT demonstrated superior safety, suggesting that our regimen can offer patients a better treatment experience and enhanced survival benefits. Similarly, when compared to data from other centers, such as CRISEC (18.8%) (38) and RATIONALE-302 (19.4%) (39), our study data also indicated a slight advantage. Although our regimen has significantly reduced the incidence of adverse events (AEs), we must remain highly vigilant, as this is crucial for ensuring patient safety. To prevent AEs, we strive to accurately assess patient risk early in treatment and implement targeted interventions, including timely medication administration. This proactive strategy aims to prevent AEs and alleviate patient discomfort, which may be essential for further reducing the incidence of adverse events.

The primary advantage of this study is its comprehensive review based on real-world data, which truthfully reflects the actual diagnostic and treatment scenarios encountered by patients in clinical practice. However, there are also limitations in this study. First, by focusing solely on patients who completed neoadjuvant therapy and underwent surgery, this study may overestimate the clinical benefits of tislelizumab. Future prospective studies should include all intention-to-treat (ITT) populations receiving neoadjuvant therapy to comprehensively evaluate real-world treatment response and resection rates. Second, as a single-center study, the representativeness of the sample is limited, resulting in reduced applicability of the research conclusions. Furthermore, the postoperative follow-up period is relatively brief, resulting in insufficient mature data to support key prognostic indicators such as OS and DFS. Additionally, as a single-arm trial, this study lacks a control group in its design, which limits the depth and persuasiveness of the research conclusions. Future studies should consider incorporating a control group to more comprehensively evaluate the clinical efficacy of the drug.

Conclusions

In summary, neoadjuvant tislelizumab combined with chemotherapy appears to be safe and feasible in locally advanced ESCC, with limited AEs, a high R0 resection rate, promising pCR rates, controllable postoperative complications, and observable short-term survival benefits. It warrants further validation in large-sample prospective studies. We have planned and initiated a long-term follow-up program and intend to publish related articles in the future, contributing new insights and evidence to the treatment of ESCC.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2099/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2099/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2099/prf

Funding: This study was funded by the Fujian Provincial Health Commission’s Young and Middle-aged Backbone Talent Project (No. 2024GGB08), the Fujian Provincial Finance Department’s Special Fund (No. BPB2022LB), and the University-Industry Research Cooperation Project of Science and Technology, Fujian Province (No. 2020Y4008).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2099/coif). The authors have no 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. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Fujian Medical University (No. [2021]300) and individual consent for this retrospective analysis was waived.

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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