Introduction

Neoadjuvant therapy preceding radical surgery has become the established standard care for patients diagnosed with locally advanced esophageal squamous cell carcinoma (ESCC)1. However, the NEOCRTEC5010 randomized clinical trial indicated that the overall 5-year recurrence rate of ESCC after neoadjuvant chemoradiotherapy (NCRT) treatment exceeds 30%2. Therefore, there is an urgent need to explore novel neoadjuvant treatment models in clinical settings.

The integration of immunotherapy into clinical practice has led to the recommendation of utilizing immune checkpoint inhibitors, such as anti-PD-1/PD-L1, in conjunction with radiotherapy and chemotherapy as the primary therapeutic approach for locally advanced and advanced esophageal cancer3,4,5,6. Recently, several clinical trials have incorporated immunotherapy into perioperative care. Various studies have investigated the efficacy and safety of combining neoadjuvant concurrent chemoradiotherapy with immunotherapy (NICRT) for locally advanced esophageal cancer, demonstrating a potentially enhanced antitumor effect. In the PALACE-1

study7 involving patients with ESCC, pembrolizumab was administered following the CROSS chemoradiotherapy regimen. Of the18 patients who underwent radical surgery, 17 achieved R0 resection, with 10 (55.6%) cases achieving pathological complete response (pCR) in the primary tumor lesions and lymph nodes, and 16 (89%) cases achieving major pathological response (MPR). In the PERFECT study8, 85% of 40 patients completed all cycles of atezolizumab, with a pathological complete response rate of 25% (10/40). NCT028440759demonstrates the effectiveness of pembrolizumab in combination with radiotherapy and chemotherapy for esophageal cancer. The trial included 28 patients, 26 of whom underwent surgery; a pathological complete response rate of approximately 46% was achieved.

NICRT has demonstrated good efficacy and acceptable toxicity as a neoadjuvant treatment. However, there are currently no studies that have directly compared it with traditional NCRT. As a result, the treatment responses,Treatment-related toxicities and postoperative complications associated with NICRT in comparison to traditional NCRT remain unclear and require further investigation.Therefore, we conducted a study involving over 300 patients with locally advanced ESCC who underwent neoadjuvant therapy and radical surgery in three hospitals over the past 5 years to investigate the real-world impact of NCRT and NICRT, and we added the data from PALACE-1 for the analysis,focusing on short-term efficacy and safety.

Methods

Patients

This retrospective study included patients diagnosed with ESCC who underwent neoadjuvant therapy and radical esophagectomy in three hospitals between January 2019 and September 2023. The inclusion criteria were patients aged 18–75 years with pathologically confirmed thoracic ESSC, clinical stage T1N + or T2-4aNany (American Joint Committee on Cancer (AJCC) TNM classification, 8th edition). The exclusion criteria included patients with other tumors, those who did not complete the standard neoadjuvant treatment, and those with incomplete treatment information. To increase the number of patients with NICRT, we included data from PALACE-1 for analysis.A total of 309 patients met the inclusion criteria, including 248 and 61 in the NCRT and NICRT groups, respectively (Fig. 1).

Fig. 1
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Flow chart of study design. ESCC esophageal squamous cell cancer, NCRT neoadjuvant chemoradiotherapy, NICRT neoadjuvant chemoradiotherapy combined with immunotherapy, PSM propensity score matching.

Neoadjuvant and surgical treatment options

Patients who underwent preoperative radiotherapy received radiation at doses ranging from 30 to 41.4 Gy(mean plus or minus standard deviation).The radiotherapy technique utilized was intensity modulated radiotherapy (IMRT). All patients were positioned under a large-aperture computed tomography (CT) system while in the supine position, with their hands placed on either side of their body. A large mask was then fixed in place, followed by the positioning of laser light and the performance of an enhanced CT scan. Finally, the CT positioning images were transmitted to the planning system. Each patient was positioned by a radiotherapist and a radiotherapy physiotherapist, with the target area primarily determined by the region affected by the lesion.The preoperative chemotherapy regimen consisted of platinum-based drugs in combination with albumin-paclitaxel (TP regimen), with the chemotherapy dose adjusted as needed based on individual patient tolerance. Additionally, the preoperative immunotherapy regimen involved the intravenous administration of various PD-1 (Programmed cell death-1) . All patients included in this study were deemed suitable candidates for radical esophagectomy. Most patients underwent esophagectomy and/or lymph node dissection under general anesthesia, typically 4–8 weeks following completion of the last neoadjuvant treatment.Surgery was performed using either thoracotomy or minimally invasive esophagectomy, which involved two or three incisions, with bifield lymph node dissection established as the standard of care. In cases with suspicious positive lymph nodes, a three-field lymph node dissection was conducted. The esophagus was reconstructed using a gastric tube, followed by either manual or mechanical cervical anastomosis.

Pathological examination

Pathological TNM staging was conducted in accordance with the AJCC/Union of International Cancer Control (UICC) Staging System, version 8. The pathological samples from each patient were assessed by two experienced pathologists. R0 resection signified curative resection with all-negative margins, whereas the pathological complete response (pCR) indicated the absence of viable tumor cells in both the primary tumor area and resected lymph nodes. The tumor regression grade (TRG) was assessed based on the College of American Pathologists (CAP)/AJCC criteria for pathological assessment following neoadjuvant therapy, serving as a measure of the tumor response to preoperative treatment1.

Postoperative complications

Safety and tolerability were assessed through the evaluation of adverse events (AEs), including serious AEs (grade 3 or higher), in accordance with the NCI Common Terminology Criteria for Adverse Events, version 5.0 (NCI-CTCAE v5.0). Additionally, immune-related adverse events (irAEs) were evaluated based on peer-reviewed management guidelines for irAEs10.Documenting all complications and adverse events occur-ring within 30 days of surgery or during the in-hospital stay after esophagectomy.Pulmonary complications include pneumonia treated with antibiotics on the ward,pleural effusion requiring additional drainage procedure,pneumothorax requiring treatment,Anastomotic Leak defined as full thickness GI defect involving esophagus, anastomosis, staple line, or conduit irrespective of presentation or method of identificatio; Cardiac complication include dysrhythmia atrial requiring treatment ,dysrhythmia ventricular requiring treatment congestive heart failure requiring treatment ,pericarditis requiring treatment11,12.

Statistical analysis

Propensity score matching (PSM) was used to create a well-balanced cohort by considering various explanatory factors. The analysis was conducted using R language (version 4.2.3) to perform 1:3 nearest neighbor matching with a caliper of 0.02 between the NICRT and NCRT groups, while adjusting for potential confounding variables.A logistic regression model was used to calculate the propensity score, which included factors such as age, sex, smoking, alcohol consumption, comorbidities, Karnofsky Performance Status (KPS) score, tumor location, and clinical stage. Categorical variables were presented as total numbers and percentages, and group comparisons were conducted using the chi-square test and Fisher’s exact test. Statistical analysis was performed using SPSS for Windows (version 27.0).

Results

Baseline patient characteristics

A total of 309 patients were included in this study, with 248 and 61 patients in the NCRT and NICRT groups, respectively. The baseline characteristics are shown in Table 1. To reduce confounding factors, we conducted 1:3 PSM with a caliper of 0.02. After matching, 145 and 55 patients were assigned to the NCRT and NICRT groups, respectively. Following PSM, there were no significant differences in the characteristics between the two groups (P > 0.05).

Table 1 Baseline characteristics before and after PSM.
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Comparison of treatment efficacy and perioperative outcomes between NCRT and NICRT

As shown in Table 2,After the PSM, all patients underwent R0 resection. The pCR was 46.90% in the NCRT group compared to 36.36% in the NICRT group (P = 0.180). Following neoadjuvant therapy for positive lymph nodes, both the NCRT and NICRT groups exhibited no significant difference, with rates of 71.93% and 64.44%, respectively (P = 0.354). Furthermore, there was no difference in postoperative TNM stage between the two groups. In terms of primary tumor withdrawal, over 60% of patients in both groups achieved major pathological response (MPR), and there was no difference in TRG between the two groups (P = 0.233).The perioperative outcomes are presented in Table 3. No significant differences were observed between the two groups regarding Operation time, intraoperative blood loss, postoperative hospitalization duration, ICU readmission rates, readmission rates, and 90-day mortality rates. However, with respect to lymph node yield, the NCRT group exhibited a lower yield compared to the NICRT group (P < 0.001).

Table 2 Comparative analysis of pathological outcomes between NCRT and NICT groups before and after PSM.
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Table 3 Perioperative outcomes.
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Comparison of treatment-related toxicities and postoperative complications between the NCRT and NICRT groups

Following neoadjuvant therapy, the majority of patients will encounter treatment-related toxicity, predominantly in the form of hematological toxicity. After PSM, no significant difference in toxicity was observed between the two treatment methods (P = 0.199, Table 4).In terms of postoperative complications, there was no significant difference between the NICRT and NCRT groups after matching(40.69% vs 49.09% P = 0.284,Table 4) . The most common pulmonary complications included pulmonary infection, pleural effusion, atelectasis, and pulmonary edema. Anastomotic leakage with no significant difference observed between the two groups.(P = 0.151,P = 0.763,Table 4) cardiac-related complications predominantly included arrhythmia and myocardial infarction and showed no differences between the two groups.(P = 0.084,Table 4).

Table 4 Incidence of treatment-related toxicities and Postoperative complications.
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Discussion

In this study, we conduceted the first multicenter retrospective analysis to compare the treatment efficacy, perioperative outcomes,treatment-related toxicities and postoperative complications associated with two neoadjuvant therapies (NCRT and NICRT) following radical surgery for locally advanced ESCC. After the PSM , the pCR rate in the NCRT group was similar to that in the NICRT group, and the pCR rates for positive lymph nodes and TRG were similar between the two groups. In addition to the lymph node yield, perioperative outcomes,treatment-related toxicities and postoperative complications did not differ significantly between the NICRT and NCRT groups.

NCRT is commonly used to treat ESCC. Notable clinical trials in this field include the CROSS13 and NEOCRTEC5010 trial2. Although the CROSS trial demonstrated promising outcomes, it primarily focused on adenocarcinoma, limiting its applicability to locally advanced ESCC. In contrast, findings from the NEOCRTEC5010 trial revealed a pCR rate of 43.2% with neoadjuvant chemoradiotherapy, which is consistent with our trial results. Patients who achieve pCR after surgery tend to have a favorable prognosis and longer disease-free survival (DFS), emphasizing the importance of striving for higher pCR rates with neoadjuvant treatments14.

Immunotherapy is used in ESCC because of the high frequency of mutations15,16; therefore, it is likely to benefit from checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) or PD-1 ligand 1 (PD-L1)17. Additionally, radiotherapy and chemotherapy can trigger immunogenic cell death in tumor cells, stimulate an antitumor immune response, enhance the expression of tumor cell surface antigens, and release tumor-related antigens18,19,20. The combination of these treatments with immunotherapy may lead to more effective antitumor outcomes.

In a phase IB clinical study (PALACE-1)7 involving patients with ESCC, pembrolizumab was administered following the CROSS chemoradiotherapy regimen. Among the 18 patients who underwent surgery, the postoperative complete response rate was 55.6%. Another study (NCT02844075)9 included 28 patients with esophageal cancer (26 who completed surgery), with a pCR rate of approximately 46% (12/26) and a 50% incidence of adverse reactions (14/28). Our trial reported a lower pCR rate than both studies, possibly because of the smaller number of patients enrolled in those trials and the inclusion of patients with stage Ib esophageal cancer in the NCT02844075 trial.

Many may assume that the combination of the three anti-tumor treatments in the NICRT group would lead to more severe postoperative complications. However, our trial analysis indicated no significant difference in the most common chest complications, cardiac complications, and anastomotic leakage between the NCRT group and the control group. The morbidity rates for anastomotic leakage and cardiac complications were found to be within acceptable ranges for both groups. Notably, the incidence of chest complications in our trial was higher than that reported in related studies21.This increase may be attributed to surgical factors, such as anastomotic leakage and recurrent laryngeal nerve injury, as well as to the primary lung disease,as well as the trauma associated with surgery and anesthesia experienced by the patients. Our high complication rate may also be influenced by our small sample size or the fact that most patients included were at locally advanced stages, resulting in greater surgical trauma. Future studies with larger sample sizes will be necessary to further assess these risks.

Although the application of immunotherapy does not demonstrate a superior pathological response compared to neoadjuvant chemoradiotherapy, it does not necessarily correlate with improved OS.Studies22,23 indicate that various neoadjuvant treatments yield differing rates of pCR while demonstrating similar OS outcomes. While the pCR rate among patients receiving neoadjuvant chemotherapy is lower than that of those undergoing neoadjuvant chemoradiotherapy, there is no significant difference in OS between the two treatment modalities, and neoadjuvant chemotherapy remains a recommended treatment option according to current guidelines1. These observations suggest that pCR attained through systemic therapy may more effectively translate into improved OS for patients compared to pCR achieved via local therapies, such as radiotherapy.The incorporation of immunotherapy into neoadjuvant treatment may enhance systemic anti-tumor efficacy and theoretically lead to improved OS for patients. However, this potential benefit requires validation through follow-up studies and large-scale, multi-center clinical trials.

However, it is important to note that this study has several limitations. Specifically, As a retrospective study, this research may be subject to potential data collection bias. Consequently,PSM was employed to mitigate any effects of such bias. Furthermore, there was insufficient clinical diagnosis of positive lymph nodes, and histological confirmation of each suspicious lymph node was not conducted via endoscopic ultrasound fine needle aspiration (EUS-FNA). the NICRT group had fewer patients and a shorter follow-up period, which prevented us from obtaining long-term results to compare the efficacy of the two treatments. Ma et al.24 examined the effectiveness and safety of anti-PD-1 antibodies in combination with chemoradiotherapy in locally advanced ESCC; the median progression-free survival in the anti-PD-1+CRT group was nearly double that of the CRT group, and the median overall survival was significantly higher in the anti-PD-1+CRT group. However, it is important to acknowledge that the patients in this study did not undergo surgical intervention and the sample size was small. Additionally, variations in chemotherapy and immunotherapy regimens between the groups may have influenced the neoadjuvant efficacy, although this is an inherent challenge.

Conclusion

Patients with ESCC who underwent NICRT did not show higher rates of a pCR, positive lymph node response, or improved TRG of the primary tumor than those who received NCRT. Furthermore, aside from the lymph node yield, no statistically significant differences observed in treatment-related toxicities, perioperative outcomes, or postoperative complication rates between the two groups. These findings suggest that the short-term efficacy and safety profile of NICRT is promising. However, a substantial number of subsequent phase III clinical trials are required to validate these results and to assess long-term survival outcomes.