Camrelizumab combined with neoadjuvant docetaxel, oxaliplatin, and S1 as induction therapy for locally advanced esophageal squamous cell cancer: a real-world single-center cohort study

Introduction

Esophageal cancer (EC) is the 11^th most common cancer worldwide and ranks as the 7^th-leading cause of cancer-related mortality (1). In China, the incidence and mortality rates of EC are particularly high, accounting for more than half of the global burden. Over 90% of Chinese patients with EC are diagnosed with esophageal squamous cell cancer (ESCC), with 70% diagnosed at an advanced stage, necessitating comprehensive treatment strategies (2).

The CROSS and NEOCRTEC-5010 trials established neoadjuvant chemoradiotherapy (nCRT) as the standard treatment for locally advanced EC. However, the emergence of immune checkpoint inhibitors (ICIs) has introduced a new therapeutic modality for this disease (3,4). Camrelizumab, a humanized anti-programmed cell death-1 (PD-1) antibody, has shown promise in combination with chemotherapy, offering clinical benefits as first-line treatment in patients with advanced or metastatic EC and as neoadjuvant therapy in locally advanced cases (5,6).

Real-world evidence is crucial for understanding treatment outcomes in a broader context, including patients with comorbidities and those who may not meet strict trial inclusion criteria. We conducted a single-arm, single-center retrospective analysis of 83 patients treated with camrelizumab combined with docetaxel, oxaliplatin, and S1 as preoperative chemotherapy and immunotherapy. Conducted in a real-world setting, this study aimed to evaluate the safety and feasibility of this combined regimen in patients with borderline resectable or unresectable locally advanced ESCC. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2248/rc).

Methods

Study design and participants

A single-arm, single-centered retrospective cohort study was conducted at the Xijing Hospital of Digestive Diseases, Fourth Military Medical University. From March 2020 to May 2023, patients with locally advanced ESCC who underwent neoadjuvant camrelizumab combined with chemotherapy were enrolled based on the following inclusion criteria: (I) age between 18 and 75 years; (II) histologically confirmed ESCC; (III) clinical stage II–IVA disease according to the American Joint Committee on Cancer (AJCC) 8^th edition tumor-node-metastasis (TNM) staging system; (IV) presence of at least one measurable lesion [≥1 cm in diameter on computed tomography (CT) or ≥2 cm in other imaging methods]; (V) the ability to tolerate a liquid diet; and (VI) without distant metastasis. Sample size was determined based on the feasibility of recruiting patients within the study timeframe, with the goal of obtaining preliminary data on treatment efficacy and safety. The experimental protocol conformed to the ethical guidelines of the Helsinki Declaration (as revised in 2013) and was approved by the Medical Ethics Committee of the First Affiliated Hospital of the Fourth Military Medical University (No. KY20212101-F-1). Written informed consent was obtained from all patients before study enrollment.

Procedures

All participants received a regimen consisting of three cycles of camrelizumab (200 mg, intravenous infusion on day 1) combined with chemotherapy. The chemotherapy regimen included docetaxel at 60 mg/m², oxaliplatin at 85 mg/m² administered intravenously on day 1, and oral S-1 on days 1–14 according to the body surface area [BSA; <1.25 m²: 40 mg/time, twice a day (bid); 1.25–1.5 m²: 50 mg/time, bid; >1.5 m²: 60 mg/time, bid], half an hour after breakfast and during dinner orally. One cycle lasted 21 days. Each patient is planned to undergo neoadjuvant camrelizumab plus chemotherapy for 3 to 6 cycles. The efficacy of treatment was assessed based on pre-treatment examination findings. Imaging studies, including contrast-enhanced CT scans of the neck, chest, and upper abdomen, as well as upper gastrointestinal angiography, were conducted before surgery to evaluate the response to neoadjuvant therapy. Surgical management involved McKeown esophagectomy with three-field lymphadenectomy. In our study, resectability was determined through a multidisciplinary team (MDT) approach. The MDT, consisting of surgeons, oncologists, radiologists, and pathologists, reviewed each patient’s case to assess the potential for surgical resection. The determination of resectability was based on the following criteria: clinical staging, performance status, and absence of distant metastasis. Patients who underwent surgical resection were considered for adjuvant therapy based on their postoperative pathological stage. In our clinical practice, treatment decisions for individual patients were based on a MDT evaluation, considering factors such as disease stage, patient comorbidities, and patient preferences for treatment options. Follow-up evaluations were scheduled at 3-month intervals during the initial 2 years following completion of neoadjuvant treatment and at 6-month intervals thereafter.

Outcomes

As this was a real-world study, some patients declined further surgical intervention due to personal reasons. For this subgroup, the primary endpoint was objective response rate (ORR), defined as the proportion of patients achieving complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria. Among patients who underwent surgery, the primary endpoint was the pathological CR (pCR) rate. pCR was defined as an absence of viable tumor cells in the surgical specimens from the primary tumor and all sampled regional lymph nodes. The secondary endpoints included the disease control rate (DCR), defined as the proportion of patients achieving CR, PR, or stable disease (SD) according to RECIST version 1.1; the R0 resection rate, defined as the proportion of patients with microscopically margin-negative resection and no residual tumor in the primary tumor bed; overall survival (OS), defined as the time from the first dose of camrelizumab to death from any cause; progression-free survival (PFS) defined as the duration from treatment initiation to disease progression or death from any cause; and treatment-related adverse events (TRAEs) as assessed using the National Cancer Institute-Common Toxicity Criteria for Adverse Events (NCI-CTCAE) version 5.0. Reactive cutaneous capillary endothelial proliferation (RCCEP) was characterized by the appearance of new, small, red-to-purple papules or nodules on the skin, which are indicative of increased capillary proliferation. The grading was as follows: grade 1: mild skin changes without significant symptoms or functional impairment, not requiring specific treatment. Grade 2: moderate skin changes causing discomfort or aesthetic concern, possibly requiring symptomatic treatment or local care. Grade 3: severe skin changes causing significant discomfort or impacting daily activities, requiring medical intervention or treatment. Grade 4: life-threatening skin changes or those requiring intensive care management.

Statistical analysis

Demographic information and baseline characteristics of the participants were thoroughly analyzed, with categorical variables being presented as counts and percentages. The continuous variables per the normal distribution were expressed by mean ± standard deviation, and a t-test was used. The classified variables were expressed by cases (%), and the Chi-squared test or Fisher exact probability method was used. The median follow-up time was determined using the reverse Kaplan-Meier method. PFS and OS were evaluated using the Kaplan-Meier method. We addressed missing data using a combination of approaches to ensure the robustness and validity of our findings. All statistical analyses were two-sided, and P<0.05 was considered statistically significant. Statistical analyses were conducted using IBM SPSS Statistics 23 (IBM Corp., Armonk NY, USA) for Windows.

Results

Patient characteristics

A total of 83 eligible patients were enrolled in this study (Figure 1), all of whom completed neoadjuvant treatment. Among these patients, 14 underwent surgery, 10 received other treatments due to PD, and 59 declined surgery due to symptomatic remission or personal reasons. The major characteristics of the patients are shown in Table 1. The median age was 61 years, and the age range was 46–75 years. The cohort comprised 75 males and 8 females. Tumors were predominantly located in the middle (n=49, 59.04%) and lower (n=23, 27.71%) regions of the esophagus. Most patients were diagnosed at stages III or IV (55.42% and 38.55%, respectively) and had an Eastern Cooperative Oncology Group performance status (ECOG PS) score between 0 and 1 (61.45% and 38.55%, respectively).

Figure 1 Flowchart of the study. ESCC, esophageal squamous cell cancer; ECOG, Eastern Cooperative Oncology Group.

Efficacy

As shown in Table 2, efficacy assessments were conducted for all 83 patients with advanced ESCC. Among the patients, 24 (28.92%) achieved CR, 40 (48.19%) achieved PR, 9 (10.84%) achieved SD, and 10 (12.05%) had progressive disease (PD). The ORR was 77.11% (64/83), and the DCR was 87.95% (73/83). Among the 14 patients who underwent surgery, the R0 resection rate was 100%, and 28.57% (4 of 14) achieved pCR.

The median follow-up time was 31.0 months. As depicted in Figure 2, the 3-year OS rate was 56.9% [95% confidence interval (CI): 50.7–63.1%], and the 3-year PFS rate was 53.7% (95% CI: 47.4–60%).

Figure 2 Median OS (A) and PFS (B) curves of the patients who received camrelizumab combined with chemotherapy for locally advanced ESCC. OS, overall survival; PFS, progression-free survival; ESCC, esophageal squamous cell cancer.

Safety

The adverse reactions that occurred in 83 patients with advanced ESCC during the administration of camrelizumab and chemotherapy were examined and recorded. Treatment-related complications occurred in 60 of the 83 patients, representing 72.29% of the cohort. Serious adverse reaction (grades 3–4) were observed in 6.02% of the patients.

As shown in Table 3, common adverse reactions (grades 1–2) included RCCEP (59.04%), alopecia (54.22%), nausea (45.78%), leukopenia (42.16%), vomiting (27.71%), fatigue (19.28%), anemia (8.43%), diarrhea (7.23%), thrombocytopenia (4.82%), and immune-mediated colitis (2.41%). Serious adverse reaction (grades 3–4) included leukopenia (3.61%), anemia (2.41%), vomiting (2.41%), thrombocytopenia (1.20%), and fatigue (1.20%). These findings indicate that the toxicity profile of camrelizumab combined with chemotherapy in patients with advanced ESCC is acceptable and manageable.

Discussion

This real-world study evaluated the efficacy and safety of neoadjuvant camrelizumab combined with chemotherapy in patients with locally advanced ESCC. The results demonstrated that this combination therapy provides significant clinical benefits, with an encouraging response rate and manageable toxicity. Among the surgical treatment group, the pCR rate was 28.57%. Additionally, clinical benefits were observed in patients who refused surgery, but the long-term benefits for this group in real-world settings warrant further observation.

The CROSS and NEOCRTEC5010 trials established neoadjuvant nCRT as the standard for neoadjuvant treatment in EC (3,4). Based on the findings of these pivotal studies, nCRT has been established as a standard perioperative treatment for EC. However, the long-term prognosis for patients with ESCC remains poor. Radiotherapy-induced complications not only increase surgical difficulty but also reduce patient quality of life, potentially contributing to worse outcomes (7). Thus far, no clear evidence demonstrating a significant difference in survival benefits between patients receiving nCRT and those receiving neoadjuvant chemotherapy has been published (8,9).

In recent years, immunotherapy combined with chemotherapy has shown exceptional efficacy in the treatment of advanced EC. Furthermore, clinical trials such as KEYNOTE-590, ESCORT-1, CheckMate-648, ORIENT-15, RATIONALE-306, and JUPITER-06 have shown the significant benefits and a manageable safety profile of an ICI combination with chemotherapy in the first-line treatment of patients with EC (10-17).

According to prior research, neoadjuvant immunotherapy combined with chemotherapy is emerging as a promising approach for locally advanced ESCC. The TD-NICE study (18) assessed the efficacy and safety of neoadjuvant therapy with tislelizumab, carboplatin, and nab-paclitaxel in treatment-naïve patients with resectable ESCC. Among the 45 enrolled patients, 80% underwent surgery, with 72% achieving major pathological response (MPR) and 50% achieving pCR. The KEYSTONE-001 trial (19), a phase-II, single-arm, single-center trial evaluated pembrolizumab combined with paclitaxel and cisplatin in patients with resectable locally advanced ESCC. The results included an MPR rate of 73.3%, a pCR rate of 42.2%, an ORR of 95.6%, and a DCR of 100%. The median follow-up was 23.3 months, with 1- and 2-year OS rates of 95.6% and 90.5%, and disease-free survival rates of 95.6% and 86.3%, respectively. The regimen demonstrated significant antitumor activity, including high rates of R0 resection and downstaging, with manageable adverse events and postoperative complications.

Camrelizumab combined with neoadjuvant chemotherapy has shown promising efficacy and manageable safety in treating patients with locally advanced ESCC. The NICE study (20) enrolled 60 patients, among whom 39.2% achieved pCR after two cycles of treatment, with a 98.0% rate of R0 resection during surgery. Common adverse events included leukocytopenia (86.7%), with 56.7% experiencing grade 3 or worse events. The ESCORT-NEO trial (21), a multicenter, randomized, phase III study compared neoadjuvant camrelizumab plus chemotherapy against chemotherapy alone in patients with locally advanced resectable ESCC. The study found that camrelizumab combined with chemotherapy (paclitaxel and cisplatin) significantly improved the pCR rate (15.4% vs. 4.7%) and MPR rates (36.2% vs. 20.9%) compared to chemotherapy (paclitaxel and cisplatin) alone. The R0 resection rates were high (95.7%, and 92.2%, respectively), with a tolerable safety profile and a similar incidence of grade ≥3 TRAEs.

In addition to clinical studies, basic research has provided significant insights into the molecular mechanisms and treatment strategies for ESCC. It is found that elevated expression of MCL1 drives the stemness of ESCC and induces resistance to radiotherapy, highlighting the role of MCL1 in tumor progression and treatment resistance (22). In another study, Liu et al. discovered that high expression of RBM15 is associated with better prognosis in ESCC, suggesting that RBM15 could serve as a potential biomarker for predicting patient outcomes (23). Additionally, a study has evaluated the efficacy of first-line induction or consolidation chemotherapy combined with concurrent chemoradiotherapy, demonstrating that this treatment approach can significantly improve survival rates in patients with ESCC (24). These findings collectively contribute to a deeper understanding of the molecular basis of ESCC and offer promising directions for future therapeutic strategies.

This study suggests that using camrelizumab combined with chemotherapy as induction therapy for patients with locally advanced and potentially resectable ESCC demonstrates strong efficacy. However, only 16.87% of patients underwent surgical treatment due to family opposition, age, or psychological factors. Despite this, clinical benefits were observed in patients who refused surgery and who opted for noninvasive radical radiotherapy or maintenance therapy with camrelizumab. This study highlights the potential significance of camrelizumab combination therapy in various clinical scenarios although a longer observation period and larger sample size are needed to confirm its efficacy and safety.

PD-1 inhibitors combined with chemotherapy in patients with locally advanced ESCC have shown benefits comparable to those in advanced ESCC. Camrelizumab combined with chemotherapy can serve as an effective induction therapy for patients with locally advanced and potentially resectable ESCC, facilitating subsequent surgery or radiotherapy. Moreover, maintenance therapy with camrelizumab extends PFS and OS in these patients.

This study involved several limitations which should be mentioned, including its single-center, retrospective design, and short follow-up period. Additionally, as a real-world study, it enrolled some patients with locally advanced disease at borderline or potentially resectable stages, which, alongside other factors, contributed to a lower surgical rate. Consequently, indicators such as R0 resection rate and pCR rate might have been biased.

Conclusions

This study provides preliminary evidence that neoadjuvant chemotherapy combined with camrelizumab can provide favorable safety and efficacy for treating patients with locally advanced ESCC in real-world clinical settings.

Acknowledgments

We thank all the patients who participated in this trial and their families, as well as the investigators and staff.

Funding: This study was supported in part by grants from the Key Research and Development Project of Shaanxi Province (No. 2022ZDLSF03-04) and the Clinical Research Special Project of Xijing Hospital (No. XJZT24LY32).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2248/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2248/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2248/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2248/coif). S.M. receives grants from Ipsen biopharmaceuticals, consulting fees from Merck, Eisai, BeiGene, BMS, and payments for lectures from Integrity CE, LLC and Academy for Continued Healthcare Learning; serves as Board Member of Esophageal Cancer Action Network, and Panel Member of NCCN, outside the submitted work. The other 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 experimental protocol conformed to the ethical guidelines of the Helsinki Declaration (as revised in 2013) and was approved by the Medical Ethics Committee of the First Affiliated Hospital of the Fourth Military Medical University (No. KY20212101-F-1). Written informed consent was obtained from all patients before study enrollment.

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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(English Language Editor: J. Gray)