Clinical efficacy and safety of immunotherapy after concurrent chemoradiotherapy in advanced esophageal cancer

Abstract

Purpose

To investigate the efficacy and feasibility of PD-1 antibody combined with concurrent chemoradiotherapy in patients with esophageal cancer.

Methods

From July 2020 to October 2023, 15 patients with esophageal cancer in Zhejiang Quhua Hospital were treated with PD-1 monoclonal antibody after concurrent chemoradiotherapy. The incidence of adverse reactions was recorded throughout the treatment period. The Kaplan-Meier survival analysis was used to estimate median overall survival (OS) and progression-free survival (PFS).

Results

All 15 patients were enrolled, with a median follow-up of 23.0 months (ranging from 6.0 to 37.5 months). The 1-year OS rate was 93.3%, and the 2-year OS rate was 46.7%. No treatment-related deaths were reported.

Conclusion

Concurrent chemoradiotherapy combined with PD-1 antibody yielded encouraging survival outcomes in patients with esophageal cancer, and this regimen deserves further clinical exploration.

Introduction

As one of the most common cancers in the world, esophageal cancer (EC) shows a higher incidence and worse prognosis in elderly patients [1]. In our clinical region, the incidence of advanced esophageal cancer is significantly higher in male patients than in females. China is one of the regions with a marked prevalence of esophageal cancer worldwide, and its morbidity and mortality account for about 50% of the world [2]. Esophageal cancer in China is mainly esophageal squamous cell carcinoma (ESCC), accounting for more than 90%. The most general treatment is surgery and radiotherapy. Although the 5-year survival rate has increased to about 50% [3], more than half of patients will relapse after surgery. The early symptoms of esophageal cancer are atypical, and most patients are diagnosed in the middle and late stages, which leads to a poor prognosis [4]. Concurrent chemoradiotherapy is the standard care for unresectable, locally advanced esophageal cancer, but its clinical benefits are very limited [5]. Nowadays, the treatment of esophageal cancer includes surgery, radiotherapy and chemotherapy, but the treatment effect remains unsatisfactory. These days, in addition to traditional regimens such as radiotherapy and chemotherapy, the use of immune checkpoint inhibitors (ICIs) has improved the prognosis of esophageal cancer patients. The immune system plays a crucial role in the development and progression of tumors, regulating the survival, growth, recognition, and elimination of tumor cells [6]. Inducing an effective anti-tumor immune response is a multi-step and complex process. Programmed cell death protein 1 (PD‑1) monoclonal antibody refers to a class of immune checkpoint inhibitors that includes camrelizumab, pembrolizumab, tislelizumab, and sintilimab. These agents act by blocking the interaction between programmed death-ligand 1 (PD-L1) on tumor cells and PD-1 on the surface of T cells, thus inhibiting their suppressive effect on T cells [7]. Compared to traditional treatment, immunotherapy has enhanced the efficacy of patients with esophageal cancer, prolonged survival, and caused minimal toxic side effects, bringing a new dawn for the treatment of esophageal cancer. Immune consolidation therapy is a form of immunotherapy administered after definitive treatment to sustain disease control and reduce the risk of recurrence. However, the lack of phase III clinical trial data on the use of PD‑1 monoclonal antibody consolidation therapy following concurrent chemoradiotherapy in esophageal cancer is a limitation. Therefore, this study aims to investigate the clinical efficacy and safety of concurrent chemoradiotherapy followed by PD-1 monoclonal antibody consolidation therapy in esophageal cancer, as well as explore the correlation between the adverse reactions of immunotherapy and the prognosis of patients.

Materials and methods

Participants information

This retrospective analysis was conducted on 15 patients with advanced esophageal cancer admitted to Quzhou Hospital of Zhejiang Medical and Health Group (Zhejiang Quhua Hospital) from July 2020 to October 2023. All eligible patients were consecutively recruited from real-world clinical cases. The cohort consisted of 14 males and 1 female, with ages ranging from 59 to 90 years; 5 patients had a history of smoking, and 4 had a drinking history. 2 patients had cancer in the upper esophagus, and 13 patients had cancer in the middle and lower esophagus. Inclusion criteria: (1) Histologically confirmed esophageal squamous cell carcinoma; (2) Stage III-IV; (3) Received radical radiotherapy ± concurrent chemotherapy; (4) According to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria, disease control (stable disease or partial response) without progression, recurrence or metastasis was confirmed by regular imaging evaluation (CT/MRI/PET-CT) at 4–8 weeks after completion of radiotherapy, with indications for immune consolidation therapy. Exclusion criteria: (1) Severe comorbidities in internal medicine; (2) History of other active or previous malignant tumors within the past 5 years; (3) Eastern Cooperative Oncology Group (ECOG) score ≥ 3 points, or difficulty in tolerating treatment; (4) Discontinuation of treatment due to serious adverse reactions. All patients signed informed consent, and the study has been approved by the ethics committee of Quzhou Hospital of Zhejiang Medical and Health Group.

Treatment

1) Radiotherapy regimen: All patients received intensity-modulated radiation therapy (IMRT), with a radiation dose of 50.4 Gy/28 fractions, 5 times per week, meanwhile the doses to organs at risk were within the reference limits.

2) Concurrent chemotherapy regimen: Adjust the dose according to the patient’s body surface area, and administer 40-60 mg of Tegio capsules orally twice daily for chemotherapy, from the first day of radiotherapy to the end of radiotherapy or from Monday to Friday of radiotherapy days.

3) Immunotherapy: 4–6 weeks after the end of radiotherapy, PD-1 monoclonal antibody was administered. Medication selection is based on the patient’s economic status, drug tolerance and personal willingness. The efficacy and safety of different PD-1 inhibitors for advanced esophageal cancer have been verified in multiple clinical studies. If there is no indication of discontinuation, immunotherapy should be continued for 2 years. Discontinuation criteria include tumor progression, initiation of other treatments, or the onset of severe treatment-related adverse reactions.

Observation Indicators

1) Efficacy and safety: The therapeutic effect in patients is evaluated 3–4 weeks after the completion of radiotherapy and after 2 cycles of immunotherapy, according to RECIST 1.1; and monitoring for the occurrence of adverse drug reactions during the treatment, through laboratory tests and physical examinations, with grading assessment according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, supplemented by the Radiation Therapy Oncology Group (RTOG) grading criteria.

2) Survival: Follow-up was conducted by phoning patients and gathering outpatient and inpatient medical records. The follow-up period started from the date of diagnosis, with a follow-up rate of 100%. No patients were lost to follow-up or withdrew from the study during the observation period. Outcome measures included objective response rate, overall survival (OS), and progression-free survival (PFS). Tumor response was assessed within 3 months after the completion of concurrent chemoradiotherapy combined with immunotherapy. PFS was defined as the time from the start of treatment to disease progression; OS was defined as the time from the start of treatment to the date of follow-up cut-off (20th September 2024) or death.

Statistical methods

SPSS 22.0 software was used for statistical analysis. Enumeration data were presented as frequencies and percentages (%). The χ² test or Fisher’s exact test was used for intergroup comparisons. Survival rate comparisons are calculated using the Kaplan-Meier method, and survival differences are compared using the log-rank test. P < 0.05 indicates statistical significance.

Results

From July 2020 to October 2023, a total of 15 patients with esophageal cancer who received concurrent chemoradiotherapy combined with PD-1 monoclonal antibody immune consolidation therapy were enrolled. The clinical characteristics of the patients are shown in Table 1. The median age of all patients was 74 years. The majority of the patients were male, and the tumor stages were mainly stage III-IV, with 11 patients in stage III and 4 patients in stage IV. Among the 15 patients, 12 received camrelizumab as consolidation therapy.

Table 1.

Characteristics of patients

Characteristic	Data (N = 15)
Age
Median (range)	74(59-90)
Sex
Male	14
Female	1
Smoking history
Yes	5
No	10
Drinking history
Yes	4
No	11
Hypertension
Yes	7
No	8
Diabetes
Yes	2
No	13
Location
Upper thoracic segment	2
Middle/inferior thoracic segment	13
T stage
T1-2	3
T3	10
T4	2
Disease stage
IIIA-IIIB	11
IV	4
PD-1 inhibitors
pembrolizumab	1
camrelizumab	12
sintilimab	1
toripalimab	1

As of September 20, 2024, all 15 patients were included in the response analysis, no one achieved complete remission, 9 cases (60%) had partial remission, 4 cases (26.7%) remained stable, and 2 cases (13.3%) showed progression. The objective response rate (ORR) was 60% and the DCR was 86.7%. Details are shown in Table 2.

Table 2.

Clinical response

Response Number of Cases (%)	Number
CR	0 (0)
PR	9 (60.0)
SD	4 (26.7)
PD	2 (13.3)
ORR	9 (60.0)
DCR	13 (86.7)

Data are n (%). CR = complete response. PR = partial response. SD = stable disease. PD= progressive disease. ORR= objective response rate. DCR= disease control rate

The main immune-related adverse event (irAE) of the patients was hematological toxicity. 13 patients had varying degrees of bone marrow suppression in total, including 2 cases of grade III or above bone marrow suppression, all within a controllable range. Non-hematological toxic adverse reactions were mainly capillary hyperplasia and drug-induced liver function damage. There were no deaths during the treatment period (Table 3).

Table 3.

Immune-related adverse events

Immune-related adverse events	All grade	≥ Grade 3
Anemia	12	2
Hypothyroidism	0	0
Dermatitis	1	0
Lung infection	1	0
Hepatic dysfunction	2	0
Autoimmune myocarditis	0	0
Reactive capillary hemangioma	3	0

Using the Kaplan-Meier method to evaluate the survival status of patients, the follow-up time of 15 patients ranged from 6 to 37.5 months, with a median follow-up time of 23 months. The median PFS was between 6 and 93 months, with a median PFS of 19 months (95%CI 6–93); the median OS reached 23 months (95%CI 11–100). The 1-year OS rate was 93.3%, and the 2-year OS rate was 46.7%, the 1-year and the 2-year PFS rates were 73.3% and 40.0%, respectively (Fig. 1).

Fig. 1.

Survival status of patients

Discussion

The incidence of malignant tumors in China is increasing year by year, especially thoracic malignant tumors represented by lung cancer and esophageal cancer. Esophageal cancer is one of the most common malignant tumors in the world, it has a high incidence and poor prognosis, especially among elderly patients [1]. For locally advanced esophageal cancer, radical chemoradiotherapy is the standard treatment, and its efficacy is equivalent to surgery [8]. However, local recurrence still occurs in 50% of patients after chemoradiotherapy. With the rapid development of immunotherapy, the treatment of ICIs in tumors has been affirmed [9]. KEYNOTE-028, as a multicenter phase I trial, represented the pivotal exploration of ICIs in the treatment of esophageal cancer. The study found that single-agent pembrolizumab treatment for esophageal cancer had an ORR of 30% and good safety. This study demonstrated that pembrolizumab has a certain anti-tumor effect on PD-L1 positive esophageal cancer patients. Compared with the landmark findings of KEYNOTE‑028, our study is consistent with those results and further support the clinical activity of PD-1 inhibitors in this population. Following KEYNOTE‑028, the subsequent publication of clinical trial results such as KEYNOTE-181, ATTRACTION-3, and ESCORT led to the inclusion of pembrolizumab and nivolumab as expert first-level recommended treatment options in the 2020 CSCO Esophageal Cancer Diagnosis and Treatment Guidelines, establishing the important position of immunotherapy in the second-line treatment of advanced esophageal squamous cell carcinoma [10]. These studies have confirmed the good clinical efficacy of immunotherapy in the treatment of advanced esophageal cancer, which has now become a standard first-line and second-line treatment option, prolonging patient survival with minimal toxic side effects.

Animal models have confirmed the synergistic effects of radiotherapy and ICIs [11–12]. Exploring the clinical benefits of chemoradiotherapy combined with immunotherapy in cancer patients has also achieved certain results. The PACIFIC study [13] is an important achievement of clinical radiotherapy combined with immunotherapy. For unresectable stage III NSCLC patients, after receiving concurrent chemoradiotherapy, the use of PD-L1 monoclonal antibody to maintain the treatment of the patient’s PFS period was extended by 11.3 months (16.9 months in the dulaglizumab group vs. 5.6 months in the placebo group), and the 5-year OS rate was 42.9%. The study results also showed that the symptoms, functions or health-related quality of life of patients treated with durvalizumab did not deteriorate. This research outcome has been incorporated into the National Comprehensive Cancer Network (NCCN) clinical practice and has become one of the treatment options for NSCLC after radical radiotherapy and chemotherapy. The ADRIATIC study presented at the 2024 American Society of Clinical Oncology (ASCO) conference [14] studies immune consolidation therapy in limited-stage SCLC. The interim analysis results showed that the mPFS of patients reached 16.6 months and the mOS was 55.9 months after concurrent chemoradiotherapy, bringing dual benefits of PFS and OS to limited-stage SCLC and establishing a new treatment model of immunotherapy consolidation after radiochemotherapy for limited-stage SCLC. Although the comprehensive treatment of radiotherapy and chemotherapy combined with immunotherapy has become the recommended treatment for some malignant tumors, there is still a lack of phase III clinical research reports on radiochemotherapy combined with immunotherapy for esophageal cancer. Similarly, the efficacy of immunotherapy in esophageal cancer is also worth anticipating. A recent systematic review and meta-analysis reported that the mortality rate due to toxic effects from immune checkpoint inhibitors ranged between 0.3% and 1.3% [15]. Among the patients in this study, the median follow-up time was 23 months (95% CI 6–93 ), the 1-year OS rate was 93.3%, the 1-year PFS rate was 73.3%. Two patients experienced Grade 3 or higher toxic reactions. In a previous study [16] (Wang et al.), the interim report showed a median follow-up time of 15 months, with no occurrence of Grade 3–4 toxic reactions, demonstrating good efficacy, but the OS and PFS have not been reached yet. A study by Zhang et al. [17] published in 2021 explored the efficacy and safety of carrelizumab combined with concurrent chemoradiotherapy as a first-line treatment for esophageal cancer. The results showed that the median follow-up of 20 patients was 23.7 months (95%CI 21.9–24.5), with 12-month OS and PFS rates of 85.0% and 65.0%, respectively. Eight patients experienced severe adverse reactions. The results of this study and our research suggest that patients with esophageal cancer may benefit from receiving immunotherapy consolidation therapy after synchronous radiochemotherapy, with good tolerance to toxic reactions. However, due to the small number of patients and the heterogeneity of patient baseline data, bias in results may occur, and future studies should aim to include a larger, multicenter cohort to validate these findings.

The results of this study show that the combination of concurrent chemoradiotherapy and PD-1 monoclonal antibody immunotherapy has an encouraging therapeutic effect on esophageal cancer patients, which can prolong the survival time of patients to a certain extent and has clinical feasibility. Commonly used chemotherapy drugs include paclitaxel, platinum agents (cisplatin/oxaliplatin/carboplatin), fluoropyrimidines (5-fluorouracil/capecitabine), etc. Patients with general conditions permit priority to consider the two-drug combination regimen. It is recommended to administer 35 cycles of PD-1 monoclonal antibody immune consolidation therapy. Due to the limited number of cases contained in this study, our results should be considered preliminary and exploratory conclusions. Additionally, this study has certain limitations, and the findings are preliminary. Therefore, the role of concurrent chemoradiotherapy combined with PD-1 monoclonal antibody immune consolidation therapy in esophageal cancer needs further large sample study to further verify the clinical value of this regimen. In addition, in the comprehensive treatment of radiotherapy combined with immunization, the selection of immunotherapy drugs, the dosage and target area of radiotherapy, and likewise the volume needs to be considered.

Author contributions

HU and LIU wrote the main manuscript text and YANG, CHEN, TONG prepared clinical data and DA, SUN prepared Fig. 1, RAO edited the article and did final checking. All authors reviewed the manuscript.

Funding

Science and Technology Innovation Guidance Fund of Hangzhou Medical College (CX2022019); Special Fund Project of Zhejiang Provincial Medical Association Clinical Medicine (2024ZYC-B100).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.