Abstract
Background/Aim: Esophageal cancer is a leading cause of death among males worldwide, including Japan, where squamous cell carcinoma is the most common type. Treatment decisions can be complicated, especially for older patients undergoing esophagectomy, which, while effective, is invasive and incurs significant risks.
Patients and Methods: A retrospective review of 126 consecutive patients with esophageal squamous cell carcinoma (ESCC) who underwent open or thoracoscopic esophagectomy between January 2010 and April 2023 was conducted. Older patients aged ≥75 years (n=24) were compared with non-older patients aged <75 years (n=102).
Results: Both estimated Glomerular Filtration Rate (eGFR) and albumin levels were notably lower in older patients with a more extensive medical history and higher American Society of Anesthesiologists Physical Status scores. However, there were no differences in sex, Body Mass Index, or pathological stage. Both groups showed similar characteristics in terms of the esophagectomy approach, field dissection, preoperative treatment, operation duration, bleeding, postoperative complications, and hospital stay. No differences were observed between non-older and older groups regarding overall survival (OS), recurrence-free survival (RFS), and disease-specific survival (DSS) (5-year OS: 63.4% vs. 29.2%, respectively, p=0.119; 5-year RFS: 48.6% vs. 33.9%, respectively, p=0.612; 5-year DSS: 73.2% and 46.2%, respectively, p=0.978). Additionally, multivariate survival analysis indicated that pathological N stage [hazard ratio (HR)=2.13; 95% confidence interval (CI)=1.10-4.12; p=0.025] and pathological T stage (HR=2.16; 95%CI=1.13-4.15; p=0.021) were independent prognostic factors for OS. However, age was not a prognostic factor.
Conclusion: Esophagectomy for patients aged 75 years or older provides comparable long-term outcomes without increasing postoperative complications compared with patients younger than 75 years.
Introduction
Esophageal cancer is a leading cause of global cancer deaths (1). In Japan, it ranks sixth among the leading causes of mortality in males (2), with squamous cell carcinoma being the most common type of esophageal cancer. Esophagectomy for esophageal cancer is highly invasive and associated with a high frequency of postoperative complications and operation-related mortality, especially in older patients aged 75 years and over (3, 4). In recent years, the incidence of postoperative complications has decreased, and survival rates have increased owing to the development of minimally invasive surgery and improved perioperative management (5). Older patients often present with comorbidities and poor nutrition before surgery, making treatment of this population difficult (6-10). This study aimed to compare the characteristics and long-term and postoperative outcomes of older and non-older patients with esophageal cancer.
Patients and Methods
Patients. A database of 153 consecutive patients diagnosed with esophageal squamous cell carcinoma (ESCC) treated with open or thoracoscopic esophagectomy between January 2010 and April 2023 was retrospectively reviewed. In our institution, patients diagnosed with dementia or who scored an American Society of Anesthesia-Performance Status (ASA-PS) rating of 4 or above were excluded from the list of surgical indications. Patients pathologically diagnosed with adenocarcinoma, basaloid squamous cell carcinoma, or melanoma were excluded, and 126 consecutive patients were enrolled. Patients aged ≥75 years were assigned to the older group (n=24), whereas those aged <75 years were assigned to the non-older group (n=102). Before surgery, all patients underwent complete blood count, biochemical tests, blood coagulation, electrocardiography, pulmonary function, and chest and abdominal radiography to evaluate their general condition. Moreover, ASA-PS was determined for each case. The patients underwent staging workups, including contrast-enhanced computed tomography, positron emission tomography, and esophagogastroduodenoscopy with biopsies, and were classified according to the Japanese Classification of Esophageal Cancer (11th edition) (11).
Surgical procedures. Conventional transthoracic esophagectomies were performed using either right thoracotomy or thoracoscopic surgery, featuring meticulous two- or three-field lymphadenectomy. Reconstruction strategies involved antesternal, retrosternal, or posterior mediastinal routes and cervical or intrathoracic anastomosis. The standard procedural adjunct is jejunostomy catheter placement to facilitate postoperative enteral nutrition.
Patient management. The treatment strategy followed the 2017 Guidelines for Diagnosis and Treatment of Carcinoma of the Esophagus of the Japan Esophageal Society (12). Patients diagnosed with clinical stage II or III ESCC received neoadjuvant chemotherapy (NAC) or radiotherapy alone. The NAC regimen included either DCF (cisplatin 70 mg/m2 on day 1, 5-fluorouracil 750 mg/m2 on days 1-5, and docetaxel 70 mg/m2 on day 1) or FP (cisplatin 80 mg/m2 on day 1 and 800 mg/m2 5-fluorouracil on days 1-5).
A maximum of three courses were administered and repeated every 3-4 weeks. In cases with Grade 3 or higher adverse events, the drug dosage was reduced by 20%. Cisplatin was discontinued in the presence of renal dysfunction.
The patients were followed up at our outpatient clinic two weeks after discharge and every 2-3 months afterward, with laboratory tests. These include the detection of serum tumor markers such as carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9. Imaging, including computed tomography (CT), was performed every six months or as needed to monitor recurrence.
Ethics statements. This study was approved by the Ethics Committee of Shinshu University School of Medicine (approval no. 4886). It was conducted in accordance with the principles outlined in the Declaration of Helsinki. All patients were provided with complete information about the study, and written informed consent was obtained from all patients before enrollment. Data were analyzed retrospectively and anonymously based on medical records, and the authors did not have access to any identifying patient information or direct access to the study participants.
Statical analysis. The χ2 test was used to compare categorical variables, while continuous variables were compared using the Mann-Whitney U-test. The log-rank test was used to assess overall survival (OS), recurrence-free survival (RFS), and disease-specific survival (DSS). OS was defined as the period from the date of surgical resection to the date of death from all causes. RFS was defined as the duration between the surgical resection date and the recurrence or death date. DSS was defined as the period from surgical resection to death due to ESCC. The Cox proportional hazards model was used for multivariate analysis of significant predictive variables in the univariate analysis and to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). p-Values<0.05 were considered statistically significant. Statistical analyses were performed using JMP Pro 17 software (SAS Institute Inc., Cary, NC, USA).
Results
Patient characteristics. Figure 1 illustrates a schematic of the study design. Between older and non-older patients, sex, Body Mass Index (BMI), pathological T stage, pathological N stage, and pathological stage had similar distributions. However, the older group had significantly lower estimated glomerular filtration rate (eGFR), lower preoperative albumin levels, more extensive medical histories, and higher ASA-PS scores (Table I).
Participant flow of this study.
Patient characteristics.
Surgical outcomes. The esophagectomy approach, number of field dissections, preoperative treatments (chemotherapy, radiation, or chemoradiation therapy), surgical time, amount of bleeding, number of postoperative complications (Grade III or higher in the Clavien-Dindo classification), and hospitalizations did not differ between the groups (Table II). Moreover, the causes of death did not differ between groups, whereas the number of deaths due to other diseases tended to be higher in the older group than in the non-older group (9.8% vs. 25.0%, p=0.062).
Surgical outcomes.
Long-term outcomes. Survival curves are shown in Figure 2. The OS, RFS, and DSS were not significantly different between non-older and older patients with ESCC (5-year OS: 63.4% vs. 29.2%, respectively; p=0.119; 5-year RFS: 48.6% vs. 33.9%, respectively; p=0.612; 5-year DSS: 73.2% and 46.2%, respectively; p=0.978) (Figure 2A-C). Additional OS curves were created based on pathological stages 0 and I (Figure 3A) or pathological stages II and III (Figure 3B). According to these curves, the OS in the non-older group was significantly better at pathologic stage 0 or I than that in the older group (5-year OS: 93.6% vs. 25.0%, respectively; p<0.001). For pathological stage II or III, the OS in the non-older group was similar to that in the older group (5-year OS: 48.1% vs. 31.4%, respectively; p=0.956).
Kaplan-Meier survival curves for older and non-older groups. A) The overall survival curves for all patients stratified based on age (p=0.119). B) The recurrence-free survival curves for all patients stratified according to age (p=0.612). C) The disease-specific survival curves for all patients stratified according to age (p=0.978).
Kaplan-Meier survival curves for the older and non-older groups based on stage. A) Overall survival curves for patients based on pathological stage 0 or I stratified by age (p<0.001). B) Overall survival curves for patients based on pathological stage II or III stratified by age (p=0.956).
Prognostic factors for long-term outcomes. Univariate survival analysis revealed that pathological N and T stages were prognostic factors for OS. Age was not a significant prognostic factor. Additionally, multivariate survival analysis indicated that pathological N stage (HR=2.13; 95%CI=1.10-4.12; p=0.025) and pathological T stage (HR=2.16; 95%CI=1.13-4.15; p=0.021) were independent prognostic factors for OS (Table III). Furthermore, pathological N stage (HR=1.96; 95%CI=1.15-3.35; p=0.014) and pathological T stage (HR=2.45; 95%CI=1.40-4.28; p=0.002) were also independent prognostic factors for RFS (Table IV). Age was not a prognostic factor for RFS.
Uni- and multivariate analyses of the prognostic factors for overall survival.
Uni- and multivariate analyses of the prognostic factors for recurrence-free survival.
Discussion
This study was conducted to examine the treatment strategies and outcomes in older patients aged 75 years or older with ESCC who underwent open or thoracoscopic esophagectomy at our institution. In Japan, patients aged 75 years or older are defined as “latter-stage” older people (13), providing a basis for the patient assignments in this study. Although eGFR, preoperative albumin level, medical history, and ASA-PS scores were worse in the older group than in the non-older group, there were no significant differences in the surgical short- and long-term outcomes among the age groups, and therefore, these did not emerge as prognostic factors. Thus, these results suggest that surgery is an appropriate treatment option for older patients.
Ando et al. reported that preoperative chemotherapy improved long-term outcomes in patients with localized advanced squamous cell carcinoma of the thoracic esophagus (14). However, they did not consider patients aged 75 years and older. In our study, the older group had a significantly higher incidence of renal dysfunction than the non-older group. However, reducing the dose of neoadjuvant chemotherapy drugs, especially cisplatin, may have contributed to the comparable long-term results between the two groups, as previously reported (15, 16).
After surgery for esophageal cancer and neoadjuvant therapy, the risk of malnutrition increases, which can affect subsequent adjuvant treatment regimens (17). Malnutrition and frailty have been shown to significantly influence prognosis and treatment outcomes in patients with esophageal cancer, particularly in older populations (18, 19). Although the optimal route for early enteral nutrition remains unclear, it is widely accepted that establishing early enteral nutrition is crucial (20–23). The older group had a significantly higher number of patients with low nutritional status than the non-older group. However, early enteral nutrition via jejunostomy may reduce complications in older patients.
Depending on the stage, it may be important to adjust treatment strategies. Specifically, in this study, there were no notable differences in OS between the older and non-older groups in patients with stage II and III disease. However, in stages 0 and I, the older group exhibited markedly inferior OS compared with the non-older group. In stages 0 and I, a notable difference in OS was observed, with a higher mortality rate from other diseases in the older group than in the non-older group. However, in stages II and III, the survival rate in the non-older group declined owing to an increase in deaths from the original disease compared with stages 0 and I. These factors may be responsible for the observed differences in OS according to the stage. Hamomoto et al. reported that in stage 0, endoscopic resection is the preferred initial treatment. If the disease is not curable, the Charlson comorbidity index can be used to determine whether surgery is necessary (23). Furthermore, it has been suggested that surgery, or chemoradiotherapy (CRT), should be considered a treatment option for stage I ESCC (24). Kato et al. concluded that CRT is a viable treatment option for stage I ESCC and is not inferior to surgery (25). However, older patients were not specifically assessed. The findings of our study indicate that less invasive treatments, such as CRT, may be a preferable option to surgery for older patients with ESCC in stages 0 and I because of the inferior outcomes observed in this patient population compared with those observed in non-older patients.
It should be noted that this study is not without limitations. First, the treatment plan for ESCC has undergone periodic changes. For example, open-chest surgery was common in the past, whereas NAC was introduced only recently. It is ideal to compare cases treated using the same treatment strategies. Second, it is important to note that this study has limitations owing to its narrow focus on a single institution and small sample size. Third, the retrospective nature of this study introduced a potential selection bias. In our institution, patients diagnosed with dementia or who had the American Society of ASA-PS rating of 4 or above were excluded from the list of surgical indications. Patients with dementia were excluded due to potential postoperative and intestinal fistula management issues. Therefore, it is crucial to discuss the suitability of esophagectomy for patients while considering their cognitive function.
In conclusion, esophagectomy in older patients produces long-term outcomes comparable to those in younger patients, without increased postoperative complications. Age alone should not discourage esophagectomy for the treatment of esophageal cancer in older patients. This highlights the feasibility of esophagectomy in older patients with ESCC.
Footnotes
Authors’ Contributions
T. Iguchi: data curation formal analysis and writing–original draft. S. Nakamura: conceptualization and data curation. M. Kitazawa: conceptualization and supervision. Y. Yamamoto: data curation. S. Miyazaki: data curation. N. Hondo: methodology. M. Kataoka: data curation. H. Tanaka: data curation. R. Aoki: data curation. P. Yonghan: data curation. Y. Soejima: conceptualization, supervision, and writing–review & editing.
Conflicts of Interest
The Authors declare no conflicts of interest in relation to this study.
Funding
This study did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors.
- Received March 15, 2025.
- Revision received April 1, 2025.
- Accepted April 2, 2025.
- Copyright © 2025 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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