Abstract
Background
This study evaluated the association between the risk factors and prognosis for metachronous esophageal squamous cell carcinoma (ESCC) after endoscopic resection (ER) of esophageal cancer in older patients.
Methods
We conducted a retrospective observational study of 127 patients with ESCC who underwent ER from 2015 to 2020. Patients were classified as non-older (≤ 64 years), early older (65–74 years), and late older (≥ 75 years). We analyzed factors associated with poor overall survival and metachronous ESCC after ER using multivariate Cox regression analysis. A metachronous ESCC prediction scoring system was examined to validate the surveillance endoscopy program.
Results
Body mass index (BMI) and Charlson Comorbidity Index (CCI) were significant risk factors for poor overall survival in the multivariate analysis (p = 0.050 and p = 0.037, respectively). Multivariate analysis revealed that age of < 64 years, Lugol-voiding lesions (grade B/C), and head and neck cancer were significantly related to metachronous ESCC (p = 0.035, p = 0.035, and p = 0.014, respectively). In the development cohort, BMI < 18.5 kg/m2, CCI > 2, age < 64 years, Lugol-voiding lesions (grade B/C), and head and neck cancer were significantly related to metachronous ESCC, and each case was assigned 1 point. Patients were classified into low (0, 1, and 2) and high (> 3) score groups based on total scores. According to Kaplan–Meier curves, the 3-year overall survival was significantly lower in the high-score group than in the low-score group (91.5% vs. 100%, p = 0.012).
Conclusions
We proposed an endoscopic surveillance scoring system for metachronous ESCC considering BMI and CCI in older patients.
Supplementary Information
The online version contains supplementary material available at 10.1007/s10388-024-01077-5.
Keywords: Older patients, Endoscopic resection, Metachronous esophageal squamous cell carcinoma, Surveillance
Introduction
Esophageal cancer is the eighth most common disease worldwide and has the sixth highest mortality rate. Further, this disease causes approximately 3.2% of all cancer-related deaths [1–4]. Endoscopic resection (ER) is a minimally invasive treatment method that allows for curative resection and can help preserve esophageal function [5]. Therefore, early diagnosis and prompt treatment are important for the management of this disease. In 2009, the World Health Organization (WHO) identified alcohol-associated acetaldehyde as a group 1 carcinogen [6]. Alcohol consumption is associated with the risk of damage to the esophageal mucosa. Specific risk factors include the amount of alcohol intake, alcohol consumption duration, and alcohol metabolism-related genotypes persisting in the esophageal mucosa [7–9]. Katada et al. [10] reported a relationship between alcohol consumption and the degree of esophageal mucosal damage in head and neck cancer (HNC) associated with field cancerization, as well as between esophageal mucosal damage grade and the risk of developing metachronous esophageal squamous cell carcinoma (ESCC) and HNC. With the advent of a super-aging society, medical care for older adults has become a major social issue. Frailty is associated with decreased quality of life and post-treatment effects among older adult patients, who are likely to have multiple comorbidities [11]. Therefore, this study aimed to evaluate the association between the risk factors and prognosis for metachronous ESCC after the endoscopic treatment of ESCC in older patients. Furthermore, this study examined the background factors associated with appropriate post-treatment care required to maintain the ability to perform activities of daily living and evaluated their associations with the prognosis.
Methods
Patients and study design
This single-center, retrospective, observational study enrolled 127 patients newly diagnosed with ESCC at Tokyo Medical University Hospital between 2015 and 2020. Patients were classified based on the WHO definition into the non-older (≤ 64 years), early-older (65–74 years), and late-older (≥ 75 years) groups [12]. The risk factors for overall survival (OS) were investigated using the American Society of Anesthesiologists (ASA)-Physical Status (PS) (ASA-PS) classification system [13] and the Charlson Comorbidity Index (CCI) [14, 15].
LVL grades
Lugol-voiding lesion (LVL) grades A, B, and C were defined as no LVLs, 1–9 lesions, and ≥ 10 lesions identified with iodine staining, respectively [10].
Follow-up endoscopic examinations post-ER
Patients with LVL grades B and C were expected to undergo endoscopy every 3–6 months while those with LVL grade A were expected to undergo endoscopy every year. The surveillance methods used included white light, narrow band imaging, and iodine staining for all cases following endoscopic treatment.
Definition of synchronous and metachronous ESCC
Synchronous lesions were defined as lesions detected at the time of endoscopy in the endoscopically treated patients, while metachronous lesions were defined as new lesions detected 3 months after-surveillance endoscopy [10, 16].
Statistical analysis
Quantitative data were compared using the Mann–Whitney U test. Categorical data were analyzed using Fisher’s exact test and the χ2 test. OS was defined as the time from ER until death or the last follow-up day. The survival time was measured from the date of the ER to the date of any death or the latest survival confirmation until January 31, 2023. Regarding the metachronous ESCC analysis, the conclusion of the follow-up period was determined to be the last endoscopy date until January 31, 2023. The duration until the metachronous ESCC occurrence was computed from the ER date to the time of detecting metachronous ESCC. Poor OS serves as a prognostic factor for OS. The cumulative incidence was determined as the cumulative morbidity of metachronous ESCC for the first event, and survival curves were calculated using the Kaplan–Meier method. The risk ratio and 95% confidence interval (CI) were estimated using the Cox proportional hazards model. Cox regression analysis was used in the development cohort to select prognostic factors for the scoring system predicting mortality post-ER. Specifically, multivariate analysis was performed for all the factors from the Cox hazard analysis, and those with p < 0.05 in the multivariable model were selected as prognostic factors for the scoring system. These statistical analyses were performed using SPSS software (version 27.0; IBM Japan, Tokyo, Japan). Statistical significance was set at p < 0.05. The optimal cut-off value for the scoring system was determined using Youden’s index, receiver operating characteristic (ROC) curve analysis, and the area under the curve (AUC). Time-dependent ROC analysis was conducted with the R package “time ROC” to handle censored survival data [17].
Results
Characteristics of patients and lesions
Overall, 127 patients were classified into the non-older (41 patients), early-older (46 patients), and late-older (40 patients) groups (Table 1). Metachronous ESCC occurrence was significantly higher in the non-older group than in the early-older and late-older groups (46.3%, 23.9%, and 25.0%, p = 0.045); they were also heavy drinkers (p = 0.004). The ASA-PS score (3–4) was significantly higher in the older (p = 0.013).
Table 1.
Patients’ characteristics
| Patients | < 64 years | 65–74 years | > 75 years | p-value |
|---|---|---|---|---|
| n = 41 | n = 46 | n = 40 | ||
| Age, median (IQR), years | 60 (55–62) | 69 (67–72.3) | 78.5 (77–81) | < 0.001 |
| Sex, male, n (%) | 34 (82.3) | 39 (84.8) | 35 (87.5) | 0.845 |
| BMI, kg/m2, n (%) | 20.8 (19.7–23.2) | 22.3 (19.2–24.9) | 21.7 (19.5–24.0) | 0.261 |
| Multiple ESCCs (1/2/3/4) | 34/5/1/1 | 42/3/1/0 | 35/3/2/0 | 0.684 |
| Metachronous ESCC, % | 46.3 | 23.9 | 25.0 | 0.045 |
| Metachronous ESCC (0/1/2/3/4/5) | 22/14/4/0/1 | 35/9/2/0/0 | 30/8/1/1/0 | 0.040 |
| Drinking alcohol (never/past/current) | 5/6/30 | 8/4/34 | 10/7/23 | 0.197 |
| Heavy alcohol consumption (never/sometimes/frequently) | 6/8/27 | 6/18/22 | 10/9/21 | 0.318 |
| Amount of alcohol intake (never/light/moderate/heavy) | 5/5/7/24 | 6/19/6/15 | 10/14/6/10 | 0.004 |
| Smoking (non-smoker/light/heavy), pack-years | 14/14/13 | 7/15/24 | 11/10/19 | 0.082 |
| Smoking (never/past/current) | 15/25/1 | 7/37/2 | 11/29/0 | 0.059 |
| Grade of LVLs (A/B/C) | 2/8/31 | 4/9/33 | 4/10/26 | 0.544 |
| Observation period, median (IQR), months | 48.3 (33.7–69.5) | 47.6 (35.0–58.4) | 42.0 (27.9–59.0) | 0.347 |
| Metachronous period, median (IQR), months | 33.6 (20.6–49.0) | 43.8 (24.8–55.4) | 33.9 (23.2–49.1) | 0.500 |
| ASA-PS, n (%) | ||||
| 1–2 | 25 (61) | 36 (78.3) | 19 (47.5) | 0.013 |
| 3–4 | 16 (39) | 10 (21.7) | 21 (52.5) | |
| CCI, n (%) | ||||
| 0.1 | 28 (68.3) | 21 (45.7) | 28 (70) | 0.871 |
| > 2 | 13 (31.7) | 14 (30.4) | 12 (30) | |
| Double primary cancer, n (%) | 8 (19.5) | 11 (23.9) | 10 (25) | 0.823 |
| Respiratory disfunction, n (%) | 1 (2.4) | 2 (4.3) | 5 (12.5) | 0.142 |
| Heart disease, n (%) | 0 | 1 (2.2) | 5 (12.5) | 0.018 |
| Liver dysfunction, n (%) | 1 (2.4) | 0 | 0 | 0.355 |
| Renal dysfunction, n (%) | 0 | 0 | 1 (2.5) | 0.377 |
| Diabetes mellitus, n (%) | 5 (12.1) | 6 (13.0) | 2 (5.0) | 0.418 |
| Antithrombotic internal rate, n (%) | 2 (4.8) | 1 (2.2) | 12 (30) | < 0.001 |
Never: < 1 U/week; light: 1–9 U/week; moderate: > 9 to 18 U/week; heavy: > 18 U/week. U = 22 g of ethanol
ASA-PS American Society of Anesthesiologists–Performance Status, BMI body mass index, CCI Charlson Comorbidity Index, ESCC esophageal squamous cell carcinoma, IQR interquartile range, LVL Lugol-voiding lesion
Treatment outcomes of ER
The en bloc resection rates of all groups were high (95.9%, 94.1%, and 98%, respectively), the median hospital stay was 7 days, and no differences were observed in adverse events for all groups. Surveillance endoscopy post-ER was performed every 6 months for all groups (Table 2).
Table 2.
Treatment outcomes of ER
| < 64 years | 65–74 years | > 75 years | p-value | |
|---|---|---|---|---|
| n = 49 | n = 51 | n = 50 | ||
| Lesions | ||||
| Size, median (IQR), mm | 19 (12–27) | 20 (11–28) | 20 (11–28) | 0.555 |
| Location (Ce/Ut/Mt/Lt) | 0/3/31/15 | 0/6/38/7 | 2/4/39/5 | 0.048 |
| Macroscopic type (elevated/flat/depressed) | 4/24/21 | 5/22/24 | 4/24/22 | 0.813 |
| EMR/ESD | 5/44 | 11/40 | 9/41 | 0.479 |
| En bloc resection rate, % | 95.9 | 94.1 | 98 | 0.794 |
| Invasion depth, n (%) | ||||
| Pre-operative diagnosis depth, n (%) | 0.409 | |||
| EP | 19 (38.8) | 20 (39.2) | 16 (32) | |
| LPM | 26 (53.1) | 23 (45.1) | 24 (48) | |
| MM/SM1 | 4 (8.2) | 8 (15.7) | 10 (20) | |
| Pathological diagnosis depth, n (%) | 0.367 | |||
| EP | 17 (34.7) | 22 (43.1) | 16 (32) | |
| LPM | 24 (49.0) | 20 (39.2) | 21 (42) | |
| MM | 5 (10.2) | 6 (11.8) | 9 (18) | |
| SM1 | 2 (4.1) | 3 (5.9) | 2 (4) | |
| SM2 | 1 (2.0) | 0 | 2 (4) | |
| Lymphovascular invasion, n (%) | 2 (4.1) | 0 | 2 (4) | 0.538 |
| Vascular invasion, n (%) | 2 (4.1) | 1 (2.0) | 5 (10) | 0.325 |
| Horizontal margin, n (%) | 5 (10.2) | 0 | 4 (8) | 0.149 |
| Vertical margin, n (%) | 2 (4.1) | 2 (3.9) | 2 (4) | 0.997 |
| Patients | < 64 years | 65–74 years | > 75 years | |
|---|---|---|---|---|
| n = 41 | n = 46 | n = 40 | ||
| Adverse events, n (%) | 4 (8.2) | 3 (5.7) | 3 (6.0) | 0.852 |
| Stenosis, n (%) | 3 (7.3) | 0 | 2 (5.0) | 0.200 |
| Perforation, n (%) | 1 (2.4) | 0 | 1 (2.5) | 0.564 |
| Pneumonia, n (%) | 0 | 1 (2.2) | 0 | 0.415 |
| Mediastinal emphysema, n (%) | 0 | 2 (3.3) | 0 | 0.169 |
| Length of hospital stay for ER, median (IQR), days | 7 (7–8) | 7 (7–9) | 7 (7–8) | 0.622 |
| Endoscopic interval, median (IQR), months | 6 (6–6) | 6 (6–7) | 6 (6–6) | 0.210 |
Ce cervical esophagus, EMR endoscopic mucosal resection, EP epithelium, ER endoscopic resection, ESD endoscopic submucosal dissection, IQR interquartile range, LPM lamina propria muscle, Lt Lower thoracic esophagus, MM muscularis mucosae, Mt middle thoracic esophagus, SM submucosal layer, Ut upper thoracic esophagus
Risk factors associated with poor 3-year survival for patients with ESCC who underwent ER
Body mass index (BMI) < 18.5 kg/m2 had a significant effect on the univariate analysis and was a significant factor in the multivariate analysis (p = 0.050). The 3-year survival rates were 99% and 89.5% according to the age groups with BMI > 18.5 and < 18.5 kg/m2, respectively (p = 0.008) (Fig. 1a). The receiver operating characteristic (ROC) curve analysis demonstrated that the area under the ROC curve was 0.757 (95% CI 0.547–0.966), and the optimal CCI cut-off value was 2. Additionally, the OS risk was investigated based on the CCI; 3-year survival rates of 98.3% and 90.3% were observed in patients with CCI 0.1 and > 2, respectively. CCI > 2 was associated with significantly lower OS rates (p = 0.006) (Fig. 1b). Multivariate analysis showed that BMI and CCI were significant risk factors for OS (p = 0.050 and p = 0.037, respectively) (Table 3). Five patients died after endoscopic treatment. Among them, 60% had a BMI < 18.5 kg/m2, 40% had ASA-PS scores of 3 or 4, and 60% had a CCI > 2. Furthermore, metachronous ESCC occurred in 40% of these patients. All deaths were caused by diseases other than ESCC, including heart disease (one patient), lung cancer (one patient), pleural mesothelioma (one patient), and HNC (two patients) (Supplementary Table).
Fig. 1.
Overall survival (OS) rates of patients undergoing endoscopic resection (ER). a OS rates based on body mass index (BMI). b OS rates stratified according to the Charlson Comorbidity Index (CCI). BMI and CCI were significantly associated with OS
Table 3.
Risk factors associated with poor OS
| Univariate analysis | Multivariate analysis | |||||
|---|---|---|---|---|---|---|
| HR | 95% CI | p-value | HR | 95% CI | p-value | |
| OS | ||||||
| Age, years | ||||||
| Continuous variable | 1.027 | 0.932–1.132 | 0.591 | 1.055 | 0.935–1.191 | 0.385 |
| BMI, kg/m2 | ||||||
| < 18.5 | 7.685 | 1.282–46.071 | 0.026 | 8.956 | 0.990–80.990 | 0.050 |
| > 18.5 | 1.0 | Reference | 1.0 | Reference | ||
| ASA-PS | ||||||
| 1–2 | 1.0 | Reference | 1.0 | Reference | ||
| 3–4 | 2.695 | 0.448–16.196 | 0.279 | 4.600 | 0.598–35.413 | 0.143 |
| CCI | ||||||
| 0.1 | 1.0 | Reference | 1.0 | Reference | ||
| > 2 | 11.458 | 1.278–102.748 | 0.029 | 13.460 | 1.171–154.751 | 0.037 |
| Curative resection | ||||||
| Noncurative | 2.508 | 0.277–22.729 | 0.414 | 0.527 | 0.035–7.844 | 0.642 |
| Curative | 1.0 | Reference | 1.0 | |||
ASA-PS American Society of Anesthesiologists-Performance Status, BMI body mass index, CCI Charlson Comorbidity Index, OS overall survival
Risk factors associated with the cumulative incidence of metachronous ESCC
Metachronous ESCC incidence in the non-older, early-older, and late-older groups were 46.3%, 23.9%, and 25.0%, respectively; this was significantly higher among non-older patients (p = 0.045). However, no difference was found in the 3-year cumulative incidence rates based on age (38.3% vs. 20.4% vs. 21.4%, p = 0.074) (Table 4, Fig. 2). Metachronous ESCC occurred at a median of 33.6, 43.8, and 33.9 months in the non-older, early-older, and late-older groups, respectively (Table 1). During the multivariate analysis, non-older age, LVLs, and HNC prevalence were significant (p = 0.035, p = 0.035, and p = 0.014, respectively).
Table 4.
Risk factors associated with the cumulative incidence of metachronous ESCC
| Univariate | Multivariate | |||||
|---|---|---|---|---|---|---|
| HR | 95% CI | p-value | HR | 95% CI | p-value | |
| Cumulative incidence | ||||||
| Age, years | ||||||
| Continuous variable | 0.957 | 0.924–0.991 | 0.014 | 0.961 | 0.925–0.997 | 0.035 |
| Sex | ||||||
| Male | 1.242 | 0.548–2.813 | 0.603 | 2.134 | 0.854–5.333 | 0.105 |
| Female | 1.0 | Reference | 1.0 | Reference | ||
| BMI, kg/m2 | ||||||
| < 18.5 | 1.276 | 0.607–2.683 | 0.521 | 0.675 | 0.284–1.603 | 0.373 |
| > 18.5 | 1.0 | Reference | 1.0 | Reference | ||
| LVLs | ||||||
| Grade A | 1.0 | Reference | 1.0 | Reference | ||
| Grade B/C | 2.181 | 1.070–4.444 | 0.032 | 2.252 | 1.059–4.786 | 0.035 |
| Heavy alcohol consumption | ||||||
| Never/sometimes | 1.0 | Reference | 1.0 | Reference | ||
| Frequently | 1.886 | 0.984–3.617 | 0.056 | 1.125 | 0.370–3.419 | 0.835 |
| Amount of alcohol intake (units/week) | ||||||
| Never/light | 1.0 | Reference | 1.0 | Reference | ||
| Moderate/heavy | 2.084 | 1.073–4.046 | 0.030 | 1.498 | 0.466–4.817 | 0.498 |
| Smoking, pack-years | ||||||
| Nonsmoker/light, < 30 | 1.0 | Reference | ||||
| Heavy, > 30 | 1.133 | 0.607–2.117 | 0.694 | 1.144 | 0.594–2.205 | 0.687 |
| Multiple ESCCs (–) | 1.0 | Reference | 1.0 | Reference | ||
| Multiple ESCCs (+) | 1.237 | 0.518–2.957 | 0.632 | 0.853 | 0.33–2.183 | 0.740 |
| Head and neck | ||||||
| Never | 1.0 | Reference | 1.0 | Reference | ||
| Past/current | 2.629 | 1.399–4.939 | 0.003 | 1.498 | 1.193–4.845 | 0.014 |
| Lung carcinoma | ||||||
| Never | 1.0 | Reference | ||||
| Past/current | 0.045 | 0.000–33.966 | 0.360 | – | ||
BMI body mass index, ESCC esophageal cell carcinoma, LVL Lugol-voiding lesion
Fig. 2.
Cumulative incidence rate of patients undergoing endoscopic resection. Cumulative incidence based on age (≤ 64 years vs. 65–74 years vs. ≥ 75 years). No difference was found in the 3-year cumulative incidence rates based on age
A summary of the causes of death after ER is provided in Supplementary table. Five patients died after endoscopic treatment. The median age of the patients who died was 70 years (interquartile range [IQR], 69–71 years), and all patients were male. Among them, 60% had a BMI < 18.5 kg/m2, 40% had ASA-PS scores of 3 or 4, and 60% had a CCI > 2. Furthermore, metachronous ESCC occurred in 40% of these patients. All deaths were caused by diseases other than ESCC, including heart disease (one patient), lung cancer (one patient), pleural mesothelioma (one patient), and HNC (two patients).
Development of a prognostic scoring system of metachronous ESCC
Cox analysis of risk factors for poor OS after-ER showed that BMI < 18.5 kg/m2 and CCI > 2, respectively, were significant factors in the multivariate analysis. Cox analysis of risk factors for metachronous ESCC after-ER showed that less than 64, LVLs (grade B/C), and history of HNC were significant factors in multivariate analysis. We assigned points proportional to the regression coefficient for each of the three predictive variables to calculate the risk score: 1 point each for BMI < 18.5 kg/m2, CCI > 2, 1 point; < 64, LVLs (B/C), and history of HNC. Therefore, the maximum score was 5 points. Using the scoring system, scores of 0, 1, 2, 3, 4, and 5 points were assigned to 2, 44, 38, 30, 10, and 3 patients in the development cohort, respectively. Time-dependent ROC analysis of OS was conducted, yielding an AUC of 0.677 and a Youden’s Index of 0.294, with a cut-off value of 2 (Fig. 3). Patients with scores of 0–2 and 3–5 points were categorized as the low- and high-score groups, respectively. The low- and high-score groups comprised 84 and 43 patients, respectively. The median recurrence period was 40 and 28 months in the low-score and high-score groups, respectively (p = 0.011) (Table 5), indicating a significantly shorter period of metachronous ESCC (p = 0.011). The 3-year OS was significantly lower in the high-score group than in the low-score group (91.5% vs. 100%, p = 0.012) (Fig. 4).
Fig. 3.
Receiver operating characteristic curve for the scoring system: time-dependent receiver operating characteristic (ROC) curve at 5 years for overall survival (OS). The area under the curve was 0.677, with an optimal cut-off value of 2
Table 5.
Characteristics of each of the score groups
| Patients | Low score | High score | p-value |
|---|---|---|---|
| n = 84 | n = 43 | ||
| Age, median (IQR), years | 72 (65–77) | 67 (60–72) | 0.011 |
| Sex, male, n (%) | 74 (88.1) | 34 (79.1) | 0.196 |
| Metachronous ESCC period, median (IQR), months | 40 (26–56) | 28 (19–44) | 0.011 |
IQR interquartile range, ESCC esophageal cell carcinoma
Fig. 4.
Development of a prognostic scoring system for metachronous esophageal squamous cell carcinoma (ESCC). Comparison of OS rates between the low- and high-score groups of patients in the validation cohort. The 3-year OS incidence rates were significantly lower in the high-score group than in the low-score group (91.5% vs. 100%, p = 0.012)
Discussion
A consensus has not been reached on the optimal surveillance endoscopy following treatment for superficial ESCC. Moreover, frequent uncertainty exists concerning the prognosis after treatment by surveillance. Therefore, we evaluated scorings, including BMI and CCI, which are significant risk factors for OS and stratified the risk contributing to OS in metachronous ESCC after endoscopic treatment.
ER is a minimally invasive procedure that can be safely performed [5, 18]. However, older individuals have high rates of comorbidities; therefore, the impact of comorbidities on treatment and factors contributing to the prognosis should be considered. The CCI is useful for predicting the prognosis of older patients [14, 19, 20]. In our study, the 3-year OS rates were 99% and 89.5% in non-older and older patients with lower BMI, respectively. Patients with CCI > 2 had significantly poorer OS rates; the 3-year OS rates were 98.3% and 90.3% for patients with CCI = 0.1 and CCI > 2, respectively. According to the univariate and multivariate analyses, BMI and CCI were significant risk factors for an adverse prognosis. BMI is positively associated with body fat percentage in patients with low skeletal muscle and plays a central role in immune function. Therefore, there may be a central predictor of prognosis in patients with esophageal cancer [21]. Different mechanisms have shown that both low nutrition and high weight are associated with poor prognosis in ESCC, with advanced tumor and tumor biologic invasiveness being the causes of poor prognosis in patients with low and high BMI, respectively [22]. However, no reports of BMI associated with metachronous ESCC post-ER exist. This may serve as a reference for future therapeutic targets for endoscopic treatment. Here, the higher number of older patients with ASA-PS scores of 3–4 suggests that thorough evaluation of the general health condition should be an essential component of the pre-operative assessment when minimally invasive endoscopic treatment is an option. Therefore, surveillance that considers BMI, CCI, and ASA-PS may be warranted. This approach underscores the potential impact of suitable surveillance on prognosis, highlighting the importance of incorporating screening for risk within such a surveillance program. Surveillance endoscopy is essential for the early diagnosis of metachronous ESCC after endoscopic treatment. Additionally, follow-up endoscopy and other imaging studies are important post-ER because ESCC is associated with the development of metachronous ESCC and secondary cancers post-ER. In this study, the cumulative incidence of metachronous ESCC was higher among non-older patients than among older patients; grade (B/C) LVLs and HNC were lower among older patients than among non-older patients, according to the Cox hazard analysis. Non-older patients with ESCC may be at higher risk of metachronous ESCC and HNC because of their greater exposure to risk factors, such as alcohol consumption and tobacco use. The incidence rate of metachronous ESCC was higher among non-older patients with HNC comorbidity than among older patients [23], and the incidence rate of secondary cancers among non-older patients was higher because of their greater exposure to alcohol consumption and carcinogens [24]. More non-older patients were heavy drinkers; however, many older patients were non-drinkers and past drinkers, which could have affected metachronous ESCC prevalence. Metachronous ESCC and HNC are associated with field cancerization [9, 10], with HNC incidence rates of 5.1–7.3% post-ER for ESCC [25]. Of the five patients who died, four (80%; two with lung cancer and two with HNC) were older. No deaths were caused by metachronous ESCC; therefore, it is important to carefully evaluate the prognostic factors associated with esophageal cancer and perform appropriate imaging evaluations to search for secondary cancers. Alongside frequent surveillance endoscopy for ESCC in patients with multiple LVLs, HNC, and lower BMI, screening may detect the early diagnosis of the disease [26]. Therefore, risk factors, including those affecting OS, such as BMI and CCI, should be systematically stratified for metachronous ESCC.
This study had some limitations. First, it was a single-institution, retrospective study with a small number of patients. Second, the effect of appropriate endoscopic treatment on the survival of older patients with metachronous ESCC may have been attributed to the availability of proper endoscopic treatment. Third, we acknowledge a limitation regarding the variation in the surveillance endoscopy intervals among attending physicians, which could potentially impact the detection rate. Fourth, information regarding the risk factors for metachronous ESCC is limited because the results were obtained from a small number of participants; therefore, a multi-institutional study should be conducted in the future. Finally, frequent surveillance endoscopy may not have affected the OS of older patients with low BMI or high CCI; therefore, another follow-up interval may be acceptable.
In conclusion, we proposed an endoscopic surveillance scoring system for metachronous ESCC, considering BMI and CCI in older patients.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
We would like to thank all patients who participated in this study and their families. We appreciate Masataka Taguri, Professor and Chair of the Department of Health Data Science, Tokyo Medical University, and Shuntaro Mukai, Associate Professor in the Department of Gastroenterology and Hepatology, Tokyo Medical University.
Author contributions
Sakiko Naito: conception and design; analysis and interpretation of the data; drafting of the manuscript. Masakatsu Fukuzawa: conception of the study; critical revision of the manuscript. Hirokazu Shinohara, Yasuyuki Kagawa, Akira Madarame, Yohei Koyama, Hayato Yamaguchi, Yoshiya Yamauchi: data collection. Takao Itoi: critical revision of the manuscript for important intellectual content; final approval of the manuscript. All authors approved the final version of this manuscript for publication.
Funding
Open access funding provided by Tokyo Medical University.
Data availability
The datasets generated and/or analyzed in this study are not publicly available but are available from the corresponding author upon reasonable request.
Declarations
Conflict of interest
Sakiko Naito, Masakatsu Fukuzawa, Hirokazu Shinohara, Yasuyuki Kagawa, Akira Madarame, Yohei Koyama, Hayato Yamaguchi, Yoshiya Yamauchi, and Takao Itoi declare that they have no conflict of interest.
Ethical statement
This study was approved by the Institutional Review Board of Tokyo Medical University Hospital (approval number: T2020-0361) and conducted in accordance with the Declaration of Helsinki 1964. The institution’s human research committee granted prior approval. Written informed consent was waived because of the retrospective nature of this study. A document describing the opt-out policy was uploaded to the Tokyo Medical University Hospital website.
Footnotes
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The datasets generated and/or analyzed in this study are not publicly available but are available from the corresponding author upon reasonable request.