Abstract
Background
Most previous studies have focused on exploring the formation mechanism of esophageal fistula (EF) and predicting its risk of occurrence. However, few studies have reported the treatment and prognosis of EF after radiotherapy (RT) in patients with esophageal cancer (EC). This study aimed to explore treatment patterns and prognostic factors of radiation-associated esophageal fistula (RAEF) in esophageal squamous cell carcinoma (ESCC).
Methods
A total of 91 EF patients were retrospectively enrolled from January 2016 to July 2023. Based on the fistula type, 39 patients presented with tracheoesophageal fistula (TEF) and 52 with esophagomediastinal fistula (EMF). Survival analyses utilized the Kaplan-Meier method. Multivariable Cox regression analysis was employed to ascertain prognosis.
Results
By the last follow-up date on June 30, 2025, all patients had died. The cohort had a median post-fistula survival time of 3.1 months, and their 3-month, 6-month, and 12-month survival rates were 51.6%, 18.7%, and 5.5%, respectively. All patients received nutritional support therapy, including nasal feeding (n=61), esophageal stenting (n=10), gastrostomy/jejunostomy (n=12), and simple fluid infusion therapy (n=8). Gastrostomy/jejunostomy was associated with the highest post-fistula survival rates (3-month: 83.3%, 6-month: 41.7%, 12-month: 25.0%). In TEF, esophageal stenting provided comparable 3-month post-fistula survival rates to gastrostomy/jejunostomy (71.4% vs. 75.0%). Among 21 patients who had EF during primary RT, those completing the planned RT after receiving nutritional support therapy achieved superior fistula closure rates compared to treatment discontinuation (77.8% vs. 25.0%). Multivariable Cox analysis identified reirradiation, simple fluid infusion therapy, persistent fistula, and hemoglobin <120 g/L as independent unfavorable prognostic factors.
Conclusions
Gastrostomy/jejunostomy is associated with improved survival in patients with RAEF. Esophageal stenting represents a viable short-term palliative option for TEF patients. Completing planned RT may promote fistula healing for EF during primary RT. Hemoglobin level serves as an accessible prognostic biomarker.
Keywords: Esophageal squamous cell carcinoma (ESCC), radiotherapy (RT), esophageal fistula (EF), prognostic factors, treatment patterns
Highlight box.
Key findings
• We show that gastrostomy/jejunostomy is associated with improved survival in patients with radiation-associated esophageal fistula (RAEF). Additionally, esophageal stenting represents a viable short-term palliative option for tracheoesophageal fistula (TEF) patients, and hemoglobin level serves as an accessible prognostic biomarker.
What is known and what is new?
• Nutritional support therapy is commonly employed for patients with esophageal fistula (EF) in clinical practice. However, the optimal regimen and therapeutic options for different types of EF still lack clear recommendations.
• Our findings are significant because we focused on this selected population in radiation-specific etiology, excluding patients with disease progression or untreated EF. Furthermore, we analyzed characteristics of different treatments.
What is the implication, and what should change now?
• These findings provide a reference for selecting nutritional support strategies in patients with RAEF and suggest that routine hematological parameters may serve as prognostic indicators.
• Whether esophageal cancer patients with EF are suitable for radiotherapy (RT) requires further investigation.
Introduction
In China, esophageal squamous cell carcinoma (ESCC) accounts for more than 90% of all esophageal cancer (EC) (1,2). Esophageal fistula (EF) is a devastating complication of EC, and its formation is predominantly attributed to tumor invasion into adjacent tissues and organs, including the pleura, pericardium, trachea, bronchi, and aorta. Additionally, while chemoradiotherapy (CRT) effectively kills tumor cells, it may also cause rapid tumor regression without adequate time for normal tissue repair, leading to the development of EF (3-5). Some studies report that the incidence of EF in EC patients after CRT ranges from 5.8% to 30.1% (6-9). EF is frequently accompanied by life-threatening complications such as severe pulmonary infection, massive hemorrhage, and cardiorespiratory failure. Thus, the prognosis for patients who develop EF is extremely poor, with a median post-fistula survival time of 2 to 4 months, and most patients die within 6 months (10,11). Although EF has attracted much attention, most previous studies focused on exploring the formation mechanism of EF and predicting the risk of its occurrence (7-10). Some studies on EF have included confounding variables like disease progression and untreated EC (11-15), thereby limiting their applicability in radiation-specific etiology. Furthermore, there are few studies reporting the treatment and prognosis of EF after radiotherapy (RT) in patients with EC, and the specific treatment patterns have not been clearly specified in National Comprehensive Cancer Network (NCCN) and Chinese Society of Clinical Oncology (CSCO) guidelines. Nutritional support therapy is commonly employed for patients with EF in clinical practice, including nasal feeding, esophageal stenting, gastrostomy/jejunostomy, and simple fluid infusion therapy (13). However, the optimal regimen and therapeutic options for different types of EF still lack clear recommendations. Particularly, RT after the development of EF remains controversial (14-16). By focusing exclusively on this selected population, this study aims to analyze the therapeutic efficacy of different treatment modalities and identify prognostic factors in patients with radiation-associated esophageal fistula (RAEF). We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1519/rc).
Methods
Patients
We retrospectively collected clinical data on ESCC patients who developed RAEF at The Fourth Hospital of Hebei Medical University between January 2016 and July 2023. Inclusion criteria: (I) age ≥18 years, (II) Eastern Cooperative Oncology Group (ECOG) score ≤2, (III) pathological diagnosis of ESCC, (IV) stage II–IV according to the American Joint Committee on Cancer (8th edition) before RT, (V) patients who received treatment based on RT of the primary esophageal lesion, (VI) EF was diagnosed by endoscopy, computed tomography (CT), or X-ray esophagography. Exclusion criteria: (I) patients with prior or concomitant malignancy, (II) fistula development prior to RT or attributed to locoregional progression, (III) underwent EC surgery, (IV) EF attributable to other causes, such as medical injury or trauma, (V) significant gaps or loss in follow-up medical records. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study protocol was reviewed and approved by the Human Ethics Committee of The Fourth Hospital of Hebei Medical University (No. 2025KS107). The need for informed consent was waived by the same ethics committee due to the retrospective nature of the study.
Data collection and diagnostic criteria
The collected clinical data mainly included age, sex, tumor length, tumor thickness, cTNM stage, tumor location, fistula location, type of EF, hematological parameters, body mass index (BMI), and treatment. Hematological parameters and BMI were collected within two weeks prior to the diagnosis of EF.
The diagnostic criteria for EF are as follows (17,18): (I) esophagography shows the contrast agent in the esophagus entering the trachea/bronchi or mediastinum; (II) CT shows that gas can be seen around the esophagus and in the mediastinum. There is a gas fistula between the esophagus and the adjacent mediastinum, and sometimes effusion can be seen in the pleural cavity; (III) the fistula of the esophageal wall can be seen. The diagnostic figures of chest CT and esophagography are shown in Figure 1.
Figure 1.
(A) X-ray esophagography shows EMF; the arrow indicates contrast leakage through the fistula; (B) X-ray esophagography shows TEF; (C) CT scan of the chest shows EMF; (D) CT scan of the chest shows TEF. CT, computed tomography; EMF, esophagomediastinal fistula; TEF, tracheoesophageal fistula.
Follow-up
Follow-up examinations included esophagography, chest/abdominal CT, and/or positron emission tomography-computed tomography (PET/CT). The post-fistula survival time was calculated from diagnosis of EF to death. The median post-fistula survival time was defined as the survival time corresponding to a survival rate of 50% from the diagnosis of EF.
Statistical analysis
The Cox proportional hazards regression model was employed to ascertain prognostic factors. The post-fistula survival time was estimated by Kaplan-Meier curves, which were compared using the log-rank test. The optimal cut-off values of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were generated using surv_cutpoint of the survminer R package. All statistical analyses were performed in R software (version 4.2.1), with a two-sided P value <0.05 defining statistical significance.
Results
Clinical data of patients
A total of 91 EF patients met inclusion criteria, comprising 67 males (73.6%) and 24 females (26.4%), with a median age of 63 years (range, 37–85 years). The median length of the esophageal tumor was 6.0 cm (range, 3.2–12.0 cm), and the median tumor thickness was 15.0 mm (range, 6.7–36.0 mm). Anatomically, 39 patients (42.9%) presented with tracheoesophageal fistula (TEF) and 52 (57.1%) with esophagomediastinal fistula (EMF). The distribution of fistula locations was as follows: upper thoracic in 29 patients (31.9%), middle thoracic in 53 patients (58.2%), and lower thoracic in 9 patients (9.9%). The optimal cut-off values of NLR and PLR were 9.6 and 413.9, respectively. Other clinical data are listed in Table 1.
Table 1. General characteristics of patients.
| Characteristics | N (%) |
|---|---|
| Sex | |
| Male | 67 (73.6) |
| Female | 24 (26.4) |
| Age | |
| <60 years | 26 (28.6) |
| ≥60 years | 65 (71.4) |
| Tumor length | |
| <6 cm | 40 (44.0) |
| ≥6 cm | 51 (56.0) |
| Tumor thickness | |
| <15 mm | 44 (48.4) |
| ≥15 mm | 47 (51.6) |
| cT stage | |
| T2–3 | 47 (51.6) |
| T4 | 44 (48.4) |
| cN stage | |
| N0–1 | 53 (58.2) |
| N2–3 | 38 (41.8) |
| cM stage | |
| M0 | 82 (90.1) |
| M1 | 9 (9.9) |
| cTNM stage | |
| II–III | 43 (37.4) |
| IVA | 39 (53.8) |
| IVB | 9 (8.8) |
| Tumor location | |
| Upper | 23 (25.3) |
| Middle | 46 (50.5) |
| Lower | 22 (24.2) |
| Fistula location | |
| Upper | 29 (31.9) |
| Middle | 53 (58.2) |
| Lower | 9 (9.9) |
| Type of EF | |
| TEF | 39 (42.9) |
| EMF | 52 (57.1) |
| BMI | |
| <18.5 kg/m2 | 27 (29.7) |
| ≥18.5 kg/m2 | 64 (70.3) |
| Hemoglobin | |
| <120 g/L | 69 (75.8) |
| ≥120 g/L | 22 (24.2) |
| Albumin | |
| <30 g/L | 37 (40.7) |
| ≥30 g/L | 54 (59.3) |
| Prealbumin | |
| <0.1 g/L | 44 (48.4) |
| ≥0.1 g/L | 47 (51.6) |
| NLR | |
| ≤9.6 | 34 (37.4) |
| >9.6 | 57 (62.6) |
| PLR | |
| ≤413.9 | 36 (39.6) |
| >413.9 | 55 (60.4) |
BMI, body mass index; EF, esophageal fistula; EMF, esophagomediastinal fistula; NLR, neutrophil-to-lymphocyte ratio; PLR, platelet-to-lymphocyte ratio; TEF, tracheoesophageal fistula.
Survival of all patients
By the last follow-up date on June 30, 2025, all patients had died. The median post-fistula survival time was 3.1 months, and their 3-month, 6-month, and 1-year survival rates were 51.6%, 18.7%, and 5.5%, respectively.
Treatment of EF
Nutritional support therapy
The proportion of patients receiving different treatment methods is shown in Figure 2, including nasal feeding (n=61, 67.0%), esophageal stenting (n=10, 11.0%), gastrostomy/jejunostomy (n=12, 13.2%), and simple fluid infusion therapy (n=8, 8.8%). The corresponding post-fistula survival rates for four treatment modalities were 45.9%, 70.0%, 83.3%, and 25.0% for 3 months; 18.0%, 10.0%, 41.7%, and 0% for 6 months; and 3.3%, 0%, 25.0%, and 0% for 1 year. Gastrostomy/jejunostomy was associated with the highest survival rates, while simple fluid infusion therapy was associated with the lowest survival rates (Figure 3A, P=0.006). The clinical characteristics of patients receiving simple fluid infusion therapy are presented in Table S1.
Figure 2.
The proportion of patients receiving different treatment methods for EMF and TEF. EMF, esophagomediastinal fistula; TEF, tracheoesophageal fistula.
Figure 3.
The post-fistula survival curve for all EF (A), TEF (B), and EMF (C) patients receiving nasal feeding, esophageal stenting, gastrostomy/jejunostomy, and simple fluid infusion therapy. (D) The post-fistula survival curve during primary RT: subsequent RT vs. no subsequent RT. EF, esophageal fistula; EMF, esophagomediastinal fistula; RT, radiotherapy; TEF, tracheoesophageal fistula.
The post-fistula survival curves for TEF and EMF are shown in Figure 3B,3C. In TEF, esophageal stenting provided comparable 3-month post-fistula survival rates to gastrostomy/jejunostomy (71.4% vs. 75.0%), and simple fluid infusion therapy was associated with the lowest survival rates (P=0.02).
Post-fistula RT
RAEF patients were categorized into four groups: fistula post-primary RT (n=51), fistula during primary RT (n=21), fistula post-reirradiation (n=13), and fistula during reirradiation (n=6). In our cohort of 91 patients with EF, the total radiation dose ranged from 5.4 to 70.0 Gy (5 days/week, 1.8–2.25 Gy/day) for patients who developed fistula during or after primary RT, and from 79.8 to 120.0 Gy (5 days/week, 1.8–2.0 Gy/day) for those who developed fistula during or after reirradiation. All patients underwent intensity-modulated radiation therapy (IMRT). Fifty-nine patients received CRT, while 32 received RT alone. The chemotherapy regimens were primarily taxane- or fluorouracil-based, combined with platinum agents. Among the 51 patients who developed EF after completing primary RT, the median time from the end of primary RT to EF diagnosis was 3.1 months (range, 0.1–14.0 months), with 48 cases (94.1%) occurring within 6 months after RT completion. Among the 13 patients who developed EF after reirradiation, the median time from the end of reirradiation to EF diagnosis was 3.0 months (range, 0.4–5.9 months). The detailed characteristics of these 21 patients are presented in Table S2. The median post-fistula survival time was 6.6 months for patients who continued RT and 3.5 months for those who discontinued RT. The 3-month, 6-month, and 1-year survival rates were 100.0%, 55.6%, 22.2% vs. 58.3%, 25.0%, 8.3%, respectively (Figure 3D, P=0.34). Among the 21 patients developing EF during primary RT, completion of the planned RT after receiving nutritional support therapy achieved fistula closure in 77.8% (7 of 9 patients) vs. 25.0% (3 of 12) in those discontinuing treatment (Figure 4). Notably, patients were categorized by pre-fistula nutritional status. Better nutritional status was defined as meeting at least two of the criteria: hemoglobin ≥120 g/L, albumin ≥30 g/L, and BMI ≥18.5 kg/m2. Among 13 patients with better nutritional status, 8 (61.5%) had fistula closure, while among remaining 8 patients with worse nutritional status, only 2 (25%) had fistula closure.
Figure 4.
(A) The post-fistula survival time, pre-fistula nutritional status, and fistula condition in 21 EF patients. (B,C) The proportion of nutritional indicators in 10 patients with fistula closure and 11 patients with persistent fistula. Better nutritional status meeting at least two of the criteria (HB ≥120 g/L, ALB ≥30 g/L, BMI ≥18.5 kg/m2). Worse nutritional status meeting one or none. ALB, albumin; BMI, body mass index; EF, esophageal fistula; HB, hemoglobin; RT, radiotherapy.
Prognostic factors
Multivariable Cox analysis identified reirradiation, persistent fistula, hemoglobin <120 g/L, and simple fluid infusion therapy as unfavorable prognostic factors (Table 2).
Table 2. Univariable and multivariable analyses of post-fistula survival in all EF patients.
| Characteristics | N | Univariate analysis | Multivariate analysis | ||
|---|---|---|---|---|---|
| P value | HR (95% CI) | P value | HR (95% CI) | ||
| Sex (male vs. female) | 67 vs. 24 | 0.27 | 1.30 (0.81–2.08) | ||
| Age (<60 vs. ≥60 years) | 26 vs. 65 | 0.68 | 1.10 (0.69–1.74) | ||
| cT stage (T2–3 vs. T4) | 47 vs. 44 | 0.29 | 0.80 (0.53–1.21) | ||
| cN stage (N0–1 vs. N2–3) | 53 vs. 38 | 0.52 | 1.15 (0.75–1.75) | ||
| cTNM stage (II–III vs. IV) | 43 vs. 48 | 0.15 | 0.74 (0.49–1.12) | ||
| Total RT dose (<60 vs. ≥60 Gy) | 31 vs. 60 | 0.11 | 1.45 (0.92–2.28) | ||
| Single RT dose (≤2 vs. >2 Gy) | 80 vs. 11 | 0.26 | 1.44 (0.76–2.72) | ||
| Reirradiation (no vs. yes) | 72 vs. 19 | <0.001 | 2.87 (1.67–4.92) | 0.004 | 2.39 (1.33–4.29) |
| Type of EF (TEF vs. EMF) | 39 vs. 52 | 0.30 | 0.80 (0.53–1.22) | ||
| Fistula closure (no vs. yes) | 75 vs. 16 | <0.001 | 0.17 (0.08–0.35) | <0.001 | 0.20 (0.09–0.42) |
| BMI (<18.5 vs. ≥18.5 kg/m2) | 27 vs. 64 | 0.002 | 0.46 (0.28–0.75) | 0.63 | 0.87 (0.50–1.51) |
| ECOG (0–1 vs. 2) | 36 vs. 55 | 0.04 | 1.58 (1.03–2.41) | 0.45 | 1.20 (0.75–1.91) |
| Hemoglobin (<120 vs. ≥120 g/L) | 69 vs. 22 | 0.04 | 0.60 (0.37–0.97) | 0.03 | 0.57 (0.34–0.95) |
| Albumin (<30 vs. ≥30 g/L) | 37 vs. 54 | 0.002 | 0.50 (0.32–0.77) | 0.13 | 0.61 (0.32–1.15) |
| Prealbumin (<0.1 vs. ≥0.1 g/L) | 44 vs. 47 | 0.02 | 0.61 (0.40–0.93) | 0.84 | 0.94 (0.53–1.68) |
| Lymphocyte (<1.0 vs. ≥1.0×109/L) | 80 vs. 11 | 0.91 | 1.04 (0.55–1.96) | ||
| Treatment (simple fluid infusion therapy vs. the other modalities) | 8 vs. 83 | 0.007 | 0.36 (0.17–0.76) | 0.02 | 0.37 (0.15–0.88) |
| NLR (≤9.6 vs. >9.6) | 34 vs. 57 | 0.009 | 1.80 (1.16–2.79) | 0.28 | 1.38 (0.77–2.49) |
| PLR (≤413.9 vs. >413.9) | 36 vs. 55 | 0.03 | 1.61 (1.04–2.50) | 0.68 | 1.13 (0.64–1.98) |
BMI, body mass index; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; EF, esophageal fistula; EMF, esophagomediastinal fistula; HR, hazard ratio; NLR, neutrophil-to-lymphocyte ratio; PLR, platelet-to-lymphocyte ratio; RT, radiotherapy; TEF, tracheoesophageal fistula.
Discussion
The management of EF after RT for EC remains a critical and unresolved challenge. Although nutritional support continues to be the cornerstone of treatment, the applicable population and efficacy of different nutritional support methods have not yet been conclusively determined. Earlier studies have indicated (13,19) that proactive interventions such as gastrostomy, nasal feeding, and esophageal stenting may be superior to conservative fluid infusion therapy alone, particularly with the benefits of gastrostomy being most evident. Xu et al. conducted an analysis of 98 EC patients with EF. Compared with simple fluid infusion therapy, gastrostomy was associated with a 59% reduction in mortality risk (19). Another retrospective cohort study involving a relatively large sample of 352 patients also demonstrated that for EC patients with EF, the median post-fistula survival time for those receiving gastrostomy, nasal feeding, esophageal stenting, and simple fluid infusion therapy was 3.0, 2.2, 2.7, and 1.0 months, respectively. Gastrostomy has shown potential superiority over esophageal stenting and nasal feeding (13). Our study also analyzed the patterns of nutritional support. In contrast, previous studies enrolled EF patients with confounding factors (EF resulting from locoregional progression and untreated EC). This study exclusively enrolled patients with RAEF, thereby providing direct evidence for treatment in this specific population. Despite differences in the study cohort, our findings presented similar outcomes: patients receiving gastrostomy/jejunostomy exhibited post-fistula survival rates of 83.3% at 3 months and 25.0% at 1 year, whereas the simple fluid infusion therapy group showed only a 25.0% survival rate at 3 months, and all patients died within 6 months. Therefore, for patients with RAEF in EC, those who receive gastrostomy/jejunostomy have a survival advantage, which may be associated with reduced stimulation of the fistula and ensured nutritional intake.
Although esophageal stenting can quickly alleviate symptoms by sealing the fistula, preventing infection, and improving oral intake, some scholars contend that it is particularly advantageous in TEF (20-22). Nevertheless, for EC patients who have undergone CRT, the insertion of an esophageal stent is more prone to cause life-threatening complications. Over time, this risk may manifest as chest pain, new perforations, hemorrhage, stent migration, and tracheal compression, all of which can be fatal (23-25). In our TEF subgroup analysis, we also observed that esophageal stenting had certain advantages in short-term efficacy, whereas its impact on long-term survival was limited. Patients who received esophageal stenting and gastrostomy/jejunostomy exhibited similar 3-month post-fistula survival rates (71.4% vs. 75.0%). However, the 6-month post-fistula survival rates dropped significantly to 0% in esophageal stenting, compared to 17.1% in gastrostomy/jejunostomy. As Russo et al. pointed out, esophageal stenting may be particularly appropriate for patients with a short life expectancy and limited treatment options (26). Overall, although esophageal stenting provides short-term benefits for patients with radiation-associated TEF, the higher incidence of fatal complications necessitates caution in its recommendation. In the future, we will further focus on identifying populations most likely to benefit from the use of esophageal stenting.
In addition to nutritional support, CRT or RT after EF is a treatment strategy that has been widely discussed in recent years. Nonetheless, its application remains controversial as the presence of a fistula was believed to be a relative contraindication to CRT or RT. Recent studies have shown that CRT or RT for patients with EF can prolong survival time and improve the fistula closure rates (14,16,27,28). Nevertheless, there are relatively few research data on EF patients during RT. Wang et al. conducted an analysis of EF patients during RT and found that subsequent CRT achieved a fistula closure rate of 67.9%. Moreover, patients who continued RT showed significantly prolonged survival compared to those who discontinued RT (2-year overall survival rate: 32.7% vs. 6.8%, P<0.01) (9). Our findings are in accord with these studies, indicating that subsequent RT for EF patients during RT achieved a fistula closure rate of 77.8%. Furthermore, patients who continued RT showed a trend toward better survival compared to those who discontinued RT (median post-fistula survival time: 6.6 vs. 3.5 months). These observations support the hypothesis that RT induces soft tissue swelling in the esophageal wall, which temporarily occludes the fistula, thereby limiting the spread of infection and improving survival time (29).
Although studies have demonstrated that EC patients with EF may benefit from RT, clear criteria for identifying patients eligible for subsequent RT remain lacking. Therefore, this study further analyzed the association between pre-fistula nutritional status and fistula closure. Among patients with better nutritional status, 61.5% achieved fistula closure, but only 25% of those with worse nutritional status did. EF patients with better nutrition demonstrate superior tissue repair capacity. We speculate that patients who have better pre-fistula nutritional status will have a higher rate of fistula closure after subsequent RT. However, whether nutritional status can be used as an indicator for subsequent RT for EF patients during the RT period still needs to be explored with a larger sample size in the future.
Multivariate Cox analysis identified reirradiation, persistent fistula, hemoglobin <120 g/L, and simple fluid infusion therapy as unfavorable prognostic factors for RAEF. Despite being a vital treatment for locally recurrent EC, reirradiation is challenging due to the legacy of initial radiation damage (vascular and tissue damage, rigid fibrotic walls, and poor blood supply). This impaired healing capacity makes the fistula difficult to close after reirradiation and is linked to an extremely poor survival rate (30-33). Additionally, the poorer prognosis may be exacerbated by the inherently high malignancy of locally recurrent EC. Apart from reirradiation factors, nutritional indicators also significantly influence prognosis. The study by Guan et al. (11) revealed that the hemoglobin level was strongly related to the survival time after EF. Hemoglobin level serves as an important indicator reflecting the physiological function and nutritional status. A retrospective study on ESCC showed that anemia is correlated with reduced overall survival (34). Low hemoglobin levels may impair the repair of normal tissue and lead to tumor hypoxia. Consequently, the resulting immune microenvironment becomes increasingly hostile to tissue repair and may exacerbate tumor aggressiveness (35,36). Although albumin was not identified as a prognostic factor in the multivariable Cox analysis of our study, Dai et al. (37) demonstrated that higher albumin levels significantly improve post-fistula survival time. This may be related to the role of albumin in promoting wound healing and alleviating oxidative damage (38,39). Therefore, as important indicators of physiological and nutritional status, nutritional indicators should be closely monitored for their dynamic trends in clinical practice to assist in prognostic assessment. These accessible biomarkers should inform clinical decision-making regarding treatment modalities.
This study had several limitations. First, this was a retrospective, single-center study that inevitably introduced confounding factors. Second, the analysis of RAEF lacked detailed RT parameters, such as RT target volume. Third, the nutritional treatment methods for EMF have not been thoroughly analyzed. There are significant differences in the number of EMF cases receiving different treatments, making it difficult to obtain reliable conclusions. Despite these limitations, our study describes treatment patterns and prognostic factors of RAEF in ESCC, a topic rarely reported previously. In the future, further large-scale studies should be conducted.
Conclusions
Gastrostomy/jejunostomy is associated with improved survival in patients with RAEF. Esophageal stenting represents a viable short-term palliative option for TEF patients. Completing planned RT may promote fistula healing for EF during primary RT. Hemoglobin level serves as an accessible prognostic biomarker.
Supplementary
The article’s supplementary files as
Acknowledgments
None.
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 study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study protocol was reviewed and approved by the Human Ethics Committee of The Fourth Hospital of Hebei Medical University (No. 2025KS107). The need for informed consent was waived by the same ethics committee due to the retrospective nature of the study.
Footnotes
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1519/rc
Funding: This work was supported by the Clinical Medicine Outstanding Talents Training Project (No. ZF2025228); Regional Scientific Research Cultivation Fund Project of the China Anti-Cancer Association in the Field of Oncology (No. CESTDQLCORP300-05); and Research Topic on Chronic Disease Management (No. GWJJMB202510022063).
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1519/coif). The authors have no conflicts of interest to declare.
Data Sharing Statement
Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1519/dss
References
- 1. Zhu H, Wang Z, Deng B, et al. Epidemiological landscape of esophageal cancer in Asia: Results from GLOBOCAN 2020. Thorac Cancer 2023;14:992-1003.. 10.1111/1759-7714.14835 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Waters JK, Reznik SI. Update on Management of Squamous Cell Esophageal Cancer. Curr Oncol Rep 2022;24:375-85.. 10.1007/s11912-021-01153-4 [DOI] [PubMed] [Google Scholar]
- 3. Zhu C, Ding J, Wang S, et al. Development and validation of a prognostic nomogram for malignant esophageal fistula based on radiomics and clinical factors. Thorac Cancer 2021;12:3110-20.. 10.1111/1759-7714.14115 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Gabrail NY, Harrison BR, Sunwoo YC. Chemo-irradiation induced aortoesophageal fistula. J Surg Oncol 1991;48:213-5.. 10.1002/jso.2930480316 [DOI] [PubMed] [Google Scholar]
- 5. Sivaraman SK, Drummond R. Radiation-induced aortoesophageal fistula: an unusual case of massive upper gastrointestinal bleeding. J Emerg Med 2002;23:175-8.. 10.1016/s0736-4679(02)00488-2 [DOI] [PubMed] [Google Scholar]
- 6. Chen HY, Ma XM, Ye M, et al. Esophageal perforation during or after conformal radiotherapy for esophageal carcinoma. J Radiat Res 2014;55:940-7.. 10.1093/jrr/rru031 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Watanabe S, Ogino I, Kunisaki C, et al. Relationship between nutritional status and esophageal fistula formation after radiotherapy for esophageal cancer. Cancer Radiother 2019;23:222-7.. 10.1016/j.canrad.2018.10.005 [DOI] [PubMed] [Google Scholar]
- 8. Xu Y, Wang L, He B, et al. Development and validation of a risk prediction model for radiotherapy-related esophageal fistula in esophageal cancer. Radiat Oncol 2019;14:181.. 10.1186/s13014-019-1385-y [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Wang S, Zhang C, Wang Y, et al. Risk factors and prognosis for esophageal fistula in patients with esophageal squamous cell carcinoma during radiotherapy. Esophagus 2022;19:660-9.. 10.1007/s10388-022-00919-4 [DOI] [PubMed] [Google Scholar]
- 10. Hu B, Jia F, Zhou H, et al. Risk Factors Associated with Esophageal Fistula after Radiotherapy for Esophageal Squamous Cell Carcinoma. J Cancer 2020;11:3693-700.. 10.7150/jca.39033 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Guan X, Liu C, Zhou T, et al. Survival and prognostic factors of patients with esophageal fistula in advanced esophageal squamous cell carcinoma. Biosci Rep 2020;40:BSR20193379.. 10.1042/BSR20193379 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Chan-Jun Z, Wen-Wen B, Ping Z, et al. Treatment mode and prognosis of esophageal perforation after radiotherapy in patients with esophageal carcinoma. Front Oncol 2022;12:961902.. 10.3389/fonc.2022.961902 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Xu W, Jiang H, Liu Y, et al. Retrospective cohort study on treatment modalities and survival time after oesophageal fistula in patients with oesophageal cancer in a regional cancer care centre in China. BMJ Open 2023;13:e069703.. 10.1136/bmjopen-2022-069703 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Koike R, Nishimura Y, Nakamatsu K, et al. Concurrent chemoradiotherapy for esophageal cancer with malignant fistula. Int J Radiat Oncol Biol Phys 2008;70:1418-22.. 10.1016/j.ijrobp.2007.08.060 [DOI] [PubMed] [Google Scholar]
- 15. Ma L, Luo GY, Ren YF, et al. Concurrent chemoradiotherapy combined with enteral nutrition support: a radical treatment strategy for esophageal squamous cell carcinoma patients with malignant fistulae. Chin J Cancer 2017;36:8.. 10.1186/s40880-016-0171-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Burt M, Diehl W, Martini N, et al. Malignant esophagorespiratory fistula: management options and survival. Ann Thorac Surg 1991;52:1222-8; discussion 1228-9.. 10.1016/0003-4975(91)90005-b [DOI] [PubMed] [Google Scholar]
- 17. Little BP, Mendoza DP, Fox A, et al. Direct and indirect CT imaging features of esophago-airway fistula in adults. J Thorac Dis 2020;12:3157-66.. 10.21037/jtd-20-244 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Wang X, Hu B, Chen J, et al. Risk factors of esophageal fistula induced by re-radiotherapy for recurrent esophageal cancer with local primary site. BMC Cancer 2022;22:207.. 10.1186/s12885-022-09319-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Xu W, Jiang H, Liu Y, et al. A retrospective cohort study on radio/chemotherapy and survival following esophageal fistula in esophageal cancer patients with prior radiotherapy. BMC Cancer 2025;25:440.. 10.1186/s12885-025-13853-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Turkyilmaz A, Aydin Y, Eroglu A, et al. Palliative management of esophagorespiratory fistula in esophageal malignancy. Surg Laparosc Endosc Percutan Tech 2009;19:364-7.. 10.1097/SLE.0b013e3181ba796d [DOI] [PubMed] [Google Scholar]
- 21. Ross WA, Alkassab F, Lynch PM, et al. Evolving role of self-expanding metal stents in the treatment of malignant dysphagia and fistulas. Gastrointest Endosc 2007;65:70-6.. 10.1016/j.gie.2006.04.040 [DOI] [PubMed] [Google Scholar]
- 22. Li G, Wang Z, Liu J, et al. Comprehensive Insights into Tracheoesophageal Fistula Pathophysiology, Diagnosis, Treatment, and Future Directions. Adv Sci (Weinh) 2025;12:e02825.. 10.1002/advs.202502825 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Lecleire S, Di Fiore F, Ben-Soussan E, et al. Prior chemoradiotherapy is associated with a higher life-threatening complication rate after palliative insertion of metal stents in patients with oesophageal cancer. Aliment Pharmacol Ther 2006;23:1693-702.. 10.1111/j.1365-2036.2006.02946.x [DOI] [PubMed] [Google Scholar]
- 24. Qiu G, Tao Y, Du X, et al. The impact of prior radiotherapy on fatal complications after self-expandable metallic stents (SEMS) for malignant dysphagia due to esophageal carcinoma. Dis Esophagus 2013;26:175-81.. 10.1111/j.1442-2050.2012.01348.x [DOI] [PubMed] [Google Scholar]
- 25. Wang MQ, Sze DY, Wang ZP, et al. Delayed complications after esophageal stent placement for treatment of malignant esophageal obstructions and esophagorespiratory fistulas. J Vasc Interv Radiol 2001;12:465-74.. 10.1016/s1051-0443(07)61886-7 [DOI] [PubMed] [Google Scholar]
- 26. Russo S, Anker CJ, Codipilly DC, et al. Executive Summary of the American Radium Society Appropriate Use Criteria for the Use of Esophageal Stents in Patients With Esophageal Cancer: Systematic Review and Guidelines. Am J Clin Oncol 2025;48:579-99.. 10.1097/COC.0000000000001222 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Ahmed HF, Hussain MA, Grant CE, et al. Closure of tracheoesophageal fistulas with chemotherapy and radiotherapy. Am J Clin Oncol 1998;21:177-9.. 10.1097/00000421-199804000-00017 [DOI] [PubMed] [Google Scholar]
- 28. Muto M, Ohtsu A, Miyamoto S, et al. Concurrent chemoradiotherapy for esophageal carcinoma patients with malignant fistulae. Cancer 1999;86:1406-13. [PubMed] [Google Scholar]
- 29. Reed MF, Mathisen DJ. Tracheoesophageal fistula. Chest Surg Clin N Am 2003;13:271-89.. 10.1016/s1052-3359(03)00030-9 [DOI] [PubMed] [Google Scholar]
- 30. Yu Y, Guan H, Dong Y, et al. Advances in dosimetry and biological predictors of radiation-induced esophagitis. Onco Targets Ther 2016;9:597-603.. 10.2147/OTT.S97019 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Qiao WB, Zhao YH, Zhao YB, et al. Clinical and dosimetric factors of radiation-induced esophageal injury: radiation-induced esophageal toxicity. World J Gastroenterol 2005;11:2626-9.. 10.3748/wjg.v11.i17.2626 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32. Zhao K, Si Y, Sun L, et al. Efficacy and toxicity of re-irradiation for esophageal cancer patients with locoregional recurrence: a retrospective analysis. Radiat Oncol 2020;15:243.. 10.1186/s13014-020-01685-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33. Zhou ZG, Zhen CJ, Bai WW, et al. Salvage radiotherapy in patients with local recurrent esophageal cancer after radical radiochemotherapy. Radiat Oncol 2015;10:54.. 10.1186/s13014-015-0358-z [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34. Zhang F, Cheng F, Cao L, et al. A retrospective study: the prevalence and prognostic value of anemia in patients undergoing radiotherapy for esophageal squamous cell carcinoma. World J Surg Oncol 2014;12:244.. 10.1186/1477-7819-12-244 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35. Zhao KL, Liu G, Jiang GL, et al. Association of haemoglobin level with morbidity and mortality of patients with locally advanced oesophageal carcinoma undergoing radiotherapy--a secondary analysis of three consecutive clinical phase III trials. Clin Oncol (R Coll Radiol) 2006;18:621-7.. 10.1016/j.clon.2006.04.015 [DOI] [PubMed] [Google Scholar]
- 36. Vaupel P, Thews O, Hoeckel M. Treatment resistance of solid tumors: role of hypoxia and anemia. Med Oncol 2001;18:243-59.. 10.1385/MO:18:4:243 [DOI] [PubMed] [Google Scholar]
- 37. Dai Q, Zhao X, Lu W, et al. The Impact of Endoscopic Closure Treatment on Outcomes in Patients with Esophageal Cancer-Associated Fistula: A Retrospective Analysis. Digestion 2026;107:299-308.. 10.1159/000547231 [DOI] [PubMed] [Google Scholar]
- 38. Doweiko JP, Nompleggi DJ. The role of albumin in human physiology and pathophysiology, Part III: Albumin and disease states. JPEN J Parenter Enteral Nutr 1991;15:476-83.. 10.1177/0148607191015004476 [DOI] [PubMed] [Google Scholar]
- 39. Mazzaferro EM, Edwards T. Update on Albumin Therapy in Critical Illness. Vet Clin North Am Small Anim Pract 2020;50:1289-305.. 10.1016/j.cvsm.2020.07.005 [DOI] [PubMed] [Google Scholar]