Preoperative risk factors for complications in esophagectomy: a systematic review

Introduction

Esophagectomy is a surgically complex procedure associated with significant morbidity and mortality, attributable in part to postoperative complications (1,2). Complications include anastomotic leaks, pulmonary adverse events [e.g., pneumonia, acute respiratory distress syndrome (ARDS)], and cardiac complications (e.g., arrhythmias), which occur in addition to surgical site infections, post-operative bleeding, and blood clots (3-6). Such complications have profound impacts on patient and healthcare system, contributing to decreases in quality of life, longer hospital length of stay (LOS), and significantly increased healthcare costs (7-9). Identifying patient risk factors for complications from esophagectomy pre-operatively is challenging, with significant heterogeneity noted amongst studies (1-4).

Enhanced recovery after surgery (ERAS) protocols are now standard, applying multimodal approaches to perioperative care that aim to accelerate patient recovery, reduce complications, and shorten hospital stays (10,11). These protocols are often applied universally without considering the impact individual patient risk factors may have on post-operative outcomes. The current trend in esophagectomy care pathways exemplifies this non-selective approach, as practices have shifted toward early initiation of oral nutrition and minimal use of surgical drains (12,13). While these strategies have shown promise in improving outcomes, universal application without consideration of an individual patient’s risk profile may lead to suboptimal results. In order to best allocate health resources to high-risk patients and optimize outcomes post-esophagectomy, it is crucial to identify and characterize individual patient risk factors and incorporate them into risk assessment tools.

Risk factors can be categorized as preoperative, intraoperative, and postoperative. Preoperative factors specifically offer an opportunity for intervention prior to surgery, with the potential to reduce morbidity and mortality while optimizing patient outcomes (14-16). While prior research has explored preoperative risk factors for esophagectomy, existing studies often focus on a limited set of variables or emphasize mortality rather than 30-day complication rates (17-19). As a result, there remains a gap in understanding how preoperative risk factors influence short-term postoperative complications. This systematic review therefore aims to identify and evaluate how preoperative risk factors influence 30-day complication rates following esophagectomy. By recognizing both modifiable and non-modifiable risk factors, we seek to establish a framework for integrating patient-specific considerations into perioperative care, including ERAS pathways. We present this article in accordance with the PRISMA reporting checklist (available at https://ccts.amegroups.com/article/view/10.21037/ccts-25-42/rc).

Methods

Literature search, screening and data extraction

The research in this article was conducted in accordance with the Cochrane Handbook. To begin, a comprehensive literature search was conducted on Embase, MEDLINE, and Web of Science from inception to July 2, 2025, with the help of a trained research librarian (R.S.). The search strategy combined relevant Medical Subject Headings (MeSH) terms and keywords related to esophagectomy, perioperative risk factors, and common complications following esophagectomy, such as anastomotic leak or pulmonary failure (Appendix 1).

The online research database search yielded a total of 3,963 papers. Literature search results were uploaded to Covidence, an online software for systematic reviews, which identified and removed 1,072 duplicates. Subsequently, 2,891 articles underwent title and abstract screening by two independent reviewers, followed by full-text screening and data extraction. Screened studies were included if they (I) focused on patients who underwent esophagectomy for malignancy; (II) reported a quantified relationship, such as odds ratio (OR) between a preoperative and 30-day post operative complication; (III) were randomized controlled trials (RCTs), cohort studies, case-control studies, or observation studies; (IV) were published in the English language; and (V) included adult participants (age ≥18 years). Studies were excluded if they (I) did not report specific pre-operative risk factors; (II) reported complications that beyond 30-days operatively; (III) did not quantify the relationship between the preoperative risk factor and complication; (IV) were case reports, reviews, letters, editorials, or conference abstracts; (V) focused solely on pediatric patients; or (VI) were non-human studies or studies conducted on cadavers. When full texts could not be obtained or when key data required for extraction (e.g., effect estimates or outcome definitions) were incomplete or unavailable after full-text review, studies were excluded.

Data extraction was performed independently by two reviewers using a standardized extraction form. Extracted variables included study design, sample size, patient demographics, preoperative risk factors, defined 30-day postoperative complications, effect estimates [ORs with 95% confidence intervals (CIs)], and covariates included in multivariable analyses. Discrepancies were resolved through discussion or consultation with a senior reviewer.

Statistical analysis

The data was cleaned on Microsoft Excel following extraction. Given the high volume of studies extracted, studies where a preoperative risk factor was mentioned less than 2 times in relation to a 30-day post-operative complication were excluded. The threshold of at least two independent reports was chosen to reduce the influence of isolated or anecdotal findings and to ensure that reported associations reflected reproducible patterns across the literature rather than single-study observations.

Categorical variables were summarized using counts and proportions, while continuous variables were summarized using means with standard deviations or medians with ranges, as reported in the original studies. Descriptive statistics were used to summarize the demographic distribution of patients across the studies included. A heat map was generated using Python to visualize the most frequently reported preoperative risk factors and their association with major 30-day complications. The range of risk ratios and CIs was reported descriptively for each preoperative risk factor in relation to the 30-day post-operative complication.

Risk of bias

In this study, given the heterogeneity of included studies, an adapted version of the Risk-of-Bias in Non-randomized Studies of Interventions (ROBINS-I) tool was used to assess for bias (20). Specifically, the modified risk of bias assessment employed a design-agnostic quality appraisal approach. Items evaluated in the modified framework included: clarity of the research question, definition of the study population and eligibility criteria, data sources and collection methods, outcome definition and measurement, handling of confounding variables, appropriateness of statistical analysis, completeness of reporting, and adequacy of follow-up (Appendix 2).

Each study’s risk-of-bias was evaluated by two independent reviewers, with discrepancies resolved through discussion or consultation with an expert reviewer. Based on the risk-of-bias assessment, studies were categorized as having low, moderate, or high risk-of-bias. High risk-of-bias studies were included in the analysis to encapsulate the extent of bias in study training and validation datasets (Appendix 3).

Results

Demographic summary of included studies

Of the studies identified in the literature search, 297 were included for data extraction. Following data extraction, the dataset was filtered by removing non-specific pre-operative risk factors and post-operative complications, as well as any risk factor-complication associations reported only once. Non-specific preoperative risk factors and postoperative complications were defined as those reported without clear clinical or operational definitions (e.g., “poor health status”, “general complications”, or composite outcomes without component-level data), which could not be meaningfully categorized or compared across studies. This resulted in the exclusion of a further 201 studies, and the remaining 96 were included in the review (Figure 1, Appendix 4).

Figure 1 PRISMA flow diagram illustrating the study selection process for the systematic review.

The included studies comprised a combination of case reports (n=5), retrospective cohort studies (n=88), and prospective cohort studies (n=3). Across these studies, the weighted mean age of participants was 62.22 years [standard devation (SD): 11.86]. The proportion of male participants was 64.2%, while female participants accounted for 35.8%. The most common comorbidities among participants included hypertension (50.1%), diabetes mellitus (DM) (20.8%), chronic obstructive pulmonary disease (COPD) (5.6%), and coronary artery disease (CAD) (5.2%). Of the 96 papers included in this review, the overall risk-of-bias was considered low for 93.7% (n=90) and moderate for 6.3% (n=6). There were no studies where the risk-of-bias was deemed to be unclear or high.

Because the included studies demonstrated substantial heterogeneity in study design, patient populations, definitions of both preoperative risk factors and postoperative complications, and statistical reporting methods, quantitative pooling was not appropriate. In addition, several outcomes were reported in fewer than three studies or without sufficient variance data. For these reasons, meta-analysis was not performed. Instead, results are summarized descriptively by reporting ranges of ORs and CIs for each risk factor-complication association.

Various preoperative risk factors were seen in relation to common 30-day complications. The most common complications included 30-day mortality (n=34), anastomotic leak (n=24), atrial fibrillation (n=12), and pneumonia (n=7). Across the included studies, age, American Society of Anesthesiologists (ASA) score, and body mass index (BMI) were the most frequently reported risk factors associated with 30-day complications, particularly with increased odds of mortality, atrial fibrillation, and anastomotic leak. Sarcopenia and vascular calcification showed consistent associations with pneumonia and mortality, respectively, alongside other frequently reported comorbidities such as hypertension. In contrast, risk factors such as sex, smoking, and tumor location were infrequently linked to early postoperative outcomes, reflecting limited or inconsistent evidence across studies. To improve readability and allow rapid comparison across studies, Table 1 provides a consolidated summary of all reported risk factor-complication associations with corresponding ranges of effect estimates, while Figure 2 presents a heat map highlighting the most frequently reported and clinically notable associations.

Figure 2 Heatmap depicting frequency of esophagectomy preoperative risk factors and their relation to notable postoperative 30-day complications with OR range >1. ALP, alkaline phosphatase; ASA, American Society of Anesthesiologists; AST, aspartate aminotransferase; BMI, body mass index; DVT, deep vein thrombosis; HbA1c, glycated hemoglobin; OR, odds ratio; VTE, venous thromboembolism.

Age

Fifty-two studies assessed age in relation to postoperative outcomes. The direction of association of age in relation to several 30-day complications had great variability. Specifically, age greater than 65 years was associated with higher odds of 30-day mortality (OR 1.04–4.33, 95% CI: 0.18–16.08), anastomotic leak (OR 0.32–3.18, 95% CI: 0.05–33.55), atrial fibrillation (OR 1.03–4.89, 95% CI: 0.51–9.47), dysphagia (OR 1.70–2.94, 95% CI: 0.91–4.93), pneumonia (OR 0.58–4.85, 95% CI: 0.23–22.03), and unspecified arrhythmia (OR 2.61–2.97, 95% CI: 1.08–6.31). No consistent associations were observed for ARDS (OR 0.91–2.09, 96% CI: 0.91–2.09), anastomotic stricture (OR 0.58–0.97, 95% CI: 0.26–1.22), delayed gastric emptying (OR 0.99–1.81, 95% CI: 0.95–3.46), deep vein thrombosis (DVT)/venous thromboembolism (VTE) (OR 1.03–2.04, 95% CI: 0.44–9.38), reflux (OR 0.99–1.09, 95% CI: 0.96–1.14), or wound infection (OR 0.99–2.93, 95% CI: 0.97–7.75) (Appendix 5).

BMI

Three studies evaluating underweight patients (BMI <18.5 kg/m²) found no consistent association with 30-day mortality (OR 0.67–7.83, 95% CI: 0.67–33.16) or dysphagia (OR 1.61–1.91, 95% CI: 0.86–3.59). In overweight patients (BMI: 25–29.9 kg/m²), higher odds were observed for pneumonia (OR 1.00–3.78, 95% CI: 0.48–12.00) and wound infection (OR 1.41–1.50, 95% CI: 0.39–5.78), whereas no consistent association was seen with 30-day mortality (OR 0.48–1.20, 95% CI: 0.42–2.38) or anastomotic leak (OR 0.40–2.80, 95% CI: 0.13–7.46). In obese patients (BMI >30 kg/m²), 30-day mortality was increased (OR 1.05–5.28, 95% CI: 0.57–18.12), with no significant association for anastomotic leak (OR 0.80–0.98, 95% CI: 0.30–2.04), pneumonia (OR 0.66–1.00, 95% CI: 0.43–2.10), or wound infection (OR 0.71–1.70, 95% CI: 0.45–6.11) (25,46,60,61,66,75,77,85-87,89).

Tumor characteristics

Patients with T1–2 tumors demonstrated lower odds of anastomotic leak (OR 0.39–2.34, 95% CI: 0.14–5.58) and pneumonia (OR 0.79–1.22, 95% CI: 0.26–2.56) compared with higher-stage disease. In contrast, T3–4 tumors were associated with higher baseline risk of 30-day mortality (OR 0.90–1.31, 95% CI: 0.33–5.13), anastomotic leak (OR 0.60–2.81, 95% CI: 0.23–10.77), and pneumonia (OR 0.88–1.49, 95% CI: 0.43–2.85). For histology, patients with squamous cell carcinoma had increased odds of 30-day mortality (OR 1.19–1.68, 95% CI: 0.33–4.30) and anastomotic leak (OR 0.98–1.82, 95% CI: 0.10–14.40) (25,30,31,36,41,43,44,46,47,64,67,69).

Tumor location was also associated with variable risk. Upper esophageal tumors demonstrated higher odds of anastomotic leak (OR 1.38–5.11, 95% CI: 0.44–13.20) but no consistent association with pneumonia (OR 0.89–1.93, 95% CI: 0.38–4.38). Middle esophageal tumors showed elevated odds of anastomotic leak (OR 1.07–2.20, 95% CI: 0.87–5.58) (46,47,67,69,71,90).

Gender

Twenty-three studies evaluated gender as a risk factor for postoperative complications. No significant association was found for 30-day mortality (OR 0.64–2.24, 95% CI: 0.32–3.50), anastomotic leak (OR 0.90–4.08, 95% CI: 0.36–28.74), anastomotic stricture (OR 0.21–1.10, 95% CI: 0.05–1.90), atrial fibrillation (OR 1.12–2.26, 95% CI: 0.73–4.37), delayed gastric emptying (OR 1.26–2.73, 95% CI: 0.65–6.81), or pneumonia (OR 0.42–6.16, 95% CI: 0.02–43.90) (21,25,35,36,40,46-48,52,56,57,62,64-67,70,72,74,76,85,88,90).

Neoadjuvant therapy

Fifteen studies assessed the impact of neoadjuvant therapy. No consistent association was observed with 30-day mortality (OR 0.80–1.69, 95% CI: 0.42–1.90), anastomotic leak (OR 0.98–4.43, 95% CI: 0.38–11.95), anastomotic stricture (OR 0.76–1.60, 95% CI: 0.31–2.90), atrial fibrillation (OR 0.70–1.92, 95% CI: 0.44–2.87), or pneumonia (OR 0.70–1.87, 95% CI: 0.35–4.06) (25,28,31,40,46,47,52,57,58,64,67,69,74,78,85).

Smoking and alcohol use

Twenty-two studies evaluated smoking history. No significant association was found for 30-day mortality (OR 0.96–2.58, 95% CI: 0.52–5.20), ARDS (OR 0.60–9.95, 95% CI: 0.52–92.70), anastomotic leak (OR 1.00–6.03, 95% CI: 0.40–49.55), atrial fibrillation (OR 1.01–1.15, 95% CI: 0.54–1.88), or pneumonia (OR 0.84–3.63, 95% CI: 0.24–8.63) (21,25,32,34,44,56,57,64,66,69,70,72,74,79,81-85,88,91,103).

Three studies evaluating alcohol use found no significant association with pneumonia (OR 0.77–1.51, 95% CI: 0.32–2.83). Two studies identified increased odds of 30-day mortality (OR 2.68–2.73, 95% CI: 1.17–6.05) (24,44,59,64,66).

ASA score

In patients with ASA scores of 1–2, no significant association was observed for anastomotic leak (OR 0.55–2.13, 95% CI: 0.30–10.68) or anastomotic stricture (OR 1.16–2.15, 95% CI: 0.25–5.72). For ASA 3, odds of 30-day mortality were increased (OR 1.04–1.29, 95% CI: 0.54–3.30), while higher ASA scores (4,5) were associated with increased risk of anastomotic leak (OR 1.19–1.80, 95% CI: 0.11–12.82) and 30-day mortality (OR 1.49–6.07, 95% CI: 0.66–18.44), but not with anastomotic stricture (OR 0.39–2.27, 95% CI: 0.04–5.20) (25,31,38,43,48,49,71,85,92).

Previous functional capacity

Radiation dose was associated with increased odds of anastomotic leak (OR 1.00–7.81, 95% CI: 1.00–51.45). Renal dysfunction increased 30-day mortality risk (OR 1.45–1.80, 95% CI: 0.42–5.00), and impaired oral care was linked to higher pneumonia incidence (OR 0.42–3.93, 95% CI: 0.21–6.42). Handgrip strength, FEV1, and vital capacity showed no consistent associations with major outcomes (25,37,41,43,62,64,69,73,78,85,93-101).

Laboratory investigations

Sarcopenia increased pneumonia risk (OR 1.08–11.40, 95% CI: 0.46–82.60). Elevated alkaline phosphatase (ALP) (>340 IU/L) (OR 1.38–1.64, 95% CI: 0.91–2.46) and aspartate aminotransferase (AST) (>35 IU/L) (OR 2.07–2.09, 95% CI: 1.41–3.05) were linked to higher 30-day mortality (21,37,46-48,64,65,67-69,72,81,82,98,102,104,105,114).

Associations between glycemic control and nutritional markers and postoperative complications were variably reported. Elevated HbA1c showed inconsistent associations with anastomotic leak across the limited number of studies evaluating this relationship (OR 1.40–4.03, 95% CI: 0.56–14.60). Similarly, lower preoperative albumin levels demonstrated variable associations with anastomotic leak (OR 0.23–4.75, 95% CI: 0.03–22.43) and pneumonia (OR 0.45–0.58, 95% CI: 0.19–1.29), with wide CIs and no consistent direction of effect across studies.

Specific pre-existing conditions

Aortic calcification (OR 2.18–7.01, 95% CI: 1.22–26.44) and congestive heart failure (OR 1.98–3.64, 95% CI: 0.89–8.05) were associated with increased complication risk. Diabetes, hypertension, and multiple comorbidities showed mixed associations without consistent trends. Positive lymph node status was associated with higher odds of anastomotic leak (OR 0.73–4.90, 95% CI: 0.37–21.84) (Appendix 5).

Discussion

This systematic review offers a comprehensive evaluation of preoperative risk factors for 30-day complications following esophagectomy. Our results strengthen current understanding of risk factors for esophagectomy complications, including validating established predictors such as ASA score, age, and BMI, but also reveal underrecognized yet clinically significant factors like sarcopenia, elevated AST, vascular calcification, radiation exposure, and lymph node positivity. Higher ASA scores (≥ III) and age >65 years were associated with increased postoperative mortality and cardiorespiratory complications, consistent with findings from existing literature (115). These patients often present with significant comorbidities, reduced physiologic reserve, and impaired cardiopulmonary function, factors that may limit their suitability for ERAS protocols given the added hemodynamic and respiratory stress of esophagectomy. An interesting factor that may interplay in this relationship is sarcopenia, which was associated with a higher likelihood of postoperative pneumonia. This finding may be explained by diminished respiratory muscle strength, impaired cough reflex, and greater overall frailty (116,117).

Although older age was consistently associated with increased mortality and cardiorespiratory complications, associations with specific infectious complications such as pneumonia showed substantial variability across studies, reflected by wide CIs and inconsistent effect directions.

Smoking was not found to consistently increase short-term (30-day) postoperative complications in this literature review. This was unexpected given the extensive evidence linking smoking with impaired wound healing, pulmonary dysfunction, and increased infection risk (118-121). It is possible that the primary effects of smoking manifest more prominently in long-term recovery or are partially mitigated in short-term outcomes by perioperative optimization measures, such as preoperative cessation protocols.

This review adds to existing literature by highlighting the importance of certain preoperative laboratory markers in predicting postoperative complications. From a practical standpoint, these findings suggest that several preoperative risk factors identified in this review could be incorporated into structured assessment and optimization pathways. Many of these variables are already available during routine preoperative workup, including cross-sectional imaging, standard laboratory testing, and functional assessments. For example, body composition measures derived from staging computed tomography (CT), basic hepatic enzyme panels, and vascular calcification scoring on preoperative imaging are increasingly accessible without additional patient burden. These data could be used to flag higher-risk patients for targeted interventions such as nutritional support, respiratory conditioning, or closer perioperative monitoring. While specific screening thresholds and standardized intervention protocols remain to be established, these examples illustrate how preoperative risk stratification may be operationalized within existing clinical workflows.

Early postoperative dysphagia was included as a 30-day outcome because it is commonly reported in the esophagectomy literature and has important clinical implications, including delayed oral intake, prolonged hospitalization, need for additional investigations or interventions, and reduced early postoperative quality of life. While dysphagia in the early postoperative period is often transient and mechanistically distinct from complications such as anastomotic leak or pneumonia, its frequent reporting and impact on recovery justified its inclusion as a postoperative outcome in this review.

High BMI correlated with post-operative complications. Overweight (BMI: 25–29.9 kg/m²) patients had increased odds of pneumonia and wound infection, whereas obesity (BMI >30 kg/m²) was associated with higher mortality. The relationship between BMI and outcomes is likely confounded by associated comorbidities such as diabetes, cardiovascular disease, and reduced pulmonary function, making it difficult to isolate the independent effect of BMI itself.

Limitations and future directions

The conclusions that can be drawn from this literature review are limited by the predominance of retrospective studies, which are subject to selection bias and incomplete adjustment for confounding variables. The publications identified and reviewed were heterogeneous in design, patient population, and outcome definitions, which necessitated reporting a range of ORs rather than pooled effect sizes. This heterogeneity, along with wide CIs for many associations, reflects variability in surgical practice, perioperative care, and complication reporting across institutions. Additionally, the inability to extract and aggregate individual patient-level data prevented more precise quantification of risk for each factor.

Conclusions

This systematic review consolidates current evidence on preoperative predictors of 30-day complications following esophagectomy, reaffirming the prognostic value of higher ASA score, older age, and BMI extremes while drawing attention to underrecognized risk factors such as sarcopenia, elevated AST, vascular calcification, prior radiation exposure, and lymph node positivity. These findings emphasize that risk is influenced not only by patient comorbidity and physiologic reserve, but also by nutritional status, hepatic function, and vascular health. Identifying these factors preoperatively provides an opportunity to implement targeted interventions, such as respiratory and nutritional prehabilitation, optimization of hepatic function, and vascular assessment, to mitigate postoperative morbidity and mortality. Integrating these predictors into standardized risk stratification models could improve patient counseling, guide surgical planning, and inform allocation of perioperative resources, ultimately enhancing recovery and short-term survival after esophagectomy. Future work should focus on using the results of this review to inform the development of standardized preoperative risk stratification tools that highlight key predictors for specific complications. Such a system could be validated in prospective multicenter cohorts or integrated into ERAS pathways, enabling targeted prehabilitation, nutritional optimization, and more judicious allocation of costly perioperative care resources.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://ccts.amegroups.com/article/view/10.21037/ccts-25-42/rc

Peer Review File: Available at https://ccts.amegroups.com/article/view/10.21037/ccts-25-42/prf

Funding: This study was funded in part by the Faculty of Medicine Summer Research Studentship.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://ccts.amegroups.com/article/view/10.21037/ccts-25-42/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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