Esophageal squamous carcinoma cell (ESCC) is the primary subtype of esophageal cancer (EC) in Asia, especially in China (1). A combination of neoadjuvant therapy and surgery is recommended as the standard treatment for locally advanced ESCC. There is still no consensus on neoadjuvant therapy. Compared with surgery alone, both neoadjuvant chemotherapy (nCT) and neoadjuvant chemoradiotherapy (nCRT) have been confirmed to improve overall survival and disease-free survival (2, 3). The nCRT pattern is recommended as the first choice in the national comprehensive cancer network (NCCN) and Chinese society of clinical oncology (CSCO) guidelines. However, due to unpromising long-term survival and the high distant recurrence incidence, the exploration of novel treatment patterns is necessary. Phase II clinical trials showed that neoadjuvant immunochemotherapy (nICT) had a promising pathological response and manageable adverse events (4, 5).

With the development of minimally invasive esophagectomy (MIE), morbidity and mortality have reduced (6); however, complications (especially pneumonia, anastomotic leakage, and atrial fibrillation) after MIE are still high, and management is still challenging. Among patients with solid cancers, patients with EC had the highest risk of atrial fibrillation [adjusted sub-distribution hazard ratio (HR) 2.69; 95% confidence interval (CI) 2.45–2.95] (7). In patients who underwent esophagectomy, postoperative atrial fibrillation (POAF) was highly associated with postoperative infectious complications (8). A recent meta-analysis showed that the incidence of POAF was 16.5%, and patients with POAF had a higher risk of anastomotic leakage, pneumonia, death, and other adverse events (9). In addition, a 21-year follow-up cohort showed that POAF was associated with poorer long-term survival after esophagectomy (HR 2.99, 95% CI=1.37–6.53). Further, POAF increased the risk of stroke, cognitive decline, and depression, reduced the quality of life, and brought a great burden to patients and the medical system (10).

Previous reports indicated that the application of neoadjuvant treatment contributed to the occurrence of POAF (11). Considering the promotion of neoadjuvant treatment plus esophagectomy, it is of clinical importance to understand the risk factors of POAF among patients receiving neoadjuvant therapy (nCT, nCRT, or nICT). The aim of the present study was to determine the risk factors of POAF among patients receiving neoadjuvant therapy and construct a nomogram model to help clinicians evaluate the risk of POAF and take personalized treatment plans. Another concern was whether POAF was associated with the types of neoadjuvant treatment.

POAF is a common complication after esophagectomy, and the overall incidence of POAF in this study was 16.83% (34/202). Compared with non-esophageal surgery, patients undergoing esophagectomy had a higher incidence of POAF (17.66% vs 7.63%) (13). There was a significant increase in postoperative hospital stay (p = 0.04), hospital expenses (p = 0.01), and CCI (p < 0.001). Therefore, the identification of independent risk factors and the development of an accurate predictive model for POAF are critical for optimal treatment planning in high-risk individuals with MIE after neoadjuvant therapy. Preoperative Alb ≦41.2 g/L, LA diameter >32.9 mm, preoperative Hb >149 g/L, and EF >67.61% were identified as the independent risk factors for POAF, and a novel nomogram model was constructed to predict POAF. The model not only showed the good discriminative ability but also had the best agreement between the predicted results and the observed results. Based on this nomogram model, each prognostic factor was quantified and visualized with a nomogram model to predict the probability of POAF. By using this predictive nomogram, physicians could judge individual risk, predict outcomes, personalize treatment, and take preventive measures for patients at high risk.

In this study, we determined LA diameter ≥32.9 mm as an independent risk factor of POAF. Nagatsuka et al. investigated 200 patients undergoing esophagectomy for EC and determined a LA diameter ≥36.0 mm [odds ratio (OR) 2.47, 95% CI 1.06–5.71] as an independent risk factor (p = 0.035) (14). A relationship between LA diameter and AF has been proposed in the general population. One hypothesized direct underlying cause of AF is the result of organic changes in the “remodeling” of the left atrium to maintain a normal sinus rhythm. Increased left ventricular diastolic blood pressure during diastolic dysfunction is associated with increased left ventricular diastolic blood pressure. With the increase of left atrial pressure, atrial wall extension increases and atrial remodeling occurs (15). Interestingly, we also found that left ventricular EF >67.61% was an independent risk factor of POAF. This finding seemed to be inconsistent with previous reports. Zacharias et al. enrolled a total of 8,051 consecutive cardiac surgery patients and found that EF <40% (OR 1.16, 95% CI 1.03–1.31) was an independent risk factor of POAF (16). However, a large cohort study (203,135 patients from Pennsylvania and 35,976 patients from New Zealand) investigated the relationship between left ventricular ejection fraction (LVEF) and mortality, and they found an HR of 1.71 (95% CI 1.64–1.77) at LVEF of ≥70% and an HR of 1.73 (95% CI 1.66–1.80) at LVEF of 35%–40%, which indicated a U curve relation between LVEF and mortality (17). Another analysis of 2,867 ICU patients (including 324 patients with EF >70%) showed that the presence of EF >70% increased 28-day mortality (OR 1.39, 95% CI 1.04–1.84) (18). This finding first suggested the association between the high LVEF and the POAF. Further studies are necessary to explore the mechanisms.

There are still limited studies focusing on the relationship between preoperative serum Alb and POAF among patients undergoing esophagectomy. Zhong et al. explored the association between serum Alb and paroxysmal AF based on a Chinese cohort of 305 patients with AF and 610 patients without AF and found that low Alb in male patients is a risk factor for paroxysmal AF (19). Liao et al. conducted a large-scale epidemiological and Mendelian randomization (MR) study and found that the serum Alb level was negatively correlated with the incidence of AF, but the causal relationship between serum Alb level and AF was not clarified (20). In this study, we found that preoperative Alb ≦41.2 g/L was associated with a higher incidence of POAF. This finding supports that low Alb contributed to the occurrence of POAF. Serum Alb plays important roles in anti-inflammatory, antioxidant, anticoagulant, antiplatelet aggregation, and colloid osmotic effects. One recent dose–response analysis showed that for each increase of 10 g/L in serum Alb, the risk of AF would decrease by 36% (21). Present evidence supports that hypoalbuminemia is a modifiable risk factor associated with cardiovascular events (22). In future studies, it would be interesting to explore the relationship between preoperative nutrition and the incidence of POAF among patients with ESCC. Similarly, there are still no reports investigating the relationship between high Hb and POAF among patients with ESCC. Recently, Nakatani et al. found that high Hb is an independent risk factor of new-onset AF among patients with heart failure with preserved EF (23). Commonly, patients with paroxysmal AF often have elevated Hb in clinical practice (24). One explanation was that polyuria induced by the excess secretion of atrial natriuretic peptide contributed to the high Hb in patients with AF.

At present, there are different opinions on whether to take preventive treatment for POAF (25). Rao et al. held the opinion that the simple prevention of POAF, including using prophylactic drugs, was unlikely to improve long-term survival and unlikely to be cost-effective (11). However, the model including age and neoadjuvant therapy established by Rao et al. only had a moderate c-statistic (0.62). Compared with previous models, the nomogram model in this study had an AUC of 0.76, which indicated a better discriminative ability. Therefore, we suggest taking measures to prevent the occurrence of POAF when the nomogram model suggests a high possibility of POAF. Although AF can occur as an isolated event, it can occur in conjunction with other complications in a population predisposed to cardiopulmonary complications. The application of enhanced recovery after surgery is necessary to reduce overall mortality and morbidity.

To the best of our knowledge, this study was the first predictive nomogram model for POAF in patients with ESCC receiving neoadjuvant therapy. However, the study has the following limitations: first, the model was analyzed based on retrospective data, which may have a potential bias due to a lack of randomization, patient selection, and some missing values. Second, although nCRT is currently the first choice for patients with low events raised by the radiotherapy, relatively few patients received nCRT in this cohort. Further, we did not conduct a subgroup analysis to evaluate the effect of radiation dose on the incidence of POAF. Third, the prediction model has good discrimination, but it has not been verified externally. Further, the case number is relatively limited. External validation is necessary before applying the nomogram model to patients at other centers. Four, whether this nomogram is suitable in patients with locally advanced esophageal adenocarcinoma remains unclear.

In summary, we determined preoperative Alb ≦41.2 g/L, LA diameter >32.9 mm, preoperative Hb >149 g/L, and EF >67.61% to be the risk factors for POAF among patients with ESCC receiving neoadjuvant therapy and MIE. A novel and useful nomogram model was constructed and validated to help clinicians evaluate the risk of POAF and take personalized treatment plans. The predictive ability and clinical value of the nomogram model were promising. For additional external validation, generalization, and application of this prediction model, large prospective multicenter studies are needed.