Esophageal cancer is the 6th leading cause of death from cancer and the 8th most common cancer in the world associated with high rates of morbidity and mortality; the 5-year survival is approximately 15%–25%, and the best prognoses are related to early diagnosis (1). Early detection and intervention can reduce adverse effects and improve the survival of patients. Although advancements in endoscopic techniques, such as endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD), have greatly benefited patients with early-stage disease, surgical resection remains the most important treatment measure. Esophagectomy is a complex procedure associated with complications such as pneumonia and anastomotic leakage that can restrict oral feeding, leading to short postoperative survival rates (2). With improvements in surgery and perioperative care resulting in reduced mortality after esophageal cancer (3), there is an urgent need to identify patients who are eligible for enhanced recovery after esophageal carcinoma resection. Enhanced recovery after surgery (ERAS) is based on a suite of clinical processes and evidence that it is on the premise of not increasing complications, it can improve comfort, shorten hospitalization time and reduce treatment costs. following a major surgery; it was initially established for colorectal surgery (4–6). Currently, ERAS has gained attention with regard to esophagectomy, and an increasing number of retrospective and prospective studies and clinical protocols are being reported. Accelerated recovery with ERAS is associated with not only reduction in the duration of hospital stay, pulmonary complications and anastomotic leakage but also decreased pain after surgery and faster return to normal life, especially oral feeding. However, to our disappointment, despite enhancement in the interventions during anesthesia and postoperative rehabilitation exercise, there is no consensus on when patients should return to oral feeding, as many patients suffer from anastomotic leakage during ERAS (7–11). Except for severe malnutrition and adverse reactions after neoadjuvant chemotherapy being considered in the exclusion criteria, there are no official guidelines to select the patients undergoing esophagectomy who are eligible for ERAS.

Systemic inflammatory responses have been demonstrated to be associated with cancer initiation and progression and poor outcomes in various malignant tumors (12–16). Inflammatory indicators such as the neutrophil to lymphocyte ratio (NLR) is suggested to include critical information that makes the NLR suitable as a serum biomarker that can reflect early complications associated with recovery, so that we may implement appropriate treatment strategies to address adverse outcomes in a wide range of patients (17–20). However, the relationship between preoperative or postoperative NLR and complications after esophagectomy is still uncertain. In this study, we aimed to determine the association between the NLR and postoperative complications to determine the potential of the NLR as an indicator for patients who are eligible for ERAS.

To the best of our knowledge, this is the first study demonstrating that the NLR (in addition to surgical factors) is a potential indicator of complications in patients after esophageal cancer resection.

In the past years, several studies have demonstrated that the Glasgow Prognostic Score (GPS) (the combination of an elevated C-reactive protein (CRP) level and hypoalbuminemia) is associated with poor survival in various cancers (24), but as the primary limitation, CRP level is not a normal examined factor in many institutions. Until now, the systemic inflammatory prognostic marker, the NLR, has received great interest because it is convenient, inexpensive and easy to evaluate by clinical doctors (25). Neutrophils infiltrate in tumor tissues that produce high levels of vascular endothelial growth factor (VEGF). Neutrophils can also produce carcinogenic element to stimulate tumor cells to secrete VEGF. High levels of VEGF can provide a suitable environment for tumor growth and proliferation and promote the formation of tumor blood vessels, thus accelerating tumor growth (26); additionally, a decrease in lymphocytes in the tumor stroma can contribute to tumor cell growth and migration and is associated with poor prognosis (27). The NLR is proven to be an effective predictive factor of prognosis in many malignant tumors (28–30). An increasing number of studies have demonstrated that inflammation plays a critical roles in malignant tumor progression and prognosis; in other words, the regulation of inflammation may benefit patients by preventing the formation of tumors and improving outcomes (31, 32). A study demonstrated that pneumonia has a negative impact on overall survival after esophagectomy, and strategies to prevent pneumonia after esophagectomy can improve outcomes after this operation (33). Several studies demonstrate that inflammation is associated with the prognosis of esophageal cancer. A study from Japan on gastric carcinoma demonstrated that the _preNLR can independently predict the development of postoperative infection-associated complications and reduced survival after gastrectomy. An elevated NLR could trigger postoperative infection and increase the risk of recurrence in patients with these postoperative complications after gastrectomy (34). An study from UK on sixty-five patients showed that an elevated NLR as early as 48 h following surgery was a highly sensitive and significant predictor of postoperative complications (35). One meta-analysis from China comprising nine studies containing 2,513 patients concluded that a high NLR might represent poor prognosis and unfavorable clinicopathologic characteristics for patients with esophageal squamous cell carcinoma (ESCC) (36). These results suggest that the _preNLR might be a precise indicator of the balance between the tumor inflammatory response and host immune response.

In this study, we first analyzed the relationship between the NLR and main complications after esophagectomy. We investigated factors that had never been studied in this context before. To eliminate the confounding effect of the operation technique, we excluded patients with complications such as postoperative bleeding, recurrent laryngeal nerve injury and pneumothorax. To eliminate the effect of injury from different surgical procedures, we excluded a large number of patients who underwent Ivor-Lewis esophagectomy, nonendoscopic esophageal cancer resection and some other surgical procedures. Additionally, we excluded patients who had taken glucocorticoids, erythropoietin, or human granulocyte colony stimulating factor, patients who recently underwent blood donation or transfusion or patients with hematological diseases or autoimmune diseases to prevent the effect or routine changes in blood. Our study demonstrated the NLR along with BMI and p stage is an independent risk factor for complications. BMI has been proven to be a risk factor of complications and prognosis after resection in many cancers (37, 38). As far as we know, BMI is related to postoperative complications of tumor in literature reports. Patients with low BMI are prone to suffer complications such as poor incision healing, due to poor nutrition status. In addition, when serious complications occur, there may rise more mortality due to poor tolerance. Patients with high BMI are at higher risk of complications such as lung infection and deep vein thrombosis due to poor activity or high blood lipid levels (39, 40). NLR is an indicator of immune status and infection in tumor microenvironment. In many literature reports, NLR can predict infection, anastomotic fistula and other complications. Meanwhile, in our study, it was also found that patients with high NLR are at high risk of postoperative complications, mainly anastomotic fistula, pulmonary infection and catheter infection. Therefore, we believe that BMI can reflect the nutritional status and wound healing ability of tumor patients after surgery, but cannot completely predict the postoperative complications of esophageal cancer. Therefore, compared with BMI, NLR can predict the occurrence of non-operative complications after esophageal cancer more exactlly.

In this study, we analyzed the _preNLR, _D0NLR and _D1NLR and found that the _preNLR was most significant indicator for the occurrence of complications. We consider that the NLR after operation is likely highly influenced by the inflammatory reaction, and thus, it is unable to accurately indicate the condition of the patient. Our univariate analysis revealed that complications after esophagectomy are related to BMI, ASA grade, operation time, intraoperative blood loss and tumor stage. For patients undergoing thoracic surgery, postoperative rehabilitation exercise is important for promoting lung function recovery and can reduce complications such as pneumonia. Patients with high BMI have difficulty reaching effective cough and sputum production and performing early activities, and thus, these patients are likely to develop pneumonia and deep vein thrombosis. Because the operation time is much longer for esophagectomy than for other surgeries and because single lung ventilation is used, anesthesia can aggravate injury to the body, especially the lung, and is more likely to cause pneumonia and other complications.

Overall, this study has some limitations. We need to perform multicenter observational studies to prove that the _preNLR is an objective indicator of complications after esophagectomy, and it may be much more appropriate to introduce reference indicators such as CRP level and interleukin levels for comparison. Then, we can proceed with survival analysis and prognostic assessment. Additionally, we can find whether non-infection complications are associated with poor prognosis.

Importantly, in most cases, the indicators are present long before the complications can be identified. Therefore, we can use these indicators as early predictive markers. As esophagectomy is a complicated and traumatic procedure, more careful evaluation and intervention are needed to improve the postoperative outcomes. ERAS is a patient-centered, surgeon-led protocol combining anesthesia, nursing, nutrition and psychology. During recent years, ERAS has obtained much attention in the field of cancer resection (41, 42). ERAS can benefit patients by reducing the discomfort of tube detention, promoting quicker recovery to the physiological status, and reducing hospital stay duration and cost. ERAS is not commonly implemented in esophagectomy because of the complexity of the surgical procedure and high morbidity associated with postoperative complications, which have limited the progress in esophagectomy.

In the treatment of traditional mode, patients need to wait for about 1 week after radical surgery for esophageal carcinoma that they can get through eating liquid, removing the chest tube and gastric tube, that is lack of individual treatment differences. However, the patients expected to have good recovery do not need 1 week of fasting, why can’t we help that patients recover from surgery more quickly. According to the concept of ERAS, early removing the gastric tube and chest tube, early eating through the mouth can improve the comfort of patients, shorten the length of hospital stay, reduce the cost of treatment, faster recovered from surgery. But perfotming the implement ERAS such as early remove the chest tube and the gastic tube will not benefit for that patients with anastomotic fistula and infection to recovery, it can even pose a fatal risk, increasing complications and mortality. According to our opinion, we hope that NLR can be used to seclect that patients with esophageal cancer who are suitable for ERAS, so as to facilitate the rapid recovery safely. In the experimental design, we have excluded surgical complications such as bleeding and chylous leakage, patients with high NLR and unsuitable for ERAS will be delayed for feeding and removing the chest tube, in case of avoid serious chest infection or even death due to blind eating and chest tube removal.

The primary factors that influence the time to oral feeding and tube removal are pneumonia, anastomotic leakage and pleural effusion. If we can detect the indications for complications, we can identify patients undergoing esophagectomy who are suitable for ERAS, and this can significantly enhance recovery and reduce the cost after surgery; additionally we can implement early interventions to address postoperative complications.

The _preNLR as an early predictor of complications can reduce postoperative mortality and improve survival rates. Herein, we consider preNLR can be used as inclusion criteria for enhanced recovery after surgery.