With the development of surgical techniques, postoperative complications of esophageal cancer have been significantly reduced4. Unfortunately, surgically related complications still occur in more than half of patients with esophageal cancer, with the most common complications being PPCs, which increased the postoperative mortality rate by nearly 10% and decreased 5-year overall survival rate by 12%24–26. Although the incidence of PPCs can be reduced by MIE, persuading patients to quit smoking before surgery, exercising respiratory related muscles before surgery, and relieving postoperative wound pain27, there is still lack of a readily available model that can effectively predict the incidence of PPCs. In this study, we finally found that smoking index, AFR, ASA physical status Ⅱ, and recurrent laryngeal nerve palsy were independent risk factors for PPCs in patients with esophageal cancer using univariate and multivariate logistic analysis. Through two types and two groups of ROC curve analysis, it was found that preoperative AFR could well predict PPCs. The AUC value were 0.817 in the training group and 0.803 in the validation group, which was the highest among the collected laboratory tests data with good sensitivity (76.2%), specificity (78.7%) and sensitivity (69.4%), specificity (85.8%) (p < 0.001). Binary AFR also demonstrated preferable prediction with AUC 0.771, sensitivity (75.4%), specificity (78.7%) and AUC 0.766, sensitivity (69.4%), specificity (83.9%) (p < 0.001).
The nutritional status of cancer patients is an important factor in determining postoperative prognosis, morbidity and mortality22. Although PNI, prognostic nutritional index, has been proven to predict postoperative complications and outcomes in varies cancer patients22,28−30, it is not the independent risk factor or the best predictive signature in our study with AUC 0.730. As mentioned above, many studies have been conducted on albumin and AFR as independent influencing factors to predict postoperative complications and prognosis in tumor patients. The results of both groups in this study indicated that lower AFR, which seems means lower albumin or higher fibrinogen, was more prone to PPCs. Increasing albumin to prevent postoperative complications is correlated with previous reports that low serum albumin may lead to a higher risk of worsening disease and poor prognosis in cancer patients13. This might be due to malnutrition can weaken the immune system, increase the chance of infection, and albumin may help stabilize the DNA replication and cell growth, regulate the body's reaction, enhance immunity, prevention of malignant disease18. Fibrinogen, a fibrin-based soluble clotting substrate that plays a central role in hemostasis and thrombosis, is associated with cardiovascular event risk and pre-thrombosis status in experimental models31, and is also widely reported as an acute phase protein involved in inflammatory response. Fibrinogen synthesis is regulated by a number of inflammatory cytokines, including interleukin-1 (IL-1) and IL-632. Thus, elevated FIB within a range may indicate a higher likelihood of thrombosis and attack by inflammatory factors. Theoretically, it may hamper the patient's recovery after surgery. As for AFR, a new indicator, represents the combined effect of the two blood factors mentioned, enhancing sensitivity to assess inflammation and nutritional status. In various models of acute ST-segment elevation myocardial infarction (STEMI)33, non small cell lung cancer (NSCLC)34, soft tissue sarcoma35, and esophageal cancer18, the combination of albumin and fibrinogen has been reported to be superior to albumin and fibrinogen alone, and has been widely recommended as a prognostic factor. It should be noted that in a report on the prediction of prognosis of esophageal cancer by AFR18, postoperative complications of patients were not included in the study, so it was not possible to assess whether the prognosis of patients after esophageal cancer was caused by the occurrence of postoperative complications. However, it remains to be further explored whether AFR or PPCs has a stronger correlation with prognosis. To our knowledge, the present study is the first to demonstrate the association between AFR and PPCs after MIE.
Plenty of studies have demonstrated that current smoking status is associated with PPCs36, and smoking cessation decrease the incidence of PPCs27,37. But none of these studies seemed to include smoking index that reflects the degree of smoking rather than the status of smoking in some aspect. When including both smoking status and smoking index in the logistic regression analysis, we found that only smoking index (OR 1.001, 95% CI 1.000-1.002, p = 0.024) was a significant risk factor and was also significantly different in validation group which might mean that the amount of smoking, rather than smoking status, is a better predictor of PPCs, although it is needed validation among large sample and multiple centers.
Similar to previous studies38–41, our work confirmed that ASA was an independent risk factor for PPCs, while only grade Ⅱ was significant taking grade Ⅰ as reference. ASA system was to assess the general health and comorbidities of patients before surgery39. Our study provides evidence for the foregoing and future related research.
The recurrent laryngeal nerve plays an important role in spinal cord coordination. RLN originates from the vagus nerve and provides ipsilateral motor innervation to the internal laryngeal muscles except the cricothyroid. These muscles play an important role in speech, swallowing and breathing27. As reported before, the incidence was from 0–29.3%42, and Ivor Lewis could decrease the incidence to 0.9%43. However, the occurrence of recurrent laryngeal nerve palsy showed a strong correlation with postoperative pneumonia44. In this study, the incidence was 3.2% in training group and 4% in validation group. Its association with PPCs was verified by both sets of data (p < 0.05).
However, there are still several deficiencies in our study. First of all, this study is a retrospective, single-center study, which is likely to cause selective bias, and it needs to be verified by prospective, multi-centers, large-sample trials in the future, which may explain why age, body mass index (BMI) and FEV1/pre5,17,22 were not independent risk factors as reported before. In addition, it is not clear whether preoperative intervention to change AFR level can reduce the incidence of PPCs. Finally, the mechanism that how AFR can predict postoperative pneumonia in patients with esophageal cancer is still unclear, and the molecular mechanism may be found through relevant basic experiments.