Esophageal cancer ranks among the most prevalent malignancies worldwide, with squamous cell carcinoma being the predominant histological type in China. Surgical intervention constitutes a primary radical approach in its treatment, complemented by radiotherapy, chemotherapy, and immunotherapy, forming integral components of its comprehensive management [25].
Nutritional challenges in patients significantly impact treatment tolerance and prognosis. The Prognostic Nutritional Index (PNI), an immune-nutrition evaluation index introduced by Japanese researcher Onodera, presents advantages of accessibility, cost-effectiveness, and predictive efficacy [26]. Reflecting both nutritional and immune statuses, PNI is based on peripheral blood lymphocyte count and serum albumin (ALB) concentration. Lymphocytes, pivotal in anti-tumor immunity, serve as key players in immune responses, and their decrease often signifies compromised immunity [27]. Plasma ALB, on the other hand, forms soluble complexes with various insoluble organic molecules and inorganic ions, aiding in maintaining constant plasma colloid osmotic pressure and facilitating histone synthesis. Recent years have witnessed growing attention to the correlations between tumor occurrence, progression, and prognosis with PNI. In esophageal cancer, multiple studies have highlighted PNI's predictive capabilities for patient prognosis. For instance, Dai et al. [28] analyzed 106 cervical esophageal cancer patients undergoing radical radiotherapy, revealing longer overall survival (OS) in the high-PNI subgroup. Similarly, Xiao et al. [29] investigated 193 ESCC patients undergoing radical radiotherapy, identifying PNI as an independent prognostic factor affecting their outcomes. Nonetheless, conflicting findings exist. Sun et al. [30] examined various nutritional indicators' prognostic value in ESCC patients in southern China, concluding that low PNI wasn't an independent predictor of poor prognosis. Likewise, Pan et al. [31] analyzed prognostic factors in 205 ESCC patients, finding PNI not to be an independent prognostic factor. In our study, we retrospectively analyzed 134 ESCC patients receiving radical or palliative radiotherapy at different clinical stages. Results demonstrated superior OS in the high-PNI subgroup compared to the low-PNI subgroup. Multivariate analysis using the Cox proportional hazard model identified PNI as an independent factor influencing overall survival. Our findings underscore the importance of addressing malnutrition before esophageal cancer radiotherapy and advocating for a high-protein diet to enhance serum ALB concentration, thereby improving patient outcomes.
There are different reports on the factors influencing the PNI. Hirahara et al. [32] showed that the PNI was related to tumor size, tumor depth, serum ALB concentration, lymphocyte count and other factors. Zhao Yan et al. [33] showed that the PNI was positively correlated with hemoglobin and the nutritional risk index (NRI) before radiotherapy. There were no significant correlations with eating status, tumor site, tumor length, GTV or BMI. Our study revealed that the PNI was significantly correlated with M stage (p = 0.017) and TNM stage (p = 0.033). The reason may be that once cancer patients have metastasis or a late TNM stage, the tumor load increases, which may lead to a decrease in appetite and deviation of the PNI status.
There is no uniform standard for the cutoff value of the PNI. Some directly use the experience value, such as 45, reported by Li Meiduan et al. [34]; others use the mean value, such as 49.2, reported by Hirahara N et al. [32]; and others draw the ROC curve to calculate the truncation value, such as 47.975, reported by Xiao L et al. [35]. In this study, the survival time of patients was used as the endpoint for drawing the ROC curve and calculating the critical value of the pre-RT PNI, which was 48.03. The critical value reported in this study was slightly different, which may be related to the differences in disease stage, age and physical status of the patients included in the study.
In previous studies, scholars have noted that the LSR is associated with the risk of malignant tumors, such as breast cancer [36] and gastric cancer [37]. Serum ALT activity has been used as an inflammatory marker for evaluating liver injury associated with various etiologies, such as hepatitis, tumors, cirrhosis and alcohol consumption, and the LSR is generally considered a good predictor of liver injury [38]. ALT and AST are commonly used indicators of liver function. Studies have shown that oxidative stress and inflammation can lead to liver injury [39], and an elevated AST/ALT ratio represents high oxidative stress and an inflammatory environment in the body, which are closely related to the development of cancer [40–42]. To date, the relationship between the LSR and ESCC survival has not been well studied.
Our study revealed that the LSR was significantly correlated with age, sex, T stage, N stage, M stage, TNM stage, and occurrence of side effects, suggesting that the later the tumor stage, the greater the age and extent of the inflammatory response. Our study revealed that the OS of patients in the high-LSR subgroup was better than that of patients in the low-LSR subgroup (p = 0.0315). The average OS of patients with a high LSR was 19.9 months, while that of patients with a low LSR was 13.7 months. However, there was no significant correlation between the LSR and patient prognosis according to the multivariate analysis. The possible reasons are as follows: 1. The LSR was calculated only before radiotherapy, and the LSR was not continuously monitored during and after radiotherapy. 2. The LSR was significantly correlated with T stage, while T stage was significantly correlated with OS according to multivariate analysis; however, the trends in the variations in the LSR and T stage were the same, suggesting that the LSR was correlated with OS according to single factor analysis. In fact, there was no significant correlation between the LSR and OS. Therefore, additional research is needed to explore this further. In addition, our study showed that radiotherapy dose higher than 54 Gy did not improve patients' PFS and OS, but it would cause a decrease in patients' PNI, which would further affect patients' PFS and OS. Therefore, it is recommended that the radiotherapy dose of esophageal cancer should not exceed 54 Gy.
Our results showed that the sensitivity of the LSR was 0.742, the specificity was 0.647, the sensitivity of the PNI was 0.621, the specificity was 0.676, and both the sensitivity and specificity were low. The analysis results may be because this study included only PNI values calculated from laboratory examination data within 1 week before the first radiotherapy, while the nutritional status of patients during, after and outside the hospital was not evaluated. This may affect the sensitivity and specificity of the PNI, resulting in a certain rate of missed diagnosis and misdiagnosis when predicting the survival outcome. So subsequent studies should measure the PNI value of patients in different periods and obtain the average value to further evaluate the ability of the PNI to predict the prognosis of esophageal cancer patients.
The PNI is an independent prognostic factor for ESCC, but its predictive sensitivity and specificity were relatively low in this study. According to the ROC curve, the AUC of the LSR-PNI was 0.775, which was greater than that of the LSR (AUC = 0.702) or the PNI (AUC = 0.689). Therefore, we further explored the value of the LSR combined with the PNI (LSR-PNI) in predicting long-term survival after radical radiotherapy in ESCC patients.
The LSR-PNI risk was closely correlated with OS and PFS (Fig. 3), and the PFS in the low-risk group was better than that in the medium-risk and high-risk groups (p = 0.0067). The mOS and cumulative 3-year survival rates were 24.1, 14.3, and 12.9 months and 24%, 14%, and 10.3%, respectively, in the low-risk, medium-risk, and high-risk groups. There were significant differences among the three groups (p < 0.001). Further pairwise comparisons revealed significant differences between the low-risk group and the medium- and high-risk groups (p values = 0.0008 and 0.0001, respectively). Patients in low-risk groups may have a better prognosis. The ability of the combined analysis to distinguish between medium-risk and high-risk patients was limited.
The results of multivariate analysis showed that sex and T stage were also independent and significant predictors of OS. The prognosis of male patients was worse than that of female patients, which was similar to the findings of Tang et al. This large sample analysis of 5999 female and 9918 male esophageal cancer patients from 1973 to 2011 revealed survival differences and major influencing factors. Sex is an independent prognostic factor for esophageal cancer, and the prognosis of male esophageal cancer patients is significantly worse than that of female esophageal cancer patients, suggesting that androgen may be one of the risk factors for the occurrence and prognosis of esophageal cancer [43]. In addition, because Chinese male patients like smoking and drinking alcohol, this sex-related difference may be traced to this unhealthy lifestyle. It is suggested that in male esophageal cancer patients with advanced clinical T stage disease, various treatment methods, such as chemotherapy and immunotherapy, may be needed after radiotherapy to further improve patient survival.