In recent years, there was rising incidence of AEG in western countries and similar trend also found in East Asia, probably for the sake of obesity, gastroesophageal reflux disease and eradication of Helicobacter pylori [1, 28, 29]. AEG had demonstrated different biological behavior and pathological features compared with either gastric or esophageal cancer. It has attracted more attention and has gradually become a distinct tumor category from esophageal and gastric cancer. Thus, we believed deeper understanding of AEG could benefit to better management of these patients.
There was accumulating evidence indicating that inflammatory response and nutritional status playing important role in malignancies[11, 12, 31–34]. Several studies had evaluated the inflammatory indexes, including NLR, PLR, GPS, as prognostic predictors in upper gastrointestinal cancers [35, 36]. In another hand, poor nutritional status, for example, decrease of preoperative albumin level or low BMI value, had demonstrated as indicators for poor prognosis [22, 23, 37]. According to previous study, we thought ALI could be a potential surrogate combining both two dimensions. ALI’s prognostic impact had been evaluated in several cancers[21, 24, 26] and it also had been showed to be independent predictor in gastric and esophageal cancer. However, in Yin’s et al  study tumor mostly located at gastric body or pylorus and Tan’s et al  study mostly included squamous cell carcinoma of esophagus. Since then, the prgnostic value of ALI for patients with AEG remain unclear.
The major finding of this study is the promising prognostic impact of ALI in patients with AEG after radical resection. Compared with the high-ALI group, patients in the low-ALI group had a worse prognosis. Multivariate analyses showed that ALI was an independent risk factor for both OS and DFS. In line with the previous studies in several other malignancies, our study indicated ALI as a feasible predictor for both OS and DFS in patients with AEG after radical resection. Even though several nomogram models had been used for the prediction of prognosis of AEG [39, 40], this is the first to incorporate ALI into the survival model of AEG patients after radical resection. The C-index of our propoesd nomogram was 0.699, showing acceptable discrimninatory ability.
In this study, besides ALI, poor differentiation, lymphovascular invasion and tumor size were also recognized as independent prognostic factors for AEG. Poor differentiation already been incorporated into the AJCC classification for esophageal cancer as histologic Grade 3. Poor differentiation was also found to be a predictor for deeper tumor invasion and lymph nodes metastasis in gastric cancer[41, 42]. Even though not well established in AEG, we believed that the prognostic value of differentiation status deserves more investigation. Lymphovascular invasion, the presence of malignant cell within endothelial-lined space, is correlated with the ability of the cancer to metastasize. In line with a previous study, it is also considered as a prognostic factor for AEG. Tumor size had been used as a staging method in several solid tumors like lung and breast cancer. Enlarged tumor mass was correlated with increased risk of other adverse pathological features. In our study, more patients in low-ALI group had enlarged tumor size (≥3.3) (p=0.003). This might be related to a larger tumor mass inducing more intense inflammatory response and consuming more host nutrition. Moreover, as tumor size increased, it might invade beyond the esophagogastric junction, leading to an increased risk of mediastinal metastasis, a unique feature for patients with AEG.
Another important finding of this study was the prognostic impact of ALI in patients with stage III/IVA AEG. Since Siewert type I and II patients are staged as esophageal cancer, tumor with T4aN2, T4bN0-2 and any T stage with N3 would be staged as stage IVA. Regarding locally advanced disease without distant metastasis, we combined stage IVA patients with stage III patients in the same subgroup for survival analysis. Up to now, the optimal management strategy for AEG is still under debate. Treatment methods had involved preoperative chemoradiotherapy, perioperative chemotherapy or postoperative chemotherapy regimens based on different RCT results [46–48]. Although multimodality therapy had improved survival outcomes compared to surgery alone, the life expectancy of AEG patients, even after radical resection, remains poor, especially in patients with advanced disease. In East Asia, the ACTS-GC study demonstrated that 1-year of S-1 administration was associated with a 5-year OS rates of 50.2% and 5-year RFS rates of 37.6% in stage IIIB gastric cancer patients, which was worse than stage II or IIIA patients (5-year OS rates, II vs IIIA, 84.2% vs 67.1%, and 5-year RFS rates, II vs IIIA, 79.2% vs 61.4%, respectively) . Our study demonstrated that low-ALI group patients with stage III/IVA had a worse prognosis. The 5-year DFS rates were 44.1% in the high-ALI group and 33.2% in the low-ALI group. The 5-year OS rates were 58.1% and 31.0% in the high-ALI group and the low-ALI group. This suggested that stage III/ IVA AEG patients with low ALI levels might have a greater chance of suffering from tumor relapse and death from any cause. We, therefore, suggest closer follow-up may be needed for patients with low-ALI. Moreover, the interim analysis of the JACCRO GC-07 study indicated that S-1 plus docetaxel had superior oncological outcome than S-1 single agent for stage III gastric cancer , suggesting that advanced stage patients could further benefit from the more intensive regimen. Whether the difference in ALI level would lead to different treatment response and help for regimen selection or dose/course adjustment needs further investigation.
Despite the promising findings of this study, there were several limitations worth mentioning. First, this was a retrospective study from a single medical institution and the sample size was relatively small. Second, the distribution of cases was uneven, i.e. relatively fewer number stage I patients, which may have affected the results obtained, to some extent. To overcome these limitations, a multicenter prospective study might be needed to clarify the clinical value of ALI in patients with AEG.