This is a large-scale research to compare the short- and long-term clinical outcomes among the absolute indication, expanded indication and beyond the expanded indication EGCC patients of endoscopic resection. Across hospitals all over the world, endoscopic resection has gain widely acceptation as a standard treatment of EGC under absolute and expanded criteria as an alternative to surgical resection of distal esophagus and proximal stomach[17–21]. ESD has advantages in lower rates of acute complications and comparable overall survival[20]. Several studies have displayed the effectiveness and safety of endoscopic resection for adenocarcinoma of EGJ[22, 23]. For the cancer located in EGJ, it encompasses both gastric cardia adenocarcinoma (GEA) and Barrett’s esophageal adenocarcinoma (BEA) due to short-segment Barrett’s esophagus. Few researches have specially focused on the clinical outcome of ESD for these gastric cardiac adenocarcinomas. Osumi et al. reported curative resection rate was higher in GCA group (81%) than BEA group (60%)[24]. Jang et al. enrolled 82 patients with gastric cardiac tumors and the en bloc resection, complete resection, and curative resection rates were 87%, 79%, and 66%[25]. A handful of researches have proved ESD is an efficient way to cure EGCC patients. Due to the small sample size, more persuasive studies needed to be conducted.
In our study, we enrolled 495 patients with 502 ESD-related EGCC lesions. The effectiveness of ESD was confirmed by comparing the short and long-term clinical consequence among the AI, EI and BEI groups. No significant difference was found in demographic statistics for these three groups. In the present study, patients in BEI group had more family history than AI and EI groups (P = 0.018). Increased tumor size, deeper tumor invasion, presence of ulcer and poor differentiated were significantly different among the three groups, which was consistent with the definition. The HP positive patients were diagnosed by (13)C-urea breath test or rapid urease tests. Multiple epidemiological studies came to the similar finding that prevalence of HP infection was about 50% in developing countries[26, 27]. H. pylori may also be a cause or co-factor for gastric cancer, and eradication of H. pylori infection was associated with a reduced incidence of gastric cancer[28]. Therefore, we recommended the patients undergo a quadruple therapy to eradicate H. pylori. In our research, atrophy of the mucosa around the tumor lesion could be found in the vast majority EGCC patients. Atrophic gastritis and intestinal metaplasia were the most significant risk factors for gastric cancer[29, 30], thus the endoscopic surveillance in these high risk patients were expected to be extremely important.
The complete resection and curative resection rates in the AI group were meaningfully higher in comparison with the other two groups (P<0.001). This was closely related to the positive vertical and lateral cutting margins in the EI and BEI groups. Suzuki et al. drew the conclusion through their research that positive margins with submucosal infiltration (odds ratio 3.6) and lymphovascular invasion (odds ratio 3.5) had significant correlation with lymph node metastasis and patients who didn’t meet curative resection especially with lymphovascular invasion or positive margin with submucosal invasion should receive additional gastrectomy[31]. Positive lateral margin was related closely to a mixed-type carcinoma, larger than 3 cm in size and the upper one third of stomach, reported by Fu et al[32]. However, there is no research about the risk factor of vertical and lateral incomplete resection in EGCC patients which needs to study in depth.
In the AI and EI group, the five-year overall and disease-specific survival rates were no statistic differences with 96.1–98.3% and 99.6–100%. No case in the AI and EI group was found lymph node metastasis until now. Only one AI patient died because of a positive vertical margin without additional surgery. These findings were consistent with the previous results and the five-year survival rate of ESD surgery was comparable to that of radical gastrectomy[33–35]. The five-year overall survival rate of mucosal EGC was 99% and the five-year overall survival rate of submucosal EGC was 96% by surgical treatment according to the National Cancer Center of Japan[7], which was consistent with the long-term outcome of EGCC patients after ESD at our center. In short, if only the tumor lesions met the absolute or expanded indication, endoscopic resection could achieve satisfactory safety and efficacy from the long-term follow-up. As a consequence, conclusion could be drawn that endoscopic resection was an effective way for the EGCC patients within the AI and EI group similar to other studies[3, 36, 37].
However, there are still many concerns in terms of the BEI group. In this study, the rate of en bloc resection arrived at 98.9% (93/94) in BEI group. Yet, The BEI group showed lower rates of complete resection (74.5%, 70/94) (P<0.001). The reason for the result was mainly related to tumor lesion size, lymphatic/vascular invasion, deep submucosal invasion and undifferentiated histology. These factors were closely related to lymph node metastasis and recurrence[38–40]. As a result, these patients were not suitable for endoscopic resection from the results of previous researches. We evaluated the tumor lesions by EUS, CT or biopsy before ESD and we found some cases were under massive submucosal invasion. Gastrectomy, especially proximal gastrectomy, is the most common surgical treatment of gastric cardiac cancer for the patients unsuitable for ESD. However, some patients suffered from severe postoperative complications, such as anastomotic leakage, reflux esophagitis and anastomotic stricture after proximal gastrectomy. According to the recent reports, the short-term and long-term gastrectomy complications rates could be up to 20% compared with less than 10% by ESD[41, 42]. These patients were aware of beyond the expanded criteria but they still insisted endoscopic resection when they met advanced age, serious underlying diseases and chose the less invasive strategy instead of the surgery. We found that the five-year overall survival rate and the disease specific survival rate for the BEI group patients up to 89.1% and 96.6% during the long-term follow-up at our center. In other centers, endoscopists found the similar results which the five-year disease-free survival rate of BEI patients after ESD could be as high as 90% or more, which was quite effective[33, 43, 44]. The rates of R0 resection and curative resection in BEI group may be lower than the patients within the indications, but in the long run, the survival rate in the BEI group patients who underwent ESD instead of radical gastrectomy still showed a favorable performance. Endoscopists would advise the BEI patients to receive additional surgery after ESD. Between the two groups with or without surgery, we concluded that there was no significant statistical difference from the K-M survival curve. Different from the previous studies[41, 45], those patients under BEI group didn’t benefit from the additional surgery neither the five-year overall survival nor the five-year disease-specific survival. Based on the eCura system, it could be a useful aid for selecting the appropriate treatment strategy after the noncurative ESD for EGCC[40]. If we followed up long enough or enrolled more cases, we might get a different conclusion.
Our study still has several limitations. First, this research is a single center retrospective cohort analysis which may leads to a section bias and referral bias. Besides, an average of 48.1 months of follow-up may not allow us to find the significant difference in the survival rate of the BEI patients with or without additional surgery. In this rather small subgroup, the survival did not show significant differences possibly because of the minor case number. In addition, we are urge to learn about the risk factors of positive margins and noncurative resection.
In conclusion, endoscopic resection of EGCC could achieve a favorable short-term and long-term prognosis for patients with absolute and expanded indication. Patients in beyond the expanded indication showed generally favorable clinical outcomes and needed to be carefully checked after ESD. ESD may be an optional treatment for the patients unsuitable for gastrectomy.