A meta-analysis of comparison of proximal gastrectomy with double-tract reconstruction and total gastrectomy for proximal early gastric cancer

Recently, with the prevalence of endoscopic techniques, the incidence of proximal gastric cancer (lesion located in the upper third of the stomach), especially proximal early gastric cancer (EGC) has been increasing in worldwide [1]. So far, for patients with proximal EGC who have lesions unsuitable for endoscopic treatment, total gastrectomy (TG) is the most major surgical procedure for the radical treatment. However, TG has many potential disadvantages, especially in hematological and nutritional status [2]. Thus, some researchers have suggested the proximal gastrectomy (PG) as an alternative to TG for proximal EGC [3]. Unfortunately, severe reflux esophagitis and anastomotic stenosis are the major factors that limit the clinical application of this surgery. Besides, the operation procedure needs to be further standardized [4, 5].

Some scholars suggested that patients with proximal EGC could be treated with proximal gastrectomy with double-tract reconstruction (PG-DT), to avoid anastomotic complications [6, 7]. It was reported that the incidences of reflux symptoms, usage of proton pump inhibitors, and anastomotic strictures were significantly lower in the double-tract anastomosis group as compared to the esophagogastrostomy group [6]. However, a recent multicenter study from the western experience showed that patients who underwent PG have an increased mortality rate and a higher risk of reflux esophagitis and anastomotic stricture [8].

In addition, in view of the prognosis of EGC is excellent, the improvement of postoperative quality of life and the safe application of minimally invasive surgery have become the research hotspot in recent years. There is no doubt that laparoscopic proximal gastrectomy (LPG) is one of the most promising treatments for patients with proximal EGC [9]. But LPG has remained controversial mainly due to a lack of evidence from large-scale studies. And there were few meta-analyses about this problem in comparison of laparoscopic proximal gastrectomy with double-tract reconstruction (LPG-DT) and laparoscopic total gastrectomy (LTG) for treatment effects. So, this meta-analysis is a comparison of the short-term and long-term outcomes of LPG-DT and LTG for proximal EGC through comprehensive retrieval and pooled analysis.

In the electronic databases of PubMed, Web of science, EBSCO and the Cochrane library, a comprehensive literature search strategy was performed by retrieving the keywords “proximal gastrectomy” and “total gastrectomy” until December 2018. To avoid omitting any potential studies, we manually reviewed the references of included literature. Non-English studies will be excluded. Institutional review board approval of our hospital was obtained for this study.

PG is theoretically the ideal treatment option for proximal EGC [18]. However, the risk of reflux esophagitis and anastomotic stenosis is a huge challenge for the widespread use of PG. To improvement these disadvantages, several modified reconstruction procedures, including jejunal interposition, jejunal pounch interposition, double-flap, and double-tract anastomosis, have been attempted [6, 19‐21]. According to previous studies, PG-DT is one of the most promising procedures, in reducing anastomotic complications (reflux esophagitis and anastomotic stenosis) and improving operative quality of life [7, 12]. Thus, the purpose of this meta-analysis is to compare the safety and feasibility of LPG-DT with LTG for patients with clinical stage I proximal gastric cancer.

In this study, the tumor size of the LTG group was significantly larger than that of the LPG-DT group. Although tumor depth and tumor staging was significantly earlier in the LPG-DT group than in the LTG group, there was no difference in lymph node metastasis. It seems that the size and depth of the tumor are factors in the choice of surgical procedure. Masuzawa et al. [22] reported that tumor size and histology could influence the size of the remnant stomach, which was an important factor in choosing the procedure. So, we believed that LPG-DT was appropriate for proximal EGC, and the tumor size was small. In terms of operation time and blood loss, no significant difference was found between the two groups. Thus, LPG-DT is not a complicated procedure, compared LTG. Although resection margins were shorter for LPG-DT, intraoperative frozen biopsies confirm disease-free resection margins (R0 resection). In other words, PG can maximize the retention of gastric stump. In addition, consistent with previous findings [20, 23], this study showed that fewer lymph nodes were retrieved every patient in the LPG-DT group because of different lymph node metastasis dissection extent. The TNM staging system recommends that no less than 16 lymph nodes should be resected for radical gastrectomy [3]. And several studies have shown that the number of lymph nodes retrieved is closely associated with postoperative pathologic staging and prognostic assessment [24, 25]. Gholami et al. [26]. demonstrated that dissection of 16 or more lymph nodes was associated with better survival in all patients. However, some studies suggested that dissection of more than 16 LNs did not show improvement in the prognosis in stage I patients [27, 28]. In our previous study [29], there was a low incidence of lymph node metastasis in EGC. So, we believed that LPG-DT with less than D2 lymph node dissection appears to be reasonable.

An et al. [30] and Rosa et al. [8] reported that PG with esophagogastrostomy resulted in a higher complication rate than TG and that PG with esophagogastrostomy led to a higher frequency of stenosis and reflux than did TG. Nishigori et al. [23] also demonstrated that PG with esophagogastrostomy had a higher probability of anastomotic stenosis. There was no significant difference in the short-term outcomes between the two groups (LPG-DT versus LTG) in this article. Whether in all complications or severe complications, the present study showed that LPG-DT was a feasible and safe technique. Most importantly, the results of this study showed that LPG-DT did not increase the incidences of reflux esophagitis and anastomotic stenosis, compared LTG. Besides, Aburatani et al. [6] suggested that the incidence of both reflux esophagitis and anastomotic stenosis was lower in the PG-DT group than in the PG with esophagogastrostomy group. We could conclude that LPG-DT was a good alternative to LTG, because of similar complication rate.

There is no doubt that the long-term quality of life is one of the important factors to evaluate the value of surgery, especially for patients with EGC. Several previous studies had reported hematological and nutritional outcomes in patients underwent PG. Cho et al. [12] reported that postoperative hematologic indexes, including hemoglobin, ferritin, transferrin saturation, and anemia, showed no significant difference between minimally invasive PG-DT and minimally invasive TG. Protein, albumin, cholesterol, and other nutritional parameters were also comparable between the two groups. They also concluded that although the proportion of patients who requiring vitamin B₁₂ supplements was smaller in the PG-DT group, the cumulative incidence of vitamin B₁₂ deficiency after PG-DT was similar to that after TG. Jung et al. [14] thought that the change rate of body weight in LPG-DT group was significantly lower than in LTG group. The serum vitamin B₁₂ level in the LPG-DT group was significantly higher than in the LTG group. Research by Kim and his colleagues [15] observed that LPG-DT was beneficial with regards to the absorption of iron and vitamin B₁₂ compared to LTG. A recent study has shown that body weight and skeletal muscle index reduction rates were lower in the LPG-DT group than in the LTG group [17].

In this present study, a significantly smaller proportion of the LPG-DT patients required vitamin B₁₂ supplementation compared to the LTG group. PG-DT preserves the gastric antrum and part of the gastric body, allowing for food reserve, which indicates that these areas of the stomach are potential sources of intrinsic factors. TG is known to have a risk of leading to vitamin B₁₂ deficiency compared to distal gastrectomy [31]. Because the main source of intrinsic factors in the stomach is parietal cells, which are mainly located in the body and fundus, the ability of PG to prevent vitamin B₁₂ deficiency is questionable. Our analysis showed that retention of the distal stomach assists in the absorption of the vitamin B₁₂, possibly due to retention of a partial gastric body.

This systematic review and meta-analysis incorporated seven articles that compared the long-term hematological and nutritional indicators, including postoperative BMI, hemoglobin, ferritin, total protein, albumin, to patients with LPG-DT and LTG. Unfortunately, the analysis of forest plots with related indicators could not be obtained due to the inability to obtain the original data. However, no study showed that the hematological and nutritional status of patients who underwent LPG-DT was worse than that of patients underwent LTG.

Finally, in terms of oncology prognosis, the two groups had similar outcomes. Yoo et al. [4] reported that PG might increase the likelihood of local recurrence, although it would not affect long-terms in terms of survival and mortality. But the study included many patients with advanced gastric cancer. In this study, almost all the patients included had EGC. There was no recurrence or death in the patients with confirmed stage I proximal gastric cancer after LPG-DT. Therefore, we believed that LPG did not negatively influence the prognosis compared to LTG in EGC.

To our knowledge, this is the first meta-analysis investigates the short-term and long-term results of LPG-DT versus LTG. Some limitations of this study need to be emphasized. All included articles were the small sample retrospective studies, which inevitably led to a decline in the level of evidence in this paper. No prospective studies or clinical trials were found through systematic and comprehensive retrieval. Meanwhile, Egger’s test of publication bias was not performed on this analysis due to the insufficient number of included studies. Finally, the participants were all from Asian countries with high incidence of gastric cancer (South Korea and Japan). The conclusions of this study cannot be directly applied to other countries. Thus, a prospective randomized trial that compare LPG-DT with LTG should be performed to confirm these observations.

This review showed that due to comparable clinical effect, LPG-DT is comparable to LTG for patients with proximal EGC. In addition, LPG-DT not only appears superior in preventing vitamin B₁₂ deficiency, but also does not increase a risk of anastomotic stricture and reflux esophagitis compared to LTG.