Laparoscopic gastrectomy (LG) for early gastric cancer (EGC) has gained wide acceptance due to benefits such as shorter hospital stays, less postoperative pain, and faster mobilization [1]. Since laparoscopic distal gastrectomy (DG) was first introduced in 1994 [2], gastric surgeons have been gaining experience and improving surgical skill. In addition, cutting-edge innovations in minimally-invasive surgical devices have attributed to the growing feasibility of applying laparoscopic surgery to more complex and difficult procedures. Hence, many surgeons are able to achieve the same benefits as LG would have had for EGC by extending their field of laparoscopy to treat resectable advanced gastric cancer (AGC).

However, the use of LG in the treatment of AGC remains controversial due to the technical difficulties associated with complete D2 lymphadenectomy and lack of evidence for oncological long-term safety. Some concerns lie in the danger of handling large tumors with long, thin laparoscopic instruments, in addition to the possible crushing effect of laparoscopic devices on tumors or metastatic lymph nodes (LN) [3]. Some retrospective studies that report the safety and feasibility of LG in AGC with satisfactory oncological outcomes [456] exist, but the number of these studies and sample sizes are still inadequate to provide sufficient evidence for its use. Additionally, most of the studies included clinically diagnosed EGC patients and were often limited to cancer in the lower thirds of the stomach with limited reports on the feasibility of laparoscopic total gastrectomy (TG) for AGC.

This study was designed to examine the long-term feasibility and safety of LG in AGC in the context of a phase II prospective study. Short-term outcomes of this study have been previously reported [7] and the final results of the study are reported in this article.

A total of 204 patients were assessed. Among them, 16 patients were excluded due to adjacent organ invasion or peritoneal seeding diagnosed via laparoscopic examination. After LG, 31 patients were diagnosed with EGC and were also excluded from the study. A resultant total of 157 patients were enrolled (Fig. 1).

Patient demographics and operative outcome are illustrated in Table 1. Men composed 105 of the enrolled patients with a mean age of 60.89±12.39 years and mean body mass index of 23.72±2.83 kg/m². DG was performed on 115 patients and TG was performed on the remaining 42 patients. The average number of resected LNs was 57.39±19.54. Seven patients had microscopic cancer cells in the margin of the specimen, consistent with an R1 resection; all other patients received an R0 resection. Among TG patients, combined splenectomy was performed in 23 total. All patients with TNM stage II or greater (137 patients, 87.1%) received adjuvant chemotherapy. The median follow-up period was 55.0±20.4 months (range 1–81 months), and there were no drop-outs during the follow-up period.

Eleven patients had open conversion during the laparoscopic surgery due to uncontrolled bleeding or vessel injury, severe adhesions from a previous surgery, arrhythmia caused by pneumoperitoneum, and severe obesity. The systemic early-complication rate was 25.5% (27.8% for DG, 19.0% for TG) and the local early-complication rate was 10.2% (7.8% for DG, 16.7% for TG). One early mortality occurred due to aggravation of a patient’s pulmonary and cardiac disease. Morbidity and mortality results of this study are further characterized in a previous study [7].

The 3-year DFS was 76.3%, and differences in 3-year DFS according to the AJCC stage are depicted in Fig. 2A. Mortality was not included in the calculation of DFS. The 3-year DFS of the DG and TG groups was 78.9% and 69.0%, respectively. There was no significant difference between the 2 DFS rates (Fig. 2A). The 5-year OS was 72.6% (Fig. 2B).

A total of 37 recurrences were observed during the follow-up period and recurrence patterns are summarized in Fig. 3. Peritoneal recurrence was observed in 13 patients, hematogenous recurrence in 6 patients, distant lymph node recurrence in 8 patients, locoregional recurrence in 1 patient, and mixed recurrence in 9 patients.

In addition to our previous study demonstrating acceptable short-term morbidity associated with LG for AGC, the survival data of this study suggest that LG for AGC is acceptable in terms of long-term oncological safety.

Although final outcomes of randomized phase III studies such as the KLASS01 trial and the JCOG0912 trial have yet to be reported, LG has currently gained wide acceptance in EGC with accumulating evidence of safety and feasibility [111]. Its application for AGC is still controversial, especially due to concern regarding D2 lymphadenectomy; few incidences have been reported in the literature. A phase II randomized trial of 180 patients showed that there was no difference in 6-month surgical outcome between open DG and laparoscopy-assisted DG with D2 lymphadenectomy for AGC [12]. Despite these reports, evidence of long-term oncologic safety is lacking. There was no difference in the incidence of recurrence or survival in the open versus laparoscopic randomized trial by Huscher et al. [13]; however, the sample size was limited to 59. In a meta-analysis published in 2016 by Quan et al. [14], the only prospective study included had a median follow-up time of 22.1 months [15]. The median follow-up time of this study was 55 months and the 3-year disease free survival data were higher than the expected 70%.

This study also collected the 5-year OS as a secondary endpoint, making it more feasible to compare the results of this study directly to reported outcomes of OS from other studies [1116171819]. The results obtained in this study are better than previously reported OS with LG for AGC [16]. This may be attributed to the fact that all operations were performed by a single skilled surgeon who averages 350 cases of LG per year and has been doing so for the past 10 years. The availability of a well-trained scopist who specializes in LG and a well-organized team may also have contributed to the results. A recent survival study of AGC after gastrectomy and adjuvant S-1 chemotherapy in Japan showed the 5-year OS for pathological stages IIA, IIB, IIIA, IIIB, and IIIC to be 96.0%, 85.5%, 81.8%, 72.0%, and 51.1%, respectively [20]. It is difficult to compare this data directly since both are single-center studies, however, there are some discrepancies in stage IIIB and IIIC that could be further investigated in future randomized controlled trials.

Although this was not designed as a comparative study, the data hint that the use of LG for AGC as compared to open gastrectomy is not an inferior method. Despite initial preconceptions regarding laparoscopy as the more difficult approach to perform lymphadenectomy, laparoscopic views may enhance the likelihood of achieving fine lymph node dissection with the help of magnified imaging. The angulation of the flexible scope can provide a brighter, magnified view of lymph nodes, such as those in the ventral side of the pancreas, which may go unnoticed in open gastrectomy relying on the naked eye. In addition, better surgical instruments, such as energy devices and staplers, are being used more frequently in the era of laparoscopic surgery as compared to the open surgeries of the past. Recognizing concerns regarding the use of laparoscopic instruments in bulky tumors [3], the data show that handling of advanced stage cancers can be safely performed with an appropriate experience level.

Analysis of recurrence patterns showed a higher rate of peritoneal recurrence, followed by hematogenous recurrence, with only one patient experiencing locoregional recurrence. A multicenter retrospective study of 1,417 patients after LG reported a recurrence pattern of 34% hematogenous, 22% peritoneal, 20% locoregional, and 4% distant LN metastasis [21]. However, their data involved mostly earlier stage cancers, and the node metastasis of their patients was not as aggressive as that of clinically diagnosed AGC patients, making it difficult to compare its results directly with this study. Another study by Yoo et al. [22] analyzed 2,328 patients diagnosed with curative gastric cancer and found peritoneal recurrence to be most common, followed by hematogenous recurrence, similar to the recurrence pattern in this study. Though not directly stated in the aforementioned study, the enrollment period of 1987 to 1995 suggests that most, if not all, of the surgeries were accomplished using an open surgical method. The study detailed in this article is the only study that analyzes the recurrence pattern of purely AGC patients undergoing LG.

Furthermore, this is the only reported prospective study that considers long-term survival benefits with a patient group of AGC only. By only including clinically diagnosed AGC patients, the TNM stages of the cohort are evenly distributed, unlike previous studies of LG in AGC that focused mainly on earlier stages of disease. The application of laparoscopic TG for AGC is uncommon in literature and this study reports the survival outcomes of a cohort of 42 people. However, it is recognized that its widespread application may be hindered by the fact that this was performed by a single surgeon in a single center. For instance, survival for stage IIB (100.0%) was higher than that for stage IIA (89.3%), and the survival for stage IIIA (88.0%) seems unnaturally high. It is because this study is a single center cohort study, and may not represent the whole patient population. As a prospective study, the data are well controlled and there was no selection bias. However, it is not a randomized controlled study, so it can only provide limited evidence when compared to open gastrectomy. At the point of study development there was no well-designed format to back evidence for the application of laparoscopy in both AGC and EGC patients. The outcomes of KLASS02, a phase III multi-center randomized control trial comparing open and laparoscopic DG in AGC are yet to be published, and the results of this study will be able to provide more definitive clinical evidence for the application of LG for AGC [23].

In conclusion, survival outcomes of LG in AGC are comparable to previously reported data on open gastrectomy and the recurrence pattern is also similar to reports of previous studies. LG for AGC is feasible in terms of long-term oncological outcomes, and with this study as a stepping stone, results of well-designed randomized controlled trials are necessary to provide better evidence for its safety.