Open surgery may no longer be a control arm of minimally invasive surgery for gastric cancer

Gastrectomy with systematic lymphadenectomy is the mainstay of gastric cancer treatment aiming for cure. Many randomized clinical trials were conducted to establish the optimal extent of resection in gastric cancer surgery (1-3), with open procedures being adopted in all trials. Although open procedure had long been the standard, the minimally-invasive approach can offer an identical extent of resection and is regarded as a viable option for gastric cancer surgery. However, the clinical as well as oncological safety of minimally invasive gastrectomy has long been argued.

We read, with great interest, the recent report focusing on the long-term outcomes demonstrated by the JCOG1401 (4), a single-arm confirmatory feasibility study of laparoscopy-assisted total or proximal gastrectomy (LATG/LAPG) in patients with cStage I gastric cancer, by Kunisaki et al. (5). The authors demonstrated excellent 5-year recurrence-free survival (RFS) and overall survival (OS), as a secondary endpoint of this study, suggesting LATG/LAPG to be acceptable and that this procedure can reasonably be regarded as one of the standard treatment options for cStage I disease when performed by experienced surgeons.

Equivalent short- and long-term outcomes have been obtained with laparoscopy-assisted distal gastrectomy as compared to open procedures for cStage I gastric cancer (6,7), and this equivalence has also been established for cStage II/III disease in phase III trials (8-12). Regarding LATG or LAPG, safety and feasibility have both been demonstrated in several retrospective studies with small sample sizes, but there were no prospective studies prior to the JCOG1401 study. Laparoscopic esophagojejunostomy, which is especially favored following Roux-en-Y reconstruction, was reportedly associated with anastomotic leakage rates ranging from 1.1% to 7.1% (13), quite high as compared with the open procedure in historical cohorts. Although esophagojejunostomy was the focus and primary challenge of LATG, optimal methods of esophagojejunal anastomosis had not as yet been standardized and were still being explored when prior studies were published. Therefore, the safety of laparoscopic esophagojejunostomy needed to initially be established prior to conducting a phase III study comparing laparoscopic and open total gastrectomy (TG)/proximal gastrectomy (PG). Likewise, the KLASS-03 trial conducted in South Korea was a single-arm prospective feasibility study of laparoscopic TG for cStage I disease, with its primary endpoint being the assessment of 30-day postoperative morbidity and mortality (14). Given that rates of esophagojejunal anastomotic leakage were 2.5% and 1.9% in JCOG1401 and KLASS-03, respectively, LATG/LAPG including esophagojejunostomy appears to be safe and feasible when performed by experienced surgeons. The CLASS-02 trial, a randomized clinical trial comparing LATG to open total gastrectomy (OTG) for cStage I gastric cancer conducted in China, provided more confirmatory evidence of comparable short-term outcomes for the two procedures (15). The overall postoperative complication rate was 18.1% in the LATG group and 17.4% in the OTG group, showing no significant difference. Eligibility criteria for surgeons performing the procedures were very stringent in all 3 Asian clinical trials, as previously noted.

In contrast, the National Clinical Database (NCD), a nationwide web-based data entry system for surgical procedures in Japan, clearly provided a higher anastomotic leakage rate in LATG (5.4%) as compared with OTG (3.6%) for pStage I disease in real-world clinical practice during the 2012 through 2013 period in Japan (16). Furthermore, the rate was similarly elevated for LATG (5.7%) as compared with OTG (3.6%) for pStage II–IV disease as well. Overall, despite a higher readmission rate within 30 days (2.7% vs. 1.7%) and a higher re-operation rate (4.5% vs. 3.3%), morbidity and mortality rates were found to be equivalent for LATG and OTG. Another prospective cohort study, using the NCD system, was conducted from August 2014 to July 2015, and showed comparable outcomes for many types of surgical complications, including anastomotic leakage (17). The overall morbidity rate was lower in the LATG group, and the mortality rate was equally low in the two groups, suggesting safety management following LATG to have been improving over time due to greater proficiency with the laparoscopic techniques.

It is important to note that Siewert type II and III adenocarcinomas of the esophagogastric junction (AEG) were not included in the JCOG1401 study protocol. Transhiatal resection of these tumors requires lower esophagectomy to ensure a negative proximal margin. Consequently, the anastomotic site would definitely be located in the lower mediastinum. In such a situation, the anastomotic leakage rate generally increases as the length of the resected esophagus increases. In fact, the rate was 17.0% in patients with tumors involving 2 cm or more of the esophagus, which was much higher than the rate of 8.8% in those with tumors involving less than 2 cm of the esophagus (18). Furthermore, the anastomotic leakage rate was associated with minimally invasive surgery (MIS) in this study (19% in the MIS group vs. 11.3% in the open group). Moreover, anastomotic leakage in the lower esophagus following transhiatal gastrectomy had the potential to cause very severe morbidity (Clavien-Dindo ≥ Grade IV) in the same study. Taken together, these results indicate LATG/LAPG with lower esophagectomy for AEG to possibly carry a potentially higher risk of anastomotic leakage than performing this procedure for gastric cancer.

Recent Japanese nationwide studies have provided clear evidence that extremely low metastatic rates to lymph node stations alongside the distal portion of the stomach from Siewert type II AEG and TG aiming at prophylactic complete dissection of these stations provided no oncological survival benefit (19,20). Extended PG, lower esophagectomy plus PG, has increasingly been employed as one of standard procedures even for T2/3/4 advanced disease, and the extent of D2 dissection was newly established in the Japanese Gastric Cancer Treatment Guidelines promulgated in 2021 (21). When employing MIS for extended proximal gastrectomy, it is important to clearly distinguish between LAPG for AEG and that for gastric cancer. Meticulous attention should be given to the higher risk of postoperative morbidity, especially anastomotic leakage, in the former.

Regarding the reconstruction method following LAPG, a very controversial issue in clinical practice, double-tract or jejunal interposition was the only option allowed in the JCOG1401 study, and no patients underwent esophagogastrostomy, thereby probably not reflecting the current Japanese clinical practice regarding proximal gastrectomy (22). Given that 45 patients among 49 receiving LAPG underwent double-tract reconstruction in the JCOG1401 study, it is important to exercise caution in the interpretation of which reconstruction method can be used safely following LAPG. Further analysis of the safety and long-term outcomes of each type of reconstruction following LAPG, especially for AEG, is necessary.

The cohort size in the JCOG1401 study was calculated based on a predicted frequency of leakage at the esophagojejunal anastomosis of 3% or less. The excellent 5-year RFS and OS of the prospective cohort in this study confirmed the retrospective evidence that MIS can provide survival outcomes comparable to those of open surgery, as shown in previous studies (23,24). No prospective studies comparing MIS and open surgery for TG and PG have, to our knowledge, been reported. However, there is now virtually no data refuting the oncological safety regarding long-term survival. MIS is already in widespread use and is becoming a standard option for gastric cancer surgery except in cases with bulky disease or tumors invading the neighboring organs, while emphasizing the importance of the surgical team being well-trained in MIS techniques. To further maintain the quality of surgical treatment for gastric cancer, the importance of mentorship in educating future generations, especially in MIS, is becoming increasingly crucial.

Acknowledgments

Funding: None.

Footnote

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