When Erich Muhe and Phillipe Mouret first described laparoscopic cholecystectomy in 1985 and 1987, respectively, no one believed that large and demanding surgical procedures would be treated the same way in the future. But back in 1993, Juan Santiago Azagra performed the first laparoscopic-assisted total gastrectomy for gastric cancer.

In 1994, Kitano performed the first laparoscopic-assisted distal gastrectomy with a modified D1 lymph node dissection for the treatment of early gastric cancer, with a high risk of lymph node metastasis. Yasuhiro Kodera et al. heralded a whole new perspective for laparoscopic gastrectomy (LG) in 2010. They performed a meta-analysis, enrolling 6 randomized controlled trials and 666 patients, and they concluded that laparoscopic surgery with D2 lymphadenectomy for early gastric cancer is feasible and safe and adheres to the oncological principles (1).

Later on, several randomized controlled trials and meta-analyses have confirmed the advantages of laparoscopic surgery in early gastric cancer, and there are indications that this may also apply in advanced distal gastric cancer (1–3). However, in Western countries, the majority of patients still present with advanced stages of the disease. Locally advanced tumors require a more technically demanding procedure, especially in the case of total gastrectomy with intracorporeal esophagojejunal anastomosis. Nevertheless, laparoscopic surgery for gastric cancer has increased in popularity during the last two decades, in both the East and the West (4, 5). In addition, recent European-based studies found treatment results comparable with their Asian counterpart (6–8).

The study objective was to evaluate the safety and effectiveness of LG, in comparison to open gastrectomy (OG), in the management of locally advanced gastric cancer.

The single-center, case–control study included 204 patients, in the convenience sampling, who underwent gastrectomy with a curative intention for locally advanced gastric cancer, between March 2013 and May 2021. Out of 204 patients, 102 underwent LG, and 102 patients underwent OG. Perioperative and postoperative data for the patients treated with LG were collected from a prospectively developed database. The OG group was a historical cohort. The study was reviewed and approved by the Clinical Centre of Serbia Institutional Review Board (decision number 187/15 dated October 20, 2016).

Through strategic change management, over the observed period, we have gradually increased the proportion of patients operated using the laparoscopic approach and decreased the proportion of patients operated using the open approach. Preoperative data did not influence the operative approach. Subsequent comparative analysis of the preoperative data did not indicate selection bias or potential confounding.

Inclusion criteria were as follows:

• patient’s age ≥18 and ≤80 years

• patients able to undergo general anesthesia and major surgery and are suitable laparoscopic surgical candidates

• patients who provided written informed consent after being informed of the study procedure and risks prior to any study-related events

• patients with documented locally advanced gastric cancer

Patients with other synchronous or metachronous neoplasms, preoperatively confirmed metastatic disease, histology other than adenocarcinoma, and poor general status with severe comorbidities were excluded from the study.

Several randomized controlled trials and meta-analyses have confirmed the advantages of LG, compared to OG, in the treatment of early gastric cancer (1–3). However, in Western countries, the vast majority of patients still present with advanced stages of the disease and often with proximal tumor localization. Thus, despite that laparoscopic surgery has increased in popularity, uptake of the MI approach in the treatment of gastric cancer in Europe is relatively slow. Nevertheless, Hawerkamp et al. in 2016 and later on Chevallay, Bracale, and others demonstrated that European-based studies found that LG can be performed in Western European patients with locally advanced gastric cancer and meets the oncological standard with a short hospital stay when performed by trained surgeons (6–8).

This study analyzed the safety and efficacy of LG for locally advanced gastric cancer in a tertiary referral center in Serbia. In this single-center, case–control study, observed groups were homogenous in respect to patient demographic characteristics, type of surgery, tumor localization, and stage of the disease. All patients in this trial were initially diagnosed with locally advanced tumors. After neoadjuvant treatment, patients were operated on, and definitive histology was clarified according to the final histopathological findings (PH). In the final analysis, there was a subgroup of patients with T1 tumors. One of many possible explanations is that clinical TNM did not match ideally with the pathological TNM staging. Another could be that, to some point, regression of the tumor could be expected with neoadjuvant treatment, but the correlation between the clinical and pathological treatment response is weak. At the end of the day, some patients with T1 (especially T1b) tumors were node positive.

This study demonstrated evidently lower complication rates in the MI group, yet not reaching a statistically significant difference (19.6% vs. 30.4%; p = 0.075). The study by Van der Wielen et al. (17) analyzed the outcome differences between East and West in MI gastrectomy versus OG. They found that the overall complication rates for the LG group were 21.69% and for OG 30.80% in the Western studies. Differently, the rates in Asian studies showed complication rates of 12.23% in the LG group and 15.79% in the OG group. Recently published Western trials found results comparable with those of the Asian counterpart. To our knowledge, the lowest quoted overall complication rate, after LG for cancer, was 15.8% (18).

The most frequent complication, in our study, was wound infection. Although statistically not significant, it was 3 times more common in the OG group compared to the LG group (2.9% vs. 8.8%). One of the most fearsome complications is anastomotic leakage. There was one patient in the OG group with type 2 leakage of the esophagojejunal anastomosis, a rate that is comparable to that of most Western and Eastern studies (6, 19). No difference was observed in MPPC, reoperation, and 30-day mortality rates.

In most trials, the number of overall complications matches complication rates according to the Clavien–Dindo classification. However, Clavien–Dindo classification does not sum up all of the complications that occurred, but only the gravest. Thus, a limitation of this classification is that events of lesser severity may not be considered, leading to an underestimation of the true overall postoperative morbidity. The CCI has been shown to yield a substantial additional value to the Clavien–Dindo classification in patients with more than 1 complication.

Prevalence of complications defined as the Clavien–Dindo grade ≥II is almost two times lower in the LG group, compared to the OG group (10.8% and 19.7% respectively); nevertheless, the difference did not reach statistical significance (p = 0.067). Similar results have been achieved when the severity of complications, with grade according to the CCI, was analyzed. The mean CCI index was 3.6 in the LG group and 6.7 in the OG group, yet not reaching the level of statistical significance.

When we look beyond the percentage of specific complications, we can find that Tsukada et al. have reported that elevated levels of inflammatory mediators like cytokines could be the cause of complications following major cancer surgery (20). When the production of cytokines was evaluated in patients undergoing major cancer surgery, lower production of cytokines was noted in the group of patients treated by utilizing the MI approach, compared to the open approach. In order to measure the invasiveness of MI esophagectomy (MIE), it might be necessary to evaluate other parameters in addition to morbidity rates. Moreover, there is a possibility that the overall number of cases in our study was too small to reach statistical significance.

The mean duration of surgery for the LG group and OG group was 290 and 270 min, respectively, and is comparable to that in most Western series (6, 7, 17) and slightly longer than that in the Asian studies (17, 21). Introducing technically demanding procedure needs must not unduly prolong operations. The effects of the learning curve in our opinion were minimized with excessive experience in other advanced upper gastrointestinal laparoscopic and thoracoscopic procedures with the same surgical team performing all operations.

The duration of routine postoperative ICU stay/recovery and hospital stay, although unreliable as a criterion of outcome among centers, is a useful parameter of the severity of the postoperative course and complication within a single center, particularly when there are defined protocols and discharge policy (15). Nevertheless, in our study, the average ICU stay and length of hospital stay were significantly reduced in the LG group when compared to the OG group, suggesting an earlier recovery in the case of LG.

Regarding oncological outcomes, significantly more lymph nodes were retrieved in the OG group, compared to the LG group, even though the mean number of harvested lymph nodes in the LG group also met the criteria for adequate radical lymphadenectomy. Our results were more comparable to those reported in Eastern studies and somewhat better than in Western studies (17, 22). Data also revealed a higher R0 rate in the LG group (92% vs. 73.1%), which can be justified by a more advanced T category and mean tumor size in the open group, with the majority of R1 resections at circumferential resection margin.

Numerous Western and Eastern studies demonstrated that the long-term survival and recurrence rates of laparoscopic gastric cancer surgery are comparable to those of open surgery for the treatment of both early and advanced stage gastric cancer (23–26). Garbarino et al., comparing laparoscopic versus open distal gastrectomy for locally advanced gastric cancer, pointed out completely different survival results. Patients with N0 or stage IB-II had better survival after LG. On the contrary, N+ and stage III patients had no survival benefit due to the laparoscopic approach (27). Observing the late outcome, our study demonstrated statistically longer survival rates for the patients in the laparoscopic group, which particularly applies to patients in the most prevalent, third stage of the disease. However, the survival inferiority of the OG group is probably related to the more advanced tumor, rather than the operative approach itself. The analyzed groups did not differ statistically in respect to the T, N, and M status and tumor stage. Nevertheless, due to the small sample size, patients were classified into the single-stage III rather than stage IIIA, IIIB, or IIIC. Out of the total number of patients in the stage III disease, in the OG group, more than 27% were in stage IIIC, while in the laparoscopic group, there were only 18% in this most advanced III stage. This observation is further supported by the multivariate statistics where survival is influenced by the stage of the disease and the presence of the surgical complications, rather than the surgical approach. Nevertheless, in the multivariate model, HR for open surgery compared to laparoscopy is 1.5. In addition, a significant difference was observed in respect to the tumor size and R status, and possible oncological impact of the higher R1 status on the OG patients should not be underestimated.

To check to what extent postoperative complications influence the positive effects of the MI approach, all patients with the Clavien–Dindo grade ≥II were excluded from the survival analysis, and further divergence of survival curves was observed. That could mean that postoperative complications could adversely affect the positive effects of the MI approach when the total population of patients is analyzed.

Our study showed that postoperative complications could diminish and blur the positive effect of the laparoscopic approach. Thus, future research focused on the evaluation of the MI approach in major cancer surgery should be focused on the patients with no complications. In addition, clinical practice should be focused on complication prediction and prevention to reduce their clinical and oncological impact.

The study has several limitations. First, the sample size is relatively small and has limited power to compare low frequencies of outcomes of interest. Second, this is a case–control study with a historical cohort and is subjected to selection biases. The importance of the MI approach in the treatment of locally advanced gastric cancer should be further tested in future, single-institution, randomized controlled trials. We strongly suggest testing the benefit of the MI approach separately in the subpopulation of patients with no significant surgical complications.

In conclusion, LG can be safely performed in patients with locally advanced gastric cancer and accomplish the oncological standard with short ICU and overall hospital stay, when performed by surgeons trained in gastric cancer and advanced laparoscopic surgery. Since postoperative complications could affect overall treatment results and diminish and blur the positive effect of the MI approach, further clinical investigations should be focused on the patients with no surgical complications and clinical practice to cut down the prevalence of complications.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by the Clinical Centre of Serbia Institutional Review Board (decision number 187/15 dated October 20, 2016). The patients/participants provided their written informed consent to participate in this study.

MB contributed to the conception and design of the study. MV organized the database. ZB performed the statistical analysis. MV wrote the first draft of the manuscript. DG, TB, RV, and DP wrote sections of the manuscript and participated in data collection. All authors contributed to manuscript revision and read and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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