Laparoscopic Surgery for Gastric Cancer: The European Point of View

Objective Multiple Asian studies have proved the feasibility of laparoscopic approach for surgical treatment of gastric cancer. The difference between Asian and European patients could limit their application in Europe. We reviewed the literature for European studies comparing open gastrectomy with laparoscopic approach in the treatment of gastric cancer. Method We searched the keywords gastric cancer and laparoscopy in MEDLINE and EMBASE. We included all studies published between 1990 and 2016 and conducted in Europe. Result We found 1 randomized and 13 cohort studies which compared laparoscopic with open gastrectomy. We found no mean difference in the number of lymph nodes harvested between laparoscopic and open group (mean difference: -0.49; 95% CI: -2.42; 1.44, p=0.62) and no difference of short-term or long-term mortality (short-term odds ratio: 0.74, p=0.47; long-term odds ratio: 0.65, p=0.11). We found a longer operative time in the laparoscopic group (mean difference: 35.75 minutes, p<0.01) but lesser reoperation rate than the open group (odds ratio: 1.55 p=0.01). Conclusion European based population studies found results comparable with their Asian counterpart. In the current state of evidence, minimally invasive surgery for gastric cancer is safe and can achieve the same oncological results.


Introduction
Gastric cancer is the 4th cause of cancer-related death in Europe [1]. Major progress has been made in its management as, for example, the introduction of perioperative chemotherapy. Surgery remains the only curative therapy. Improvement has also been made in this particular area. Extent of lymphadenectomy has undergone progressive changes to find the one associated with the best staging and survival. D2 lymphadenectomy is actually recommended as a standard for all TNM stages N+ and above T2 gastric cancer in Japanese guidelines [2]. The next step in surgical development is minimally invasive surgery. The oncological principle with adequate lymphadenectomy and negative resection margin needs to be equivalent as open procedure. Inability to offer the same quality to their patient discourages surgeons to use new techniques without strong evidence. Laparoscopy has already proven its superiority over open surgery for colorectal cancer with shorter hospital stay [3] and similar long-term oncological outcomes [4]. Kitano et al. [5] performed the first laparoscopic distal gastrectomy for gastric adenocarcinoma in 1994 with a modified D1 lymph node dissection. After this preliminary result, the technique has spread in Asia with several cases series confirming its safety and feasibility. The first European experience is published in 1999. Azagra et al. [6] reported a series of 13 gastric cancer cases operated with a laparoscopic approach in Belgium. Majority of the evidence for laparoscopic surgery for gastric cancer comes from Asian studies. Conclusions of this evidence should be extrapolated to the European population with caution. Several differences exist between the Asian and European population: first, European patients have higher BMI. Visceral fat can make the laparoscopic approach more difficult. Second, tumors are more advanced in Europe. Nationwide screening programs in Japan [7] and Korea [8] diagnose early cancer suitable for surgery. Finally, the surgical caseload is higher in Asia with high volume hospital. Surgeons reach the peak of their learning curve faster than a surgeon in low incidence area. In order to synthesize the European evidence, we conduct a systematic review of the European studies comparing laparoscopic and open gastrectomy for gastric cancer.

Search Strategy, Selection Criteria, and Data Extraction.
We searched the keywords "laparoscopic" and "open" and "gastric cancer" and "gastrectomy" in Pubmed, EMBASE, Cochrane Library, and ClinicalTrials.gov databases. Cochrane Centre, The Cochrane Collaboration, 2014). We used difference in means for continuous variable and odds ratio for dichotomous variable with 95 % confidence interval (CI). The statistical significance was set for p-value < 0.05. We estimated the heterogeneity for each outcome by calculating the I 2 value. If the I 2 value was superior to 25%, we assumed that the studies heterogeneity was high. We used in these cases a random effect meta-analysis model. When the I 2 value was inferior to 25%, we used a fixed effect meta-analysis model. For each outcome, we assessed publication bias with funnel plots and used Egger's test to detect asymmetry [24]. In cases where values were reported as median, we used the Hozo formula [25] to estimate the corresponding mean and standard deviation.

Histological Results.
One study [17] included only early gastric cancer defined as T1-T2 cancer. The others studies treated all stage of gastric cancer.

Overall and Oncological Survival.
We found an expression of mean follow-up period in 5 studies [10,11,15,17,18]. The shorter follow-up was 18 months in both groups [18] and the longer was 49 and 52 months in the open and laparoscopic group, respectively [11].

Discussion
Minimally invasive surgery is the next step in gastric cancer surgical management. More than half of the worldwide cases of gastric cancer are diagnosed in East Asia (China, Japan, and Korea) each year [26]. Despite the disadvantage of lower incidence, European countries manage to acquire experience. The studies included in this review totalize 1490 patients treated with laparoscopic approach and this serves as a basis for European evidence. The European studies confirm the superiority of laparoscopic procedures with less blood loss and a shorter hospitalization. Li et al. [27] showed in their meta-analysis, which included randomized controlled trials mostly Asian (13 for only 1 European), a mean difference of 100.20 mL (95%CI, -131.68 to -68.72, I 2 =90%) in blood loss and -0.84 in hospital stay (95% CI, -1.35 to -0.32; I 2 =76%). Xiong et al. [28]   Operative time follows the same pattern. In our review, we found a mean difference of 30 minutes between laparoscopic and open procedure. In the two meta-analyses, Li et al. [27] and Xiong et al. [28] showed also a higher mean operative time in laparoscopic group, respectively, mean difference of 48.25 and 68.96 minutes. Minimally invasive surgery has a longer operative time due to technical difficulties. Surprisingly, the mean difference of operative time is lower in European studies. This can be explained by the expansion of laparoscopic indication in upper gastrointestinal pathologies. Even in low case volume of gastric cancer, laparoscopic experience can be obtained through other indications. One example is the use of minimally invasive surgery in the management of infracarinal oesophageal carcinomas. Historically, oesophagectomy was performed with Ivor-Lewis procedure with open approach: laparotomy and right-thoracotomy. An emerging approach is hybrid minimally invasive oesophagectomy in which the abdominal step is conducted by laparoscopy [29]. The laparoscopic approach can be applied to certain stage of the intervention while maintaining the adequacy of oncological resection at the thoracic stage. Gastrectomy for gastric cancer should respect oncological principles such as a minimal number of lymph node retrieval and negative resection margin. The review of the different studies conducted in Europe comparing laparoscopic and open procedure showed no difference in lymph node retrieval especially when D2 lymphadenectomy was performed. The work from Li et al. [27] and Xiong et al. [28] showed also no mean difference between number of lymph node during open and laparoscopic approach (respectively, mean difference: -1.27 (95% CI: -3.03 to 0.49) and -2.49 (95%CI: -5.18 to 0.21)).
Since 1997, the American Joint Committee for Cancer (AJCC) [29] proposed a minimal number of 15 dissected nodes for the accurate prognosis of N status. The exact number of lymph nodes has been since questioned. The authors of an international retrospective study [30] have concluded that improvement in survival was obtained when an optimum of 29 lymph nodes retrieval was achieved. Regardless of the surgical approach, the lymph node goal should be this number.
In our experience, minimally invasive approach was associated with higher risk of positive margin than open procedure. Asian meta-analysis did not report the rate of positive resection margin. This result should be moderate with the fact that only half of the studies reported their resection margin rate. A difference exists between West and East: Western guidelines [31] propose a resection margin of 4-5 cm whereas the Japanese Gastric Cancer Association [32] ranges the adequate margins from 2 to 5 cm according to the T status. One explanation is that the plateau of gastrectomy learning curve in Europe was not reached during these studies. Resection margin is an area of improvement for European minimal invasive surgery.
The rate of duodenal leakage was higher in the open group in European studies. However, one study [16] had a high rate of leakage. The author hypothesis for this high rate of duodenal leakage was that they did not use a running suture for the duodenal stump. When this study was excluded from the analysis, the open and laparoscopic approach did not differ in terms of duodenal and anastomosis leakage.
A cutoff for the learning curve was not set by European studies. In an observational study, Kim et al. [32] showed that improvement on surgical parameters and postoperative course was seen after a cutoff value of 46 cases. Improvement of operative time was also seen after 50 cases in another observational study [33].
They are limitations to our review. The studies were different in their designs: only one was a randomized clinical trial and the others were retrospectives. Methods of the studies were not standardized with multiples types of reconstruction and lymphadenectomy. Neoadjuvant chemotherapy was reported in only two studies and this could have been another bias. Finally, the male gender was overrepresented in the open approach group and this could have led to introduce a selection bias.
For future direction, two European trials are being conducted. The first, LOGICA-trial [34], from Netherlands, is a multicenter, randomized clinical trial comparing laparoscopic and open gastrectomy for gastric cancer (ClinicalTrials.gov identifier: NCT02248519). The second, STOMACHtrial [35], is also a multicenter, randomized clinical trial comparing laparoscopic and open gastrectomy but after neoadjuvant chemotherapy and is international (Germany, Netherland, Spain, United Kingdom) (ClinicalTrials.gov Identifier: NCT02130726).

Conclusion
Laparoscopic procedure for gastric cancer in Europe causes less blood loss, and shorter hospital stays with similar number of lymph nodes harvested. These European results are similar to their Asian counterparts. Asian evidence remains stronger with more randomized clinical trials. In order to fill this gap, two Europeans trials are ongoing to determine the best surgical approach in the era of neoadjuvant treatment.

Disclosure
This manuscript was presented during an oral presentation at the 104th Annual Congress of the Swiss Society of Surgery.

Conflicts of Interest
The authors declare that they have no conflicts of interest.