Comparisons of perioperative and long-term outcomes of laparoscopic versus open gastrectomy for advanced gastric cancer after neoadjuvant therapy: an updated pooled analysis of eighteen studies

Gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide [1, 2]. For patients with locally advanced gastric cancer (AGC), radical gastrectomy combined with D2 lymphadenectomy has been regarded as the only promising technique for curing the disease in both eastern and western countries [3]. In addition, the implementation of perioperative multi-mode therapy can also improve the oncological outcomes of patients [4]. Currently, several large-scale clinical trials such as MAGIC [5], FLOT4 [6], RESONANCE [7] and RESOLVE [8] have confirmed that neoadjuvant therapy (NAT) combined with surgical resection can improve the chances of R0 resection, eliminating possible micro-metastases and improve long-term survival relative to upfront surgery [9, 10]. The National Comprehensive Cancer Network (NCCN) recommends that NAT should be administered to all AGC patients, and it has been included in the standardized multi-mode treatment of AGC in many countries around the world [11].

Since Kitano et al. [12] first reported the application of laparoscopic technique for distal gastrectomy (LG) in 1994, LG has emerged as a standard surgical approach for the treatment of early GC due to the comparable surgical and long-term results relative to open gastrectomy (OG). In recent years, three large-scale randomized controlled trials (RCTs) from JLSSG0901 [13], KLASS-02 [14] and CLASS-01 [15] have further extended the indications of LG to AGC. However, in the context of NAT, therapy-induced tissue edema and fibrosis, vascular fragility, and normal anatomic disappearance pose new challenges to the application of laparoscopic technique in those patients [16, 17]. Laparoscopic technique has the advantages of a magnified surgical field and good maneuverability. A previous meta-analysis by Liao et al. [18] demonstrated that patients in the LG group had a quasi-significantly less complication rate and faster time to flatus than patients in the OG group, while other clinical outcomes were not significantly different between the two groups. Nevertheless, this meta-analysis included 6 studies with only 704 patients available, making many of the findings less statistically powerful. Therefore, it remains uncertain whether laparoscopic techniques can be used as an alternative to open surgery in AGC patients receiving NAT.

In the last 2 years, a growing body of additional research has been addressed to further explore the application value of LG in neoadjuvant gastric cancer patients. Therefore, based on existing evidence, we performed an updated meta-analysis to investigate the perioperative and survival outcomes of LG relative to OG in AGC patients following NAT.

Our meta-analysis was accomplished in line with the requirements from PRISMA statement, to identify studies comparing the perioperative and long-term outcomes of LG vs. OG for AGC patients who underwent NAT. The prospective protocol was registered with PROSPERO (CRD42022359126).

In clinical practice, laparoscopic gastrectomy has been widely accepted as an alternative to open gastrectomy for AGC in both Eastern and Western countries due to its relatively better short-term outcomes without compromising long-term outcomes. [44‐46]. Nowadays, the application of NAT to AGC patients has rapidly increased owing to its potential oncological benefits [5, 28, 31]. Nevertheless, before applying LG as the standard treatment option for AGC patients receiving NAT, much more evidence is required to confirm the true benefits of LG over OG, thereby aiding surgical decision-making.

In the present meta-analysis, we enrolled 18 studies with 2096 patients and demonstrated that LG offers better perioperative outcomes and comparable survival results compared to OG. In detail, the present study highlighted less estimated blood loss, faster time to liquid intake, shorter length of hospital stay, fewer minor complication rate, but longer operative time in the LG group, except for a reduced overall complication rate and faster time to flatus. Nonetheless, the previous meta-analysis [18] failed to detect these differences due to the limited number of studies included. Also, benefiting from a larger sample size, informative meta-regression and subgroup analyses can be further performed to investigate sources of heterogeneity and robustness of these pooled results with significant heterogeneities. As shown in Additional file 1: Figs. S1–S6, nearly all of those subset analyses revealed that these perioperative outcomes in the LG group were not inferior to those in the OG group. In addition, Begg’s tests showed no significant risk of bias in those pooled results, which further convincing us of the feasibility of LG in AGC patients following NAT.

Surveying the surgical parameters, the estimated blood loss in the LG group was significantly less than that in the OG group. This result may be related to the fine dissection and meticulous hemostasis of edematous and fibrotic tissue under a magnified surgical view by advanced laparoscopic instruments [26]. In addition, the LG group showed a faster recovery of gastrointestinal function, as indicated by the earlier onset of flatus and oral intake. Time to pull gastric tube and drainage tube, however, was similar between the two groups. Moreover, LG was also associated with a significant reduction in hospital stay, which may be a combined result of less blood loss, faster recovery of bowel function and lower postoperative complication rate. On the other hand, a longer operative time was observed in the LG group. Numerous studies have shown that the prolonged operative time is closely associated with the technical complexity as well as a relatively long learning curve of laparoscopic surgery [47], which may be particularly true in the context of NAT. With the popularization of laparoscopic technique and the improvement of surgical proficiency of surgeons, the operative time is expected to be shortened in future clinical practice.

Regarding postoperative morbidity, LG was related to a lower overall complication rate and a lower minor complication rate. These results may be related to the inherent benefit of laparoscopy in terms of better exposure and visual magnification, which allows delicate manipulation of the organs, vessels and nerves during LG [48]. In addition, the use of sophisticated equipment such as Harmonic Scalpel and Ligasure during LG may facilitate decreasing the surgery damage to normal tissues, therefore reducing morbidity [49]. Nevertheless, it is not surprising that in our pooled result, the minimally invasive nature of LG had less impact on reducing major complications, because accumulating reports have suggested that the occurrence of major complications may be mainly related to the proficiency of the surgeons as well as the surgical devices, rather than the surgical approach [48, 50]. In terms of specific complications, although there were no significant differences between the two groups found in our study, lower odds ratios for most complications were observed in the LG group, such as pulmonary infection. Certainly, part of the reason for this evidence can be explained by the minimally invasive nature of laparoscopic approach, which allows minor surgical incision length and less immune-suppression [48]. Besides, the minor tension sutures can reduce postoperative pain, thereby improving the patient’s respiratory dynamics and leading to fewer pulmonary infection [51].

With respect to the evaluation of oncological adequacy, our results demonstrated that LG was equal to OG in the proximal margin, distal margin, R1/R2 resection rate and number of harvested lymph nodes. In particular, retrieving enough lymph nodes for pathological examination and achieving identical extent of lymphadenectomy to OG have been regarded as the most essential index for assessing the feasibility of LG in gastric cancer patients [52‐54]. The 8th AJCC guideline recommends that at least 16 lymph nodes are required for GC patients to ensure accurate N staging, regardless of receiving NAT or not [11]. In addition, a recent study involving 4337 cases suggested that the retrieval of at least 23 lymph nodes could provide a better survival for patients receiving NAT [55]. In our study, the mean number of lymph nodes retrieved in the LG and OG groups was 31.84 and 31.87, indicating that LG is as oncologically adequate as OG in patients undergoing NAT. Consistently, the OS, DFS and RFS rates between the two approaches were unsurprisingly comparable. Therefore, once the basic principles of negative margins and adequate lymphadenectomy have been secured, the survival results are largely determined by the biological characteristics of the tumor itself rather than by the surgical approach [47].

This meta-analysis has several limitations. First, among included studies, there were only 2 RCTs and most of them were retrospective in nature, which may increase the risk of selective bias. Second, the quality of the included studies varied. Even though those pooled results were of low heterogeneities or remained consistent in the subgroup of high-quality studies (RCTs and propensity-score matched studies), this may have some effect on the strength of evidence of our study. Third, the preoperative treatment regimens varied a lot among the included studies. This heterogeneity may have an impact on the perioperative and survival outcome analyses.

This meta-analysis suggests that LG is a safe and feasible technique for AGC patients who received NAT in terms of superior short-term and comparable long-term results. Nevertheless, high-quality multicenter RCTs are warranted to validate our findings.