Eider Talavera-Urquijo ,Bas P.L.Wijnhoven

1Department of Surgery,University Hospital of Donostia,Donostia-San Sebastián 20014,Spain;2 Department of Surgery,Erasmus University Medical Centre Rotterdam,Rotterdam 3000,the Netherlands

Abstract Laparoscopic gastrectomy has evolved differently in Eastern and Western countries.Feasibility,safety and oncological outcomes of laparoscopic gastrectomy were addressed step-by-step by several randomized controlled trials from the East.Few phase III studies were published from the West that largely did not show a difference between the laparoscopic and open approach.Despite this,laparoscopic gastrectomy is seen as the standard for the surgical treatment of early and advanced gastric cancer in many European countries.Here,we review and comment on some important studies on laparoscopic gastrectomy for gastric cancer from Eastern and Western countries and also comment on current and future challenges.

Keywords: Laparoscopic gastrectomy;minimally invasive surgery;gastric cancer

Introduction

Gastric cancer is the 5th most common cancer and the 4th leading cause of cancer death worldwide (1).The highest incidence and mortality rates are observed in Eastern Asia,i.e.Japan,Mongolia,and the Republic of Korea (2).Other parts of the world face a decrease in gastric cancer incidence,possibly linked to improvements in food preservation practices as well as a reduction in the prevalence ofHelicobacter pyloriinfection (2).However,increases of gastric cancer in young adults were also observed,suggesting the role of lifestyle and modifiable factors such as salt intake,smoking,obesity,and alcohol consumption (2).

Gastrectomy with lymphadenectomy remains the cornerstone of multimodality treatment.Laparoscopic gastrectomy has been implemented in many centers across the world.Interestingly,the scientific evidence supporting minimally invasive gastrectomy has evolved differently in Eastern and Western countries.

Laparoscopic gastrectomy for gastric cancer in the West

In 2005,early (30 d) and 5-year outcomes of a randomized controlled trial (RCT) comparing open and laparoscopic subtotal gastrectomy for early and advanced gastric cancer were reported (3).No differences were seen between groups for duration of surgery,resection margin status and number of resected lymph nodes,postoperative morbidity,mortality and overall and disease-free survival.As expected,laparoscopic gastrectomy was associated with less intraoperative blood loss,earlier resumption of oral intake,and earlier hospital discharge.However,the internal and external validity of this study is weak as this was a singlecenter study including a small number of participants(n=59).Moreover,primary and secondary endpoints were not defined and a formal sample size calculation was not reported. Furthermore,no details on peri-operative oncological therapies were given.As the study ran between November 1992 and February 1996,results may be difficult to extrapolate to current practice.Multimodal treatment has been introduced,staging of gastric cancer has improved and laparoscopic equipment,techniques,training,and practice have evolved since then.It took another 15 years before two other RCTs from the West were published.In the meantime several observational studies on laparoscopic gastrectomy in the West have been published.A metaanalysis by Garbarinoet al.(4) showed that most of the 34 comparative and non-comparative studies published between 2003 and 2021 had a moderate to poor study design (retrospective,single-center) and included small number of patients.Clearly,selection bias is an issue in these studies.Most studies reported some benefits for laparoscopic gastrectomy (blood loss,analgesic requirement,time to first oral intake,minor complications and shorter hospital stay).Equivalence was shown for the number of resected lymph nodes,rate of major postoperative complications and overall survival,if reported at all.Despite the lack of level I evidence,laparoscopic gastrectomy was widely implemented in Europe,including the Netherlands where between 2011-2012 and 2017-2018 the percentage of patients that underwent minimally invasive gastrectomy increased from 7% to 64% (5).The perception of surgeons was that minimally invasive surgery is better,likely supported by data from RCTs in colorectal cancer.The widespread use of laparoscopic gastrectomy persisted despite studies reporting that minimally invasive total gastrectomy may even be associated with a higher anastomotic leak rate and that oncological safety still had to be proven.Many European centers are low-volume institutions (＜30-40 resections per year) compared to Asian institutions (＞100 per year) and adaption of a new technique may cause harm to patients before a learning curve is passed (6).

In 2021,a multicenter,randomized controlled,openlabel,superiority trial comparing laparoscopic with open gastrectomy (LOGICA-trial) was published (7).It was hypothesized that hospital stay would be less after laparoscopic gastrectomy.Health-related quality of life was included as a secondary outcome measure.Results showed however that hospital stay was not different between the groups at a median of 7 [interquartile range (IQR) 5-9] d.Also,postoperative patient-reported pain scores and global health-related quality of life did not differ between the treatment groups.The third RCT,published in 2020,was the STOMACH trial,a non-inferiority,multi-center,international,RCT performed in 13 hospitals around Europe (8).The study included 96 patients who underwent total open or laparoscopic gastrectomy after neoadjuvant chemotherapy.Similar to the LOGICA trial,the STOMACH trial also did not show a difference in postoperative pain scores,duration of hospital stay,complications and oncological parameters.No differences were seen in the 1-year survival,although the study was not powered to show a difference in disease-free and overall survival.

Why is it that in these Western RCTs postoperative pain,hospital stay,complications,and quality of life is no better for laparoscopic gastrectomy? In countries/institutions with a low volume of gastric cancer patients and resections,the learning curve for minimally invasive gastrectomy may not have been passed by many surgeons and differences between techniques may not stand out as compared to Asian studies (see below).Quality standards were defined and formal training programs were run but still the required number of laparoscopic gastrectomies in order to participate in the study were low (20 procedures per center).As surgical procedures in STOMACH and LOGICA trials were performed in a relatively recent period (between 2015 and 2018),well after the awareness and introduction of enhanced recovery programs,perioperative care has become much better and focussed on quick discharge for open as well as laparoscopic procedures.Interestingly,patient-reported pain scores were similar and most patients in the open group from the LOGICA study received epidural pain control compared to systemic and/or local anesthetic in the laparoscopic group.Postoperative pain scores were low and comparable.Apparently,good pain control after open surgery enables patients to go home as quickly as patients in the minimally invasive group.Assessors and patients were not blinded in both trials.One may expect that patients after laparoscopic surgery are discharged earlier just by the fact that the physician feels that the patient is able to go home quicker after minimally invasive surgery having smaller cuts.Patients may also have been educated this way before the surgery.In latest years,median hospital stay after gastrectomy in the Netherlands has decreased further and is around 7 (IQR,5-11) d (5).Blinding patients and assessors would have been interesting and may have reduced bias.In the ROMIO-trial comparing minimally invasive esophagectomy with open surgery,patients and assessors were blinded for surgical approach.Preliminary analyses,but not yet published,did not show a difference in hospital stay,complications and quality of life between the groups (9).This observation once more supports the non-inferiority of open surgery for advanced cancers in times when long-term survival of minimally invasive surgery is still to be awaited.Long-term results of the Western RCTs should be awaited cause,apart from survival and quality of life outcomes,it would be interesting to know if laparoscopy offers benefits in long-term complications such as intestinal occlusion and woundrelated complications (herniation) as recently shown for the KLASS-02 trial (10).

Laparoscopic gastrectomy for gastric cancer in the East

The feasibility,safety and finally oncological outcomes of minimally invasive gastrectomy in the East were addressed step-by-step by several landmark trials.All studies were performed mainly in China,Korea and Japan,countries with a high incidence of gastric cancer (2).Participating institutions and surgeons have a large experience in gastric cancer surgery.In 2014,laparoscopic subtotal gastrectomy for clinical stage I gastric cancer was first described by the Japanese gastric cancer treatment guidelines as a treatment option in high-volume centers (11).This was based on a prospective phase II study (JCOG0703) which demonstrated the safety of the laparoscopic approach performed within the study by certified surgeons with sufficient experience (12).Furthermore,better short-term outcomes were reported by small-scale randomized trials and meta-analyses (11).Shortly thereafter,in 2016,the initial pivotal phase III studies on early distal gastric cancer were published [KLASS-01 in Korea (13) and JCOG0912 in Japan (14)].These studies demonstrated better shortterm results for laparoscopic gastrectomy compared to open surgery (shorter hospital stay,less blood loss,and fewer wound complications) with comparable primary outcomes of 5-year overall and disease-specific survival at later reports.Furthermore,the JCOG0912 trial also analyzed health-related quality of life results at 1,3,12,and 36 months after surgery,favoring laparoscopic distal gastrectomy especially in the early phase after surgery (at 1 and 3 months) (15).Later,several other RTCs have been published comparing laparoscopic and open distal gastrectomy for advanced gastric cancer.Among them,CLASS-01 from China (16) and KLASS-02 from Korea(10) have already reported their long-term results at five years.A very recent meta-analysis including mainly Asian RCTs (eight in China,two in Korea,one in Italy,and one in the Netherlands) about laparoscopic gastrectomy for advanced gastric cancer concluded that the laparoscopic approach offers improved short-term outcomes including shorter hospital stays and fewer blood loss,with comparable postoperative complications,short-term mortality,and survival rate at 1,3,and 5 years when compared to the open approach (17).When the 5th edition of the Japanese gastric cancer treatment guidelines in 2018 came out,these long-term results were not available and so there was still no recommendations on the place of laparoscopic gastrectomy for advanced gastric cancer (18).With these and the upcoming long-term results of the Japanese trial JLSSG0901 on advanced distal gastric cancer(19),the next edition will probably consider the minimally invasive approach also for advanced stages.

Asian studies demonstrated benefits on short-term outcomes for the laparoscopic approach,while Western studies (LOGICA and STOMACH trials) did not.Patient demographics,tumor biology,hospital and surgeon volume,surgical routine,and differences in multimodal treatments need to be taken into account when comparing studies from the East and West.Asian studies had large sample sizes powered to show non-inferiority of laparoscopic distal gastrectomy for survival.Western RCTs were smaller,powered for short-term results,and included advanced proximal tumors testing the laparoscopic total gastrectomy after neoadjuvant treatment.Acknowledging that results from trials performed in the East may be difficult to extrapolate to the Western context,the National Comprehensive Cancer Network (NCCN)clinical practice guidelines in gastric cancer (updated in February 2022) (20) and the European Society for Medical Oncology (ESMO) guidelines for gastric cancer (released in July 2022) (21) recognize the possible benefits and safety of laparoscopic gastrectomy and recommend the minimally invasive gastrectomy for early and advanced gastric cancer by experienced surgeons.But what the criteria are for proficiency in laparoscopic gastrectomy is not described and is currently largely unknown.

Current challenges and future perspectives

In the East,phase II single-arm feasibility trials on laparoscopic total gastrectomy for early gastric cancer have been published [KLASS-03 in Korea (22) and JCOG1401 in Japan (23)],but RCTs evaluating laparoscopic total gastrectomy in advanced gastric cancer are still awaited.In the West,the long-term results (overall survival) of the recently published RCTs are not available yet.Some speculate that after preoperative chemotherapy the benefits of a minimally invasive approach would be more evident,and more patients would be able to start earlier and complete postoperative adjuvant chemotherapy (24).Future studies in the West could evaluate these aspects given the current standard of FLOT (fluorouracil,leucovorin,oxaliplatin and docetaxel) perioperative chemotherapy.Health-related quality of life is a highly relevant aspect when comparing surgical approaches and more emphasis should be put in exploring patient’s preferences regarding treatment regimes including surgery.As minimally invasive surgery is continuously evolving,the role of robot-assisted gastrectomy will have to be defined.Initial reports about robotic gastrectomy compared to laparoscopic gastrectomy are promising (25,26),but whether this leads to clinically relevant benefits is unclear.Randomized controlled trials comparing laparoscopic and open gastrectomy in the East and West are shown inTable 1.

Acknowledgements

None.

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.