Laparoscopic surgery for gastric cancer: comparative-effectiveness research and future trends

Research and technology have revolutionized surgery. Patient-oriented scientific efforts drive biomedical science advances. Improving patient’s outcomes dramatically, minimally invasive approaches represent a rapidly growing field. However, high-quality evidence for incorporating new medical devices, technology and surgical techniques into public healthcare with safety, efficiency and considering cost–effectiveness analysis is required [1]. In the beginning of the new decade, laparoscopic surgery in the multidisciplinary and multimodal treatment of solid tumors will probably experience a boom in clinical practice. In a 2020 vision, a progressive increase in the clinical use rates of laparoscopic and robotic-assisted tumor resections can be expected. We discuss here the perspectives, questions, limitations, potential harms in individual patients and public health, and challenges of laparoscopic gastrectomy for gastric cancer.

Among gastrointestinal cancers, tumors located in the colorectum and stomach are the most common, with approximately 1.9 million new cases each year worldwide, resulting in high mortality rates [2]. Over the past few decades, open surgery has been standard. Adequate resection of the primary tumor and of regional lymph nodes resulting in complete resection with no macroscopic or microscopic evidence of residual tumor (R0 resection) has been established as standard approach either before or after adjuvant chemotherapy and radiotherapy. Is laparoscopic R0 gastrectomy feasible, safe and equally effective, compared with open surgery?

Patient-friendly minimal invasive approaches in the treatment of gastrointestinal cancer include endoscopic submucosal dissection for very early, small-size tumors and laparoscopic or robotic resection for more advanced, larger tumors. Any new development or innovation, including medical devices, surgical techniques, drugs and biomarkers, requires rigorous evaluation and validation before it can be approved for wide clinical use. For example, it is now recommended by the editors of high-impact journals, such as Nature, that scientists straddling the boundary between bench and bedside must conduct and report their research with the rigor that each individual community expects [3].

In the era of post-evidence-based medicine, US health reform and economic crisis, requirements and rules for approving new diagnostic and therapeutics have become more intensive and will almost certainly emphasize on more relevant and robust evidence. In deciding whether to pay for new medical technologies, the Centers for Medicare and Medicaid Services (CMS) is becoming more specific about its requirements for evidence of improved health outcomes in the Medicare population [4]. A recent example involves the CMS decision not to cover computed tomography colonography because of insufficient evidence for screening benefits [4]. The heightened emphasis on evidence will almost certainly continue as more people recognize that the old approach is unsustainable. The US$1.1 billion for comparative-effectiveness research (CER) included in the American Recovery and Reinvestment Act underscores an emerging appreciation that we need improved mechanisms for generating relevant evidence and for enabling patients, clinicians and payers to use that evidence in decision making [4,5]. The best tools of CER are thought to be randomized controlled trials (RCTs) and meta-analyses [6].

Under these highly demanding evidence criteria and requirements set by the US FDA, CER and CMS, what is the grade of evidence supporting laparoscopic surgery for gastrointestinal cancer, particularly for gastric cancer? What do the general terms quality of life (QoL) and oncological outcome include? Which requirements define the safety, efficiency and superiority of laparoscopic versus open surgery?

Conclusive evidence for laparoscopic gastrointestinal cancer surgery has only emerged for laparoscopic colectomy in patients with colon cancer. Results from RCTs and a meta-analysis have demonstrated the equal safety and efficiency regarding oncological outcomes and a QoL superiority for laparoscopic colectomy, compared with open colectomy, for stages I–III colon cancer patients [7,8]. Rapidly accumulating results from small RCTs and retrospective studies suggest benefits for rectal cancer patients treated by laparoscopic or robotic-assisted rectal cancer resections. But the results of ongoing Phase III RCTs should be awaited before drawing robust conclusions [7,9–12]. What is the current grade of evidence for laparoscopic surgical treatment of gastric cancer?

Laparoscopic gastrectomy: CER

Seven RCTs [13–19] incorporating 688 patients and a recent meta-analysis [20] comparing laparoscopic versus open gastrectomy for gastric cancer have recently been reported. Table 1 summarizes these results as well as data from two large retrospective studies with approximately 1200 patients each [21,22]. In all these studies, laparoscopic-assisted distal gastrectomy (LADG) with a D1+ or D2 lymphadenectomy was compared with open distal gastrectomy. Except for one trial, the remaining six RCTs enrolled only patients with a clinically assessed early gastric cancer (EGC).

Although for the six trials with LADG for EGC the operating time was longer (mean difference [MD]: 86.64 min; p < 0.00001]), compared with open distal gastrectomy, there was less postoperative early morbidity (risk ratio: 0.61; p = 0.01), similar mortality, decreased intraoperative blood loss (MD: -108.33 ml; p = 0.001), forwarded time to oral intake (MD: -0.48 days; p = 0.32), and shortened hospital stay (MD: -2.03 days; p = 0.14) in the LADG group. Based on meta-analysis findings, Chen and colleagues conclude that LADG could slightly improve short-term QoL for patients with EGC [20]. The authors note an unfavorable increase in the operation time, a decrease in the number of harvested lymph nodes and the need for further follow-up results for conclusions on long-term survival.

Prognosis of patients with EGC is excellent. Although further long-term results are required it is very likely that LADG will have no negative effect on long-term survival. However, several questions remain unanswered. First, as EGC in the Western world is uncommon and most of the time can be treated by endoscopic submucosal dissection, interest has been focused on laparoscopic gastrectomy in more advanced tumor stages. How feasible, safe and effective is this approach? Second, what about laparoscopic total gastrectomy for proximal tumors and the modern totally intracorporeal laparoscopic gastrectomy?

Perspectives

As more and more patients with gastrointestinal cancer and their physicians seek better healthcare and the concurrence among hospitals and surgeons is growing, manufacturers have refined and improved laparoscopic surgical devices. The field of laparoscopic surgery is rapidly evolving and surgeons’ experience, essential for good outcomes, is growing.

Totally laparoscopic gastrectomy represents the evolution of laparoscopic-assisted gastrectomy. Refinement of devices has allowed intracorporeal stapled anastomosis and specimen removal through a slightly enlarged 12-mm port-site incision via an ENDO CATCH™ bag. This technique, sparing minilaparotomy, reduces the risk of postoperative infectious complications, hematoma, hernia and pain. Recent results of retrospective studies demonstrate the feasibility, safety and efficiency of totally laparoscopic gastrectomy when it is performed by high-volume laparoscopic surgeons even by a relatively prolonged operating time [23,24]. To reduce this time a modification of intracorporeal-stapled anastomosis has been developed. Using only linear staplers under direct laparoscopic guidance, Lee and colleagues performed totally intracorporeal anastomoses avoiding the time-consuming intracorporeal closure of enterotomies and the cumbersome maneuvers involved in reconstruction through an extended laparoscopic wound [25].

Evidence is scarce to answer the question of whether laparoscopic gastrectomy is safe for patients with advanced, resectable gastric cancer. Totally laparoscopic D2 gastrectomy for stage II and III disease is a highly demanding procedure. The safety and efficiency of this approach requires surgeon’s skill, experience and a prolonged operating time. Moreover, there are some oncological concerns. First, once the necessity of D2 lymphadenectomy in patients with node-positive disease has been widely accepted in Asia and the Western world [26–29], it becomes clear that D2 lymphadenectomy should be complete and standard in node-positive patients undergoing laparoscopic R0 resection. Second, peritoneal dissemination still remains the most common treatment failure after D2 surgery and postoperative adjuvant chemotherapy [30], and possibly even the addition of trastuzumab in HER2-positive advanced disease [31], is required. A potential increase in the risk of peritoneal recurrence through laparoscopic surgery in patients with serosa-positive gastric cancer cannot, at the present time, be excluded, RCTs are required to compare the risk of peritoneal failure in patients with advanced disease treated by laparoscopic and open surgery.

Conclusion

Modern totally laparoscopic gastrectomy represents the most promising approach for improving short-term QoL of patients with resectable gastric cancer. However, in the era of evidence-based medicine, CER and CMS, more data from RCTs are required to support wide clinical use of laparoscopic gastrectomy. Patients with EGC not meeting the criteria for endoscopic submucosal dissection are those who may benefit from laparoscopic approach. Yet there is skepticism for patients with serosa-positive cancer, even if laparoscopic D2 gastrectomy is performed by high-volume surgeons in specialized hospitals. The oncological outcomes, particularly peritoneal recurrence, should be considered when designing new randomized studies for assessing the impact of laparoscopic surgery in advanced resectable disease. Despite these concerns, we predict a dramatic increase in the rate of laparoscopic gastrectomy over the next 10 years. Progress can emerge only owing to innovative research and CER, and this requires rigorous evaluation of more patients enrolling into clinical trials.

Table 1. Results from randomized controlled trials and large retrospective studies comparing laparoscopic versus open distal gastrectomy for distal gastric cancer.

Study (year)	Patients (n)	Tumor stage	Surgery^†	Morbidity (n)^‡	Blood loss (MD, ml)	Longer operating time (MD, min)^§	QoL^¶	Long-term survival	Ref.
Kim (2008)	342	cT1,2aN0,1M0	LADG vs ODG	17 (10.5%)	NA	NA	Better	NA, still ongoing	[13]
Kim (2008)	164	cT1,N0,M0	LADG vs ODG	0	141	82	Better	NS	[14]
Huscher (2005)	59	cT1,4N0,2M0	LADG vs ODG	8 (26.6%)	162	28	Better	NS	[15]
Lee (2005)	47	cT1,N0,M0	LADG vs ODG	3 (12.5%)	-42	128.6	Better	NA	[16]
Kitano (2002)	28	cT1,N0,M0	LADG vs ODG	2 (14.3%)	155.6	56	Better	NS	[17]
Hayashi (2005)	28	cT1,N0,M0	LADG vs ODG	5 (35.7%)	160	143	Better	NA	[18]
Fujii (2003)	20	cT1,N0,M0	LADG	2 (20%)	71.5	45.9	Better	NA	[19]
Meta-analysis
Chen (2009)	629	cT1,N0,M0	LADG vs ODG	32 (9.9%)	108.8	86.6	Better	NA	[20]
Retrospective studies
Kitano (2007)	1294	cT1,2N0,1M0	LADG^†	167 (12.7%)	NA	45	NA	NS	[21]
Kim (2008)	1237	cT1,2N0,M0	LADG	162 (13.1%)	221.2	53	Better	NA	[22]

^†Type of surgery: lymphadenectomy (D1 + [a,b], D2); resection of the: distal two thirds (LADG), a few patients with proximal tumors were treated by total gastrectomy (LADG); reconstruction of the gastrointestinal tract after resection, through Billroth-I or II, or Roux-en-Y method and anastomosis through a 5- to 7-cm-long minilaparotomy incision.

^‡Morbidity: overall rates of intraoperative and postoperative complications. These complications include bleeding, anastomotic leakage, infectious complications and others.

^§Longer operating time in LADG group versus ODG.

^¶General term for improving QoL due to laparoscopic surgery includes less intraoperative blood loss, less postoperative pain, faster recovery, earlier return to normal bowel function with earlier oral intake and early discharge from hospital.

LADG: Laparoscopic-assisted distal gastrectomy; MD: Mean differences; NA: Not available; NS: Not significant; ODG: Open distal gastrectomy; QoL: Quality of life.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.