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Laparoscopic Gastrectomy and Personal Genomics : High-Volume Surgeons and Predictive Biomedicine May Govern the Future for Resectable Gastric Cancer

To the Editor: In the largest study on laparoscopic gastrectomy, published in the November issue of Annals of Surgery, Kim et al report on 1237 patients with early gastric cancer who underwent a laparoscopy-assisted distal gastrectomy (LADG) with standardized D2 lymphadenectomy. The authors evaluated the safety of the procedure and particularly the role of comorbidity in surgical outcomes. Overall, in-hospital postoperative mortality was 0.6% and morbidity was 13%. This study raises 2 critical questions for Western evidence-based medicine. First, can LADG become a standard approach in the absence of randomized controlled trials? Second, in the age of personal genomics and global gene expression profiling, how may complete genome scans and predictive biomedicine influence adjuvant therapeutic decisions toward personalized treatment of gastric cancer? Will a local laparoscopic gastrectomy and a systemic patient-tailored adjuvant treatment guide the future management of gastric cancer? Indeed, laparoscopic surgical resection and selection of the best combination of empirical chemotherapy and targeted agents represent the primary goals for improving both quality of life and long-term survival. Open D2 gastrectomy has been the standard of care for localized gastric cancer in Japan and Korea. Two recent pivotal studies for advanced stage II/III gastric cancer from Japan were recently published in the NEJM. The first phase III randomized controlled trial, compared D2 lymphadenectomy alone or D2 plus para-aortic nodal dissection. No patient received adjuvant treatment; Sasako et al report the best global 5-year survival results of approximately 70% in both groups. On this basis, that is, no survival benefit derived from D2 plus para-aortic nodal dissection, D2 surgery has been the standard approach. The second, a phase III randomized trial compared D2 surgery alone versus D2 surgery plus postoperative S-1 adjuvant chemotherapy. Due to a significant difference in the 3-year survival rate in favor of S-1 chemotherapy, which was assessed in the planned interim analysis, the study was stopped. D2 plus S-1 postoperative chemotherapy is the standard treatment of stage II/III gastric cancer in Japan. Yet, similar results have not been achieved in Europe or United States. Worldwide, quality of surgery plays a predominant role in local control and favorable outcomes for gastric cancer. But, in the absence of evidence from positive randomized trials, there is still controversy on the potential survival benefit of D2 gastrectomy. Data are still limited whether perioperative, preoperative only, or postoperative chemotherapy should be added to D2 surgery or limited D1 gastrectomy. Locoregional tumor control is important for improving both recurrence-free survival and overall survival. Therefore, every effort should be made to prevent local or nodal recurrence due to standardized D2 surgery in the West taking lessons from the excellent results reported with D2 surgery from Japan. Precondition however, is that this procedure can be safely and efficiently applied by high-volume surgeons. Laparoscopic D2 gastrectomy demands the highest level of a surgeon’s skill and experience. Kim et al confirm that this is a retrospective multicenter study. Only 10 surgeons from 10 hospitals in Korea performed the LADG. The surgeons’ experience in laparoscopy-assisted gastrectomy and comorbidity were related to postoperative local complications. Does laparoscopic gastrectomy affect survival of patients with early gastric cancer? Although there is some skepticism about a potential negative effect, it appears that survival in closed gastrectomy is as good as it is in open gastrectomy. However, there is no evidence that laparoscopic gastrectomy improves survival. Despite this absence of survival benefit, laparoscopic D2 gastrectomy will attract more patients in the future, due to its apparent superiority in early postoperative quality of life, when compared with open D2 surgery. Given that no survival benefit can be expected from a change of open to closed D2 gastrectomy, research efforts have reliably focused on personal genomics, genetics, genome-wide association studies (GWAS), and predictive biomedicine toward a patient-tailored treatment strategy. Indeed, in the age of personal genomics, personalizing decisions on extent of surgery and adjuvant systemic treatment of solid cancer begins to seem like a realistic goal reachable in the near future. Human genetic variation makes each of us unique. Similarly, genetic variants like single-nucleotide-polymorphisms and copynumber-variations may be involved in cancer initiation and recurrence. If this is true, then identifying these variants may lead to the development of single-nucleotide-polymorphisms/copy-number-variations-based markers both to predict recurrence risk and to develop novel agents targeting these genetic alterations, and the deregulated signaling pathways. Once the goal of identifying genetic risk variants are achieved the next step is much more complicated. It appears to be an unsolvable problem: how can we understand the complex gene-gene and gene-environment interactions? Promises toward this fundamental network modeling, provide predictive biomedicine based on systems biology and computational networking biology. A rational way is to develop innovative algorithmic approaches and novel sophisticated computational-mathematical (in silico) models to predict a genotype (DNA changes)— phenotype (cancer heterogeneity) map. If this scientific endeavor can be achieved, then we could hope for personalized cancer management and medicine. There are the limitations for routine use of laparoscopic D2 gastrectomy in the West. The absence of phase III randomized trials, the absence of high-volume surgeons in laparoscopic-assisted D2 gastrectomy, and the limited number of patients diagnosed with early disease in the West are obstacles for wider use of LADG. However, despite these limitations, as patients and their physicians seek out the best hospital for high-quality treatment, we expect that highly specialized hospitals will attract a rapidly increasing number of patients with gastric cancer. Beyond treatment, prophylactic laparoscopic total gastrectomy has been increasingly considered for primary prevention for people at very high risk ( 75%) of developing diffuse gastric cancer, because of heritable high-penetrance mutations in the CDH1 gene. Advances in surgical quality and personal genomics may improve oncological outcomes.