The Clinical Outcomes Of Laparoscopic Gastrectomy For Advanced Gastric Cancer And Vatimin B12 Metabolism In Gastrectomized Patients

Gastric cancer remains the fourth most common cancer worldwide and the second leading cause of cancer-related deaths. Although there has been a significant decrease of prevalence in Western countries, the highest rates of this disease continue to be among the East Asia. It has been reported that approximately 42% of worldwide cases occurs in China (300,000-400,000 cases/year). Also to mention that different from Japan and Korea where the majority of patients are diagnosed as early gastric cancer (EGC),80-90% of cases are considered as advanced gastric cancer (AGC) in China and the survival are still a great challenge.To date, laparoscopic surgery, as a revolutionary minimally invasive technique, has been widely applied in the treatment of early gastric cancer. Its safety and oncologic efficacy have been suggested by several prospective studies with high level evidence. With the rapid development of devices and accumulation of surgical experiences, laparoscopic surgeons in China, Japan and Korea have been trying to expand the indication into locally advanced gastric cancer patients, so that more patients suffering from gastric cancer would benefit from its minimally invasive advantages. However, traditional open surgery remains to be the "golden standard" in the treatment of locally advanced gastric cancer. Under this circumstances, the following key issues begins to draw the attention of surgeons and researchers:1) how to strictly follow the oncologic principles during laparoscopic surgeries;2) how to standardize the lymphadenectomy when treating more advanced-staged cancer, rather than EGC; 3) how to avoid unexpected complications in relation with expanded lymphadenectomy; 4) what might be the short-and long-term adverse event following laparoscopic surgery.To find answers regarding the above issues, retrospective and prospective clinical trials would be the best choice. To be specific, the purpose of clinical trials should be set on evaluating the safety and oncologic efficacy of laparoscopic surgery for AGCs.Undoutedly, the survival of patients with gastric cancer has improved significantly with treatment modalities. To those patients with anticipated long survival, the quality of life after gastrectomy is a great concern. Vitamin B12 dificiency,which causes megaloblastic anemia and neuropsychiatric symptoms, is one metabolic sequela after gastrectomy.However, little is known about vitamin B12 deficiency after gastrectomy with regard to the exact time to deficiency and associated risk factors. In previous studies conducted several decades ago, the subjects were patients with gastric or duodenal benign ulcers who underwent partial gastrectomy. Among which, the surgical principles were different from cancer surgeries and the treatment strategy has changed a great deal. Thus, there is no established standard postoperative management protocol for monitoring and correcting vitamin B12 deficiency for gastrectomized patients with gastric cancer. Only after these issues be clarified, clinical management strategies could be made to improve the quality of life of gastrectomized patients with gastric cancer sufferingfrom potential vitamin B12 deficiency.Hereby, the study is consisted of the following four parts:Part Ⅰ:Surgical and oncologic outcomes of laparoscopic gastrectomy for advanced gastric cancer:a large-scale multicenter retrospective cohort studyPurpose:To evaluate the surgical safety and oncologic outcomes of laparoscopic gastrectomy for advanced gastric cancer and identify the risk factors forrecurrence and survival.Methods:Clinicopathological and follow-up data of a total of 1789 patients with gastric cancer were collected from the CLASS database and finally 1184 patients with advanced gastric cancerwho underwent laparoscopic gastrectomy with curative intent were retrospectively analyzed. Survival rates were estimated using the Kaplan-Meier method. Risk factors for recurrence and survival were evaluated using the Cox regression models.Results:Postoperatively,121 patients (10.2%) experienced complications and mortality occurred in 1 patient (0.1%). The cumulative 3-year overall survival (OS) and disease-free survival (DFS) rates were 75.3% and 69.0%, respectively. The 3-year OS and DFS rates were 89.7% and 88.9% for stage Ⅰ tumors,85.0% and 77.0% for stage Ⅱ,60.5% and 59.3% for stage Ⅲ. Independent risk factors for recurrence were tumor size> 40mm, intraoperative blood transfusion, and advanced tumor stage. For survival, age> 65 years, tumor size> 40mm, and advanced tumor stage were independent risk factors.Part Ⅱ:A multicenter matched case-control study of laparoscopic versus open gastrectomy for advanced gastric cancerPurpose:To compare the surgical and oncologic outcomes of laparoscopicgastrectomy with open surgery for advanced gastric cancer.Methods:A 1:1 matched (sex, age, type of gastrectomy, TNM stage, participating institution, and operation period) case-control study was performed using the CLASS database. A total of 698 patients out of 1789 underwent laparoscopicgastrectomy and 698 patients out of 1666underwent open gastrectomy were matched and analyzed. The clinicopathologic characteristics, surgical outcome and follow-up results were compared between the laparoscopic gastrectomy (LAG) and open gastrectomy (OG) group.Results:The postoperative morbidity rate was 11.0% in the LAG group and 10.3% in the OG group (p=0.665). There was no mortality case in the LAG group, when a rate of 0.3% in the OG group (P=0.500). Stratifying by TNM stage, the cumulative 3-year overall survival between the LAG and OG group was 95.8% and 95.4% (P=0.620) for stage Ⅰ,84.1% and 81.8%(P=0.519) for stage Ⅱ,50.9% and 50.5% (P=0.332) for stage Ⅲ, respectively. The cumulative 3-year disease-free survival between the LAG and OG group was 90.5% and 91.9%(P=0.422) for stage Ⅰ,70.9% and 72.5%(P=0.443) for stage Ⅱ,43.9% and 41.8%(P=0.283) for stage Ⅲ, respectively.Part Ⅲ:Prospective randomized controlled multicenter study for comparison of long-term outcomes between laparoscopic and open distal subtotal gastrectomy with D2 lymphadenectomy for locally advanced gastric cancerPurpose:To compare the surgical and long-term oncologic outcome of laparoscopic versus open distal subtotal gastrectomy with D2 lymphadenectomy for locally advanced (T2-4a, N0-3, M0) distal gastric cancer.Methods:A multicenter, randomized, open label, parallel design and non-inferiority test was adopted. The 3-year disease free survival rate, postoperative morbidity and mortality were endpoints.Results:A total of 607 consecutive patients were recruited and randomly assigned into either LG group (n=308) or OG group (n=299) between September 2012 and January 2014. The rate of conversion to open surgery was 4.5%. There was no significant differences between the LG group and OG group in the incidence of intraoperative complication (5.8% vs.4.3%; P=0.402), morbidity (18.8% vs.14.7%; P=0.175), and mortality (0.6% vs.0; P=0.499). The patterns of severity grading were also comparable between the two groups. (P=0.372).Part Ⅳ:Vitamin B12 deficiency after gastrectomy for gastric cancer:an analysis of clinical patterns and risk factorsPurpose:To identify risk factors for post-gastrectomy vitamin B12 deficiency and the time course of its development.Methods:The data and serum samples of patients underwent distal (DG) or total gastrectomy (TG) were collected. The cumulative vitamin B12 deficiency rates were estimated using the Kaplan-Meier method, to identify risk factors associated with vitamin B12 deficiency, univariate and multivariate analyses were conducted using Cox proportional hazards model.Results:Cumulative vitamin B12 deficiency rates were 100% for TG and 15.7% for DG 4 years after surgery (p< 0.001). The median time to vitamin B12 deficiency was 15 months after TG. Preoperative vitamin B12 level was the only risk factor for vitamin B12 deficiency after TG, whereas both preoperative vitamin B12 level and age were risk factors following DG. There was positive linear correlation between preoperative vitamin B12 levels and the time to vitamin B12 deficiency after either TG (p<0.001) or DG (p=0.017).Based on the results from above study, following conclusions could be reached:1. Laparoscopic distal gastrectomy with D2 lymphadenectomy for the treatment of locally advanced gastric cancer is a technical feasible and surgical safe procedure in experienced hands, which could yield similar short-term oncologic outcomes with open surgery.2. Vitamin B12 deficiency is an inevitable and rather early metabolic sequela after total gastrectomy. Elderly patients with low preoperative vitamin B12 levels are more likely to experience vitamin B12 deficiency after distal gastrectomy. Preoperative evaluation and regular monitoring of serum vitamin B12 after gastrectomy is helpful for improving the patients’quality of life.The innovation in the present study:1. The surgical safety and oncological efficacy of laparoscopic surgery for advanced gastric cancer was illustrated in different evidence-leveled studies based on Chinese population.2. The natural course and risk factors of vitamin B12 deficiency in gastrectomized patients with gastric cancer were clarified, which were helpful for further study on prevention and early intervention of the vitamin B12 deficiency.