Effect of Laparoscopic Proximal Gastrectomy With Double-Tract Reconstruction vs Total Gastrectomy on Hemoglobin Level and Vitamin B12 Supplementation in Upper-Third Early Gastric Cancer: A Randomized Clinical Trial.

Importance: Patients undergoing proximal gastrectomy (PG) with double-tract reconstruction (DTR) have been reported to have an incidence of reflux esophagitis that is as low as that observed after total gastrectomy (TG). It is unclear whether PG has an advantage over TG for the treatment of patients with upper early gastric cancer (GC). Objective: To evaluate the effect of laparoscopic PG with DTR (LPG-DTR) vs laparoscopic TG (LTG) on levels of hemoglobin and vitamin B12 supplementation required among patients with clinically early GC in the upper third of the stomach (upper-third early GC). Design, Setting, and Participants: This multicenter open-label superiority randomized clinical trial was conducted at 10 institutions in Korea. A total of 138 patients with upper-third cT1N0M0 GC were enrolled between October 27, 2016, and September 9, 2018. Follow-up ended on December 3, 2020. Interventions: Patients were randomized to undergo either LPG-DTR or LTG. Main Outcomes and Measures: The primary co-end points were change in hemoglobin level and cumulative amount of vitamin B12 supplementation at 2 years after LPG-DTR or LTG. The secondary end points included morbidity, postoperative reflux esophagitis, quality of life, overall survival, and disease-free survival. Quality of life outcomes were assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) 30-item core questionnaire (C30) and the EORTC QLQ stomach cancer-specific questionnaire at 3 months, 12 months, and 24 months. Results: Among 138 patients (mean [SD] age, 60.0 [10.9] years; 87 men [63.0%]; all of Asian race and Korean ethnicity), 68 (mean [SD] age, 56.7 [10.4] years; 39 men [57.4%]) were randomized to receive LPG-DTR and 69 (mean [SD] age, 61.3 [11.3] years; 48 men [69.6%]) were randomized to receive LTG. The mean (SD) changes in hemoglobin levels from baseline to month 24 were -5.6% (7.4%) in the LPG-DTR group and -6.9% (8.3%) in the LTG group, for an estimated difference of -1.3% (95% CI, -4.0% to 1.4%; P = .35). The mean (SD) cumulative amount of vitamin B12 supplementation was 0.4 (1.3) mg in the LPG-DTR group and 2.5 (3.0) mg in the LTG group, for an estimated difference of 2.1 mg (95% CI, 1.3-2.9 mg; P < .001). The late complication rates in the LPG-DTR and LTG groups were 17.6% and 10.1%, respectively (P = .31). The incidence of reflux esophagitis was not different between the LPG-DTR and LTG groups (2.9% vs 2.9%; P = .99). Compared with the LTG group, the LPG-DTR group had better physical functioning scores (85.2 [15.6] vs 79.9 [19.3]; P = .03) and social functioning scores (89.5 [17.9] vs 82.4 [19.4]; P = .03) on the EORTC QLQ-C30. Two-year overall survival (98.5% vs 100%; P = .33) and disease-free survival (98.5% vs 97.1%; P = .54) did not significantly differ between the LPG-DTR vs LTG groups. Conclusions and Relevance: In this study, patients with upper-third early GC who received LPG-DTR required less vitamin B12 supplementation than those who received LTG, with no increase in complication rates and no difference in overall and disease-free survival rates. There was no difference in change in hemoglobin level between groups. In addition, the LPG-DTR group had better physical and social functioning than the LTG group. These findings suggest that LPG-DTR may be as safe as LTG and may be a function-preserving procedure for the treatment of patients with upper-third early GC. Trial Registration: ClinicalTrials.gov Identifier: NCT02892643.

Twelve-Year Trajectory of Disease Burden and Mortality by Obesity Level in Korea: Analysis of the National Health Insurance Service Database.

INTRODUCTION: Despite increases in obesity prevalence, awareness of obesity as a disease requiring active treatment remains lacking in Korea. We investigated differences in medical problems and expenditures and mortality across obesity categories using 12-year data from the National Health Insurance Service. MATERIALS AND METHODS: Individuals aged 40-79 years who underwent medical examinations during 2003-2004 (n = 415,201) were divided based on Asian body mass index (kg/m2) criteria: normal weight (18.5 to < 23.0, 36.4%), overweight (23.0 to < 25.0, 28.3%), obesity (25.0 to < 30.0, 32.5%), and severe obesity (≥ 30.0, 2.8%). Medical problems and expenditures were fitted to linear mixed models. Mortality was analyzed via Cox proportional-hazards model. RESULTS: More severe obesity was associated with a higher rate of medical problems, relative to normal weight: coefficient = 0.31 (95% confidence interval [CI], 0.30-0.32) for overweight, 0.61 (0.60-0.61) for obesity, and 1.07 (1.04-1.09) for severe obesity. A similar association was observed for medical expenditure: coefficient = 8.85 (95%CI, 6.80-10.89) for overweight, 20.04 (18.07-22.01) for obesity, and 48.76 (43.66-53.86) for severe obesity. Relative to overweight participants, those with normal weight and severe obesity exhibited a higher mortality risk (hazard ratio [HR] 1.21 [95%CI, 1.18-1.25] for normal; 1.27 [1.19-1.36] for severe obesity). In age-specific analyses, mortality risk was the highest for participants with severe obesity, aged < 60 years (HR, 1.58 [95%CI, 1.41-1.77]). CONCLUSION: Disease burden including medical problems and expenditure, and mortality in middle-aged adults, increased proportionally to the degrees of obesity. Health policies and medical systems aimed at reducing the burden of obesity may help reduce the burden of disease on society.

Effect of perioperative oral nutritional supplementation in malnourished patients who undergo gastrectomy: A prospective randomized trial.

BACKGROUND: The aim of this study was to examine the effect of a perioperative oral nutritional supplement in malnourished patients who undergo gastrectomy. METHODS: Patients who were determined as being moderately or severely malnourished according to a patient-generated subjective global assessment or who had a body mass index <18.5, were enrolled. The oral nutritional supplement group received 500 mL/d of standard oral nutritional supplement for 2 weeks before gastrectomy and for 4 weeks postoperatively. The primary endpoint was postoperative complications (Clavien-Dindo classification ≥II). The secondary endpoints included body weight changes, biochemical parameters, and quality of life survey results. RESULTS: A total of 127 patients (65 in the oral nutritional supplement group and 62 in the control group) were enrolled. The complication rates were not significantly different (29.2% versus 37.1%, P = .346). However, the incidences of overall complications, complications persisting until postoperative week 3 or 5, and severe complications (grade ≥IIIa) were significantly lower in the oral nutritional supplement group for patients with patient-generated subjective global assessment grade C. Total lymphocyte counts were significantly higher in the oral nutritional supplement group at postoperative weeks 3 and 5. For most patients, oral nutritional supplement was well tolerated preoperatively. However, only 26.2% and 50.8% of the patients in the oral nutritional supplement group could consume >250 mL/d of oral nutritional supplement postoperatively during the 2nd and 4th weeks, respectively. CONCLUSIONS: The routine application of perioperative oral nutritional supplement is not recommended for malnourished patients receiving gastrectomy. However, perioperative standard oral nutritional supplement administration may reduce the incidence, severity, and duration of complications after gastrectomy in severely malnourished patients (patient-generated subjective global assessment grade C).

Minimal-invasive gastrectomy: what the west can learn from the east?

Minimal-invasive gastrectomy has been established as commonly used method for the early gastric cancer in Korea and Japan. From the first laparoscopic cancer gastrectomy in 1992 in Japan, numerous prospective randomized trials from these two countries have gained the evidence for non-inferiority or even specific benefits compared to open surgery. In Korea, the "Korean Laparoscopic Gastrointestinal Surgical Study Group" (KLASS group) founded, in 2004, successfully gained evidence not only in regards of oncological safety of laparoscopic gastrectomy, but also for the impact of different reconstruction methods and alternative extents of luminal resection on postoperative outcome and quality of life. Awaited results of latest studies from Korea, Japan, and China may suggest laparoscopic approaches as an option even in advanced gastric cancers. These studies could potentially be the starting point to find the role of laparoscopic gastrectomy in the west, where the incidence of gastric cancer is rather lower; the cancers are mostly diagnosed in advanced stages, and often, a perioperative chemotherapy is applied. Robotic (-assisted) gastrectomy was not shown to be superior to laparoscopic resection in Korea, but new technological developments should continuously be evaluated in clinical trials regarding a potentially favorable learning curve, which might play a key role in regards of the limited case load per center of gastric cancer in the west. This review summarizes the history of laparoscopic cancer gastrectomy in Asia and points out the important steps of establishing a nation-wide scientific network to support the surgical routine by the necessary evidence with a focus on Korea.

The Korean Gastric Cancer Cohort Study: Study Protocol and Brief Results of a Large-Scale Prospective Cohort Study.

PURPOSE: This study aimed to establish a large-scale database of patients with gastric cancer to facilitate the development of a national-cancer management system and a comprehensive cancer control policy. MATERIALS AND METHODS: An observational prospective cohort study on gastric cancer was initiated in 2010. A total of 14 cancer centers throughout the country and 152 researchers were involved in this study. Patient enrollment began in January 2011, and data regarding clinicopathological characteristics, life style-related factors, quality of life, as well as diet diaries were collected. RESULTS: In total, 4,963 patients were enrolled until December 2014, and approximately 5% of all Korean patients with gastric cancer annually were included. The mean age was 58.2±11.5 years, and 68.2% were men. The number of patients in each stage was as follows: 3,394 patients (68.4%) were in stage IA/B; 514 patients (10.4%), in stage IIA/B; 469 patients (9.5%), in stage IIIA/B/C; and 127 patients (2.6%), in stage IV. Surgical treatment was performed in 3,958 patients (79.8%), endoscopic resection was performed in 700 patients (14.1%), and 167 patients (3.4%) received palliative chemotherapy. The response rate for the questionnaire on the quality of life was 95%; however, diet diaries were only collected for 27% of patients. CONCLUSIONS: To provide comprehensive information on gastric cancer for patients, physicians, and government officials, a large-scale database of Korean patients with gastric cancer was established. Based on the findings of this cohort study, an effective cancer management system and national cancer control policy could be developed.

Asian Consensus Guidelines for the Diagnosis and Management of Gastrointestinal Stromal Tumor.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors originating in the gastrointestinal tract. With the introduction of molecular-targeted therapy for GISTs which has yielded remarkable outcomes, these tumors have become a model of multidisciplinary oncological treatment. Although Western clinical guidelines are available for GISTs, such as those published by the National Comprehensive Cancer Network (NCCN) and the European Society of Medical Oncology (ESMO), the clinical situations in Asian countries are different from those in Western countries in terms of diagnostic methods, surgical approach, and availability of new targeted agents. Accordingly, we have reviewed current versions of several GIST guidelines published by Asian countries (Japan, Korea, China, and Taiwan) and the NCCN and ESMO and discussed the areas of dissensus. We here present the first version of the Asian GIST consensus guidelines that were prepared through a series of meetings involving multidisciplinary experts in the four countries. These guidelines provide an optimal approach to the diagnosis and management of GIST patients in Asian countries.

One-Year Experience Managing a Cancer Survivorship Clinic Using a Shared-Care Model for Gastric Cancer Survivors in Korea.

Given the rapid growth of the population of cancer survivors, increased attention has been paid to their health problems. Although gastric cancer is one of the most common cancers, empirical evidence of survivorship care is limited. The objectives of this study were to describe the health care status of gastric cancer survivors and to report the experience of using the shared-care model during a one-year experience at the cancer survivorship clinic in Seoul National University Hospital. This is a descriptive, single-center study of 250 long-term gastric cancer survivors who were referred to the survivorship clinic. The status of their health behaviors, comorbid conditions, secondary cancer screenings, and survivorship care status were investigated through questionnaires and examining the medical records. Among the survivors, 7.2% were current smokers, 8.8% were at-risk drinkers, and 32.4% were physically inactive. Among the patients who did not know their bone density status, the majority were in the osteopenic (37.1%) or osteoporotic range (24.1%). Screening among the eligible population within the recommended time intervals were 76.3% for colorectal cancer, but only 13.6% for lung cancer. All of the survivors were provided with counseling and medical management at the survivorship clinic, as appropriate. In conclusion, Long-term gastric cancer survivors have various unmet needs. Shared-care through survivorship clinics can be an effective solution for providing comprehensive care to cancer survivors.

Adjuvant capecitabine plus oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): 5-year follow-up of an open-label, randomised phase 3 trial.

BACKGROUND: The CLASSIC trial was done to compare adjuvant capecitabine plus oxaliplatin versus observation after D2 gastrectomy for patients with stage II or III gastric cancer. The planned interim analysis of CLASSIC (median follow-up 34 months) showed that adjuvant capecitabine plus oxaliplatin significantly improved disease-free survival, the primary endpoint, compared with observation after D2 gastrectomy. We report the 5-year follow-up data from the trial. METHODS: CLASSIC was a phase 3, randomised, open-label study done at 35 cancer centres, medical centres, and hospitals in China, South Korea, and Taiwan. Patients with stage II-IIIB gastric cancer who underwent curative D2 gastrectomy were randomly assigned (1:1) after surgery to receive adjuvant chemotherapy with capecitabine and oxaliplatin (eight 3-week cycles of oral capecitabine 1000 mg/m(2) twice daily on days 1-14 plus intravenous oxaliplatin 130 mg/m(2) on day 1) for 6 months or observation alone. Randomisation was stratified by country and disease stage with a permuted block (size four) design. Neither patients nor investigators were masked to treatment assignment. The primary outcome was 3-year disease-free survival in the intention-to-treat population. This analysis presents the final preplanned assessment of outcomes after 5 years. The study is registered with ClinicalTrials.gov, NCT00411229. FINDINGS: We enrolled 1035 patients: 520 were randomly assigned to adjuvant capecitabine and oxaliplatin, and 515 to observation. Median follow-up for this analysis in the intention-to-treat population was 62·4 months (IQR 54-70). 139 (27%) patients had disease-free survival events in the adjuvant capecitabine and oxaliplatin group versus 203 (39%) patients in the observation group (stratified hazard ratio [HR] 0·58, 95% CI 0·47-0·72; p<0·0001). Estimated 5-year disease-free survival was 68% (95% CI 63-73) in the adjuvant capecitabine and oxaliplatin group versus 53% (47-58) in the observation alone group. By the clinical cutoff date, 103 patients (20%) had died in the adjuvant capecitabine and oxaliplatin group versus 141 patients (27%) in the observation group (stratified HR 0·66, 95% CI 0·51-0·85; p=0·0015). Estimated 5-year overall survival was 78% (95% CI 74-82) in the adjuvant capecitabine and oxaliplatin group versus 69% (64-73) in the observation group. Adverse event data were not collected after the primary analysis. INTERPRETATION: Adjuvant treatment with capecitabine plus oxaliplatin after D2 gastrectomy should be considered for patients with operable stage II or III gastric cancer. FUNDING: F Hoffmann La-Roche and Sanofi.

Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial.

BACKGROUND: D2 gastrectomy is recommended in US and European guidelines, and is preferred in east Asia, for patients with resectable gastric cancer. Adjuvant chemotherapy improves patient outcomes after surgery, but the benefits after a D2 resection have not been extensively investigated in large-scale trials. We investigated the effect on disease-free survival of adjuvant chemotherapy with capecitabine plus oxaliplatin after D2 gastrectomy compared with D2 gastrectomy only in patients with stage II-IIIB gastric cancer. METHODS: The capecitabine and oxaliplatin adjuvant study in stomach cancer (CLASSIC) study was an open-label, parallel-group, phase 3, randomised controlled trial undertaken in 37 centres in South Korea, China, and Taiwan. Patients with stage II-IIIB gastric cancer who had had curative D2 gastrectomy were randomly assigned to receive adjuvant chemotherapy of eight 3-week cycles of oral capecitabine (1000 mg/m(2) twice daily on days 1 to 14 of each cycle) plus intravenous oxaliplatin (130 mg/m(2) on day 1 of each cycle) for 6 months or surgery only. Block randomisation was done by a central interactive computerised system, stratified by country and disease stage. Patients, and investigators giving interventions, assessing outcomes, and analysing data were not masked. The primary endpoint was 3 year disease-free survival, analysed by intention to treat. This study reports a prespecified interim efficacy analysis, after which the trial was stopped after a recommendation by the data monitoring committee. The trial is registered at ClinicalTrials.gov (NCT00411229). FINDINGS: 1035 patients were randomised (520 to receive chemotherapy and surgery, 515 surgery only). Median follow-up was 34·2 months (25·4-41·7) in the chemotherapy and surgery group and 34·3 months (25·6-41·9) in the surgery only group. 3 year disease-free survival was 74% (95% CI 69-79) in the chemotherapy and surgery group and 59% (53-64) in the surgery only group (hazard ratio 0·56, 95% CI 0·44-0·72; p<0·0001). Grade 3 or 4 adverse events were reported in 279 of 496 patients (56%) in the chemotherapy and surgery group and in 30 of 478 patients (6%) in the surgery only group. The most common adverse events in the intervention group were nausea (n=326), neutropenia (n=300), and decreased appetite (n=294). INTERPRETATION: Adjuvant capecitabine plus oxaliplatin treatment after curative D2 gastrectomy should be considered as a treatment option for patients with operable gastric cancer. FUNDING: F Hoffmann-La Roche and Sanofi-Aventis.

The value of palliative gastrectomy in gastric cancer with distant metastasis.

PURPOSE: The purpose of this study was to examine the value of surgical resection and to find prognostic factors for metastatic gastric cancer. METHODS: Clinicopathological data of 257 cM1 gastric cancer patients who underwent an operation at Seoul National University Hospital from January 1999 to December 2004 were reviewed. Patients were grouped into the resection (RS, n=165) and nonresection groups (NR, n=92). To evaluate whether there was any selection bias, patients were stratified according to chemotherapy and preoperative CT findings were compared. RESULTS: There were no significant differences in clinicopathologic features and preoperative CT findings between the RS and NR groups. For chemotherapy, the RS group had a survival benefit (median survival; 12.7 vs. 11.2 months, p=0.0107). In the subanalysis, there was a survival benefit to the RS group when metastasis was confined to one site (14 vs. 9.7 months, p=0.04). In patients with no chemotherapy, the RS group had no benefit (p=0.151). In univariate and multivariate analyses, resection (p=0.001), chemotherapy (p<0.001), the number of organs with metastatic lesions (p=0.003), and elective operation (p<0.001) were significant prognostic factors. CONCLUSIONS: This retrospective study suggests that surgical resection in metastatic gastric cancer may improve survival when combined with chemotherapy, especially when metastasis is confined to one site.

Increasing nodal ratio is a poor prognostic factor for survival in stage III-IV (M0) gastric cancer patients who received curative surgery followed by adjuvant chemotherapy: a retrospective study.

OBJECTIVE: The aim of this study is to evaluate the efficacy of adjuvant chemotherapy with 5-fluorouracil and cisplatin in gastric cancer patients and to assess prognostic factors affecting relapse and survival. METHODS: We retrospectively reviewed the data of 153 patients with Stage III-IV (M0) gastric cancer. The patients were given adjuvant 5-fluorouracil/cisplatin chemotherapy after curative gastric resection with D2 dissection from November 1995 to November 2003. Chemotherapy consisted of cisplatin (60 mg/m(2) as 15 min i.v. infusion) and 5-fluorouracil (1200 mg/m(2) as 12 h continuous i.v. infusion for 4 days) in every 21 days up to six cycles. RESULTS: During a median follow-up period of 72.9 months (range: 2.0-135.0 months), a total of 105 patients relapsed (locoregional 19.0% vs. systemic 81.0%). The median disease-free survival and overall survival were 19.8 and 32.2 months, respectively. Univariate analysis revealed T stage, TNM stage and lymph node ratio as prognostic factors for survival (P = 0.002, <0.0001 and <0.0001, respectively). After stepwise selection of the factors, multivariate analysis confirmed the impact of the lymph node ratio and T stage on overall survival and disease-free survival. CONCLUSIONS: In patients with Stage III-IV (M0) gastric cancer, adjuvant 5-fluorouracil/cisplatin chemotherapy was tolerable, but did not seem to confer survival advantage. And the lymph node ratio was found as an independent prognostic factor in this population. This evidence suggests that the clinical trial using more active chemotherapeutic agents is mandatory.

Isoflavones from phytoestrogens and gastric cancer risk: a nested case-control study within the Korean Multicenter Cancer Cohort.

BACKGROUND: The role of soybean products in gastric cancer risk is not clear in epidemiologic studies due to measurement error from dietary intake questionnaires and due to different degrees of bias according to study design. To examine the association between soybean products and gastric cancer risk, we measured phytoestrogen biological markers in a nested case-control study. METHODS: The study population was composed of 131 cases and 393 matched controls within the Korean Multicenter Cancer Cohort. The concentrations of the four biomarkers in the plasma samples were measured using time-resolved fluoroimmunoassay. Conditional and unconditional logistic regression models were used to compute the odds ratio (OR) and 95% confidence intervals (CI). RESULTS: Median plasma concentrations of genistein (229 nmol/L for controls, 181.8 nmol/L for cases; P=0.07) and daidzein (131.2 nmol/L for controls, 80.5 nmol/L for cases; P=0.04) in cases were lower than in controls, whereas equol concentrations were similar. Compared with the reference group, gastric cancer risk decreased in the highest groups for genistein (OR, 0.54; 95% CI, 0.31-0.93) and daidzein (OR, 0.21; 95% CI, 0.08-0.58). Higher equol concentrations were associated with a decreased risk for gastric cancer (OR, 0.50; 95% CI, 0.27-0.90). The combination of the highest concentrations for each isoflavone category was associated with a 0.09-fold decreased risk for gastric cancer compared with the combination of the lowest concentrations for each category. There was no association between plasma lignan concentrations and gastric cancer. CONCLUSIONS: High serum concentrations of isoflavones were associated with a decreased risk for gastric cancer. IMPACT: These results suggest a beneficial effect of high soybean product intake for gastric cancer risk.

Metastasis-associated protein S100A4 and p53 predict relapse in curatively resected stage III and IV (M0) gastric cancer.

PURPOSE: Pathologic stage is the most important predictive factor of relapse in gastric cancer after curative resection. However, patients with the same stage often have different risks of relapse. Here, we investigated whether the expressions of molecular markers can supplement the current staging system in terms of relapse prediction. PATIENTS AND METHODS: One hundred and nine stage III or IV (M0) patients who had received curative gastrectomy followed by adjuvant 5-fluorouracil and cisplatin chemotherapy were included in this study. The expressions of molecular markers including p53, p27, COX-2, HER-2, EGFR, maspin, S100A4, E-cadherin, Sp1, and p97 were analyzed by immunohistochemistry in cancer and paired normal tissues. RESULTS: The overall relapse rate was 58.7%, and pathologic stage was a significant predictive factor of relapse (42% in stage IIIA, 48% in IIIB, 76% in IV, p = 0.005). Of the 10 markers examined, p53 and S100A4 were expressed only in tumor tissues, and S100A4 expression was significantly associated with a higher relapse rate (85% vs. 53%, p = 0.008). In multivariate analysis including tumor stage, S100A4 and p53 expression were independent predictive factors of relapse (relative risk, 6.98; 95% confidence interval [CI], 1.608-30.342, 3.49; 95% CI, 1.328-9.186, respectively). On comparing patients who expressed S100A4 or p53 with those who expressed neither, relapse rates were 58% vs. 25% in stage III (p = 0.011) and 95% vs. 59% in stage IV (M0) (p = 0.003). CONCLUSION: In addition to staging system, the expressions of S100A4 and p53 were significant predictive factors of relapse in gastric cancer after curative resection and adjuvant chemotherapy.

Computed tomography gastrography with volume-rendering technique: correlation with double-contrast barium study and conventional gastroscopy.

The volume-rendering technique uses computed tomography data to produce simulated images of conventional barium and endoscopic studies of the stomach. Various gastric lesions are detected on volume-rendered images, and submucosal tumors are easily differentiated from mucosal lesions by means of the overlying bridging fold. Lesions that are only manifested by a change of mucosal color (early gastric cancer type 2b) or a loss of mucosal detail (gastritis) are difficult to detect from volume-rendered images, however. In cases of gastric neoplasm and varix, both the extraluminal pathologies of the lesion and the relation between the intraluminal and extraluminal components can be evaluated simultaneously.