Hitoshi Katai

Five-Year Outcomes of a Randomized Phase III Trial Comparing Adjuvant Chemotherapy With S-1 Versus Surgery Alone in Stage II or III Gastric Cancer

PURPOSE The first planned interim analysis (median follow-up, 3 years) of the Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer confirmed that the oral fluoropyrimidine derivative S-1 significantly improved overall survival, the primary end point. The results were therefore opened at the recommendation of an independent data and safety monitoring committee. We report 5-year follow-up data on patients enrolled onto the ACTS-GC study. PATIENTS AND METHODS Patients with histologically confirmed stage II or III gastric cancer who underwent gastrectomy with D2 lymphadenectomy were randomly assigned to receive S-1 after surgery or surgery only. S-1 (80 to 120 mg per day) was given for 4 weeks, followed by 2 weeks of rest. This 6-week cycle was repeated for 1 year. The primary end point was overall survival, and the secondary end points were relapse-free survival and safety. RESULTS The overall survival rate at 5 years was 71.7% in the S-1 group and 61.1% in the surgery-only group (hazard ratio [HR], 0.669; 95% CI, 0.540 to 0.828). The relapse-free survival rate at 5 years was 65.4% in the S-1 group and 53.1% in the surgery-only group (HR, 0.653; 95% CI, 0.537 to 0.793). Subgroup analyses according to principal demographic factors such as sex, age, disease stage, and histologic type showed no interaction between treatment and any characteristic. CONCLUSION On the basis of 5-year follow-up data, postoperative adjuvant therapy with S-1 was confirmed to improve overall survival and relapse-free survival in patients with stage II or III gastric cancer who had undergone D2 gastrectomy.

Genetic variation in PSCA is associated with susceptibility to diffuse-type gastric cancer

Gastric cancer is classified into intestinal and diffuse types, the latter including a highly malignant form, linitis plastica. A two-stage genome-wide association study (stage 1: 85,576 SNPs on 188 cases and 752 references; stage 2: 2,753 SNPs on 749 cases and 750 controls) in Japan identified a significant association between an intronic SNP (rs2976392) in PSCA (prostate stem cell antigen) and diffuse-type gastric cancer (allele-specific odds ratio (OR) = 1.62, 95% CI = 1.38–1.89, P = 1.11 × 10−9). The association was far less significant in intestinal-type gastric cancer. We found that PSCA is expressed in differentiating gastric epithelial cells, has a cell-proliferation inhibition activity in vitro and is frequently silenced in gastric cancer. Substitution of the C allele with the risk allele T at a SNP in the first exon (rs2294008, which has r2 = 0.995, D′ = 0.999 with rs2976392) reduces transcriptional activity of an upstream fragment of the gene. The same risk allele was also significantly associated with diffuse-type gastric cancer in 457 cases and 390 controls in Korea (allele-specific OR = 1.90, 95% CI = 1.56–2.33, P = 8.01 × 10−11). The polymorphism of the PSCA gene, which is possibly involved in regulating gastric epithelial-cell proliferation, influences susceptibility to diffuse-type gastric cancer.

Gastric cancer treated in 1991 in Japan: data analysis of nationwide registry

The Japanese Gastric Cancer Association Registration Committee reported the treatment results and causes of death of patients with primary gastric cancer treated in 1991 at the leading hospitals in Japan. Data of 8851 patients with primary gastric cancer were collected from 113 hospitals, and data of 7935 patients with gastric resection were finally analyzed. The lost-to-follow-up rate was 6.9%; the direct death rate was 1.0%. The cumulative 5-year survival rate (5YSR) of all the patients was 68.2%; 89.9% for Stage I, 69.1% for Stage II, 43.5% for Stage III, and 9.9% for Stage IV. Characteristic findings of the analyzed data were (1) high proportion of early-stage cancer, (2) high resection rate, (3) low mortality rate, (4) low incidence of upper-third cancer, (5) poor treatment results in cases with scirrhous cancer, infiltrating growth, and marked lymphatic or venous invasion, and (6) predominance of systematic (D2) and extended lymphadenectomies possibly resulting in reducing local recurrence and improving survivals.

Safety and feasibility of laparoscopy-assisted distal gastrectomy with suprapancreatic nodal dissection for clinical stage I gastric cancer: a multicenter phase II trial (JCOG 0703)

BackgroundAlthough the number of patients undergoing laparoscopy-assisted distal gastrectomy (LADG) has been increasing, a prospective study with a sample size sufficient to investigate the benefit of LADG has never been reported. We conducted a multi-institutional phase II trial to evaluate the safety of LADG with nodal dissection for clinical stage I gastric cancer patients.MethodsThe subjects comprised patients with clinical stage I gastric cancer who were able to undergo a distal gastrectomy. LADG with D1 plus suprapancreatic node dissection was performed. The primary endpoint was the proportion of patients who developed either anastomotic leakage or a pancreatic fistula. The secondary endpoints included surgical morbidity and short-term clinical outcome.ResultsBetween November 2007 and September 2008, 176 eligible patients were enrolled. The proportion of patients who developed anastomotic leakage or a pancreatic fistula was 1.7%. The overall proportion of in-hospital grade 3 or 4 adverse events was 5.1%. The short-term clinical outcomes were as follows: 43.2% of the patients requested an analgesic on postoperative days 5–10; the median time from surgery until the first episode of flatus was 2 days; and 88 patients (50.0%) had a body temperature of 38 °C or higher during their hospital stay.ConclusionsThis trial confirmed the safety of LADG performed by credentialed surgeons in terms of the incidence of anastomotic leakage or pancreatic fistula formation. A phase III trial (JCOG 0912) to confirm the noninferiority of LADG to an open gastrectomy in terms of overall survival is ongoing.

Impact of expression of human epidermal growth factor receptors EGFR and ERBB2 on survival in stage II/III gastric cancer.

Purpose: EGF receptor (EGFR) and HER2 positivity are considered to be negative prognostic factors in gastric cancer. Biomarker analysis was conducted to evaluate the impact of EGFR and HER2 expression on the outcome of patients enrolled in the Adjuvant Chemotherapy Trial of TS-1 for Gastric Cancer (ACTS-GC), a randomized controlled trial comparing postoperative adjuvant S-1 therapy with surgery alone in 1,059 patients with stage II/III gastric cancer. Experimental Design: Formalin-fixed, paraffin-embedded surgical specimens were retrospectively examined in 829 patients (78.3%). The effects of EGFR and HER2 positivity on survival were analyzed on the basis of the 5-year survival data from the study. EGFR positivity was defined as an immunohistochemistry (IHC) score of 3+, and HER2 positivity as an IHC score of 3+ or an IHC score of 2+ with a positive dual-color in situ hybridization status. Results: EGFR and HER2 were positive in 75 (9.0%) and 113 (13.6%) patients, respectively. The overall and relapse-free survival rates were significantly lower in EGFR-positive patients than in EGFR-negative patients, whereas they were similar in HER2-positive and HER2-negative patients. Multivariate analysis showed that EGFR positivity correlated with poor outcomes [HR = 1.504; 95% confidence interval (CI) = 1.020–2.149; P = 0.040]. Treatment with S-1 improved survival compared with surgery alone, irrespective of EGFR and HER2 status. Conclusions: EGFR positivity, but not HER2 positivity, was associated with poor patient outcomes after curative resection of stage II/III gastric cancer. There was no interaction between S-1 and EGFR or HER2 status with respect to survival outcome. Clin Cancer Res; 18(21); 5992–6000. ©2012 AACR.

Changing trends in the proportion of adenocarcinoma of the esophagogastric junction in a large tertiary referral center in Japan

Introduction:  A dramatic increase in incidence of adenocarcinoma of the esophagogastric junction (EGJ) over the past two decades has been reported in the West. However, epidemiological data from Asian countries have not shown a similar trend. The aim of this study was to determine the incidence of adenocarcinoma of the EGJ in a cohort of consecutive patients operated on for gastric adenocarcinoma at a major cancer referral center in Japan.

Prospective study of proximal gastrectomy for early gastric cancer in the upper third of the stomach

Total gastrectomy with D2 dissection is the standard treatment in Japan for early upper‐third gastric cancer. The purpose of this study was to confirm the safety and radicality of proximal gastrectomy as an alternative operation.

Endoscopic evaluation of the remnant stomach after gastrectomy: proposal for a new classification

Abstract.Abstract.Background: In Japan, approximately half of gastric cancers are diagnosed in the early stage. Longer survival has been provided for patients with early gastric cancer (EGC). Several new surgical procedures have been employed for some EGCs. To compare the functional results of these techniques with those of classic distal gastrectomy, it is important to evaluate the remnant stomach in relation to quality of life (QOL) and secondary cancers. We propose a new endoscopic classification, regarding several aspects of the remnant stomach, which enables common understanding and description of the condition.Methods: Of 651 patients who underwent a distal gastrectomy or pylorus-preserving gastrectomy (PPG), 324 had at least one upper gastrointestinal (GI) endoscopy during the follow-up period. Ninety-three of the 324 patients underwent a Roux-en-Y reconstruction (RY); 175, Billroth type 1 (B1); and 56, PPG. Endoscopic findings regarding residual food, gastritis, and bile reflux in the gastric stump were investigated for these patients. We classified the amount of residual food into five grades, the degree and the extent of gastritis into five grades, and bile reflux into two grades. First, we evaluated the consistency of diagnosis between two endoscopists, in the first 200 patients, and then we applied the classification to all 324 patients to examine the usefulness of this classification.Results: Consistency of diagnosis was obtained between two endoscopists who classified the patients independently. The agreement rate was 98.5% for residual food, 93% for gastritis, and 100% for bile reflux. Residual food was observed in 14.0% of the RY group, 22.3% of the B1 group, and 37.5% of the PPG group. These differences were significant (RY versus B1; P < 0.05 and RY versus PPG; P < 0.01). The remnant stomach after B1 showed significantly more severe and extensive gastritis than that after RY and PPG (P < 0.01). As for bile reflux, there was no significant difference among the three groups.Conclusion: The classification (RGB classification: Residue, Gastritis, Bile) can be used easily and is practical. The results suggest some important differences among methods of reconstruction. This classification seems to be useful to describe these findings and to further evaluate these reconstructive methods.

Treatment strategy after non-curative endoscopic resection of early gastric cancer.

Endoscopic resection (ER) is indicated for patients with early gastric cancer who have a negligible risk of lymph node metastasis (LNM). Histological examination of the resected specimen may indicate a possible risk of LNM or a positive resection margin. These patients are considered to have undergone non‐curative ER. The aim of this study was to determine the appropriate treatment strategy for such patients.

Influence of Overweight on Surgical Complications for Gastric Cancer: Results From a Randomized Control Trial Comparing D2 and Extended Para-aortic D3 Lymphadenectomy (JCOG9501)

BackgroundThe impact of overweight on the outcome of gastrectomy with lymphadenectomy is controversial, and data from a well-controlled, randomized study are needed to identify a possible relationship.MethodsWe used data from 523 patients registered for a prospective randomized trial comparing D2 and extended para-aortic D3 lymphadenectomy to compare the effects of body mass index (BMI) and the extent of lymphadenectomy for the development of general or major surgical complications (anastomotic leakage, abdominal abscess, and pancreatic fistula).ResultsSeventy-seven patients were classified as overweight with BMI ≥ 25, and 38 and 39 of these patients underwent a D2 or D3 lymphadenectomy, respectively. Among the 446 patients classified as nonoverweight with BMI < 25, 225 received D2 and 221 received D3 lymphadenectomy. Surgical complications, operation time, and blood loss were statistically significantly associated with BMI, and logistic regression analysis revealed that overweight directly affected the occurrence of surgical complications even after considering operation time and blood loss as intermediate factors instead of outcome variables. Among patients undergoing D2 lymphadenectomy, being overweight increased the risk for surgical complications and blood loss, whereas overweight was associated with only blood loss and operation time among patients receiving D3 lymphadenectomy.ConclusionsOverweight increased the risk of surgical complications in patients undergoing gastrectomy both directly and indirectly through operation time and blood loss. The impact of overweight on surgical complications was more evident in patients undergoing a D2 dissection.