Sook Ryun Park

Bevacizumab in Combination With Chemotherapy As First-Line Therapy in Advanced Gastric Cancer: A Randomized, Double-Blind, Placebo-Controlled Phase III Study

PURPOSE The Avastin in Gastric Cancer (AVAGAST) trial was a multinational, randomized, placebo-controlled trial designed to evaluate the efficacy of adding bevacizumab to capecitabine-cisplatin in the first-line treatment of advanced gastric cancer. PATIENTS AND METHODS Patients received bevacizumab 7.5 mg/kg or placebo followed by cisplatin 80 mg/m(2) on day 1 plus capecitabine 1,000 mg/m(2) twice daily for 14 days every 3 weeks. Fluorouracil was permitted in patients unable to take oral medications. Cisplatin was given for six cycles; capecitabine and bevacizumab were administered until disease progression or unacceptable toxicity. The primary end point was overall survival (OS). Log-rank test was used to test the OS difference. RESULTS In all, 774 patients were enrolled; 387 were assigned to each treatment group (intention-to-treat population), and 517 deaths were observed. Median OS was 12.1 months with bevacizumab plus fluoropyrimidine-cisplatin and 10.1 months with placebo plus fluoropyrimidine-cisplatin (hazard ratio 0.87; 95% CI, 0.73 to 1.03; P = .1002). Both median progression-free survival (6.7 v 5.3 months; hazard ratio, 0.80; 95% CI, 0.68 to 0.93; P = .0037) and overall response rate (46.0% v 37.4%; P = .0315) were significantly improved with bevacizumab versus placebo. Preplanned subgroup analyses revealed regional differences in efficacy outcomes. The most common grade 3 to 5 adverse events were neutropenia (35%, bevacizumab plus fluoropyrimidine-cisplatin; 37%, placebo plus fluoropyrimidine-cisplatin), anemia (10% v 14%), and decreased appetite (8% v 11%). No new bevacizumab-related safety signals were identified. CONCLUSION Although AVAGAST did not reach its primary objective, adding bevacizumab to chemotherapy was associated with significant increases in progression-free survival and overall response rate in the first-line treatment of advanced gastric cancer.

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.

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.

Management of gastric cancer in Asia: resource-stratified guidelines

Gastric cancer is the fourth most common cancer globally, and is the second most common cause of death from cancer worldwide. About three-quarters of newly diagnosed cases in 2008 were from Asian countries. With a high mortality-to-incidence ratio, management of gastric cancer is challenging. We discuss evidence for optimum management of gastric cancer in aspects of screening and early detection, diagnosis, and staging; endoscopic and surgical intervention; and the concepts of perioperative, postoperative, and palliative chemotherapy and use of molecularly targeted therapy. Recommendations are formulated on the basis of the framework provided by the Breast Health Global Initiative, using the categories of basic, limited, enhanced, and maximum level. We aim to provide a stepwise strategy for management of gastric cancer applicable to different levels of health-care resources in Asian countries.

A randomised multicentre phase II trial of capecitabine vs S-1 as first-line treatment in elderly patients with metastatic or recurrent unresectable gastric cancer

This randomised multicentre phase II study was conducted to investigate the activity and safety of two oral fluoropyrimidines, capecitabine or S-1, in elderly patients with advanced gastric cancer (AGC). Elderly (⩾65 years) chemo-naive patients with AGC were randomly assigned to receive capecitabine 1250 mg m−2 two times daily on days 1–14 every 3 weeks or S-1 40–60 mg two times daily according to body surface area on days 1–28 every 6 weeks. Ninety-six patients were enrolled and 91 patients were randomised to capecitabine (N=46) or S-1 (N=45). Overall response rate, the primary end point, was 27.2% (95% CI, 14.1–40.4, 12 of 44 assessable patients) with capecitabine and 28.9% (95% CI, 15.6–42.1, 13 of 45) with S-1. Median times to progression and overall survival in the capecitabine arm (4.7 and 9.5 months, respectively) were similar to those in the S-1 arm (4.2 and 8.2 months, respectively). The incidence of grade 3–4 granulocytopenia was 6.8% with capecitabine and 4.8% with S-1. Grade 3–4 nonhaematologic toxicities were: asthenia (9.1% with capecitabine vs 7.1% with S-1), anorexia (6.8 vs 9.5%), diarrhoea (2.3 vs 0%), and hand–foot syndrome (6.8 vs 0%). Both capecitabine and S-1 monotherapies were active and tolerable as first-line treatment for elderly patients with AGC.

Technical feasibility and safety of laparoscopy‐assisted total gastrectomy in gastric cancer: A comparative study with laparoscopy‐assisted distal gastrectomy

Only a few surgeons with much experience of laparoscopic surgery perform laparoscopy‐assisted total gastrectomy (LATG), because of its technical difficulty and concern about subsequent complications. The aim of this study was to evaluate the technical feasibility and safety of LATG as compared with laparoscopy‐assisted distal gastrectomy (LADG) in gastric cancer.

Covered versus uncovered self-expandable metallic stents for palliation of malignant pyloric obstruction in gastric cancer patients: a randomized, prospective study.

BACKGROUND Self-expandable metallic stents (SEMSs) provide effective palliation of malignant pyloric obstruction in patients with inoperable gastric cancer. OBJECTIVE To compare the effectiveness and side effects of covered and uncovered SEMSs for the palliation of malignant pyloric obstruction. DESIGN Prospective, randomized, single-center study. SETTING Tertiary-care cancer center hospital. PATIENTS This study involved 80 patients with pyloric obstruction related to inoperable gastric cancer. INTERVENTION Covered or uncovered SEMS placement. MAIN OUTCOME MEASUREMENTS Technical and clinical success rates as well as the patency rate at 8 weeks after placement. RESULTS Both groups had a technical success rate of 100% with no immediate complications. Both groups also had comparable clinical success rates (covered SEMS, 95% [38 of 40] and uncovered SEMS, 90% [36 of 40], P = .68) and 8-week patency rates (covered SEMS, 61.3% [19 of 31] and uncovered SEMS, 61.1% [22 of 36], P > .99). Stent migration within 8 weeks was more common in the covered SEMS group (25.8% [8 of 31]) than in the uncovered SEMS group (2.8% [1 of 36], P = .009), whereas re-stenosis because of tumor ingrowth was more common in the uncovered SEMS group (25.0% [9 of 36] vs 0% [0 of 31] in the covered SEMS group, P = .003). Overall patient survival and stent patency did not differ between groups (P = .27 and 0.61 by log-rank test, respectively). LIMITATIONS The study population was limited to gastric cancer patients, and stent designs were changed in the midst of the study period. CONCLUSION Both the covered and uncovered SEMSs are effective and have comparable 8-week patency in patients with malignant pyloric obstruction, despite different patterns of late stent failure.

A Functional Single Nucleotide Polymorphism in Mucin 1, at Chromosome 1q22, Determines Susceptibility to Diffuse-Type Gastric Cancer

BACKGROUND & AIMS Two major types of gastric cancer, intestinal and diffuse, develop through distinct mechanisms; the diffuse type is considered to be more influenced by genetic factors, although the mechanism is unknown. Our previous genome-wide association study associated 3 single nucleotide polymorphisms (SNPs) with diffuse-type gastric cancer (DGC); 1 was a functional SNP (rs2294008) in prostate stem cell antigen (PSCA), but the loci of the other 2 were not investigated. METHODS We performed high-density mapping to explore a linkage disequilibrium status of the 2 SNPs at chromosome 1q22. A DGC case-control study was conducted using DNA from 606 cases and 1264 controls (all Japanese individuals) and validated using DNA from Japanese (304 cases, 1465 controls) and Korean (452 cases, 372 controls) individuals. The effects of SNPs on function were analyzed by reporter assays and analyses of splice variants. RESULTS A region of a strong linkage disequilibrium with the 2 SNPs contained mucin 1 (MUC1) and other 4 genes and SNPs significantly associated with DGC (rs2070803: P = 4.33 × 10(-13); odds ratio [OR], 1.71 by meta-analysis of the studies on the 3 panels) but not with intestinal-type gastric cancer. Functional studies demonstrated that rs4072037 (P = 1.43 × 10(-11); OR, 1.66 by meta-analysis) in MUC1 affects promoter activity and determines the major splicing variants of MUC1 in the gastric epithelium. Individuals that carry both SNPs rs2294008 in PSCA and rs4072037 in MUC1 have a high risk for developing DGC (OR, 8.38). CONCLUSIONS MUC1 is the second major DGC susceptibility gene identified. The SNPs rs2070803 and rs4072037 in MUC1 might be used to identify individuals at risk for this type of gastric cancer.

Effect of repeated endoscopic screening on the incidence and treatment of gastric cancer in health screenees.

Objectives Early gastric cancer (EGC) can be treated by minimally invasive endoscopic resection and has an excellent prognosis. The aim of this study was to investigate whether repeated esophagogastroduodenoscopy (EGD) screening is an effective method for detecting EGC that can be treated by endoscopic resection. Methods For patients diagnosed with gastric cancer in the Korean National Cancer Center screening program, we analyzed the incidence of gastric cancer, clinicopathological characteristics, and treatment modality according to whether they had (repeated screening group) or not (infrequent screening group) undergone EGD screening within 2 years before diagnosis. Results Of the 18 414 patients who underwent EGD, 81 (0.44%) were found to have gastric cancer. Incidence of gastric cancer in repeated screening group was lower than that of infrequent screening group (multiple adjusted odds ratio=0.45, 95% confidence interval: 0.26–0.77, P=0.004). The proportion of EGCs was 96% (25 of 26) n the repeated screening group and 71% (34 of 48) in the infrequent screening group (P=0.01). Mean (SD) tumor size was smaller [1.9 (1.2) vs. 3.0 (1.6) cm, P=0.01] and the proportion of intramucosal cancer was higher [81% (21 of 26) vs. 50% (24 of 48), P=0.02] in the former than in the latter. Endoscopic resection was performed more frequently in the repeated screening group [54% (14 of 26) vs. 23% (11 of 48), P=0.007]. Conclusion Repeated endoscopic screening within 2 years decreased the incidence of gastric cancer and endoscopic resection could be applied to more patients who underwent EGD screening within 2 years.

Weekly docetaxel in combination with capecitabine in patients with metastatic gastric cancer.

Docetaxel (T) and capecitabine (X) are active agents against gastric cancer with synergistic antitumor effects. We conducted the current phase II study to assess the response rate and toxicity of combination TX regimen in patients with metastatic gastric cancer. Eligible patients were treated with docetaxel (36 mg/m2 intravenously) on days 1 and 8 and capecitabine (1000 mg/m2 orally twice a day) on days 1–14 of a 3-week schedule until progression occurred. From December 2001 to May 2003, 55 patients with median age of 54 years (range, 22–73 years) were enrolled; 47 patients had measurable lesions. A total of 358 courses of treatment were given, with a median of 5 (range, 1–22+) per patient. Objective responses were documented in 19 of 47 patients with measurable lesions (response rate, 40.4%; 95% confidence interval [CI], 25.9–54.9), with the median response duration of 5.6 months (range, 2.1–13.6+). At a median follow up of 15.9 months for all of 55 study patients, the median time to progression and survival were 4.5 months (95% CI, 3.4–5.6) and 12.0 months (95% CI, 7.5–16.6), respectively. Hematologic toxicities were mild to moderate, and the observed grade 3 nonhematologic toxicities, the most frequent of which was stomatitis, were generally manageable. Four patients experienced pneumonitis, but all of them responded to steroid treatment. The TX regimen was relatively well tolerated and effective against metastatic gastric cancer, with the added advantage of being an outpatient regimen.