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Purpose: This study aimed to screen targeted agents as second-line treatment with a standard-of-care (SOC) controlled umbrella trial design in advanced gastric cancer (AGC)., Patients and Methods: Patients with HER2-negative AGC from eight Korean cancer centers were screened for druggable targets using immunohistochemistry (IHC) and in situ hybridization, and randomly assigned to the biomarker versus control group at a 4:1 ratio. In the biomarker group, patients were treated with specific targeted agent plus paclitaxel: pan-ERBB inhibitor for epidermal growth factor receptor (EGFR) 2+/3+ patients (afatinib; EGFR cohort), PIK3Cβ inhibitor for phosphatase and tensin homolog (PTEN) loss/null patients (GSK2636771; PTEN cohort), and anti-PD-1 inhibitor for PD-L1+, deficient mismatch repair/microsatellite instability-high, or Epstein-Barr virus-related cases (nivolumab; NIVO cohort). NONE cohort in the biomarker group without predefined biomarkers and control group received SOC (paclitaxel with or without ramucirumab). The primary end point was progression-free survival (PFS), and the secondary end points were efficacy and safety., Results: A total of 318 patients were randomly assigned into the control (n = 64) and biomarker (n = 254; EGFR, n = 67; PTEN, n = 37; NIVO, n = 48; NONE, n = 102) groups. Median follow-up was 35 months. Median PFS and overall survival (OS) were 3.7 (95% CI, 3.1 to 4.1) and 8.6 (95% CI, 7.6 to 9.8) months in the biomarker group and 4.0 (95% CI, 3.0 to 4.6) and 8.7 (95% CI, 7.1 to 9.9) months in the control group. Afatinib addition led to marginal survival benefits to patients with EGFR 3+ compared with SOC (PFS, 4.0 v 2.2 months; P = .09), but GSK2636771 did not prolong the survival of patients with PTEN loss. Addition of nivolumab showed a durable survival benefit (median OS, 12.0 v 7.6 months; P = .08)., Conclusion: Although biomarker group did not show better survival than the control group, IHC-based screening and allocation of patients with AGC to the second-line treatment in an umbrella design were feasible for effective early screening of novel agents.

Background: We conducted a trial to evaluate the efficacy and safety of nivolumab and paclitaxel as second-line therapy for immune-related biomarker-enriched advanced gastric cancer (AGC)., Methods: This open-label, single-arm, phase Ib/II study was a part of multi-institutional, biomarker-integrated umbrella study conducted in Korea. In phase Ib, patients received nivolumab (3 mg/kg) on Days 1 and 15 and paclitaxel (dose level 1, 70 mg/m 2 or dose level 2, 80 mg/m 2 ) on Days 1, 8, 15 every four weeks. In phase II, patients with Epstein-Barr virus-related, deficient mismatch repair or programmed cell death-ligand-1-positive AGC were enrolled. The primary endpoints were recommended phase II dose (RP2D, phase Ib) and progression-free survival (PFS, phase II). Secondary endpoints included objective response rate (ORR), overall survival (OS), safety, and exploratory biomarker analysis., Results: Dose level 2 was selected as RP2D. In phase II, 48 patients were enrolled. The median PFS and OS were 3.9 and 11.2 months, respectively. The ORR was 23.3%, and the median response duration was 16.7 months. Grade 3 or higher treatment-related adverse events, mainly neutropenia, occurred in 20 patients (41.7%). Targeted sequencing revealed that patients with RTK/RAS pathway alterations or the HLA-A02 supertype had better survival. Patients with elevated baseline interleukin-1 receptor antagonist levels had worse survival., Conclusions: Although the study did not meet its primary end point, nivolumab and paclitaxel for AGC demonstrated a durable response with manageable toxicity profiles. Genomic analysis or plasma cytokine analysis may provide information for the selection of patients who would benefit more from immunotherapy combined with chemotherapy., (© 2023. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

Background: This study analyzed the clinical results of palliative radiotherapy for bleeding control in patients with unresectable advanced gastric cancer., Methods: We retrospectively reviewed the medical records of patients who met the following inclusion criteria between January 2002 and June 2018: histologically proven gastric cancer, gastric tumor bleeding confirmed by upper gastrointestinal endoscopy, and palliative radiotherapy performed for hemostasis. The median radiotherapy dose was 30 Gy, with a daily dose ranging from 1.8 to 3 Gy., Results: Sixty-one patients were included in this analysis. The study population was predominantly male (72.1%), with a median age of 62 years (range: 32-92). The median baseline hemoglobin level was 7.1 g/dL, and the most common presenting symptom of gastric tumor bleeding was melena (85.2%). Bleeding control was achieved in 54 (88.5%) patients. The median levels of hemoglobin at 1, 2, and 3 months after completion of radiotherapy were 10.1 g/dL, 10.2 g/dL, and 10.4 g/dL, respectively; these values were significantly different from that before radiotherapy (7.1 g/dL; p < 0.001). The median overall survival was 4.8 months. Among the 54 patients who achieved bleeding control after radiotherapy, 19 (35.2%) experienced re-bleeding during the follow-up period. The median time to re-bleeding was 6.0 months. Multivariate analysis demonstrated that a higher radiation dose (p = 0.007) and additional chemotherapy after radiotherapy (p = 0.004) were significant factors for prolonging the time to re-bleeding., Conclusions: Tumor bleeding was adequately controlled by radiotherapy in patients with unresectable advanced gastric cancer.

Background: In East Asia, S-1 plus cisplatin (SP) is one of the standard first-line chemotherapy regimens for metastatic or recurrent gastric cancer (MRGC). Oxaliplatin is generally less toxic and more convenient to administer than cisplatin., Patients and Methods: This was a multicenter, phase III study assessing whether S-1/oxaliplatin (SOX) was non-inferior/superior to SP in terms of progression-free survival (PFS). Patients with MRGC were randomized 1:1 to receive either SOX (S-1 80 mg/m 2 /day on days 1-14; oxaliplatin 130 mg/m 2 on day 1; every 3 weeks) or SP (S-1 80 mg/m 2 /day on days 1-14; cisplatin 60 mg/m 2 on day 1; every 3 weeks [SP3])., Results: Between October 2012 and October 2014, 338 patients were randomized. The median age was 56 years, and 51% of patients had measurable lesions. SOX was significantly non-inferior but not superior to SP3 in terms of PFS [median 5.6 versus 5.7 months; hazard ratio (HR) 0.85; 95% confidence interval (CI) 0.67-1.07]. In patients with measurable disease, objective response rates were similar between SOX and SP3 (58% versus 60%). Overall, the survival in both groups did not differ (median 12.9 versus 11.4 months; HR 0.86; 95% CI 0.66-1.11). Treatment was well tolerated in both arms. Anemia, leucopenia, neutropenia, febrile neutropenia, and oral mucositis were more common with SP3. In contrast, thrombocytopenia, nausea, vomiting, and peripheral neuropathy were more common with SOX., Conclusions: SOX was non-inferior to SP3. The two regimens were well tolerated with different toxicity profiles. The SOX regimen can be recommended as a first-line treatment for MRGC., Trial Registration: ClinicalTrials.gov: NCT01671449.

Background/aim: Oxaliplatin-based chemotherapy is associated with hepatic sinusoidal obstruction syndrome (SOS)., Patients and Methods: We analyzed patients from two prospective trials, in which capecitabine/oxaliplatin (XELOX, 8 cycles; n=51) and S-1/oxaliplatin [SOX, continuous (SOX-C, n=50), or intermittent (discontinuation after cycle 6 and restart on progression, SOX-I, n=50)] were administered. We compared severity (splenomegaly, thrombocytopenia, liver enzyme levels, and hepatic parenchymal heterogeneity), clinical significance (delay or dose-reduction of chemotherapy), and reversibility of SOS (splenomegaly and thrombocytopenia after stopping chemotherapy) between SOX and XELOX in gastric cancer patients., Results: SOX was more likely to be associated with splenomegaly, thrombocytopenia, hyperbilirubinemia, and hepatic parenchymal heterogeneity than XELOX. Splenomegaly was partially reversible after stopping chemotherapy in both regimens, but recovery rate was lower in SOX. Proportion of delayed or dose-reduced chemotherapy cycles due to thrombocytopenia was significantly higher in SOX-C than in XELOX., Conclusion: S-1 combination is more likely to worsen oxaliplatin-induced hepatic sinusoidal injuries than capecitabine in gastric cancer patients., (Copyright© 2021, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Although discordance in HER2 positivity between primary and metastatic lesions is well established, changes in HER2 positivity after anti-HER2 therapy have not been well evaluated in gastric cancer. We aimed to evaluate whether HER2 expression in gastric cancer is affected by trastuzumab therapy., Methods: We enrolled 48 HER2-positive advanced gastric cancer patients treated with trastuzumab-containing first-line chemotherapy and had paired biopsies at baseline and after progression., Results: At baseline, HER2 was positive, with immunohistochemistry (IHC) 2+ and in situ hybridization (ISH)+ in five patients, and with IHC 3+ in 43 patients. Fourteen patients (29.1%) exhibited loss of HER2 positivity on post-progression biopsy: 10 with IHC 0 or 1+, and four with IHC 2+/ISH-. HER2 remained positive on second biopsy in 34 patients: four with IHC 2+/ISH+, and 30 with IHC 3+. Median H-scores decreased from 225 to 175 (p = 0.047). HER2 genetic heterogeneity was defined in one of 34 ISH-assessable patients (2.9%) at baseline and seven of 32 (21.9%) at second biopsy. Among 13 patients who received second-line trastuzumab emtansine, three showed HER2-negative conversion; they had no objective response and short progression-free survival (1.2, 1.3, and 3.4 months). Patients with stable HER2 status had a 44% response rate and median progression-free survival of 2.7 (0.4-36.8) months., Conclusion: A substantial portion of HER2-positive patients showed HER2-negative conversion with increased HER2 genetic heterogeneity after failure of trastuzumab-containing chemotherapy. Loss of HER2 positivity could be predictive of second-line anti-HER2 treatment, suggesting a need to reexamine HER2 status before initiating second-line anti-HER2 therapy.

Background: Doublet chemotherapy of platinum and 5-fluorouracil is a standard first-line treatment for patients with unresectable gastric cancer. Although the addition of taxane or irinotecan to this regimen has yielded promising efficacy, its use has been limited due to severe toxicities. To overcome this limitation, we evaluated the efficacy and safety of the combination of irinotecan, oxaliplatin, and S-1 (OIS) for the treatment of advanced gastric cancer., Methods: Chemotherapy-naïve patients with pathologically proven advanced gastric adenocarcinoma were assessed for eligibility. Irinotecan (135 mg/m 2 ) and oxaliplatin (65 mg/m 2 ) were administered intravenously on day 1, and S-1 (80 mg/m 2 /day) was administered orally on days 1-7 of every 2-week cycle., Results: Forty-four patients (median age 57 years) were enrolled and all but one patient had a good performance status (ECOG 0 or 1). A total of 529 cycles were administered, with a median of 9.5 (range 1-31) cycles per patient. The overall response rate was 61.4% (95% confidence interval [CI] 46.6-74.3). The median progression-free survival and overall survival were 10.8 months (95% CI 7.6-14.0) and 15.4 months (95% CI 12.6-18.2), respectively. Major toxicities included grade 3/4 neutropenia (38.6%), febrile neutropenia (13.6%), abdominal pain (9.1%), and diarrhea (9.1%)., Conclusion: These data suggest that the OIS regimen is effective and relatively well tolerated in patients with advanced gastric cancer. Given that all the patients treated, but one, had a good performance status, these results must be confirmed in a patient population more representative of regular clinical practice., Trial Registration: ClinicalTrials.gov Identifier: NCT02527785.

Background: Some clinicopathological variables are known to influence the survival of patients with advanced gastric cancer. A comprehensive model based on these factors is needed for prediction of an individual's survival and appropriate patient counseling., Methods: A nomogram for predicting 1-year survival in patients with advanced gastric cancer in the palliative chemotherapy setting was developed using clinicopathological data from 949 patients with unresectable or metastatic gastric cancer who had received first-line doublet cytotoxic chemotherapy from 2001 to 2006 at the National Cancer Center, Korea (Baseline Nomogram). For 836 patients whose initial response to chemotherapy is known, another nomogram (ChemoResponse-based Nomogram) was constructed using the response to chemotherapy as additional variable. Nomogram performance in terms of discrimination and calibration ability was evaluated using the C statistic and Hosmer-Lemeshow-type χ 2 statistics., Results: Two different nomograms were developed and subjected to internal validation. The baseline nomogram incorporated 13 baseline clinicopathological variables, whereas the chemoresponse-based nomogram was composed of 11 variables including initial response to chemotherapy. Internal validation revealed good performance of the two nomograms in discrimination: C statistics = 0.656 (95% confidence interval, 0.628-0.673) for the baseline and 0.718 (95% confidence interval, 0.694-0.741) for the chemoresponse-based nomogram, which showed significantly better discrimination performance than the baseline nomogram (Z statistics = 3.74, p < 0.01)., Conclusion: This study suggests that individual 1-year survival probability of patients receiving first-line doublet cytotoxic chemotherapy for advanced gastric cancer can be reliably predicted by a nomogram-based method incorporating clinicopathological variables and initial response to chemotherapy.

Background: Paclitaxel is currently only available as an intravenous (i.v.) formulation. DHP107 is a novel oral formulation of lipid ingredients and paclitaxel. DHP107 demonstrated comparable efficacy, safety, and pharmacokinetics to i.v. paclitaxel as a second-line therapy in patients with advanced gastric cancer (AGC). DREAM is a multicenter, open-label, prospective, randomized phase III study of patients with histologically/cytologically confirmed, unresectable/recurrent AGC after first-line therapy failure., Methods and Materials: Patients were randomized 1 : 1 to DHP107 (200 mg/m2 orally twice daily days 1, 8, 15 every 4 weeks) or i.v. paclitaxel (175 mg/m2 day 1 every 3 weeks). Patients were stratified by Eastern Cooperative Oncology Group performance status, disease status, and prior treatment; response was assessed (Response Evaluation Criteria in Solid Tumors) every 6 weeks. Primary end point: non-inferiority of progression-free survival (PFS); secondary end points: overall response rate (ORR), overall survival (OS), and safety. For the efficacy analysis, sequential tests for non-inferiority were carried out, first with a non-inferiority margin of 1.48, then with a margin of 1.25., Results: Baseline characteristics were balanced in the 236 randomized patients (n = 118 per arm). Median PFS (per-protocol) was 3.0 (95% CI 1.7-4.0) months for DHP107 and 2.6 (95% CI 1.8-2.8) months for paclitaxel (hazard ratio [HR] = 0.85; 95% CI 0.64-1.13). A sensitivity analysis on PFS using independent central review showed similar results (HR = 0.93; 95% CI 0.70-1.24). Median OS (full analysis set) was 9.7 (95% CI 7.1 - 11.5) months for DHP107 versus 8.9 (95% CI 7.1-12.2) months for paclitaxel (HR = 1.04; 95% CI 0.76-1.41). ORR was 17.8% for DHP107 (CR 4.2%; PR 13.6%) versus 25.4% for paclitaxel (CR 3.4%; PR 22.0%). Nausea, vomiting, diarrhea, and mucositis were more common with DHP107; peripheral neuropathy was more common with paclitaxel. There were only few Grade≥3 adverse events, most commonly neutropenia (42% versus 53%); febrile neutropenia was reported infrequently (5.9% versus 2.5%). No hypersensitivity reactions occurred with DHP107 (paclitaxel 2.5%)., Conclusions: DHP107 as a second-line treatment of AGC was non-inferior to paclitaxel for PFS; other efficacy and safety parameters were comparable. DHP107 is the first oral paclitaxel with proven efficacy/safety for the treatment of AGC., Clinicaltrials.gov: NCT01839773.

Purpose: The purpose of this study was to evaluate the efficacy and safety of induction chemotherapy with docetaxel, capecitabine, and cisplatin (DXP) plus bevacizumab (BEV) on initially unresectable locally advanced gastric cancer (LAGC) or paraaortic lymph node (PAN) metastatic gastric cancer (GC)., Materials and Methods: Patients with LAGC or unresectable PAN metastatic GC received six induction chemotherapy cycles (60 mg/m 2 docetaxel intravenously on day 1, 937.5 mg/m 2 capecitabine orally twice daily on days 1-14, 60 mg/m 2 cisplatin intravenously on day 1, and 7.5 mg/kg BEV intravenously on day 1 every 3 weeks), followed by conversion surgery. The primary endpoint was R0 resection rate., Results: Thirty-one patients with invasion to adjacent organs but without PAN metastasis (n=14, LAGC group) or with PAN metastasis regardless of invasion (n=17, PAN group) were enrolled between July 2010 and December 2014. Twenty-seven patients (87.1%) completed six chemotherapy cycles. The most common grade ≥ 3 toxicities were neutropenia (71%), neutropenia with fever/infection (22.6%/3.2%), and stomatitis (16.1%). The clinical response and R0 resection rates were 64.3% (95% confidence interval [CI], 46.6 to 82.0) and 64.5% (LAGC group, 71.4%; PAN group, 58.8%), respectively. The pathological complete regression rate was 12.9%. After a median follow-up of 44.5 months (range, 39.4 to 49.7 months), the median progression-free survival and overall survival were 13.1 months (95% CI, 8.9 to 17.3) and 38.6 months (95% CI, 22.0 to 55.1), respectively., Conclusion: Induction chemotherapy with DXP+BEV displayed antitumor activities with encouraging R0 resection rate and manageable toxicity profiles on patients with LAGC or PAN metastatic GC.

Objective: This study investigated the efficacy and safety of S-1 versus capecitabine in elderly patients with metastatic gastric cancer (MGC), and examined the association between cytochrome P450 2A6 (CYP2A6) polymorphisms and treatment outcomes., Materials and Methods: MGC patients 70-85 years old with Eastern Cooperative Oncology Group (ECOG) performance status 0-2 or 65-70 years old with ECOG PS 2 were randomized to receive S-1 40 mg/m, twice daily, or capecitabine 1250 mg/m, twice daily, on days 1-14 every 3 weeks., Results: From May 2007 up to July 2010, 107 patients were enrolled. G3/4 neutropenia developed in 3.8% of each arm, and the most common G3/4 nonhematological toxicities were anorexia and fatigue. Vomiting and tearing were more frequent with S-1 and hand-foot syndrome with capecitabine. The primary endpoint, the overall response rate, was 26.4% (14/53, 95% confidence interval: 14.5-38.3%) in S-1 and 24.1% (13/54, 95% confidence interval: 12.7-35.5%) in capecitabine, both of which exceeded the null hypothesis response rate of 10%. The median time to progression (TTP; 3.2 vs. 3.4 months, P=0.813) and overall survival (OS; 8.5 vs. 10.3 months, P=0.691) were similar in both arms. CYP2A6 polymorphisms were associated with S-1 efficacy. In the S-1 arm only, patients with CYP2A6 variant/variant alleles had worse TTP and OS than those with wild/wild or wild/variant alleles, and in multivariate analysis, the CYP2A6 genotype was predictive for TTP and OS., Conclusion: Both S-1 and capecitabine were active and tolerable for elderly MGC patients. The CYP2A6 genotyping might guide treatment selection.

Background: This study was conducted to determine the recommended dose (RD) of intraperitoneal docetaxel (ID) in combination with systemic capecitabine and cisplatin (XP) and to evaluate its efficacy and safety at the RD in advanced gastric cancer (AGC) patients with peritoneal metastasis., Methods: AGC patients with peritoneal metastasis received XP ID, which consists of 937.5 mg/m 2 of capecitabine twice daily on days 1-14, 60 mg/m 2 of intravenous cisplatin on day 1, and intraperitoneal docetaxel at 3 different dose levels (60, 80, or 100 mg/m 2 ) on day 1, every 3 weeks. In the phase I study, the standard 3 + 3 method was used to determine the RD of XP ID. In the phase II study, patients received RD of XP ID., Results: In the phase I study, ID 100 mg/m 2 was chosen as the RD, with one dose-limiting toxicity (ileus) out of six patients. The 39 AGC patients enrolled in the phase II study received the RD of XP ID. The median progression-free survival was 11.0 months (95% CI 6.9-15.1), and median overall survival was 15.1 months (95% CI 9.1-21.1). The most frequent grade 3/4 adverse events were neutropenia (38.6%) and abdominal pain (30.8%). The incidence of abdominal pain cumulatively increased in the later treatment cycles., Conclusions: Our study indicated that XP ID was effective, with manageable toxicities, in AGC patients with peritoneal metastasis. As the cumulative incidence of abdominal pain was probably related to bowel irritation by ID, it might be necessary to modify the dose.

Objectives: We compared continuous versus stop-and-go chemotherapy after disease stabilisation with induction chemotherapy in the first-line treatment of metastatic gastric cancer (MGC)., Methods: MGC patients who achieved disease control after 6 cycles of S-1/oxaliplatin (SOX) were randomised to receive either continuous SOX until progression (continuous arm) or to have a chemotherapy-free interval followed by SOX reintroduction at progression (stop-and-go arm). The primary end-point was overall survival (OS)., Results: Of the 250 patients enrolled, 247 participated in the induction phase. Of these, 121 patients were randomised to the continuous arm (n = 59) or the stop-and-go arm (n = 62). Progression-free survival (PFS) was significantly longer in the continuous arm than in the stop-and-go arm (10.5 versus 7.2 months; hazard ratio [HR] 0.55, 95% CI, 0.37-0.81; P = 0.002). Duration of disease control (DDC) and OS, however, were comparable between the two arms: median DDC, 10.5 versus 11.3 months, HR 0.92 (95% CI, 0.62-1.36; P = 0.674); median OS, 22.6 versus 22.7 months, HR 0.78 (95% CI, 0.50-1.23; P = 0.284). Adverse events including grade ≥3 fatigue (28.8% versus 8.1%; P = 0.003) and sensory neuropathy (25.4% versus 9.7%; P = 0.022) occurred more frequently in the continuous arm than in the stop-and-go arm. Quality of life (QOL) including global health status, physical/role functioning and other symptom scores significantly favoured the stop-and-go arm., Conclusion: Compared with the stop-and-go strategy, maintenance chemotherapy improved PFS but not DDC and OS and had a negative impact on QOL, suggesting the stop-and-go strategy may be an appropriate option in MGC patients following induction chemotherapy., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Purpose: This study evaluated the re-challenge of S-1 or cisplatin in combination with docetaxel in metastatic gastric cancer (MGC) that had progressed on a cisplatin plus either S-1 or capecitabine regimen., Materials and Methods: Patients with progressive disease after first-line cisplatin plus S-1 or capecitabine were randomized to receive 3-week cycles of docetaxel 75 mg/m 2 intravenously (IV) on D1 (D), docetaxel 60 mg/m 2 IV plus cisplatin 60 mg/m² IV on D1 (DC), or docetaxel 60 mg/m 2 IV D1 plus oral S-1 30 mg/m 2 twice a day on D1-14 (DS)., Results: Seventy-two patients were randomized to the D (n=23), DC (n=24), or DS (n=25) group. The confirmed response rate was 4.3% (95% confidence interval [CI], 0% to 12.6%), 4.3% (95% CI, 0% to 12.6%), and 8.7% (95% CI, 0% to 20.2%) for the D, DC, and DS groups, respectively. Compared to the D arm, the DS arm had a better progression-free survival (2.7 months vs. 1.3 months, p=0.034) without any deterioration in safety or quality of life, whereas the DC arm had a similar progression-free survival (1.8 months vs. 1.3 months, p=0.804) and poorer overall survival (5.6 months vs. 10.0 months, p=0.035)., Conclusion: A re-challenge with S-1, but not cisplatin, in combination with docetaxel has potential anticancer benefits over docetaxel alone in MGC with progression after prior cisplatin plus S-1 or capecitabine.

Background: Gastrointestinal stromal tumours (GISTs) with high-risk features have poor prognosis even if adjuvant treatment is given. Neoadjuvant imatinib may increase the cure rate by shrinking large GISTs and preserve organ function., Methods: We conducted an Asian multinational phase II study for patients with gastric GISTs ≥10 cm. Patients received neoadjuvant imatinib (400 mg/day) for 6-9 months. The primary end point was R0 resection rate., Results: A total of 56 patients were enroled in this study. In the full analysis set of 53 patients, neoadjuvant imatinib for ≥6 months was completed in 46 patients. Grade 3-4 neutropenia and rash occurred in 8% and 9%, respectively, but there were no treatment-related deaths. The response rate by RECIST was 62% (95% CI, 48-75%). The R0 resection rate was 91% (48/53) (95% CI, 79-97%). Preservation of at least half of the stomach was achieved in 42 of 48 patients with R0 resection. At the median follow-up time of 32 months, 2-year overall and progression-free survival rates were 98% and 89%, respectively., Conclusions: Neoadjuvant imatinib treatment for 6-9 months is a promising treatment for large gastric GISTs, allowing a high R0 resection rate with acceptable toxicity.

Although Fibroblast growth factor receptor (FGFR) 2 gene amplification and its prognostic significance have been reported in resectable gastric cancers, information on these features remains limited in the metastatic setting. The presence of FGFR2 amplification was assessed in formalin-fixed, paraffin-embedded tissues using a quantitative PCR-based gene copy number assay with advanced gastric cancer cohorts. A total of 327 patients with tumor portion of ≥70% were analyzed for clinical features. Among these patients, 260 who received first-line fluoropyrimidine and platinum chemotherapy were analyzed for survival.Sixteen of 327 patients (4.9%) exhibited FGFR2 amplification. The amplification group showed associations with age <65 years, Borrmann type 4 disease, poor performance status, poorly differentiated histology, extra-abdominal lymph node metastases, and bone metastases. The median overall survival (OS) and progression-free survival (PFS) were found to be 12.7 and 5.8 months, respectively. In univariate analysis, PFS did not differ between amplification and no amplification groups (hazard ratio [HR]=1.34, 95% confidence interval [CI]: 0.78-2.31, p=0.290), although the OS was significantly shorter in the amplification group (HR=1.92, 95% CI: 1.13-3.26, p=0.015). However, multivariate analysis indicated that FGFR2 amplification was not an independent prognostic factor for OS (HR=1.42, 95% CI: 0.77-2.61, p=0.261).Although FGFR2 amplification is associated with poorer OS, it does not appear to be an independent prognostic predictor in patients with advanced gastric cancer treated with palliative fluoropyrimidine and platinum chemotherapy.

Background: Irinotecan-based chemotherapy is a standard backbone of therapy in patients with metastatic colorectal cancer (CRC) or gastric cancer (GC). However, there is still a paucity of information concerning the efficacy and safety of irinotecan-based regimens in elderly patients., Patients and Methods: Using the patient cohort ( n  = 1,545) from the UGT1A1 genotype study, we compared the efficacy and safety between elderly and nonelderly patients with metastatic CRC ( n  = 934) or GC ( n  = 611) who received first- or second-line FOLFIRI (irinotecan, leucovorin, and 5-fluorouracil) chemotherapy., Results: Despite lower relative dose intensity in elderly patients, progression-free survival and overall survival were similar between elderly (age ≥70 years) and nonelderly (<70 years) patients in the CRC cohort (hazard ratio [HR], 1.117; 95% confidence interval [CI], 0.927-1.345; p  = .244, and HR, 0.989; 95% CI, 0.774-1.264; p  = .931, respectively) and the GC cohort (HR, 1.093; 95% CI, 0.854-1.400; p  = .479, and HR, 1.188; 95% CI, 0.891-1.585; p  = .241, respectively). In both cohorts, febrile neutropenia (22.1% vs. 14.6% in CRC cohort and 35.2% vs. 22.5% in GC cohort) and asthenia (grade 3: 8.4% vs. 1.7% in CRC cohort and 5.5% vs. 2.9% in GC cohort) were more frequent in elderly patients. In the CRC cohort, mucositis and anorexia were more frequent in elderly patients. In the GC cohort, nausea and vomiting were less frequent in elderly patients., Conclusion: The efficacy of the FOLFIRI regimen was similar between elderly and nonelderly patients in both the CRC and the GC cohorts. However, special attention should be paid to elderly patients because of increased risk for febrile neutropenia and asthenia. The Oncologist 2017;22:293-303 IMPLICATIONS FOR PRACTICE: The efficacy of FOLFIRI (irinotecan, leucovorin, and 5-fluorouracil) chemotherapy in elderly patients with metastatic colorectal cancer or gastric cancer was similar to that in nonelderly patients. However, special attention should be paid to elderly patients because of the increased risk for febrile neutropenia and asthenia. These data suggest that the FOLFIRI regimen could be considered as a standard backbone of therapy in elderly patients with metastatic colorectal cancer or gastric cancer and that the clinical decision between doublet and singlet chemotherapy may not be based solely on age. However, the data require further assessment of frailty and performance status., (© AlphaMed Press 2017.)

Lessons Learned: Ideally, patients should have access to an oral formulation of paclitaxel, as well as an intravenous formulation, to allow development of regimens exploring alternate schedules and to avoid reactions to Cremophor EL (BASF Corp., Ludwigshafen, Germany, https://www.basf.com).DHP107 is a novel oral paclitaxel formulation that is a tolerable and feasible regimen for patients with gastric cancer, with data suggesting efficacy similar to that of intravenous paclitaxel., Background: We evaluated the maximum tolerated dose (MTD) of DHP107, a novel oral paclitaxel formulation, and the efficacy and safety of the agent in patients with advanced solid tumors., Patients and Methods: Phase I study: cohorts of 3-6 patients with advanced solid tumors received escalating DHP107 doses. Phase IIa study: patients with measurable advanced gastric cancer received DHP107, 200 mg/m 2 b.i.d., on days 1, 8, and 15 every 4 weeks. Pharmacokinetics, safety, and efficacy were analyzed., Results: Phase I: 17 patients received a dose-escalating regimen of DHP107, 150-250 mg/m 2 b.i.d. Dose-limiting toxicities were neutropenia and febrile neutropenia. The MTD (recommended dose) for phase IIa was 200 mg/m 2 b.i.d. Phase IIa: 11 patients with measurable advanced gastric cancer in whom first-line therapy failed received DHP107 (MTD). Three confirmed partial responses were observed. Median progression-free survival of gastric cancer patients ( n  = 16) treated at the MTD was 2.97 (95% confidence interval, 1.67-5.40) months (Fig. 1). The most frequent grade 3/4 adverse events were neutropenia (35.3%) and leukopenia (17.6%) at the MTD (phase I and IIa combined; n  = 17)., Conclusion: DHP107 showed good antitumor efficacy and was tolerable. The MTD (200 mg/m 2 b.i.d.) is recommended for use in further studies comparing DHP107 with standard intravenous paclitaxel therapy. The Oncologist 2017;22:129-e8., (© AlphaMed Press; the data published online to support this summary is the property of the authors.)

Objective: Postoperative chemotherapy with S-1 or capecitabine plus oxaliplatin is a standard treatment for resectable gastric cancer (GC). However, survival outcomes of stage IIIB-IV (M0) GC cases are still poor. We investigated the efficacy and safety of docetaxel, capecitabine, and cisplatin (DXP) in patients with stage IIIB-IV GC., Methods: This was a single-arm phase 2 study that included patients with stage IIIB-IV GC who underwent D2 gastrectomy. Patients received six cycles of docetaxel [60 mg/m 2 on day 1 (D1)], capecitabine (1,875 mg/m 2 /day on D1-14), and cisplatin (60 mg/m 2 on D1) every 3 weeks. The primary end-point was recurrence-free survival (RFS)., Results: A total of 46 GC patients between January 2007 and August 2008 were included. After a median follow-up of 56.1 months (range 52.2-64.1), the median RFS and overall survival (OS) were 26.9 months (95 % CI 7.5-46.4) and 43.9 months (95 % CI 29.2-58.7), respectively. The 5-year RFS and OS rates were 39.1 and 41.3 %, respectively. The most common grade 3/4 toxicities were neutropenia (40 %), anorexia (22 %), and febrile neutropenia (15 %)., Conclusions: Adjuvant DXP is feasible and effective for patients with stage IIIB-IV GC. A phase 3 study comparing triplet and doublet regimens for these patients is ongoing.

Background: Oral fluoropyrimidine S-1 contains tegafur, which is metabolized to 5-fluorouracil by cytochrome P450 2A6 (CYP2A6). We here examined associations between CYP2A6 polymorphisms and treatment outcomes of adjuvant S-1 in gastric cancer patients., Methods: Patients received adjuvant S-1 (40 mg/m 2 twice daily, days 1-28, every 6 weeks for eight cycles) after curative surgery for pathological stage II-III gastric cancer. We analyzed the wild-type allele (W) (CYP2A6*1) and four variant alleles (V) (CYP2A6*4, *7, *9, *10) that abolish or reduce this enzyme activity., Results: Patients (n = 200) were enrolled between November 2007 and July 2013 with the following clinical characteristics: median age, 57 years (range, 32-83 years); 128 men, 72 women. With a median follow-up of 46.4 months, the 3-year relapse-free survival (RFS) and overall survival (OS) rates were 83.1 % (95 % CI, 77.7-88.5 %) and 94.8 % (95 % CI, 91.6-98.0 %), respectively. Genotype distributions were as follows: W/W (n = 49, 24.5 %), W/V (n = 94, 47.0 %), and V/V (n = 57, 28.5 %). Overall toxicity did not differ according to genotype for any grade (p = 0.612) or grade ≥3 (p = 0.143). However, RFS differed significantly according to CYP2A6 genotype. The 3-year RFS rates were 95.9 % for W/W, 83.1 % for W/V, and 72.5 % for V/V (p = 0.032). Carriers of W/V and V/V genotypes had a poorer RFS with a hazard ratio of 3.41 (95 % CI, 1.01-11.52; p = 0.049) and 4.03 (95 % CI, 1.16-13.93; p = 0.028), respectively, compared with the W/W genotype., Conclusions: CYP2A6 polymorphisms are not associated with toxicity of S-1 chemotherapy, but correlate with the efficacy of S-1 in the adjuvant setting for gastric cancer.

Signet ring cell carcinoma (SRC) more commonly presents as metastatic disease and renders patients to be considered for chemotherapy. While treatment options are limited overall, trastuzumab has been shown to be effective for HER2 positive SRC cases. The current algorithm for HER2 evaluation heavily relies on positive membrane-specific staining by immunohistochemistry (IHC), but several anecdotal reports have suggested that SRCs may be susceptible to misinterpretation due to non-specific staining in the marginated cytoplasm with/without nucleus. Results of two FDA-approved IHC methods of HER2 evaluation, Pathway and HercepTest, along with silver in situ hybridisation were interpreted retrospectively and compared in 155 primary SRC cases. IHC results were discrepant between the two assays in SRC even at the strongest IHC scores. Discordance indeed occurred due to dark, non-specific staining obscured by the unique SRC morphology. True HER2 positive SRC was identified in three cases (3/155, 1.9%). In this study, we demonstrate the importance of recognising potential discrepancy in interpreting HER2 status depending on the assay used. Understanding this possible pitfall may prevent unnecessary trastuzumab in SRC patients., (Copyright © 2016 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Background: We conducted a phase II study to evaluate the efficacy and safety of perioperative S-1 plus docetaxel in locally advanced gastric cancer (LAGC) and to investigate the association between CYP2A6 genotype and outcome., Methods: Patients with LAGC [clinical stage III-IV (M0) by the Japanese staging system] received three cycles of pre- and postoperative chemotherapy (S-1 40 mg/m(2) twice daily on days 1-14; intravenous docetaxel 35 mg/m(2) on days 1 and 8, every 3 weeks) followed by gastrectomy with D2 dissection. We also performed a pharmacokinetic and CYP2A6 genotyping study (*1, *4, *7, *9, *10) for S-1., Results: From October 2006 to June 2008, 44 patients entered the study. 43 eligible patients completed preoperative chemotherapy and 40 completed postoperative chemotherapy. The most common G3/4 toxicities during pre- and postoperative chemotherapy were neutropenia, stomatitis, and abdominal pain. The clinical response rate by RECIST was 74.4 % (95 % CI, 61.4-87.4 %), and the R0 resection rate was 97.7 %. Clinical downstaging in T or N occurred in 41.9 % of patients. The 3-year progression-free survival (PFS) rate was 62.8 % and 5-year overall survival (OS) rate was 69.6 %. PFS and OS differed significantly according to clinical response, clinical downstaging, and CYP2A6 genotype. Patients with CYP2A6 variant/variant genotypes had a higher tegafur C max and worse survival than those with wild/wild or wild/variant genotypes., Conclusion: Perioperative S-1 plus docetaxel is active with a manageable toxicity in patients with LAGC receiving D2 surgery. Clinical tumor response, clinical downstaging, and CYP2A6 genotype may predict efficacy.

Purpose: The intratumoural heterogeneity of human epidermal growth factor receptor 2 (HER2) expression in gastric cancer is a major challenge when identifying patients who might benefit from HER2-targeting therapy. We investigated the significance of re-evaluation of HER2 status in primary sites and metastatic or recurrent sites in advanced gastric cancer patients whose primary tumours were initially HER2-negative., Patients and Methods: In part I of this study, we evaluated the significance of repeat endoscopic biopsy in unresectable or metastatic gastric cancer patients whose tumours were initially HER2-negative. In part II, we examined the HER2 positivity rate in metastatic or recurrent sites in patients whose primary tumours were HER2-negative in biopsy or surgical specimens., Results: In part I (n = 183), we identified patients with HER2-positive tumours for a rescued HER2 positivity rate of 8.7% (95% confidence interval [CI], 4.6-12.8%) that was associated with tumour location (diffuse stomach versus other = 0% versus 11.7%, P = 0.013), Bormann type (IV versus others = 0% versus 11.7%, P = 0.013), and initial biopsy HER2 immunohistochemistry score (0 versus 1 versus 2=6.7% versus 15.4% versus 25.0%, P = 0.028). Part II (n = 175) resulted in HER2 positivity of 5.7% (95% CI 2.3-9.1%) that was significantly associated with metastatic site (liver versus others = 17.2% versus 3.4%, P = 0.012). When compared with a historical control that showed HER2 positivity on initial assessment, patients who had rescued HER2 positivity had similar treatment benefits from trastuzumab-containing first-line chemotherapy., Conclusion: Repeat HER2 assessment in primary and metastatic or recurrent sites is recommended in patients with advanced gastric cancer whose primary tumour is initially HER2-negative., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Purpose: This phase I trial evaluated the question of whether the standard starting dose of axitinib could be administered in combination with therapeutic doses of cisplatin/capecitabine in patients with previously untreated advanced gastric cancer, and assessed overall safety, pharmacokinetics, and preliminary antitumor activity of this combination., Materials and Methods: Patients in dose level (DL) 1 received axitinib 5 mg twice a day (days 1 to 21) with cisplatin 80 mg/m(2) (day 1) and capecitabine 1,000 mg/m(2) twice a day (days 1 to 14) in 21-day cycles. Maximum tolerated dose (MTD) was the highest dose at which ≤ 30% of the first 12 patients experienced a dose-limiting toxicity (DLT) during cycle 1. Ten additional patients were enrolled and treated at the MTD in order to obtain additional safety and pharmacokinetic data., Results: Three DLTs occurred during cycle 1 in three (25%) of the first 12 patients: ruptured abdominal aortic aneurysm, acute renal failure, and > 5 consecutive days of missed axitinib due to thrombocytopenia. DL1 was established as the MTD, since higher DL cohorts were not planned. Common grade 3/4 non-hematologic adverse events in 22 patients treated at DL1 included hypertension (36.4%) and decreased appetite and stomatitis (18.2% each). Cisplatin/capecitabine slightly increased axitinib exposure; axitinib decreased capecitabine and 5-fluorouracil exposure. Eight patients (36.4%) each had partial response or stable disease. Median response duration was 9.1 months; median progression-free survival was 3.8 months., Conclusion: In patients with advanced gastric cancer, standard doses of axitinib plus therapeutic doses of cisplatin and capecitabine could be administered in combination. Adverse events were manageable.

Background: Five-weekly S-1 plus cisplatin (SP5) is one of the standard first-line regimens for advanced gastric cancer (GC), proven in a Japanese phase III study. To enhance the dose intensity of cisplatin, 3-weekly S-1 plus cisplatin (SP3) was developed., Patients and Methods: This multicenter, randomized, open-label, phase III study evaluated whether SP3 (S-1 80 mg/m(2)/day on days 1-14 and cisplatin 60 mg/m(2) on day 1) was noninferior/superior to SP5 (S-1 80-120 mg/day on days 1-21 and cisplatin 60 mg/m(2) on day 1 or 8) in terms of progression-free survival (PFS). Chemotherapy-naive patients with metastatic, recurrent gastric or gastroesophageal junction adenocarcinoma were randomized 1 : 1 to receive either SP3 or SP5. The trial is registered at ClinicalTrials.gov (NCT00915382)., Results: Between February 2009 and January 2012, 625 patients were randomized at 42 sites in Korea and Japan. With a median follow-up duration of 32.4 months (range, 13.3-48.6 months) in surviving patients, SP3 was not only noninferior but also superior to SP5 in terms of PFS [median 5.5 versus 4.9 months; hazard ratio (HR) = 0.82; 95% confidence interval (CI) 0.68-0.99; P = 0.0418 for superiority). There was no difference in overall survival (OS) between the groups (median 14.1 versus 13.9 months; HR = 0.99; 95% CI 0.81-1.21; P = 0.9068). In patients with measurable disease, the response rates were 60% in the SP3 arm and 50% in the SP5 arm (P = 0.065). Both regimens were generally well tolerated, but grade 3 or higher anemia (19% versus 9%) and neutropenia (39% versus 9%) were more frequent in SP3., Conclusions: SP3 is superior to SP5 in terms of PFS. However, since the improvement in PFS was only slight and there was no difference in OS, both SP3 and SP5 can be recommended as first-line treatments for patients with advanced GC., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: This study aimed to validate the prognostic relevance of macroscopic serosal changes in patients with resected gastric cancer. Prospectively collected databases of two multicenter randomized phase III trials of adjuvant chemotherapy were analyzed., Methods: For this study, 655 patients in the control groups of AMC 0101 and 0201 trials were selected. Macroscopic serosal changes were determined according to disruptions in serosal continuity, such as changes in color or nodular texture by the operating surgeon. Correlations with recurrence-free survival (RFS), overall survival (OS), and time to peritoneal recurrence were analyzed., Results: Macroscopic serosal changes were identified intraoperatively in 432 patients (66 %) and found to be significantly associated with multifocal or diffuse involvement (p = 0.001), Borrmann type 4 (p = 0.005), advanced pathologic T (p < 0.001), N (p < 0.001), overall stage (p < 0.001), and total gastrectomy (p < 0.001). In multivariate analyses, which included prognostic factors of localized gastric cancer, macroscopic serosal changes were significantly associated with poor RFS [hazard ratio (HR) 2.0; 95 % confidence interval (CI), 1.4-2.7; p < 0.001] and OS (HR 2.1; 95 % CI 1.5-3.0; p < 0.001). The changes also were significantly related to shorter time to peritoneal recurrence (HR 2.9; 95 % CI 1.7-5.0; p < 0.001)., Conclusions: Intraoperatively assessed macroscopic serosal changes confer a poor prognosis and increased peritoneal recurrence for patients with curatively resected gastric cancer. Macroscopic assessment of serosal changes may be a useful indicator that allows better risk stratification of patients with resected gastric cancer in terms of prognosis and peritoneal recurrence.

S-1 is an oral 5-fluorouracil agent containing tegafur, 5-chloro-2, 4-dihydroxypyridine (CDHP), and potassium oxonate. This study explored the pharmacokinetics of S-1 and pharmacokinetic changes after gastric surgery in patients with resectable gastric cancer who received pre- and postoperative S-1 plus docetaxel. Serial blood was drawn before and after gastrectomy from 37 patients for pharmacokinetic analysis. The pharmacokinetics of tegafur, 5-fluorouracil, and CDHP were analyzed by noncompartmental analysis (NCA) methods and by modeling. In modeling analysis, CHDP concentrations were incorporated in the model as a time-varying covariate that inhibits the clearance of 5-fluorouracil following an inhibitory Emax model. In NCA, the pharmacokinetics of tegafur and 5-FU before and after gastric surgery were similar, although average maximum concentrations of 5-FU were decreased with statistical significance after gastrectomy. Median Tmax of tegafur was shorter after surgery without statistical significance. In modeling analysis, tegafur was best fitted by mixed zero and first-order absorption. The only difference in the final pharmacokinetic model around gastrectomy was the presence of an absorption lag of 0.23 hours before surgery. Incorporation of CDHP concentrations significantly improved the model. Although some pharmacokinetic results showed statistically significant changes after gastrectomy, these differences seem to be too small to have any clinical implication., (© 2015, The American College of Clinical Pharmacology.)

Objectives: Fibroblast growth factor receptor 2 (FGFR2) amplification has been reported to be a target for treatment in gastric cancer. However, an optimal tissue source and method for evaluating FGFR2 have yet to be established., Methods: Copy numbers were compared by quantitative polymerase chain reaction (qPCR) using frozen vs formalin-fixed, paraffin-embedded (FFPE) tissue and biopsy vs surgical specimens. We correlated the results of qPCR and immunohistochemistry (IHC) with fluorescence in situ hybridization (FISH) using stage IV gastric cancer biopsy specimens and validated the results in surgical specimens., Results: FFPE tissues were suitable for qPCR, and biopsy specimens were equivalent to or better than surgical specimens. qPCR and IHC results exhibited an excellent correlation with FISH at eight or more copies by qPCR in any kind of tissue, 5% or more by IHC in biopsy specimens, and 10% or more by IHC in surgical specimens. FGFR2 amplification was 6.6% in stage IV gastric cancers, and 42% of these showed heterogeneous amplification and overexpression. IHC indicated a good correlation with FISH even in the heterogeneous cases., Conclusions: FFPE biopsy tissues are an adequate source for FGFR2 evaluation in gastric carcinomas, and a qPCR-based copy number assay can be used for screening. IHC is also a valid and practical method for evaluating FGFR2, considering frequent heterogeneity., (Copyright© by the American Society for Clinical Pathology.)

Background: Everolimus (RAD001) is an orally administered mTOR inhibitor that is well known for its antitumor efficacy and that has been approved for the treatment of several solid tumors, including renal cell carcinoma. In gastric cancer (GC), despite previous preclinical and phase I/II studies suggesting the promising efficacy of everolimus in previously treated AGC, more recent trials revealed that only certain subsets of patients might benefit from treatment with everolimus., Case Presentation: A 26-year-old man with metastatic gastric cancer with multiple liver lesions was treated with everolimus after failure of 1st-line and 2nd-line chemotherapy. A durable partial response was achieved for over 2 years. After progression from initial everolimus treatment, sequential cytotoxic chemotherapies were tried but failed rapidly. Everolimus was re-tried as salvage chemotherapy (re-treatment), and the patient achieved stable disease for 1 year until his death. Subsequent mutational analysis and immunohistochemical (IHC) staining with the tumor tissues just before re-treatment with everolimus revealed a PIK3CA hotspot mutation and pS6 overexpression in the primary tumor. After two cycles of everolimus re-treatment, the overexpression of pS6 became nearly absent in follow-up IHC staining., Conclusions: Everolimus monotherapy was satisfactory in a patient with refractory metastatic GC harboring PIK3CA and pS6 aberrations. These molecular alterations might be potential biomarkers that can predict the treatment response of everolimus, particularly in the terms of durable disease control. This case suggests and emphasizes that close evaluation of biomarkers in tumor tissue may be essential for identifying highly favorable groups among various subpopulations with AGC.

Background: Trastuzumab has been approved for use in combination with fluoropyrimidine plus cisplatin for the treatment of human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer (AGC). Although capecitabine plus oxaliplatin (XELOX) is a standard first-line regimen for AGC, combination trastuzumab plus XELOX has not been studied., Methods: Patients with metastatic or unresectable HER2-positive AGC were diagnosed by either HER2 immunohistochemistry (IHC) 3+ or IHC 2+/fluorescence in-situ hybridisation (FISH)+ received intravenous trastuzumab (8mg/m(2) for first cycle and 6mg/m(2) for subsequent cycles on day 1) plus oral capecitabine (1000mg/m(2) twice daily on days 1-14) and intravenous oxaliplatin (130mg/m(2) on day 1), every 3 weeks. The primary end-point was the objective response rate, and secondary end-points included progression-free survival (PFS), overall survival (OS) and toxicity profiles., Results: Fifty-five HER2-positive AGC patients were enrolled between August 2011 and February 2013. The median age was 57years (range=29-74). The confirmed objective response rate was 67% (95% confidence interval (CI)=54-80%). After a median follow-up period of 13.8 months (range=6.1-23.9), the median PFS and OS were 9.8 months (95% CI=7.0-12.6) and 21.0 months (95% CI=6.4-35.7), respectively. Frequently encountered grade 3-4 toxicities included neutropenia (18%), anaemia (11%), and peripheral neuropathy (11%). There was a treatment-related death caused by severe diarrhoea and complicated sepsis., Conclusion: Combination of trastuzumab and XELOX is well tolerated and highly effective in patients with HER2-positive AGC., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: The prognosis of patients with positive surgical resection margins is dismal in gastric cancer. However, the influence of positive margin itself on prognosis is still uncertain, especially in advanced gastric cancer (AGC). The aims of the present study were to evaluate the prognostic impact of microscopic tumor involved resection margins in stage III-IV AGC after gastric resection in comparison with other well-known factors., Methods: Among 1,536 consecutive gastric cancer patients who received intentional curative resection for stage III-IV AGC between April 2001 and December 2011 at the National Cancer Center, 35 patients (2.28 %) had positive resection margins on their final histology. A comparison of clinicopathologic characteristics, recurrence pattern, overall survival (OS), and disease-free survival (DFS) was made between positive margin (PM) patients and negative margin (NM) patients., Results: Among the 35 PM patients, 15 (42.9 %) had proximal involved margins, 21 (60.0 %) had distal involved margins, and one (2.9 %) had both involved margins. Twenty-eight PM patients (80.0 %) were stage III, and 7 (20.0 %) were stage IV. Recurrence was significantly higher in PM than NM (63.6 % vs. 39.7 %, respectively; p = 0.005). The OS and DFS rates were significantly lower in the PM group than in the NM group (14.9 vs. 36.3 months, p < 0.001 and 11.6 vs. 27.1 months, p = 0.005, respectively). The presence of PM was an independent risk factor for both OS and DFS., Conclusions: The presence of PM is an independent risk factor for OS and DFS. Considering the prognostic impact of PM, a sufficient resection margin should be ensured when determining the resection line in gastrectomy with curative intent. The reoperation to secure clear resection margins should be considered as a treatment of choice in the case of PM.

Background: Self-expandable metallic stents are used widely to relieve malignant gastric outlet obstruction (GOO). However, restenosis or migration of first stents is a frequent complication. The purpose of this retrospective cohort study was to evaluate the effectiveness of second stents as an approach to manage failure of first stents in patients with malignant GOO., Methods: A total of 222 patients with gastric cancer received first stents due to inoperable GOO at National Cancer Center in Korea between January 2008 and June 2011. Monthly follow-up interviews were performed, and second stents (stent-in-stent or stent-after-migration) were inserted in 59 patients by June 2012. Technical and clinical successes and long-term complications were evaluated., Results: The technical and immediate clinical success rates were 98.3 % (58/59) and 91.5 % (54/59), respectively. Patients who received a second stent due to late complications involving the first stent (migration, restenosis, and fracture) showed a higher clinical success rate (95.8 % [46/48]) than patients who received a second stent due to immediate clinical failure of the first stent (72.7 % [8/11], p = 0.04). The immediate clinical success rate of stent-after-migration (100 % [11/11]) was not different from that of stent-in-stent (89.6 % [43/48], p = 1.0). The stent dysfunction rate of stent-after-migration (27.3 % [3/11]) also was similar to that of stent-in-stent (29.2 % [14/48], p = 1.0). The median patencies of stent-in-stent and stent-after-migration were 27.4 and 58.4 weeks, respectively (p = 0.177). There were no significant prognostic factors for patency of second stents., Conclusions: Insertion of a second stent is effective for treating the first-stent failure in gastric cancer patients with GOO, especially if the immediate outcome of the first stent was successful.

Background: We evaluated the maximum tolerated dose (MTD) and safety of sunitinib plus capecitabine/cisplatin (XP) or capecitabine/oxaliplatin (XELOX) in Korean patients with advanced gastric cancer (GC)., Methods: Sunitinib (37.5 or 25 mg/day) was administered on a 2-week-on/1-week-off schedule with chemotherapy. Assessments included dose-limiting toxicity (DLT), safety, pharmacokinetics, and antitumor activity., Results: Twenty-eight patients received sunitinib/XP; 48 received sunitinib/XELOX. The MTDs were: sunitinib 25 mg/day, cisplatin 80 mg/m(2), and capecitabine 1,000 mg/m(2); sunitinib 37.5 mg/day, oxaliplatin 110 mg/m(2), and capecitabine 800 mg/m(2); and sunitinib 25 mg/day, oxaliplatin 110 mg/m(2), and capecitabine 1,000 mg/m(2). DLTs at the MTDs comprised grade (G) 4 febrile neutropenia plus G3 diarrhea (n = 1; sunitinib/XP), dose delays due to hematologic toxicity (n = 2; both sunitinib/XP), G3 bleeding (menorrhagia; n = 1; sunitinib/XELOX), and G3 increased alanine aminotransferase levels (n = 1; sunitinib/XELOX). There was a high frequency of G3/4 hematologic adverse events observed with both treatment regimens, particularly with sunitinib/XP. Frequent non-hematologic, G3/4 adverse events were nausea, stomatitis, and hypophosphatemia with sunitinib/XP and hypophosphatemia and pulmonary embolism with sunitinib/XELOX. No drug-drug interactions were apparent. At the MTDs, median progression-free survival was 6.4 months and 5.5-8.0 months for sunitinib/XP and sunitinib/XELOX, respectively; and the objective response rate was 46.7% and 43.5-45.5% for sunitinib/XP and sunitinib/XELOX, respectively., Conclusions: At the MTD, sunitinib/XELOX had an acceptable safety profile in patients with advanced GC.

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., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Purpose: We conducted a phase I study of S-1 combined with irinotecan and oxaliplatin (TIROX) to determine the maximum-tolerated dose (MTD) and recommended dose (RD) and to assess its safety, pharmacokinetics, pharmacogenetics, and preliminary efficacy in patients with metastatic colorectal cancer (MCRC) or metastatic gastric cancer (MGC)., Methods: Patients received escalating doses of S-1 (30-40 mg/m² b.i.d.) orally on days 1-14, an escalating dose of intravenous irinotecan (120-150 mg/m²) on day 1, and a fixed dose of intravenous oxaliplatin (85 mg/m²) on day 1 every 3 weeks., Results: Twenty-three patients (10 MCRC, 13 MGC; 13 chemonaive, 10 previously treated for metastatic disease) were treated across six dose levels. Because only one patient experienced a dose-limiting toxicity of grade 3 anorexia at the highest dose level (S-1 40 mg/m² b.i.d., irinotecan 150 mg/m², and oxaliplatin 85 mg/m²) (n = 8), the MTD was not obtained, and this level was established as the RD. With a median of 10 cycles per patient, the most common grade 3 or 4 adverse events included neutropenia (43 %), diarrhea (13 %), and nausea (13 %). In 22 efficacy-evaluable patients, the objective tumor response rate was 59.1 % (75 % for both MCRC and MGC in the first-line setting) and the disease control rate was 100 %. The exploratory pharmacokinetic/pharmacogenetic study showed that CYP2A6 variants (*4, *7, *9) are associated with a lower metabolic ratio of S-1 (exposure ratio of 5-fluorouracil to tegafur)., Conclusions: The new triplet TIROX regimen has shown promising antitumor activity and a favorable toxicity profile in patients with MCRC and MGC.

Background: PEP02 is a novel highly stable liposomal nanocarrier formulation of irinotecan. This randomized phase II study evaluated the efficacy and safety of single agent PEP02 compared with irinotecan or docetaxel in the second-line treatment of advanced oesophago-gastric (OG) cancer., Patients and Methods: Patients with locally advanced/metastatic disease who had failed one prior chemotherapy regimen were randomly assigned to PEP02 120 mg/m(2), irinotecan 300 mg/m(2) or docetaxel (Taxotere) 75 mg/m(2) every 3 weeks. The primary end point was objective response rate (ORR). Simon's two-stage design was used and the ORR of interest was 20% (α = 0.05, type II error β = 0.10, null hypothesis of ORR was 5%)., Results: Forty-four patients per arm received treatment, and 124 were assessable for response. The ORR statistical threshold for the first stage was reached in all arms. In the intent-to-treat (ITT) population, ORRs were 13.6% (6/44), 6.8% (3/44) and 15.9% (7/44) in the PEP02, irinotecan and docetaxel arms, respectively. The median progression-free survival (PFS) and overall survival were similar between the trial arms. Commonest grade 3-4 adverse event reported was diarrhoea in the PEP02 and irinotecan groups (27.3% versus 18.2%)., Conclusion: The ORR associated with PEP02 was comparable with docetaxel and numerically greater than that of irinotecan. PEP02 warrants further evaluation in the advanced gastric cancer setting.

Background and Aims: The best therapeutic modality has not been established for gastric low-grade adenomas or dysplasia (LGD), which can progress to invasive carcinoma despite a low risk. This study aims to investigate the clinical efficacy, safety, and local recurrence after argon plasma coagulation (APC) treatment of gastric LGD compared with endoscopic submucosal dissection (ESD)., Patients and Methods: A total of 320 patients with gastric LGD ≤ 2.0 cm treated with APC or ESD between 2004 and 2011 were retrospectively analyzed. We compared local recurrence rate, complication rate, procedure time, and admission to hospital between APC and ESD groups., Results: Of the 320 patients, 116 patients were treated with APC and 204 with ESD. During follow-up, local recurrence was more common in the APC group (3.8 %, 4/106) than the ESD group (0.5 %, 1/188; log-rank test P = 0.036). However, all patients with local recurrence (n = 5) were treated by additional APC, and followed up without further recurrences. ESD was complicated by two perforations (1.0 %, 2/204) compared with no perforations in the APC group (0 %, 0/116). Bleeding complications were not different between the APC (1.7 %, 2/116) and ESD (2.0 %, 4/204) groups. Procedure time was shorter in the APC (7.8 ± 5.1 min) than the ESD (53.1 ± 38.1 min) group (P < 0.001). The proportion of hospitalization was less in the APC group (31.0 %, 36/116) than the ESD group (100.0 %, 204/204) (P < 0.001)., Conclusions: APC can be a good treatment option for patients with LGD ≤ 2.0 cm.

Purpose: To compare chemotherapy alone with chemoradiation therapy in stage III-IV(M0) gastric cancer treated with R0 gastrectomy and D2 lymph node dissection., Methods and Materials: The chemotherapy arm received 5 cycles of fluorouracil and leucovorin (FL), and the chemoradiation therapy arm received 1 cycle of FL, then radiation therapy of 45 Gy concurrently with 2 cycles of FL, followed by 2 cycles of FL. Intent-to-treat analysis and per-protocol analyses were performed., Results: Between May 6, 2002 and June 29, 2006, a total of 90 patients were enrolled. Forty-four were randomly assigned to the chemotherapy arm and 46 to the chemoradiation therapy arm. Treatment was completed as planned by 93.2% of patients in the chemotherapy arm and 87.0% in the chemoradiation therapy arm. Overall intent-to-treat analysis showed that addition of radiation therapy to chemotherapy significantly improved locoregional recurrence-free survival (LRRFS) but not disease-free survival. In subgroup analysis for stage III, chemoradiation therapy significantly prolonged the 5-year LRRFS and disease-free survival rates compared with chemotherapy (93.2% vs 66.8%, P=.014; 73.5% vs 54.6%, P=.056, respectively)., Conclusions: Addition of radiation therapy to chemotherapy could improve the LRRFS in stage III gastric cancer treated with R0 gastrectomy and D2 lymph node dissection., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background and Study Aim: Chemotherapy has been suggested to affect the outcome of pyloric stent placement. This study aimed to investigate the association between the response to chemotherapy and pyloric stent outcome., Patients and Methods: Data from 113 patients with inoperable gastric cancer who received chemotherapy after pyloric stent placement at the National Cancer Center hospital were analyzed retrospectively. Chemotherapy response was assessed using the Response Evaluation Criteria in Solid Tumors. A Cox proportional hazards model was used to evaluate the effect of chemotherapy response on the complications of stents., Results: The stent migration rate was 15.9% (18/113) and the re-stenosis rate was 30.1% (34/113). The response rates to chemotherapy were higher in the first-line group than in the salvage chemotherapy group (second-line or more) (44.8% [26/58] vs. 3.6% [2/55], respectively; P < 0.001). The proportion of patients with long time-to-progression (> 8 weeks) was also higher in the first-line than the salvage chemotherapy group (81.0% [47 /58] vs. 61.8% [34 /55], respectively; P = 0.036). Although, the response to chemotherapy was not associated with stent migration or re-stenosis, a long time-to-progression (adjusted hazard ratio [aHR] = 0.29, 95% confidence interval [CI] 0.13-0.67) and first-line chemotherapy (aHR = 0.45, 95%CI 0.22-0.93) were protective factors against re-stenosis in the multivariate analysis. In patients who received first-line chemotherapy, the median duration of patency of covered and uncovered stents was 20 weeks (95%CI 11-29) and 33 weeks (95 %CI 18-48), respectively (P = 0.317)., Conclusions: A long time-to-progression and first-line chemotherapy were significant protective factors against re-stenosis. In chemotherapy-naïve gastric cancer patients with pyloric obstruction, placement of an uncovered stent followed by chemotherapy can be considered to increase stent patency., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background/aims: The aim of this study was to assess the pattern of body weight change after gastrectomy for gastric cancer and its association with prognosis., Methodology: From February 2001 to June 2005, 1554 patients who underwent gastrectomy for gastric cancer were included. The pattern of body weight change according to the preoperative body mass index was analyzed and compared with recurrence, survival., Results: Body weight in 1057 (68.0%) patients stabilized before 6 months. As preoperative BMI is low, weight was stabilized on early time after surgery (p<0.001). There were 228 (14.7%) recurrences of 1554 patients. One hundred and fifty three (9.8%) patients experienced recurrence within 2 years after gastric cancer surgery whereas 75 (4.8%) patients experienced recurrence 2 years after operation. Weight loss was associated with poor prognosis and weight loss more than 30% at postoperative 6 months was significantly associated with early recurrence (p=0.020, OR=6.524)., Conclusions: Body weight measure after gastric cancer surgery would be a simple but important method during follow-up period. Physician should pay attention to patients if they experience severe weight loss at 6 months after gastrectomy for gastric cancer due to the possibility of early recurrence.

Purpose: Family history of gastric cancer is a major risk factor for the disease. In this study, we investigated the prognoses of patients with gastric cancer with a family history., Patients and Methods: We retrospectively reviewed data from 1,273 patients with gastric adenocarcinoma who had undergone gastrectomy between 2001 and 2005 at a tertiary cancer center hospital. A positive family history was defined as a self-reported history of cancer in first- or second-degree relatives. Patients were followed up until December 2009 for death or recurrence. Clinicopathologic characteristics were compared by family history. Kaplan-Meier plots and Cox proportional hazards regressions were applied for disease-free survival (DFS), recurrence-free survival (RFS), and overall survival (OS)., Results: Of 1,273 patients, 263 patients (20.6%) had first-degree relatives with a history of gastric cancer. First-degree family history of gastric cancer was associated with better DFS, RFS, and OS (P = .012, .006, and .005, respectively). In patients with stage I or II gastric cancer, first-degree family history was not associated with survival. However, it was associated with a reduced risk of recurrence or mortality in patients with stage III or IV gastric cancer. Compared with patients without a family history, the adjusted hazard ratios for those with a first-degree family history of gastric cancer were 0.49 (95% CI, 0.29 to 0.84) for DFS, 0.51 (95% CI, 0.30 to 0.87) for RFS, and 0.47 (95% CI, 0.26 to 0.84) for OS in patients with stage III or IV gastric cancer., Conclusion: A first-degree family history of gastric cancer is associated with improved survival after curative-intent surgery in patients with stage III or IV gastric cancer.

Aims: The authors aimed to compare the surgical performance and the short-term clinical outcomes of robotic assisted laparoscopic distal gastrectomy (RADG) with laparoscopy-assisted distal gastrectomy (LADG) in distal gastric cancer patients., Method: From April 2009 to August 2010, 62 patients underwent LADG and 30 patients underwent RADG for preoperative stage I distal gastric cancer by one surgeon at the National Cancer Center, Korea. Surgical performance was measured using lymph node (LN) dissection time and number of retrieved LNs, which were viewed as surrogates of technical ease and oncologic quality., Results: In clinicopathologic characteristics, mean age, depth of invasion and stage were significantly different between the LADG and RADG group. Mean dissection time at each LN station was greater in the RADG group, but no significant intergroup difference was found for numbers of retrieved LNs. Furthermore, proximal resection margins were smaller, and hospital costs were higher in the RADG group. In terms of the RADG learning curve, mean LN dissection time was smaller in the late RADG group (n = 15) than in the early RADG group (n = 15) for 4sb/4d, 5, 7-12a stations, but numbers of retrieved LNs per station were similar., Conclusion: With the exception of operating time and cost, the numbers of retrieved LNs and the short-term clinical outcomes of RADG were found to be comparable to those of LADG, despite the surgeon's familiarity with LADG and lack of RADG experience. Further studies are needed to evaluate objectively ergonomic comfort and to quantify the patient benefits conferred by robotic surgery., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: The purpose of this study was to compare the clinical usefulness of the seventh Union Internationale Contre le Cancer/American Joint Committee on Cancer (AJCC/UICC) staging system vs the sixth AJCC/UICC staging system in patients with gastric cancer., Study Design: Included were 1,799 patients who underwent surgery for gastric cancer between January 2001 and June 2005 at the National Cancer Center (South Korea). For the sixth and seventh AJCC/UICC staging systems, survival outcomes stratified by stage, by T classification, and by N classification were summarized using Kaplan-Meier curves and compared statistically using a log rank test; survival differences were quantified using hazard ratios estimated from a Cox regression model. The 2 systems were compared in terms of prognostic performances using the linear trend chi-square test, likelihood ratio chi-square test, and Akaike information criterion (AIC) in the Cox regression analysis., Results: Significant survival differences between each stage were not found using the seventh staging system, especially for stages IB, IIA, and IIB (p = 0.14 and p = 0.11). The sixth staging system had higher linear trend chi-square score and likelihood ratio chi-square score, which means better discriminatory ability, monotonicity, and homogeneity, and had smaller AIC, which indicates better optimistic prognostic stratification, especially in the N classification. The modified staging system combining the T classification of the seventh AJCC/UICC system and the N classification of the sixth system showed better prognostic performance compared with each separate version (sixth or seventh) of the staging system., Conclusions: The seventh AJCC/UICC staging system is not more clinically useful than the sixth system in surgically treated patients with gastric cancer because of an inappropriate N classification. A new TNM system is required with a different N classification., (Copyright © 2012 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

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.

Background and Aim: Helicobacter pylori infection is a risk factor for gastric cancer. We evaluated whether H. pylori infection and premalignant histological changes are more prevalent in siblings of young gastric cancer patients., Methods: Young (age ≤ 40) gastric cancer patients (n = 185), their young siblings (n = 130), and young control participants (n = 287) were recruited. H. pylori infection and histological changes were assessed using the updated Sydney system in biopsy specimens from three regions. We analyzed the association of H. pylori infection and histological changes with gastric cancer using logistic regression analysis., Results:   The H. pylori infection rate was significantly higher in young cancer patients than their siblings (odds ratio [OR]= 2.42, P = 0.001) or control participants (OR = 3.60, P < 0.001). In H. pylori-infected subjects, corpus gastritis and premalignant changes of the corpus lesser curvature (LCv) were also more prevalent in patients than in siblings or controls. In terms of the antrum, intestinal metaplasia was more prevalent in H. pylori-infected patients than in siblings or controls, while atrophy was not affected. Siblings also had a higher H. pylori infection rate (OR = 1.60, P = 0.046) and higher prevalence of intestinal metaplasia at the corpus LCv (OR = 2.88, P =0.027) than control participants., Conclusions: Even in young adults, H. pylori infection is a risk factor for gastric cancer. Young adults with histological findings including corpus predominant gastritis, corpus atrophy, or intestinal metaplasia are at increased risk. Since young siblings share risk factors, screening and treatment should be considered for these family members., (© 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.)

Background: Self-expandable metallic stents (SEMSs) provide effective palliation for inoperable malignant gastric outlet obstruction (GOO). The objective of this study was to evaluate the effectiveness of SEMSs in patients with recurrent gastric cancer after radical gastrectomy., Methods: We retrospectively analyzed data from patients with gastric cancer who underwent endoscopic SEMS placement. The patients had obstructive symptoms due to recurrent gastric cancer after curative-intent subtotal or total gastrectomies. Technical and clinical success rates of stent placement were evaluated and clinical outcomes were compared according to operation types., Results: A total of 15 patients underwent total gastrectomies with esophagojejunostomies and Roux-en-Y reconstructions, 8 underwent subtotal gastrectomies with Billroth I reconstructions, and 12 underwent subtotal gastrectomies with Billroth II reconstructions. Four patients in the Billroth II group received stents in afferent and efferent loops, so a total of 39 stents were placed. Technical success was achieved with 92% (36/39) of stents, and clinical success occurred with 90% (35/39) of stents, with no significant differences among surgery groups or between stent types (covered vs. uncovered). The GOO score (preprocedure: 0.45±0.62) increased by 1 week (2.06±0.51, p<0.001) and was maintained up to 1 month (1.71±1.15, p<0.001 compared with initial score). Complications occurred with 17 of 39 stents (44%) and included 2 perforations, 3 migrations, and 12 restenoses. Median stent patency duration was 10.7 weeks and median survival was 21.3 weeks; these did not significantly differ by surgery group (p=0.25 and 0.93, respectively) or stent type (covered vs. uncovered, p=0.51 and 0.96, respectively)., Conclusion: Endoscopic SEMS placement for obstruction due to recurrent cancer after total or subtotal gastrectomy is feasible and provides effective short-term palliation, independent of the type of surgical procedure or stent (covered vs. uncovered) used.

Background: The aim of this study was to investigate the efficacy and safety of S-1/irinotecan/oxaliplatin (TIROX) in metastatic gastric cancer (MGC) and the association between treatment outcome and uridine diphosphate-glucuronosyltransferase (UGT) 1A polymorphisms., Patients and Methods: Patients with previously untreated MGC received S-1 40 mg/m(2) b.i.d. on days 1-14 and irinotecan 150 mg/m(2) plus oxaliplatin 85 mg/m(2) on day 1 every 3 weeks., Results: Forty-four patients were enrolled. In intent-to-treat analysis, the objective response rate was 75%, including the complete response (CR) rate of 14%. The median time to progression and overall survival was 10.2 and 17.6 months, respectively. Ten (26%) of the 39 patients with primary gastric tumor showed biopsy-confirmed gastric CR. Grade 3/4 neutropenia developed in 66% of patients and grade 3 febrile neutropenia in 16%. The most common grade 3 nonhematologic toxic effects were abdominal pain (18%), anorexia (16%), and diarrhea (14%). UGT1A polymorphisms were associated with significantly higher incidence of grade 4 leukopenia (UGT1A1*6), neutropenia (UGT1A1*6, UGT1A6*2, and UGT1A7*3), grade 3/4 febrile neutropenia (UGT1A1*6), and grade 3 abdominal pain (UGT1A1*6)., Conclusions: The TIROX regimen induced marked tumor reduction and promising survival with a manageable toxicity profile in MGC patients. UGT1A genotype may be predictive of TIROX toxicity., (© The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Background: We evaluated the association between polymorphisms of cytochrome P450 2A6 (CYP2A6)/excision repair cross-complementation group 1 (ERCC1)/X-ray repair cross-complementing group 1(XRCC1) and treatment outcomes of metastatic gastric cancer (MGC) patients treated with S-1/cisplatin., Methods: Among MGC patients (n=108), who received S-1 (40 mg m(-2) b.i.d., days 1-14) and cisplatin (60 mg m(-2), day 1) every 3 weeks, we analysed the wild-type allele (W) and variants (V) of CYP2A6 (*4, *7, *9, *10), and the polymorphisms of ERCC1 (rs11615, rs3212986) and XRCC1 (rs25487)., Results: Patients having fewer CYP2A6 variants had better response rates (W/W vs W/V other than *1/*4 vs V/V or *1/*4=66.7 vs 58.3 vs 32.3%; P=0.008), time to progression (TTP) (7.2 vs 6.1 vs 3.5 months, P=0.021), and overall survival (23.2 vs 15.4 vs 12.0 months, P=0.004). ERCC1 19442C>A (rs3212986) was also associated with response rate (C/C, 46.7% vs C/A, 55.3% vs A/A, 87.5%) (P=0.048) and TTP (4.4 vs 7.6 vs 7.9 months) (P=0.012). Patients carrying both risk genotypes of CYP2A6 (V/V or 1/*4) and ERCC1 19442C>A (C/C) vs those carrying none showed an adjusted odds ratio of 0.113 (P=0.004) for response, and adjusted hazard ratios of 3.748 (P=0.0001) for TTP and 2.961 (P=0.006) for death., Conclusion: Polymorphisms of CYP2A6 and ERCC1 19442C>A correlated with the efficacy of S-1/cisplatin.

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., (Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.)