Association of adipocytokines and adipocytokine ratios with cardiovascular risk factors in Japanese preadolescents.

OBJECTIVES: Asians are particularly susceptible to obesity-associated disorders and rapid progression of obesity from childhood to adulthood. Data on the association between adipocytokine parameters, particularly adipocytokine ratios, and cardiovascular risk factors in childhood remain limited. Herein, we assessed the association of resistin, adiponectin, and leptin levels and leptin/adiponectin and resistin/adiponectin ratios with selected cardiovascular risk factors and the influence of unhealthy weight on such associations in children aged 9-10 years. METHODS: We included 380 children aged 9-10 years from three public elementary schools in Japan. RESULTS: The body mass index (BMI) was significantly higher in male preadolescents than in female adolescents (median 16.5 kg/m2 vs. 16.2 kg/m2, p=0.032). No differences in height, weight, waist circumference (WC), waist/height ratio (W/Hr), total cholesterol and high-density lipoprotein cholesterol levels, or atherosclerosis index (AI) were observed between the sexes. Of the adipocytokine levels and ratios analyzed, only the leptin level and leptin/adiponectin ratio (L/Ar) were strongly and significantly positively correlated with the cardiovascular risk factors WC, W/Hr, and BMI (all p<0.05). The AI was not strongly correlated with any adipocytokine levels or ratios. Apart from the strong positive correlation between the L/Ar and W/Hr, no other significant associations were observed between any of the adipocytokine levels or ratios and the selected cardiovascular risk factors. CONCLUSIONS: Our findings confirmed the value of adipocytokine ratios in risk assessment in pediatric populations, with leptin levels and leptin/adiponectin ratios strongly correlating with risk factors in children aged 9-10 years.

Clinical biomarkers in adjuvant chemotherapy for gastric cancer after D2 dissection by a pooled analysis of individual patient data from large randomized controlled trials.

BACKGROUND: Adjuvant therapy for gastric cancer is a standard among the world with no regimen selection criteria. Also, prognostic factors except for tumor staging have not been established. We aimed to identify prognostic and predictive markers for gastric cancer adjuvant therapy from large randomized controlled trials with standard lymph node dissection. METHODS: Three studies: ACTS-GC, CLASSIC, and SAMIT were found and selected for a pooled analysis, following PRISMA guideline. The integrity of individual participant data (IPD) was verified in the eligible 3527 patients registered, and fixed-effect model was used. The primary endpoint was relapse-free survival (RFS) and the secondary endpoint was overall survival (OS). RESULTS: Age was a significant prognostic factor in addition to tumor stages both in "surgery alone" and "adjuvant" groups. Adjuvant therapy was effective for every TN stage; however, it tended to be more effective in T1-2 than in T3-4. Also, it was more effective in low- or middle-BMI than in high-BMI group with Hazard ratio [HR]s: 0.58, 0.58, and 1.05, respectively. Capecitabine plus oxaliplatin (CAPOX) was more effective than S-1 for T1-2, N2-3, and differentiated type with HRs between 0.59 and 0.70, but with no difference among TNM stages. Combining histology to TN; the HRs in differentiated T1-2 N1-3 groups were between 0.29 and 0.45. For T3-4 N0-1 group, S-1 was likely to be effective, not significant. CONCLUSIONS: Age is a significant prognostic factor both in surgery alone and adjuvant group. CAPOX is more effective for differentiated T1-2 tumors with lymph node metastasis.

Differences in disease status between patients with progression after first-line chemotherapy versus early relapse after adjuvant chemotherapy who undergo second-line chemotherapy for gastric cancer: Exploratory analysis of the randomized phase III TRICS trial.

BACKGROUND: Second-line chemotherapy (SLC) improves survival in advanced gastric cancer (AGC). Patients receiving SLC are categorized into two disease status groups: tumour progression after first-line chemotherapy and early recurrence after adjuvant chemotherapy. Differences between these groups have not yet been clarified. PATIENTS AND METHODS: A total of 163 eligible patients registered in the randomized phase III TRICS trial evaluating SLC for patients with AGC was classified into the progressive disease (PD) group (n = 55) or the early relapse (ER) group (n = 108). We compared overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and safety. Adjusted OS and adjusted PFS were estimated using inverse probability of treatment weighting (IPTW). RESULTS: The ER group had a lower median age than the PD group (66 vs. 72 years; P = 0.016), performance status (PS) 0 was more frequently seen in the ER group (87% vs. 71%; P = 0.012). The adjusted median OS was 13.7 months in the ER group and 13.6 months in the PD group (IPTW hazard ratio [HR]: 1.023; P = 0.854). The adjusted median PFS was 4.9 months in the ER group and 4.4 months in the PD group (IPTW HR: 0.707; P = 0.004). ORR was significantly better in the ER group than the PD group (21.3% vs. 4.9%; P = 0.020). No significant differences were observed in the incidence of adverse events. CONCLUSIONS: ER was associated with improved PFS and better ORR than PD, although no difference in survival was demonstrated. From the viewpoint of treatment outcome, it seems appropriate to treat patients with ER in the same way as patients with PD. CLINICAL TRIAL REGISTRATION: UMIN 000002571.

Detection of atypical data in multicenter clinical trials using unsupervised statistical monitoring.

BACKGROUND/AIMS: A risk-based approach to clinical research may include a central statistical assessment of data quality. We investigated the operating characteristics of unsupervised statistical monitoring aimed at detecting atypical data in multicenter experiments. The approach is premised on the assumption that, save for random fluctuations and natural variations, data coming from all centers should be comparable and statistically consistent. Unsupervised statistical monitoring consists of performing as many statistical tests as possible on all trial data, in order to detect centers whose data are inconsistent with data from other centers. METHODS: We conducted simulations using data from a large multicenter trial conducted in Japan for patients with advanced gastric cancer. The actual trial data were contaminated in computer simulations for varying percentages of centers, percentages of patients modified within each center and numbers and types of modified variables. The unsupervised statistical monitoring software was run by a blinded team on the contaminated data sets, with the purpose of detecting the centers with contaminated data. The operating characteristics (sensitivity, specificity and Youden's J-index) were calculated for three detection methods: one using the p-values of individual statistical tests after adjustment for multiplicity, one using a summary of all p-values for a given center, called the Data Inconsistency Score, and one using both of these methods. RESULTS: The operating characteristics of the three methods were satisfactory in situations of data contamination likely to occur in practice, specifically when a single or a few centers were contaminated. As expected, the sensitivity increased for increasing proportions of patients and increasing numbers of variables contaminated. The three methods showed a specificity better than 93% in all scenarios of contamination. The method based on the Data Inconsistency Score and individual p-values adjusted for multiplicity generally had slightly higher sensitivity at the expense of a slightly lower specificity. CONCLUSIONS: The use of brute force (a computer-intensive approach that generates large numbers of statistical tests) is an effective way to check data quality in multicenter clinical trials. It can provide a cost-effective complement to other data-management and monitoring techniques.

A study of second-line irinotecan plus cisplatin vs. irinotecan alone in platinum-naïve patients with early relapse of gastric cancer refractory to adjuvant S-1 monotherapy: exploratory subgroup analysis of the randomized phase III TRICS trial.

BACKGROUNDS: Many patients with gastric cancer relapse during or early after adjuvant chemotherapy. The standard treatment for early relapse patients is a second-line chemotherapy (SLC) based on irinotecan, taxanes, or a platinum-based chemotherapy. The platinum-containing biweekly irinotecan plus cisplatin (IRI/CDDP) combination was assumed to be promising in several reports of clinical trials as SLC. TRICS trial, a randomized phase III study of IRI/CDDP vs. IRI in platinum-naïve gastric cancers refractory to S-1 monotherapy, revealed that both irinotecan-based chemotherapies were effective and well tolerated. METHODS: This study analyzed 108 patients in the TRICS trial who experienced early relapse. Patients receiving IRI/CDDP (IRI, 60 mg/m2; CDDP, 30 mg/m2, q2w) versus IRI (150 mg/m2, q2w) were compared regarding overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and safety. RESULTS: The OS was 14.0 (95% confidence interval [CI]: 11.0-21.2) and 14.0 (95% CI: 10.7-16.5) months for IRI/CDDP and IRI, respectively (hazard ratio [HR]: 0.782; 95% CI: 0.515-1.188, P = 0.249). No significant differences were observed for PFS (5.0 vs. 4.5 months, respectively; HR: 0.802; 95% CI: 0.543-1.185, P = 0.268) or ORR (19.6% [95% CI: 9.4-33.9%] vs. 23.3% [95% CI: 11.8-38.6%], respectively). The incidence of grade 3-4 anemia was higher for IRI/CDDP than for IRI (20% vs. 0%, respectively; P = 0.0006). CONCLUSION: Our study showed no significant survival differences between IRI/CDDP and IRI in platinum-naïve patients who relapsed during or within 6 months after S-1 adjuvant therapy; therefore, IRI may be a good option in this population. CLINICAL TRIAL INFORMATION: UMIN 000002571.

A randomised phase II trial of capecitabine plus cisplatin versus S-1 plus cisplatin as a first-line treatment for advanced gastric cancer: Capecitabine plus cisplatin ascertainment versus S-1 plus cisplatin randomised PII trial (XParTS II).

BACKGROUND: Capecitabine plus cisplatin (XP) is a standard global regimen, while S-1 plus cisplatin (SP) is a Japanese standard for first-line treatment of advanced gastric cancer (AGC). We conducted a phase II trial comparing XP with SP for patients with AGC to confirm whether these regimens can be used as controls in a phase III study and to explore whether histological subtypes favour XP or SP. PATIENTS AND METHODS: Eligible patients were randomised to receive either S-1 40 mg/m2 for 21 days plus cisplatin 60 mg/m2 (q5w) or capecitabine 1000 mg/m2 for 14 days plus cisplatin 80 mg/m2 (q3w). The primary end-point was progression-free survival (PFS). The secondary end-points were overall survival (OS), overall response rate (ORR) and safety. RESULTS: In 110 eligible patients, 24-week PFS was higher in both groups (SP 50.9%, XP 43.5%) than the protocol-specified threshold of 40%. The median PFS for SP versus XP was 5.6 and 5.1 months (hazard ratio [HR], 1.126; p = 0.5626); OS was 13.5 and 12.6 months (HR, 0.942; p = 0.7769) and the ORR was 42.4% and 69.4% (p = 0.0237), respectively. The most common grade ≥3 adverse events with SP/XP were anaemia (16%/20%), neutropenia (9%/18%) and anorexia (18%/13%). Subgroup analysis by histological classification showed no statistical difference between treatments. CONCLUSIONS: XP and SP are comparable and can be recommended as control arms in a phase III study for AGC. Histological subtypes were not sensitive markers for the selection of XP or SP. CLINICAL TRIAL REGISTRATION: NCT00140624.

Administration of thiamazole for Graves' disease might trigger the onset of type 1 diabetes.

Thiamazole might trigger the onset of type 1 diabetes.

A phase II trial of capecitabine plus cisplatin (XP) for patients with advanced gastric cancer with early relapse after S-1 adjuvant therapy: XParTS-I trial.

BACKGROUNDS: In Japan, standard regimens for advanced gastric cancer (AGC) include S-1 chemotherapy. The standard treatment for early relapse after adjuvant chemotherapy with fluoropyrimidine alone is platinum-based chemotherapy, while the standard treatment for early relapse after adjuvant chemotherapy with fluoropyrimidine plus platinum is second-line chemotherapy. To evaluate the efficacy and safety of capecitabine plus cisplatin (XP) treatment for AGC patients who relapse within 6 months after S-1-based therapy, we conducted a multicenter phase II trial (NCT01412294). METHODS: HER2-negative gastric cancer patients treated with adjuvant chemotherapy including S-1 for more than 12 weeks and relapsed within 6 months were treated with capecitabine 1000 mg/m2 bid for 14 days plus cisplatin 80 mg/m2 on day 1 of a 3-week cycle. The primary endpoint was PFS; secondary endpoints were OS, time to treatment failure, overall response rate (ORR) and safety. RESULTS: Forty patients (median age 64) were enrolled; of those, 37 (92.5%) received adjuvant S-1 monotherapy. Median PFS was 4.4 months (95% CI 3.6-5.1), which was longer than the 2-month protocol-specified threshold (p < 0.001). Median OS was 13.7 months (95% CI 9.0-17.7) and ORR was 8/30 (26.7%) (95% CI 14.2-44.4). Most common grade ≥ 3 adverse events were neutropenia (23%), anemia (18%), elevated serum creatinine (18%), fatigue (13%), diarrhea (7.5%), and anorexia (7.5%). CONCLUSIONS: XP was safe and effective in patients with early relapse after S-1 adjuvant chemotherapy for curatively resected gastric cancers. XP may be a good option for the treatment of patients after early failure after adjuvant S-1. TRIAL REGISTRATION: NCT01412294.

Possible Long-Term Efficacy of Sitagliptin, a Dipeptidyl Peptidase-4 Inhibitor, for Slowly Progressive Type 1 Diabetes (SPIDDM) in the Stage of Non-Insulin-Dependency: An Open-Label Randomized Controlled Pilot Trial (SPAN-S).

INTRODUCTION: We tested the hypothesis that dipeptidyl peptidase-4 (DPP-4) inhibitors are effective in preserving the ß-cell function for long-term periods in patients with slowly progressive type 1 diabetes (SPIDDM) or latent autoimmune diabetes in adults (LADA). METHODS: In the present open-label, randomized, controlled trial, 14 non-insulin-requiring diabetic patients with glutamic acid decarboxylase autoantibodies (GADAb) were randomly assigned to receive either sitagliptin (S group) or pioglitazone (P group). As a historical control, the Tokyo Study, in which non-insulin-dependent patients with SPIDDM were assigned to receive treatment by either insulin or sulfonylurea (SU), was used. RESULTS: On average, the ∑C-peptide values during the oral glucose tolerance test through the follow-up periods showed a nonsignificant increase in the S group (n = 6, n = 5 at 48 months) compared to the P group (n = 5, n = 2 at 48 months). In comparison to the data in the Tokyo Study, treatment by sitagliptin significantly influenced the longitudinal changes in the ∑C-peptide values with a more increased direction than insulin or SU, especially in patients with 48 months of follow-up (p = 0.014 and p = 0.007, respectively). Although the titers of GADAb were not significantly different between the S and P groups during the study, the change ratio of the GADAb titers from baseline was significantly inversely correlated with the change ratio of the ∑C-peptide values from baseline in the S group (p = 0.003); in particular, when the GADAb titers decreased from baseline, the ∑C-peptide values frequently increased. CONCLUSION: The present pilot trial suggests that treatment of SPIDDM/LADA by sitagliptin, a DPP-4 inhibitor, may be more effective in preserving the ß-cell function than insulin treatment for at least 4 years, possibly through the immune modulatory effects of DPP-4 inhibitors. CLINICAL TRIAL REGISTRATION: Japanese Clinical Trials Registry UMIN000003693.

Feasibility of weekly intraperitoneal versus intravenous paclitaxel therapy delivered from the day of radical surgery for gastric cancer: a preliminary safety analysis of the INPACT study, a randomized controlled trial.

BACKGROUND: Peritoneal carcinomatosis is common after curative resection of gastric cancer. Intraperitoneal administration of paclitaxel (PTX) is known to control ovarian peritoneal metastases. PATIENTS AND METHODS: Patients with either linitis plastica or T4 cancer with high risk of peritoneal metastasis or recurrence but whose cancer was considered resectable were preregistered. After their cancer had been confirmed intraoperatively as resectable, the patients were randomized into either group A (PTX at 60 mg/m2 intraperitoneally on the day of surgery and on days 14, 21, 28, 42, 49, and 56) or group B (PTX at 80 mg/m2 administered intravenously by the identical schedule) before being treated by evidence-based chemotherapy. The primary end point was the 2-year survival rate. Safety, the secondary end point, was also analyzed. The study has been registered as UMIN000002957. RESULTS: Of 177 preregistered patients, 83 underwent treatment (39 by intraperitoneal administration and 44 by intravenous administration). There was no difference in patient demographics between the two groups. The incidences of surgical complications were similar between the groups, except for transient bowel obstruction observed exclusively in group A. The relative dose intensity of PTX was 81.4 % for group A and 76.3 % for group B. There was one death due to pulmonary thrombosis and a case of anaphylaxis that led to termination of the protocol treatment (group B). Other adverse events were mild and manageable. CONCLUSIONS: Intraperitoneal administration of PTX from the day of gastrectomy did not result in a higher incidence of surgical complications and adverse reactions when compared with intravenous administration of PTX.

Changes in the Composition of Adiponectin Fractions over a 3-Year Period in Children: A Population-Based Cohort Study.

BACKGROUND: Little information is available regarding changes in adiponectin fractions. The objective of this study was to examine changes in the composition of differing adiponectin fractions using a population-based, prospective pediatric cohort. METHODS: A total of 358 fourth graders (9-10 years old) from Ina town in Saitama, Japan, were followed up for 3 years. BMI and total adiponectin (TAD), high-molecular weight adiponectin (HAD), medium-molecular weight adiponectin, and low-molecular weight adiponectin levels were measured in these subjects at baseline and at the end of the follow-up. RESULTS: Of the fourth graders participating in the study, 326 (172 boys and 154 girls; follow-up rate, 91.1%) became available for follow-up. No significant changes were observed in TAD values after 3 years. HAD values were significantly decreased in both the boys (2.4 to 2.2 µg/mL: p < 0.001) and girls (3.1 to 2.7 µg/mL: p = 0.005). All values in the parameters examined at baseline and after 3 years were significantly correlated. A negative correlation was found between the ratios of follow-up compared to baseline values for BMI and those for TAD (boys, r = -0.322, p < 0.001; girls, r = -0.433, p < 0.001) as well as those for HAD (boys, r = -0.353, p < 0.001; girls, r = -0.351, p < 0.001). CONCLUSIONS: HAD had the most robust correlation between its values at baseline and those after 3 years in both boys and girls. The changes in HAD also had the most robust correlation between the changes in BMI in 3 years.

Survival results of a randomised two-by-two factorial phase II trial comparing neoadjuvant chemotherapy with two and four courses of S-1 plus cisplatin (SC) and paclitaxel plus cisplatin (PC) followed by D2 gastrectomy for resectable advanced gastric cancer.

BACKGROUND: The prognosis for stage III gastric cancer is unsatisfactory by D2 gastrectomy and S-1 adjuvant chemotherapy. Both S-1 plus cisplatin (SC) and paclitaxel plus cisplatin (PC) are promising regimens as neoadjuvant chemotherapy; however, the optimal duration remains unclear. PATIENTS AND METHODS: In this 2×2 randomised phase II trial, stage III gastric cancer patients, those with a prognosis corresponding to stage III, and macroscopically resectable stage IV cases were randomised to two or four courses of S-1 (80 mg/m(2) for 21 d with 1 week rest)/cisplatin (60 mg/m(2) at day 8) or PC (80 and 25 mg/m(2), respectively, on days 1, 8, and 15 with 1 week rest) as neoadjuvant chemotherapy. The primary end-point was the 3-year overall survival (OS). RESULTS: Between October 2009 and July 2011, 83 patients received 2 courses of SC (n=21), 4 courses of SC (n=20), 2 courses of PC (n=21) and 4 courses of PC (n=21). The 3-year OS was 60.9% for SC and 64.3% for PC and 64.3% for the two courses and 61.0% for the four courses. Subset analyses demonstrated no subgroup which showed any potential survival benefit by PC in comparison to SC or by four courses as in comparison to two courses. CONCLUSIONS: Two courses of SC as neoadjuvant chemotherapy are recommended as a test arm of a future phase III study for patients with locally advanced gastric cancer. CLINICAL TRIAL NUMBER: UMIN-000002595.

Feasibility and Safety of Transhiatal Approach and D2 Total Gastrectomy after Neoadjuvant Chemotherapy for Adenocarcinoma of the Esophago-Gastric Junction: A Subset Analysis of the COMPASS Trial.

BACKGROUND: It was unclear whether the transhiatal approach and D2 total gastrectomy after neoadjuvant chemotherapy (NAC) for adenocarcinoma of the esophago-gastric (AEG) junction are as feasible and safe as D2 gastrectomy following NAC. PATIENTS AND METHODS: We clarified the short-term surgical results in AEG and non-AEG patients in a subset analysis of the COMPASS trial. RESULTS: Eighty-three patients, 24 with AEG and 59 with non-AEG, were registered in the study. Among 24 patients with AEG, 5 were classified to have Siewert type I, 11 to have type II and 8 to have type III. The tumor progression, completion of NAC, and clinical and pathological responses were similar between the groups. Twenty-four AEG and 51 non-AEG patients proceeded to surgery. The extent of dissection (D1/D2) was 3/21 in the AEG and 3/48 in the non-AEG patients. The R0 resection rate was 69% in the non-AEG and 88% in the AEG patients. Neither grade 3b/4 morbidity nor surgical mortality was observed in either group. CONCLUSIONS: The transhiatal approach and D2 total gastrectomy after NAC seem to be as safe and feasible as D2 gastrectomy for non-AEG cancer.

Randomised phase III trial of second-line irinotecan plus cisplatin versus irinotecan alone in patients with advanced gastric cancer refractory to S-1 monotherapy: TRICS trial.

AIM: The optimal second-line regimen for treating advanced gastric cancer (AGC) remains unclear. While irinotecan (CPT-11) plus cisplatin (CDDP) combination therapy and CPT-11 monotherapy have been explored in the second-line setting, the superiority of second-line platinum-based therapies for AGC patients initially treated with S-1 monotherapy has not yet been evaluated; therefore, we aimed to examine the survival benefit of CPT-11/CDDP combination over CPT-11 monotherapy. METHODS: AGC patients showing progression after S-1 monotherapy for advanced cancer or recurrence within 6 months after completion of S-1 adjuvant therapy were randomly allocated to CPT-11/CDDP (CPT-11, 60 mg/m(2); CDDP, 30 mg/m(2), q2w) or CPT-11 (150 mg/m(2), q2w). RESULTS: Sixty-eight advanced and 95 recurrent cases were evaluated. The median overall survivals were 13.9 (95% confidence interval [CI]: 10.8-17.6) and 12.7 (95% CI: 10.3-17.2) months for CPT-11/CDDP and CPT-11, respectively (hazard ratio: 0.834; 95% CI: 0.596-1.167, P = 0.288). No significant differences were observed in the secondary end-points, including progression-free survival (4.6 [95% CI: 3.4-5.9] versus 4.1 [95% CI: 3.3-4.9]months) and response rate (16.9% [95% CI: 8.8-28.3] versus 15.4% [95% CI: 7.6-26.5]). The incidences of grade 3-4 anaemia (16% versus 4%) and elevated serum lactate dehydrogenase levels (5% versus 0%) were higher for CPT-11/CDDP than for CPT-11. Exploratory subgroup analysis revealed that CPT-11/CDDP was significantly more effective for intestinal-type AGC, compared with CPT-11 (overall survival: 15.8 versus 14.0 months; P = 0.019). CONCLUSION: No survival benefit was observed upon adding CDDP to CPT-11 after S-1 monotherapy failure.

A genome-wide association study for diabetic retinopathy in a Japanese population: potential association with a long intergenic non-coding RNA.

Elucidation of the genetic susceptibility factors for diabetic retinopathy (DR) is important to gain insight into the pathogenesis of DR, and may help to define genetic risk factors for this condition. In the present study, we conducted a three-stage genome-wide association study (GWAS) to identify DR susceptibility loci in Japanese patients, which comprised a total of 837 type 2 diabetes patients with DR (cases) and 1,149 without DR (controls). From the stage 1 genome-wide scan of 446 subjects (205 cases and 241 controls) on 614,216 SNPs, 249 SNPs were selected for the stage 2 replication in 623 subjects (335 cases and 288 controls). Eight SNPs were further followed up in a stage 3 study of 297 cases and 620 controls. The top signal from the present association analysis was rs9362054 in an intron of RP1-90L14.1 showing borderline genome-wide significance (Pmet = 1.4×10(-7), meta-analysis of stage 1 and stage 2, allele model). RP1-90L14.1 is a long intergenic non-coding RNA (lincRNA) adjacent to KIAA1009/QN1/CEP162 gene; CEP162 plays a critical role in ciliary transition zone formation before ciliogenesis. The present study raises the possibility that the dysregulation of ciliary-associated genes plays a role in susceptibility to DR.

Sequential paclitaxel followed by tegafur and uracil (UFT) or S-1 versus UFT or S-1 monotherapy as adjuvant chemotherapy for T4a/b gastric cancer (SAMIT): a phase 3 factorial randomised controlled trial.

BACKGROUND: The prognosis for locally advanced gastric cancer is poor despite advances in adjuvant chemotherapy. We did the Stomach cancer Adjuvant Multi-Institutional group Trial (SAMIT) to assess the superiority of sequential treatment (paclitaxel then tegafur and uracil [UFT] or paclitaxel then S-1) compared with monotherapy (UFT or S-1) and also the non-inferiority of UFT compared with S-1. METHODS: We did this randomised phase 3 trial with a two-by-two factorial design at 230 hospitals in Japan. We enrolled patients aged 20-80 years with T4a or T4b gastric cancer, who had had D2 dissection and a ECOG performance score of 0-1. Patients were randomly assigned to one of four treatment groups with minimisation for tumour size, lymph node metastasis, and study site. Patients received UFT only (267 mg/m(2) per day), S-1 only (80 mg/m(2) per day) for 14 days, with a 7-day rest period or three courses of intermittent weekly paclitaxel (80 mg/m(2)) followed by either UFT, or S-1. Treatment lasted 48 weeks in monotherapy groups and 49 weeks in the sequential treatment groups. The primary endpoint was disease-free survival assessed by intention to treat. We assessed whether UFT was non-inferior to S-1 with a non-inferiority margin of 1·33. This trial was registered at UMIN Clinical Trials Registry, number C000000082. FINDINGS: We randomly assigned 1495 patients between Aug 3, 2004, and Sept 29, 2009. 374 patients were assigned to receive UFT alone, 374 to receive S-1 alone, 374 to received paclitaxel then UFT, and 373 to receive paclitaxel then S-1. We included 1433 patients in the primary analysis after at least 3 years of follow-up (359, 364, 355, and 355 in each group respectively). Protocol treatment was completed by 215 (60%) patients in the UFT group, 224 (62%) in the S-1 group, 242 (68%) in the paclitaxel then UFT group, and 250 (70%) in the paclitaxel then S-1 group. 3-year disease-free survival for monotherapy was 54·0% (95% CI 50·2-57·6) and that of sequential treatment was 57·2% (53·4-60·8; hazard ratio [HR] 0·92, 95% CI 0·80-1·07, p=0·273). 3-year disease-free survival for the UFT group was 53·0% (95% CI 49·2-56·6) and that of the S-1 group was 58·2% (54·4-61·8; HR 0·81, 95% CI 0·70-0·93, p=0·0048; pnon-inferiority=0·151). The most common grade 3-4 haematological adverse event was neutropenia (41 [11%] of 359 patients in the UFT group, 48 [13%] of 363 in the S-1 group, 46 [13%] of 355 in the paclitaxel then UFT group, and 83 [23%] of 356 in the paclitaxel then S-1 group). The most common grade 3-4 non-haematological adverse event was anorexia (21 [6%], 24 [7%], seven [2%], and 18 [5%], respectively). INTERPRETATION: Sequential treatment did not improve disease-free survival, and UFT was not non-inferior to S-1 (and S-1 was superior to UFT), therefore S-1 monotherapy should remain the standard treatment for locally advanced gastric cancer in Japan. FUNDING: Epidemiological and Clinical Research Information Network.

Low creatinine clearance is a risk factor for D2 gastrectomy after neoadjuvant chemotherapy.

BACKGROUND: The feasibility and safety of D2 surgery following neoadjuvant chemotherapy (NAC) has not been fully evaluated in patients with gastric cancer. Moreover, risk factor for surgical complications after D2 gastrectomy following NAC is also unknown. The purpose of the present study was to identify risk factors of postoperative complications after D2 surgery following NAC. METHODS: This study was conducted as an exploratory analysis of a prospective, randomized Phase II trial of NAC. The surgical complications were assessed and classified according to the Clavien-Dindo classification. A uni- and multivariate logistic regression analyses were performed to identify risk factors for morbidity. RESULTS: Among 83 patients who were registered to the Phase II trial, 69 patients received the NAC and D2 gastrectomy. Postoperative complications were identified in 18 patients and the overall morbidity rate was 26.1 %. The results of univariate and multivariate analyses of various factors for overall operative morbidity, creatinine clearance (CCr) ≤ 60 ml/min (P = 0.016) was identified as sole significant independent risk factor for overall morbidity. Occurrence of pancreatic fistula was significantly higher in the patients with a low CCr than in those with a high CCr. CONCLUSIONS: Low CCr was a significant risk factor for surgical complications in D2 gastrectomy after NAC. Careful attention is required for these patients.

Accuracy of CT staging of locally advanced gastric cancer after neoadjuvant chemotherapy: cohort evaluation within a randomized phase II study.

BACKGROUND: Accuracy of the radiologic diagnosis of gastric cancer staging after neoadjuvant chemotherapy remains unclear. METHODS: Patients enrolled in the COMPASS trial, a randomized phase II study comparing two and four courses of S-1 plus cisplatin and paclitaxel and cisplatin followed by gastrectomy, were examined. The radiologic stage was determined by using thin-slice computed tomography (CT) or multidetector low CT by following Habermann's method. RESULTS: A total of 75 patients registered in the COMPASS study who underwent surgical resection were examined in this study. The radiologic T and pathologic T stages were not significantly correlated (p = 0.221). The radiologic accuracy and rates of underdiagnosis and overdiagnosis were 42.7, 10.7, and 46.7%, respectively. When patients were stratified according to the pathologic response of the primary tumor, the correlation was not significant in either the responders (n = 32, p = 0.410) or the nonresponders (n = 43, p = 0.742). The radiologic accuracy was 37.5% in the responders and 42.7% in the nonresponders. The radiologic N and pathologic N stages were significantly correlated (p = 0.000). The radiologic accuracy and rates of underdiagnosis and overdiagnosis were 44, 29.3, and 26.7%, respectively. When stratifying the patients with measurable lymph nodes according only to the radiologic response, the correlation was significant in the nonresponders (n = 23, p = 0.035) but not in the responders (n = 28, p = 0.634). The radiologic accuracy was 39.3% in the responders and 52.1% in the nonresponders. CONCLUSIONS: Restaging using CT after neoadjuvant chemotherapy for gastric cancer is considered to be inaccurate and unreliable. In particular, the radiologic T-staging determined after neoadjuvant chemotherapy should not be considered in clinical decision-making.

Induction of a pathological complete response by four courses of neoadjuvant chemotherapy for gastric cancer: early results of the randomized phase II COMPASS trial.

BACKGROUND: The prognosis for stage 3 gastric cancer is not satisfactory, even with S-1 adjuvant chemotherapy. A randomized phase II trial was conducted to compare two and four courses of neoadjuvant S-1/cisplatin (SC) and paclitaxel/cisplatin (PC) using a two-by-two factorial design for locally advanced gastric cancer. The primary endpoint was overall survival. We clarified the impact of these regimens on the secondary endpoints, including the clinical and pathological responses, chemotherapy-related toxicities, and surgical results. METHODS: Patients received S-1 (80 mg/m(2) for 21 days with 1 week's rest)/cisplatin (60 mg/m(2) at day 8) or paclitaxel/cisplatin (80 and 25 mg/m(2), respectively, on days 1, 8, and 15 with 1 week's rest) as neoadjuvant chemotherapy. RESULTS: Eighty-three patients were assigned to arm A (two courses of SC, n = 21), arm B (four courses of SC, n = 20), arm C (two courses of PC, n = 21), and arm D (four courses of PC, n = 21). Pathological response rate was 43 % in arm A, 40 % in arm B, 29 % in arm C, and 38 % in arm D. Pathological complete response was only observed in arms B (10 %) and D (10 %). Most bone marrow toxicities, nausea, vomiting, alopecia, and fatigue were slightly higher but acceptable in arms B and D. Grade 3/4 surgical morbidities were not commonly observed in all four arms. CONCLUSIONS: Pathological complete response could be induced by four courses of neoadjuvant chemotherapy without a marked increase of toxicities, regardless of a SC or PC regimen.