Meta-analysis of three randomized trials of capecitabine plus cisplatin (XP) versus S-1 plus cisplatin (SP) as first-line treatment for advanced gastric cancer.

BACKGROUND: S-1 plus cisplatin (SP) and capecitabine plus cisplatin (XP) are standard first-line regimens for advanced gastric cancer (AGC) worldwide. We conducted a meta-analysis using individual participant data (IPD) to investigate which is more suitable. METHODS: IPD from three randomized trials were collected. In these trials, patients with AGC were randomly allocated to SP (S-1 80-120 mg for 21 days plus cisplatin 60 mg/m2 (q5w)) or XP (capecitabine 2000 mg/m2 for 14 days plus cisplatin 80 mg/m2 (q3w)). RESULTS: In 211 eligible patients, median overall survival (OS) for SP versus XP was 13.5 and 11.7 months (hazard ratio [HR], 0.787; p = 0.114), progression-free survival (PFS) was 6.2 and 5.1 months (HR, 0.767; P = 0.076), and TTF was 5.1 and 4.0 months (HR, 0.611; P = 0.001). The most common grade ≥ 3 adverse events with SP or XP were neutropenia (18% vs. 29%) and anorexia (16% vs.18%). Subgroup analysis demonstrated significant interaction between treatment effect and performance status > 1 (HR, 0.685; P = 0.036), measurable lesion (HR, 0.709; P = 0.049), primary upper third tumor (HR, 0.539; P = 0.040), and differentiated type (HR, 0.549; interaction, 0.236; P = 0.019). For the differentiated type, OS was significantly longer in the SP group (13.2 months) than in the XP group (11.1 months) (HR, 0.549; P = 0.019). For the undifferentiated type, OS was similar in the SP group (14.2 months) and in the XP group (12.4 months) (HR, 0.868; P = 0.476). CONCLUSIONS: SP and XP were both effective and well tolerated. SP might be suitable for the pathological differentiated subtype of AGC. CLINICAL TRIAL REGISTRATION: The HERBIS-2, HERBIS-4A, and XParTS II trials were registered with UMIN-CTR as UMIN000006105, UMIN000006755, and UMIN000006045, respectively.

Machine-learning model derived gene signature predictive of paclitaxel survival benefit in gastric cancer: results from the randomised phase III SAMIT trial.

OBJECTIVE: To date, there are no predictive biomarkers to guide selection of patients with gastric cancer (GC) who benefit from paclitaxel. Stomach cancer Adjuvant Multi-Institutional group Trial (SAMIT) was a 2×2 factorial randomised phase III study in which patients with GC were randomised to Pac-S-1 (paclitaxel +S-1), Pac-UFT (paclitaxel +UFT), S-1 alone or UFT alone after curative surgery. DESIGN: The primary objective of this study was to identify a gene signature that predicts survival benefit from paclitaxel chemotherapy in GC patients. SAMIT GC samples were profiled using a customised 476 gene NanoString panel. A random forest machine-learning model was applied on the NanoString profiles to develop a gene signature. An independent cohort of metastatic patients with GC treated with paclitaxel and ramucirumab (Pac-Ram) served as an external validation cohort. RESULTS: From the SAMIT trial 499 samples were analysed in this study. From the Pac-S-1 training cohort, the random forest model generated a 19-gene signature assigning patients to two groups: Pac-Sensitive and Pac-Resistant. In the Pac-UFT validation cohort, Pac-Sensitive patients exhibited a significant improvement in disease free survival (DFS): 3-year DFS 66% vs 40% (HR 0.44, p=0.0029). There was no survival difference between Pac-Sensitive and Pac-Resistant in the UFT or S-1 alone arms, test of interaction p<0.001. In the external Pac-Ram validation cohort, the signature predicted benefit for Pac-Sensitive (median PFS 147 days vs 112 days, HR 0.48, p=0.022). CONCLUSION: Using machine-learning techniques on one of the largest GC trials (SAMIT), we identify a gene signature representing the first predictive biomarker for paclitaxel benefit. TRIAL REGISTRATION NUMBER: UMIN Clinical Trials Registry: C000000082 (SAMIT); ClinicalTrials.gov identifier, 02628951 (South Korean trial).

Preoperative risk factors for postoperative intra-abdominal infectious complication after gastrectomy for gastric cancer using a Japanese web-based nationwide database.

BACKGROUND: Postoperative intra-abdominal infectious complication (PIIC) after gastrectomy for gastric cancer worsens in-hospital death or long-term survival. However, the methodology for PIIC preoperative risk assessment remains unestablished. We aimed to develop a preoperative risk model for postgastrectomy PIIC. METHODS: We collected 183,936 patients' data on distal or total gastrectomy performed in 2013-2016 for gastric cancer from the Japanese National Clinical Database and divided into development (2013-2015; n = 140,558) and validation (2016; n = 43,378) cohort. The primary outcome was the incidence of PIIC. The risk model for PIIC was developed using 18 preoperative factors: age, sex, body mass index, activities of daily living, 12 comorbidity types, gastric cancer stage, and surgical procedure in the development cohort. Secondarily, we developed another model based on the new scoring system for clinical use using selected factors. RESULTS: The overall incidence of PIIC was 4.7%, including 2.6%, 1.7%, and 1.3% in anastomotic leakage, pancreatic fistula, and intra-abdominal abscess, respectively. Among the 18 preoperative factors, male [odds ratio, (OR) 1.92], obesity (OR, 1.52-1.96), peripheral vascular disease (OR, 1.55), steroid use (OR, 1.83), and total gastrectomy (OR, 1.89) strongly correlated with PIIC incidence. The entire model using the 18 factors had good discrimination and calibration in the validation cohort. We selected eight relevant factors to create a simple scoring system, using which we categorized the patients into three risk groups, which showed good calibration. CONCLUSION: Using nationwide clinical practice data, we created a preoperative risk model for postgastrectomy PIIC for gastric cancer.

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.

Meta-analysis of two randomized phase III trials (TCOG GI-0801 and ECRIN TRICS) of biweekly irinotecan plus cisplatin versus irinotecan alone as second-line treatment for advanced gastric cancer.

BACKGROUND: Biweekly irinotecan (CPT-11) plus cisplatin (CDDP) combination (BIRIP) and CPT-11 alone are both expectable options for treating advanced gastric cancer (AGC) in a second-line setting. We conducted a meta-analysis to compare the efficacy and safety of these two regimens in patients enrolled two randomized phase III trials. PATIENTS AND METHODS: Individual patient-level data from two randomized phase III trials were collected for this study. In both trials, patients with AGC refractory to S-1-based chemotherapy were randomly allocated to BIRIP (CPT-11, 60 mg/m2; CDDP, 30 mg/m2, q2w) or to CPT-11 (150 mg/m2, q2w). RESULTS: Cumulative data from 290 eligible patients were evaluated. The OS was 12.3 months [95% confidence interval (CI) 10.5-14.1] in the BIRIP group and 11.3 months (95% CI 10.0-13.2) in the CPT-11 group (hazard ratio 0.87; 95% CI 0.68-1.12, P = 0.272), while PFS was significantly longer in the BIRIP group (4.3 months [95% CI 3.5-5.1]) than in the CPT-11 group (3.3 months [2.9-4.1]; HR 0.77; 95% CI 0.61-0.98, P = 0.035). The response rate was 20.5% in the BIRIP group and 16.0% in the CPT-11 group (P = 0.361). However, the disease control rate was significantly better in the BIRIP group (72.1%) than in the CPT-11 group (59.2%) (P = 0.032). The two groups did not differ significantly in the incidences of grade 3 or worse adverse events. CONCLUSIONS: Both BIRIP and CPT-11 may be good therapeutic options for patients with AGC as second-line treatment. CLINICAL TRIAL REGISTRATION: UMIN 000025367.

Current status of perioperative chemotherapy for locally advanced gastric cancer and JCOG perspectives.

Perioperative treatment for locally advanced gastric cancer has been inconsistent between Japan and the Western countries. In Japan, D2 gastrectomy followed by adjuvant chemotherapy is regarded as standard treatment, while neoadjuvant or perioperative chemotherapy is considered to be a standard in the Western countries. Stomach Cancer Study Group of Japan Clinical Oncology Group (JCOG) has conducted many perioperative chemotherapy trials. After the publishing of positive results of ACTS-GC trial, stage-specific adjuvant chemotherapy protocols are planned. JCOG1104 was conducted as to demonstrate the non-inferiority of four courses of S-1 to standard eight courses of S-1, because the efficacy of S-1 appears to be sufficient in stage II. The trial failed to demonstrate the non-inferiority of four courses of S-1. S-1 for 1 year is still recognized to be a standard for stage II gastric cancer. For stage III, studies with more intensive treatments were planned as the efficacy of S-1 monotherapy seems to be insufficient. As in the Western countries, JCOG planned the perioperative chemotherapy. However, the clinical staging is a serious issue to select optimal patients for perioperative chemotherapy. JCOG conducted a prospective cohort study to evaluate the validity of clinical staging in JCOG1302A. From the results of this study, cT3-4 and cN1-3 are selected as optimal candidate for perioperative chemotherapy. JCOG1509 was conducted to demonstrate the superiority of perioperative chemotherapy to adjuvant chemotherapy in these cohorts. Perioperative chemotherapy for marginally resectable tumours such as linitis plastica or extensive nodal disease and special type of cancer like HER2 positive are also conducted.

An integrated analysis of two phase II trials (JCOG0001 and JCOG0405) of preoperative chemotherapy followed by D3 gastrectomy for gastric cancer with extensive lymph node metastasis.

BACKGROUND: Gastric cancer with extensive lymph node metastasis is commonly regarded as unresectable, while preoperative chemotherapy followed by gastrectomy has been tested since 2000 in JCOG (JCOG0001 and JCOG0405). The survivals were quite different between the trials despite the similar eligibility criteria. The aim of this study was to investigate if survival is still better in JCOG0405 after adjusting baseline factors and if there is any subset of patients who benefit more from either treatment. METHODS: Eligibility criteria for both trials included histologically proven gastric adenocarcinoma; bulky nodal involvement around the celiac artery and its major branches (bulky N) and/or para-aortic lymph node (PAN); cM0 (except PAN); negative lavage cytology; not linitis plastica type; PS of 0 or 1. Patients received two or three cycles of preoperative chemotherapy of irinotecan plus cisplatin in JCOG0001, or S-1 plus cisplatin in JCOG0405, followed by D3 gastrectomy. Multivariable analysis for overall survival adjusting baseline and treatment factors was performed with the Cox regression model. RESULTS: After adjusting baseline factors, S-1 plus cisplatin was superior to irinotecan plus cisplatin for overall survival (HR = 0.39: 95% CI 0.22-0.67). The 5-year overall survival was poor for patients with bulky N+/PAN+ (19.2%) compared with bulky N+/PAN- (50.7%) or bulky N-/PAN+ (43.5%). CONCLUSIONS: S-1 plus cisplatin was shown to be a favorable preoperative treatment for gastric cancer with extensive lymph node metastasis by multivariable analysis, while poor prognosis in patients having both bulky N+ and PAN+ may necessitate further treatment improvement.

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.

Frequent Coamplification of Receptor Tyrosine Kinase and Downstream Signaling Genes in Japanese Primary Gastric Cancer and Conversion in Matched Lymph Node Metastasis.

OBJECTIVE: To establish the gene copy number status of receptor tyrosine kinase (RTK) and downstream signaling (DSS) genes genes in primary gastric cancer (primGC) and matched lymph node metastases (LNmet). BACKGROUND: Evidence suggests that coamplification between RTKs and DSSs and conversion between primGC and LNmet are associated with resistance to targeted therapy. METHODS: DNA from 237 Japanese primGC and 103 matched LNmet was analyzed using a newly developed multiplex ligation-dependent probe amplification (MLPA) probemix to investigate RTK (EGFR, HER2, FGFR2, and MET) and DSS (PIK3CA, KRAS, MYC, and CCNE1) gene copy number status. Results were compared between primGC and LNmet and related to clinicopathological data including survival. RESULTS: A total of 150 (63%) primGC had either RTK or DSS amplification. DSS coamplification was more frequent than RTK coamplification in primGC and LNmets. Moreover, 70 (30%) GC showed a disconcordant RTK and/or DSS gene copy number status between primGC and LNmet, most common was negative conversion for DSS genes (n=40 GC). The presence of RTK amplification in primGC was related to poorer survival in univariate analysis (P=0.04). CONCLUSIONS: This is the first and most comprehensive study in gastric cancer investigating the concordance between gene copy number status of targetable RTKs and downstream signaling oncogenes in primGC and LNmets. Future studies need to establish whether the relative high frequency of RTK and DSS coamplification and/or the relative high rate of negative conversion in LNmet can potentially explain recent failures of RTK targeted therapy in gastric cancer patients.

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.

Adjuvant capecitabine plus oxaliplatin after D2 gastrectomy in Japanese patients with gastric cancer: a phase II study.

BACKGROUND: Adjuvant chemotherapy with XELOX (capecitabine plus oxaliplatin) has been shown to be beneficial following resection of gastric cancer in South Korean, Chinese, and Taiwanese patients. This phase II study (J-CLASSIC-PII) was undertaken to evaluate the feasibility of XELOX in Japanese patients with resected gastric cancer. METHODS: Patients with stage II or III gastric cancer who underwent curative D2 gastrectomy received adjuvant XELOX (eight 3-week cycles of oral capecitabine, 1000 mg/m2 twice daily on days 1-14, plus intravenous oxaliplatin 130 mg/m2 on day 1). The primary endpoint was dose intensity. Secondary endpoints were safety, proportion of patients completing treatment, and 1-year disease-free survival (DFS) rate. RESULTS: One hundred patients were enrolled, 76 of whom completed the study as planned. The mean dose intensity was 67.2 % (95 % CI, 61.9-72.5 %) for capecitabine and 73.4 % (95 % CI, 68.4-78.4 %) for oxaliplatin, which were higher than the predefined age-adjusted threshold values of 63.4 % and 69.4 %, respectively, and the study therefore met its primary endpoint. The 1-year DFS rate was 86 % (95 % CI, 77-91 %). No new safety signals were identified. CONCLUSIONS: The feasibility of adjuvant XELOX in Japanese patients with resected gastric cancer is similar to that observed in South Korean, Chinese, and Taiwanese patients in the Capecitabine and Oxaliplatin Adjuvant Study in Stomach Cancer (CLASSIC) study. Based on findings from this study and the CLASSIC study, the XELOX regimen can be considered an adjuvant treatment option for Japanese gastric cancer patients who have undergone curative resection.

Usefulness of Surgical Apgar Score on Predicting Survival After Surgery for Gastric Cancer.

BACKGROUND: Complete surgical resection is essential for a cure for most gastric cancer. Recently it was reported that surgical Apgar score (SAS) can predict postoperative complication and that postoperative complication is associated with poor long-term survival. The aim of this study is to assess whether SAS can predict overall survival (OS) after surgery for gastric cancer. METHODS: We retrospectively compared clinicopathological characteristics and survival between high and low SAS score groups in patients who underwent gastrectomy for gastric cancer. RESULTS: Low-scored SAS group (group L) was significantly more common among ASA-PS 2, open approach, total gastrectomy, D2 lymph node dissection, postoperative complication grade 2-4, deep tumor invasion, lymph node metastases, and advanced pathological TNM stage than high-scored SAS group (group H). The 5-year OS of group H and group L were 81.6 and 55.9 %, respectively (p < .001); OS of group L tended to be poorer than that of group H in stage III patients (p = .060) and in stage IV patients (p < .001). In multivariate analysis, pathological stage and SAS were identified as independent predictors for OS. CONCLUSIONS: SAS is useful for predicting survival after surgery for gastric cancer.

Validity of the Japanese version of functional assessment of cancer therapy-gastric (FACT-Ga) and its sensitivity to ascites volume change: a retrospective analysis of Japanese clinical trial participants.

PURPOSE: The functional assessment of cancer therapy-gastric (FACT-Ga) questionnaire was designed to evaluate quality of life (QOL) in patients with gastric cancer. We aimed to explore the reliability and validity of FACT-Ga in Japanese patients, and assess the sensitivity of the gastric cancer subscale for detecting changes in cancer-related variables over time. METHODS: The Japanese version of FACT-Ga was used, and data were obtained from Japanese patients who participated in either of two clinical trials: treatment for advanced or recurrent gastric cancer with ascites (advanced-GC group), or adjuvant chemotherapy after curative resection of gastric cancer (adjuvant group). Psychometric data including data used to determine reliability, internal consistency, and clinical validity were analyzed. Clinical validity was evaluated by comparing subscale scores for patients in the two groups, and by comparing subscale scores for patients with different performance status scores. Correlation between gastric cancer subscale scores and gastric cancer-related variables was also examined. In addition, sensitivity of the gastric cancer subscale to changes in ascites volume, abdominal girth, and Eastern Cooperative Oncology Group (ECOG) performance status (PS) was examined by evaluating their correlation in the advanced-GC group. RESULTS: We collected data on 156 patients (62 advanced-GC group patients and 94 adjuvant group patients). Response rates for the subscales were over 80 % at most time points for both the groups. Cronbach's coefficient alpha revealed good internal consistency for each subscale. At baseline, the adjuvant group had higher QOL scores than the advanced-GC group (P < 0.05), and QOL scores for patients with different performance status scores differed significantly. Changes in gastric cancer subscale scores showed statistically significant correlation with changes in ascites volume (Spearman's rank correlation coefficient, 0.5; P < 0.05). CONCLUSIONS: FACT-Ga is reliable and clinically valid for Japanese patients with gastric cancer. Detection of QOL changes that correlate with ascites volume changes suggests that it could be used more broadly; FACT-Ga scores could be used as an endpoint for patients with gastric cancer-related ascites.

Surgical advantages of reduced-port laparoscopic gastrectomy in gastric cancer.

BACKGROUND: Although a few studies have reported the use of reduced-port laparoscopic gastrectomy (RPG) in gastric cancer patients, the feasibility of routinely using this technique remains unclear. It is therefore important to evaluate the surgical advantages of this technique in this patient group. METHODS: Between August 2010 and July 2015, 165 patients underwent RPGs at our hospital, performed by a single surgeon. Of these patients, 88 underwent reduced-port laparoscopic distal gastrectomy (RPLDG) and 77 underwent reduced-port laparoscopic total gastrectomy (RPLTG). In addition to short-term surgical outcomes after RPG, survival times and the surgical learning curve were also evaluated. RESULTS: Blood losses during lymph node dissection in the RPLDG and RPLTG groups were not significantly different (p = 0.160). Conversion to open surgery was necessary in only two patients. Postoperative morbidities were observed in 14.8 % of the RPLDG group and 14.3 % of the RPLTG group, but there were no deaths. Most patients expressed high cosmetic satisfaction in both groups. In the RPLDG group, operation time during reconstruction decreased over the first 50 cases and then plateaued, as the surgeon's experience of the technique increased. In contrast, in the RPLTG group, operation times dropped with surgical experience for both lymph node dissection, plateauing after 40 cases, and for reconstruction, plateauing after 30 cases. Only three patients died of gastric cancer in the follow-up period and three patients died of other diseases. Five-year overall survival and 5-year disease-specific survival were 95.6 and 98.0 %, respectively. CONCLUSIONS: We have shown that reduced-port gastrectomy (RPG) could be an acceptable and satisfactory procedure for treating gastric cancer for an experienced laparoscopic gastric surgeon who has sufficient previous experience of conventional laparoscopic gastrectomies.

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.

Introduction of the non-technical skills for surgeons (NOTSS) system in a Japanese cancer center.

PURPOSE: Non-technical skills rating systems, which are designed to support surgical performance, have been introduced worldwide, but not officially in Japan. We performed a pilot study to evaluate the "non-technical skills for surgeons" (NOTSS) rating system in a major Japanese cancer center. METHODS: Upper gastrointestinal surgeons were selected as trainers or trainees. The trainers attended a master-class on NOTSS, which included simulated demo-videos, to promote consistency across the assessments. The trainers thereafter commenced observing the trainees and whole teams, utilizing the NOTSS and "observational teamwork assessment for surgery" (OTAS) rating systems, before and after their education. RESULTS: Four trainers and six trainees were involved in this study. Test scores for understanding human factors and the NOTSS system were 5.89 ± 1.69 and 8.00 ± 1.32 before and after the e-learning, respectively (mean ± SD, p = 0.010). The OTAS scores for the whole team improved significantly after the trainees' education in five out of nine stages (p < 0.05). There were no differences in the NOTSS scores before and after education, with a small improvement in the total scores for the "teamwork and communication" and "leadership" categories. CONCLUSION: These findings demonstrate that implementing the NOTSS system is feasible in Japan. Education of both surgical trainers and trainees would contribute to better team performance.

Signatures of tumour immunity distinguish Asian and non-Asian gastric adenocarcinomas.

OBJECTIVE: Differences in gastric cancer (GC) clinical outcomes between patients in Asian and non-Asian countries has been historically attributed to variability in clinical management. However, recent international Phase III trials suggest that even with standardised treatments, GC outcomes differ by geography. Here, we investigated gene expression differences between Asian and non-Asian GCs, and if these molecular differences might influence clinical outcome. DESIGN: We compared gene expression profiles of 1016 GCs from six Asian and three non-Asian GC cohorts, using a two-stage meta-analysis design and a novel biostatistical method (RUV-4) to adjust for technical variation between cohorts. We further validated our findings by computerised immunohistochemical analysis on two independent tissue microarray (TMA) cohorts from Asian and non-Asian localities (n=665). RESULTS: Gene signatures differentially expressed between Asians and non-Asian GCs were related to immune function and inflammation. Non-Asian GCs were significantly enriched in signatures related to T-cell biology, including CTLA-4 signalling. Similarly, in the TMA cohorts, non-Asian GCs showed significantly higher expression of T-cell markers (CD3, CD45R0, CD8) and lower expression of the immunosuppressive T-regulatory cell marker FOXP3 compared to Asian GCs (p<0.05). Inflammatory cell markers CD66b and CD68 also exhibited significant cohort differences (p<0.05). Exploratory analyses revealed a significant relationship between tumour immunity factors, geographic locality-specific prognosis, and postchemotherapy outcomes. CONCLUSIONS: Analyses of >1600 GCs suggest that Asian and non-Asian GCs exhibit distinct tumour immunity signatures related to T-cell function. These differences may influence geographical differences in clinical outcome, and the design of future trials particularly in immuno-oncology.

HER2 expression in locally advanced gastric cancer with extensive lymph node (bulky N2 or paraaortic) metastasis (JCOG1005-A trial).

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) is likely overexpressed and/or amplified in locally advanced gastric cancer with extensive (bulky N2 or paraaortic) lymph node metastasis, and patients may benefit from treatment with anti-HER2 antibodies. This study evaluated the frequency of HER2 overexpression and amplification in The Japanese Gastric Cancer Association (JGCA)-N3 and JGCA-bulky N2 tumors and the correlation between HER2 status and survival. METHODS: HER2 status was assessed using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) in tumor tissue samples from 89 patients with gastric adenocarcinoma enrolled in the phase II JCOG0001 and JCOG0405 trials. HER2 positivity was defined as IHC3+ or IHC2+ with confirmatory FISH results. RESULTS: Of the 89 tumor samples, 24 (27 %) showed HER2 positivity, including 16 scored as IHC3+ and 8 as IHC2+ and FISH positive. Multivariate analysis showed that the HER2 positivity rate was significantly higher in evaluable differentiated tumors than in undifferentiated tumors [18/44 (40.9 %) vs. 5/42 (11.9 %)]. Although the apparent OS curve of HER2 positive was superior to that of HER2 negative patients, HER2 status was not a statistically significant prognostic factor in multivariate analysis. CONCLUSION: The HER2 positivity rate was relatively high in patients with JGCA-bulky N2 and JGCA-N3 gastric adenocarcinoma, suggesting that HER2 evaluation is essential to select the therapeutic regimen for neoadjuvant chemotherapy for this group of patients.

[A Case of Resected Advanced Gastric Cancer Exhibiting Pathological Complete Response after Neoadjuvant Che-motherapy(DTX/CDDP/S-1:DCS)].

A 71-year-old man was diagnosed with gastric cancer (LM, Less, type 2, T4aN2M0, cStageⅢb). A diagnostic laparoscopic surgery revealed serosal invasion without peritoneal dissemination. Two courses of neoadjuvant chemotherapy (NAC) for locally advanced gastric cancer using DCS (DTX: 20 mg/m2 on day 1, CDDP: 50 mg/m2 on day 1, S-1: 120 mg/day, twice a day on days 1-14) was performed, which resulted in a clinical partial response. Consequently, distal gastrectomy with D2 lymph node dissection, and BillrothⅠreconstruction were carried out. Histopathological examination revealed no residual cancer cells both in the primary lesion and in the lymph nodes, indicating a pathological complete response (grade 3). Six courses of S-1 (120 mg/day on days 1-28, followed by 2 weeks of rest) were administered as adjuvant chemotherapy. At the 2 years 10 months follow-up after adjuvant therapy, the patient has had no recurrence. Combination chemotherapy with NAC-DCS can be a safe and effective regimen for locally advanced gastric cancer.

[A Case of Advanced Gastric Cancer Responding to Neoadjuvant Docetaxel/CDDP/S-1 Therapy with Metallic Stent Placement, Leading to Curative Surgery].

A 59-year-old man presented with epigastralgia. A diagnosis of advanced gastric cancer MLU, Circ, Type 3, 160 mm, tub2, cT4b (SI: panc), cN1, cM0, cH0, cP0, cCY0, cStage ⅢB was made. Because of difficulty with oral intake due to malignant outlet obstruction and tumor bleeding, endoscopic self-expanding metallic stent placement was performed. We administered chemotherapy involving docetaxel, cisplatin, and S-1(DCS). After 2 courses of chemotherapy, the primary lesion and regional lymph nodes had reduced in size. His response was judged as SD according to the RECIST criteria. The patient elected to undergo explorative laparotomy for assessment of the gastric cancer. The intraoperative findings showed that there was no pancreatic invasion, peritoneal dissemination, or distal metastasis, so a total gastrectomy and D2 lymph node dissection was performed. The pathological findings showed that there were very few cancer cells in the primary lesion, and a lymph node metastasis was found. The final stage was gastric cancer MLU, Circ, Type 3, 100 mm, muc, ypT4a(SE), ypN3a (13/51), ypM0, ypH0, ypP0, ypCY0, ypStage ⅢC. The therapy evaluation was Grade 1b. In summary, we encountered a patient with gastric cancer in whom curative surgery was made possible by undergoing chemotherapy and metallic stent placement.