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/m
2
twice daily on days 1–14, plus intravenous oxaliplatin 130 mg/m
2
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.
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.
Adjuvant chemotherapy aims to eradicate micrometastatic tumor cells before and after curative surgery. Many Phase III trials have been conducted to study the efficacy of postoperative adjuvant ...chemotherapy; however, most trials have failed to show any survival benefit because of their low statistical power and/or poor patient compliance. Since 2000, two pivotal Phase III trials, the ACTS-GC and the CLASSIC, have demonstrated the efficacy of postoperative adjuvant chemotherapy following D2 gastrectomy. Although treatment with S-1 for 1 year or combination therapy with capecitabine and oxaliplatin for 6 months is effective, more intensive chemotherapy is necessary to further improve the survival rates. In Europe, two Phase III trials, the MAGIC and the FNCLCC/FFCD, have produced results that strongly suggest that neoadjuvant chemotherapy is beneficial. The advantages of neoadjuvant chemotherapy include a high rate of R0 resection, tumor regression, high compliance and the avoidance of unnecessary surgery. The disadvantage of neoadjuvant chemotherapy is over-diagnosis. In Japan, the Japan Clinical Oncology Group has conducted several clinical trials using neoadjuvant chemotherapy to target extensive nodal disease and/or scirrhous carcinomas. The optimal courses and regimens of neoadjuvant chemotherapy should, therefore, be clarified in the future.
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.
Background
Neoadjuvant chemotherapy may improve outcomes in gastric cancer. Tumor responses can be evaluated with RECIST, Japanese Classification of Gastric Carcinoma (JCGC), and histological ...criteria. These approaches have not yet been compared.
Methods
We analyzed two phase II trials of neoadjuvant chemotherapy using S-1 plus cisplatin. JCOG0210 included patients with linitis plastica and large ulcero-invasive tumors, whereas JCOG0405 comprised those with para-aortic or bulky lymph node metastases. Radiologic evaluations were conducted using RECIST in JCOG0405 and JCGC criteria in JCOG0210, because the latter included many patients without measurable lesions. A histological responder was defined as a patient in whom one third or more of the tumor was affected. The hazard ratios (HR) for death between responders and non-responders and response rate differences between short- and long-term survivors were estimated.
Results
In JCOG0210 (
n
= 49), HR was 0.54 in JCGC responders (
P
= 0.059) and 0.40 in histological responders (
P
= 0.005). The difference in response rates between short- and long-term survivors using histological criteria (34 %,
P
= 0.023) was greater than that using JCGC criteria (24 %,
P
= 0.15). In JCOG0405 (
n
= 51), HR was 0.67 in RECIST responders (
P
= 0.35) and 0.39 in histological responders (
P
= 0.030). In short- and long-term survivors, respectively, RECIST response rates were 62 and 67 % (
P
= 0.77), whereas histological response rates were 33 and 63 % (
P
= 0.048).
Conclusions
Histological criteria showed higher response assessment validity than RECIST or JCGC criteria and yielded the best surrogate endpoint for overall survival.
Background
We clarified the incidence of adenocarcinoma of the esophagogastric junction (AEG) at a Japanese high-volume cancer center and its clinicopathological features between the Siewert ...subtypes.
Methods
Patients with AEG were selected from a prospective database of gastric and esophageal tumors established by Kanagawa Cancer Center. The Siewert subtypes were determined retrospectively by examining pathological pictures of the resected specimens and by evaluating the pathology and endoscopy findings.
Results
From January 1986 to December 2005, 147 (4.0%) patients were determined to have AEG; 2,794 (75.8%) were diagnosed to be true gastric cancer, whereas 745 (20.2%) were true esophageal cancer. Of these 147 patients with AEG, 5 (3.4%) were classified as type I, 82 (55.8%) as type II, and 60 (40.8%) as type III tumors. The depth of tumor invasion was deeper and the nodal metastases were more frequent in type III compared with type II. The risk factors for nodal metastases included the depth and size of the tumor, but not the Siewert subtypes itself. Mediastinal nodal metastases were strongly influenced by a thoracotomy and the extent of the dissection. The pathological grade was higher in type III than in type II. Although the 5-year survival rate was significantly higher in type II than in type III tumors, the survival difference disappeared when the patients were restricted to an R0 resection, even though type III patients demonstrated a more advanced stage.
Conclusions
The proportions of AEG were strikingly different between Japan and western countries. Although each Siewert subtype had some different characteristics, nodal metastases were determined by both the tumor progression and the extent of the nodal dissection. An R0 resection was a key for the survival in AEG.
Background
Multidetector-row CT (MDCT) may provide accurate preoperative staging of resectable gastric cancer. However, the standard methods and criteria to diagnose the T and N stages to select the ...patients who are good candidates for neoadjuvant chemotherapy have not been established yet.
Methods
The aim of this prospective study was to evaluate the accuracy of MDCT to diagnose the serosal invasion and nodal metastases of gastric cancer. Patients who had gastric adenocarcinoma underwent MDCT scanning using a standardized method. The T and N stage were diagnosed by prespecified criteria. The analyses were performed in the patients who had cN0–2 and M0 tumors and underwent curative gastrectomy as a primary treatment. The accuracy was calculated by comparing the results of MDCT with the histopathological findings.
Results
A total of 315 patients were analyzed. The overall diagnostic accuracy (95 % confidence interval) of T staging was 71.4 % (225 of 315, 66.2–76.1). The accuracy, sensitivity, and specificity for serosal invasion were 85.7 % (81.4–89.1), 54.5 % (42.6–66.0), and 94.0 % (90.3–96.3), respectively. The false-positive rate for serosal invasion was 6.0 % (2.9–7.7). The overall diagnostic accuracy of N staging was 75.9 % (239 of 315, 70.9–80.3). The accuracy, sensitivity, and specificity for nodal metastases were 81.3 % (76.6–85.2), 46.4 % (36.8–56.3), and 96.8 % (93.5–98.4), respectively. The false-positive rate for nodal metastases was 3.2 % (1.6–6.5 %).
Conclusions
These results suggest that MDCT provides an accurate diagnosis with high specificity and a low false-positive rate and can be used to select the patients who are candidates for preoperative chemotherapy.
Mutation spectrum of TP53 in gastric cancer (GC) has been investigated world-widely, but a comparison of mutation spectrum among GCs from various regions in the world are still sparsely documented. ...In order to identify the difference of TP53 mutation spectrum in GCs in Eastern Europe and in East Asia, we sequenced TP53 in GCs from Eastern Europe, Lujiang (China), and Yokohama, Kanagawa (Japan) and identified the feature of TP53 mutations of GC in these regions.
In total, 689 tissue samples of GC were analyzed: 288 samples from East European populations (25 from Hungary, 71 from Poland and 192 from Romania), 268 from Yokohama, Kanagawa, Japan and 133 from Lujiang, Anhui province, China. DNA was extracted from FFPE tissue of Chinese, East European cases; and from frozen tissue of Japanese GCs. PCR products were direct-sequenced by Sanger method, and in ambiguous cases, PCR product was cloned and up to 8 clones were sequenced. We used No. NC_000017.11(hg38) as the reference sequence of TP53. Mutation patterns were categorized into nine groups: six base substitutions, insertion, deletion and deletion-insertion. Within G:C > A:T mutations the mutations in CpG and non-CpG sites were divided. The Cancer Genome Atlas data (TCGA, ver.R20, July, 2019) having somatic mutation list of GCs from Whites, Asians, and other ethnicities were used as a reference for our data.
The most frequent base substitutions were G:C > A:T transition in all the areas investigated. The G:C > A:T transition in non-CpG sites were prominent in East European GCs, compared with Asian ones. Mutation pattern from TCGA data revealed the same trend between GCs from White (TCGA category) vs Asian countries. Chinese and Japanese GCs showed higher ratio of G:C > A:T transition in CpG sites and A:T > G:C mutation was more prevalent in Asian countries.
The divergence in mutation spectrum of GC in different areas in the world may reflect various pathogeneses and etiologies of GC, region to region. Diversified mutation spectrum in GC in Eastern Europe may suggest GC in Europe has different carcinogenic pathway of those from Asia.
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.
Objective
The purpose of this study was to clarify the priority of nodal dissection in Siewert types II and III adenocarcinoma of the esophagogastric junction (AEG).
Methods
The priority of nodal ...dissection was evaluated based on the therapeutic value index calculated by multiplying of the frequency of metastasis to each station and the 5-year survival rate of patients with metastasis to that station.
Results
A total of 176 patients (95 type II and 81 type III) were examined. Among the lymph nodes that had a metastatic incidence exceeding 10 %, the stations showing the first to fourth highest index were the paracardial and lesser curvature nodes (Nos. 1, 2, and 3) and the node at the root of the left gastric artery (No. 7) in the total cohort, as well as in each type. The next station was the lower thoracic paraesophageal lymph node (No. 110), followed by the nodes along the proximal splenic artery (No. 11p) in type II, whereas it was the nodes along the proximal splenic artery (No. 11p) followed by the para-aortic nodes (No. 16a2), the nodes at the celiac artery (No. 9), and the nodes around the splenic hilum (No. 10) in type III.
Conclusions
These results suggest that the highest priority nodal stations to be dissected were the paracardial and lesser curvature nodes (Nos. 1, 2, and 3) and the nodes at the root of the left gastric artery (No. 7), regardless of the Siewert subtype, but the subsequent priority was different depending on the subtype.
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