Re-evaluation of phenotypic expression in undifferentiated-type early gastric adenocarcinomas using mucin core protein and CDX2

Background

Undifferentiated-type early gastric adenocarcinomas are generally classified into two groups: pure undifferentiated-type adenocarcinomas, which naturally develop as undifferentiated-type without a glandular component; and mixed differentiated/undifferentiated-type adenocarcinomas, which are associated with some vestigial glandular component and presumably develop from differentiated-type adenocarcinoma. The differences in phenotypic expression between these two groups were examined using mucin core protein and CDX2.

Methods

A total of 210 lesions of undifferentiated-type early gastric adenocarcinoma less than 25 mm in diameter were classified into four categories (gastric type, gastrointestinal type, intestinal type, and null type) based on their MUC5AC, MUC6, MUC2, and CDX2 immunoprofiles.

Results

Gastric type was significantly (p < 0.01) decreased and gastrointestinal type was significantly (p < 0.01) increased both in pure undifferentiated-type adenocarcinomas and in mixed differentiated/undifferentiated-type adenocarcinomas when CDX2 was applied to mucin core protein. In the pure undifferentiated-type adenocarcinomas, gastric type decreased and gastrointestinal type increased as tumor size increased (p < 0.05). In contrast, in the mixed differentiated/undifferentiated-type adenocarcinomas, gastrointestinal type was most common even in small-sized (≤10 mm) carcinomas and was generally stable regardless of tumor size. In submucosal carcinomas, gastrointestinal type decreased and gastric type and intestinal type increased during carcinoma invasion from the intramucosal to submucosal parts (p < 0.05). The positivity rates for all phenotypic markers, especially gastric markers, tended to decrease during submucosal invasion.

Conclusions

CDX2 is a sensitive marker for assessing intestinal phenotypic expression, and it is likely that there are two different pathways of tumor progression in undifferentiated-type adenocarcinoma of the stomach, according to phenotypic expression.     

Can We Resect EGC with Signet Ring Cells in Europe?

Purpose

The proposed guideline for performing endoscopic resection of early gastric carcinoma (EGC) in Paris classification is a well-differentiated carcinoma with maximum involvement Sm1. Signet ring cell carcinomas (SRC) are excluded from this recommendation. Authors from Eastern countries have proposed extending this resection to include selected undifferentiated EGC. Via an analysis of a series of cases of signet ring carcinoma, we will discuss whether it is possible to resect EGC with signet ring cells in Europe.

Methods

We retrospectively included patients with histological classification pT1 of EGC showing SRC. Data was extracted from the hospital gastrectomy register. Lymphadenomectomy D1.5 was performed on all patients. Histology results were retrospectively obtained from the electronic patient file.

Results

Twelve patients (mean age?=?55.4, four women, eight men) underwent surgery, without previous chemotherapy, between 2000 and 2012, for EGC with SRC. Mean size of the lesions was 20.2 mm (5–35 mm). Seven lesions were located in the antrum, five in the fundus. In the case of nine patients, histology showed no lymphovascular involvement. None of these nine patients presented lymph node metastases (LNM). Five patients had intramucosal carcinoma, four were classified as Sm1, one patient was Sm2, and one patient was Sm3. On surgery, the three patients with lymphovascular invasion showed LNM.

Conclusion

Endoscopic resection of EGC with SRC does not systematically imply complementary treatment by surgery, although criteria for endoscopic resection are difficult to determine because of the lack of data in Europe.     

Risk of lymph node metastases from intramucosal gastric cancer in relation to histological types: how to manage the mixed histological type for endoscopic submucosal dissection

Background

The behavior of early gastric cancer (EGC) with mixed-type histology (differentiated and undifferentiated) is incompletely understood. This study aimed to clarify the clinicopathological features of EGC with mixed-type histology in relation to lymph node (LN) metastasis.

Methods

Clinicopathological data from 410 patients who underwent surgical resection for intramucosal EGC were reviewed. Lesions were classified into four types according to the proportion of differentiated and undifferentiated components at histopathology: pure differentiated (PD) type, mixed predominantly differentiated (MD) type, mixed predominantly undifferentiated (MU) type, and pure undifferentiated (PU) type. We examined the clinicopathological differences between PD and MD, and between PU and MU, and the rate of LN metastasis according to tumor size and ulceration.

Results

Moderately differentiated adenocarcinoma was the primary component in MD relative to PD (90.7 vs. 46.1 %). Signet ring cell carcinoma was the main component in PU relative to MU (81.5 vs. 33.3 %). LN metastasis was more common in MU than PU (19.0 vs. 6.0 %). For intramucosal tumors larger than 20 mm without lymphovascular invasion and without ulceration, the rate of LN metastasis was 0 % for MD and 24 % for MU. For intramucosal lesions less than 30 mm with ulceration but without lymphovascular invasion, the rate of LN metastasis was 0 % for MD and 20 % for MU.

Conclusions

Histologically mixed-type EGC with a predominantly undifferentiated component should be managed as an undifferentiated-type tumor. Further investigation is required to determine whether mixed-type EGC with a predominantly differentiated component could be managed the same way as a differentiated-type EGC.     

Early gastric cancer: diagnosis, staging, and clinical impact. Evaluation of 530 patients. New elements for an updated definition and classification

Background

The prevention and early diagnosis of gastric cancer permit clinicians to discover the tumor in the initial phase, during which time it can be completely eradicated, endoscopically or surgically. Since Murakami gave the definition of early gastric cancer (EGC) in 1971, many authors have identified various subtypes of EGC with different morphological characteristics and clinical behaviour.

Methods

We evaluated retrospectively 530 patients: the median follow-up time was 10.4 months (range 0.3–29.2). All tumors were classified according to the macroscopic and microscopic criteria proposed by the Japanese Society of Gastroenterology and Endoscopy and Lauren, respectively. The infiltrative growth pattern was evaluated according to Kodama’s classification. Only tumor-related death was considered as an endpoint of interest for the survival analysis.

Results

The overall survival rates of our patients were 94 % (95 % CI, 92–96) and 90 % (95 % CI, 87–93) at 5 and 10 years, respectively. Only 44 patients (8.3 %) died of the disease. Kodama’s type (p < 0.0001), lymph node status, both for number and pathological stage according to the 7th Edition of TNM (p < 0.0001), and depth of infiltration (p = 0.0006) were significant prognostic factors in univariate analysis. The multivariate analysis identified Kodama’s PENA type (HR, 3.91; 95 % CI, 2.08–7.33; p < 0.0001) and lymph node status for more than three positive nodes versus negative nodes (HR, 12.78; 95 % CI, 5.37–30.43; p < 0.0001) as the only independent prognostic factors in our series.

Conclusion

Lymph node status, especially when more than three lymph nodes are involved, is the most important prognostic factor in EGC. However, it is also important to evaluate the infiltrative growth pattern of the cancers in their early phase according to Kodama’s classification, considering PEN A type lesions to be more aggressive than the other EGC types. Then, we propose new elements for an updated definition and classification of EGC, with an important clinical impact on the treatment of patients.     

Histologic purity of signet ring cell carcinoma is a favorable risk factor for lymph node metastasis in poorly cohesive,submucosa-invasive early gastric carcinoma

Background

The prediction of biologic behavior of poorly cohesive early gastric carcinoma (EGC) is an important issue in the selection of the treatment modality. To elucidate the risk factors for lymph node metastasis (LNM) of poorly cohesive EGC, we focused on the histologic purity of the poorly cohesive component and evaluated the impact of this factor on LNM.

Methods

We divided poorly cohesive EGC into (1) pure signet ring cell (SRC) carcinoma, which was defined as composed only of signet ring cells or poorly cohesive cells and (2) mixed SRC carcinoma, defined as poorly cohesive carcinoma with minor tubular components. We reviewed the clinicopathologic features, including age, sex, location, size, depth, lymphovascular invasion (LVI), LNM, ulceration, and intestinal metaplasia between the two groups in a large series of poorly cohesive, submucosa-invasive EGC (n = 317).

Results

LNM was found in 58 cases (18.3 %). Mixed SRC carcinoma histologic type (p < 0.001), larger tumor size (more than 2 cm) (p = 0.012), and the presence of LVI (p < 0.001) were associated with LNM. Pure SRC carcinomas accounted for 56.2 % (178/317) of the cases. Fourteen pure SRC carcinomas (7.8 %) showed LNM, whereas 44 mixed SRC carcinomas (31.9 %) exhibited LNM (p < 0.001). On multivariate logistic regression, the presence of LVI (odds ratio 6.737; 95 % confidence interval 2.714–16.720; p < 0.001) and mixed SRC carcinoma histologic type (odds ratio 4.674; 95 % confidence interval 2.370–9.216; p < 0.001) were independent predictors of LNM in poorly cohesive, submucosa-invasive EGC.

Conclusions

The presence of a tubular component in SRC carcinoma was a risk factor for LNM in poorly cohesive, submucosa-invasive EGC. On the basis of this finding, we propose that the presence of a minor tubular component or the purity of the poorly cohesive/SRC carcinoma component should be reported in daily pathologic practice.

     

Is the eCura system useful for selecting patients who require radical surgery after noncurative endoscopic submucosal dissection for early gastric cancer? A comparative study

Background

We have established a risk-scoring system, termed the “eCura system,” for the risk stratification of lymph node metastasis in patients who have received noncurative endoscopic submucosal dissection (ESD) for early gastric cancer (EGC). We aimed to clarify whether this system contributes to the selection of patients requiring radical surgery after ESD.

Methods

Between 2000 and 2011, 1,969 patients with noncurative ESD for EGC were included in this multicenter study. Depending on the treatment strategy after ESD, we had patients with no additional treatment (n = 905) and those with radical surgery after ESD (n = 1,064). After the application of the eCura system to these patients, cancer recurrence and cancer-specific mortality in each risk category of the system were compared between the two patient groups.

Results

Multivariate Cox analysis revealed that in the high-risk category, cancer recurrence was significantly higher (hazard ratio = 3.13, p = 0.024) and cancer-specific mortality tended to be higher (hazard ratio = 2.66, p = 0.063) in patients with no additional treatment than in those with radical surgery after ESD, whereas no significant differences were observed in the intermediate-risk and low-risk categories. In addition, cancer-specific survival in the low-risk category was high in both patient groups (99.6 and 99.7%). A limitation of this study is that it included a small number of cases with undifferentiated-type EGC (292 cases).

Conclusions

The eCura system is a useful aid for selecting the appropriate treatment strategy after noncurative ESD for EGC. However, caution is needed when applying this system to patients with undifferentiated-type EGC.

     

Prognosis of patients with advanced gastric cancer by HER2 status and trastuzumab treatment

Background

The purpose of this study was to evaluate the impact of human epidermal growth factor receptor 2 (HER2) status and trastuzumab treatment on the prognosis of patients with advanced gastric cancer (AGC).

Methods

We retrospectively analyzed 364 AGC patients who received systemic chemotherapy. To evaluate the impact of trastuzumab exposure during any type of chemotherapy, our analysis used time-varying covariates to avoid a possible lead-time bias.

Results

Among the 364 patients, 58 (15.9 %) were HER2-positive. The median overall survival of the HER2-positive patients treated with trastuzumab (n = 43) was significantly longer than that of the HER2-negative patients [n = 306; 24.7 vs. 13.9 months, with an adjusted hazard ratio (HR) of 0.58; 95 % confidence interval (CI), 0.36–0.95; P = 0.03]. Notably, 22 patients continued with trastuzumab beyond the date of progression. By contrast, the HER2-positive patients not treated with trastuzumab (n = 15) showed survival similar to that of the HER2-negative patients (13.5 vs. 13.9 months, with an adjusted HR of 1.04; 95 % CI, 0.52–2.11; P = 0.91). According to the multivariate analysis, exposure to trastuzumab was independently associated with a better prognosis (HR 0.56; 95 % CI; 0.33–0.93; P = 0.026).

Conclusions

Recent HER2-positive AGC patients have a better prognosis than HER2-negative patients, particularly when treated with trastuzumab.     

A retrospective comparison of S-1 plus cisplatin and capecitabine plus cisplatin for patients with advanced or recurrent gastric cancer

Background

Based on the results of the SPIRITS trial, combination chemotherapy of S-1 plus cisplatin (SP) is now considered the standard treatment for patients with advanced gastric cancer (AGC) in Japan. On the other hand, several non-Japanese studies have shown the efficacy of capecitabine plus cisplatin (XP), which has been used as the reference arm in recent global studies of AGC.

Methods

We retrospectively compared the efficacy and safety of SP and XP in first-line treatment for patients with AGC.

Results

From August 2006 to November 2008, 26 AGC patients received XP in the context of 2 global trials (AVAGAST and ToGA), and 50 patients received SP during the same period. The objective response rate was 43.2 % in the SP group and 50 % in the XP group, with no significant difference (p = 0.62). There were also no significant differences in progression-free survival (median 5.8 vs. 5.2 months; p = 0.91) and overall survival (median 13.8 vs. 13.5 months; p = 0.97) between the SP and XP groups. The frequencies of hematological toxicities of grade 3 or more and non-hematological toxicities were not significantly different between the 2 groups. Although grade 1 or 2 hand–foot syndrome was more common in the XP group, no patients experienced grade 3 or more.

Conclusions

Although the retrospective nature of this study and the small number of patients is a major limitation, SP and XP were associated with similar efficacy and safety in patients with AGC.     

Pre-treatment neutrophil to lymphocyte ratio as a prognostic marker to predict chemotherapeutic response and survival outcomes in metastatic advanced gastric cancer

Background

Several studies have shown that the neutrophil to lymphocyte ratio (NLR) in peripheral blood is a prognostic factor of various cancers. However, there is limited information on the clinical and prognostic significance of NLR in patients with metastatic advanced gastric cancer (AGC). Therefore, we examined whether the NLR can be used as a prognostic marker for predicting chemotherapeutic response and survival outcomes in metastatic AGC patients who are receiving palliative chemotherapy.

Method

A total of 268 patients diagnosed with metastatic AGC were enrolled. NLR was calculated from complete blood cell count taken before the first chemotherapy treatment. Patients were divided into two groups according to the median value of NLR: a high NLR group and a low NLR group.

Result

The median follow-up period was 340 days (range 72–1796 days) and median NLR was 3.06 (range 0.18–18.16). The high NLR group (NLR >3.0) contained 138 patients and the low NLR group (NLR ≤3.0) contained 130 patients. Low NLR group patients had a significantly higher chemotherapeutic disease control rate (90.0 % vs. 80.4; P = 0.028), and longer progression-free survival (PFS) and overall survival (OS) than the high NLR group patients (186 vs. 146 days; P = 0.001; 414 vs. 280 days; P < 0.001, respectively). In multivariate analysis, NLR showed a significant association with PFS (HR 1.478; 95 % CI 1.154–1.892; P = 0.002) and OS (HR 1.569; 95 % CI 1.227–2.006; P < 0.001).

Conclusion

Pretreatment NLR is a useful prognostic marker in patients with metastatic AGC who are undergoing palliative chemotherapy.     

Correlation between overall survival and other endpoints in clinical trials of second-line chemotherapy for patients with advanced gastric cancer

Background

The correlation between progression-free survival (PFS) or time to progression (TTP) and overall survival (OS) has been evaluated in patients with advanced gastric cancer (AGC) who received first-line chemotherapy. No corresponding analysis has been done in patients who have undergone second-line chemotherapy.

Methods

We evaluated the correlation between PFS, TTP, objective response rate (ORR), disease control rate (DCR), and OS in patients with AGC who underwent second-line chemotherapy. Correlations were evaluated by Spearman rank correlation coefficient (ρ).

Results

Sixty-four trials, including 10 randomized studies, were selected for analysis. Median PFS/TTP moderately correlated with OS (ρ = 0.56). The correlation tended to be stronger in non-Asian trials (ρ = 0.74) than in Asian trials (ρ = 0.37). ORR and DCR did not strongly correlate with OS (ρ = 0.38 for ORR; ρ = 0.54 for DCR). The hazard ratio of PFS and OS in each of the arms of the 10 randomized studies also showed a low correlation (ρ = 0.36).

Conclusions

PFS/TTP, ORR, and DCR did not correlate sufficiently with OS to be used as surrogate endpoints in patients with AGC who have undergone second-line chemotherapy. Further research is needed based on individual patient data from ongoing randomized trials.     

Comparison of safety and efficacy of S-1 monotherapy and S-1 plus cisplatin therapy in elderly patients with advanced gastric cancer

Background

Although S-1 plus cisplatin (SP) therapy is recognized as the standard treatment for advanced gastric cancer (AGC) in Japan, its safety and efficacy in elderly patients have not been investigated sufficiently.

Methods

We retrospectively reviewed the data of 58 patients with AGC selected from 82 consecutive patients who were ≥70 years old and were treated with SP or S-1 monotherapy as the first-line therapy. In SP, S-1 (40 mg/m², bid) was administered for 3 weeks and cisplatin (60 mg/m²) on day 8, every 5 weeks. In S-1 monotherapy, S-1 (40 mg/m², bid) was administered for 4 weeks, every 6 weeks.

Results

SP and S-1 was administered in 21 and 37 patients, respectively. There were some differences in patient characteristics between the treatment groups, such as histological type (P = 0.16); the presence of liver metastasis (P = 0.07); and the presence of peritoneal metastasis (P = 0.02). The incidences of grade 3/4 hematological toxicities were 57% (12/21) in the SP and 35% (13/37) in the S-1 group (P = 0.17). Those of non-hematological toxicities were 14% (3/21) and 14% (5/37) for anorexia, 10% (2/21) and 14% (5/37) for fatigue, and 5% (1/21) and 5% (2/37) for nausea in the SP and S-1 groups, respectively. Median progression-free survival and median overall survival in the SP and S-1 groups were 5.0 and 5.2 months, and 14.4 and 10.9 months, respectively.

Conclusion

SP and S-1 therapy were both feasible in elderly patients, though there is the risk of a high incidence of hematological toxicities.     

Is signet-ring cell carcinoma a specific entity among gastric cancers?

Background

The prognosis and chemoresistance of signet-ring cell (SRC) gastric adenocarcinoma have been reported and debated, and the utility of perioperative chemotherapy for such a tumor has been questioned. This study was performed to assess the impact of the SRC type on survival following resection of gastric adenocarcinoma, and to assess whether the prognostic factors (including perioperative chemotherapy) for non-SRC adenocarcinoma differed from those for SRC adenocarcinoma.

Methods

1799 cases of adenocarcinoma that were consecutively treated from 1997 to 2010 in 19 French centers by subtotal or total gastrectomy were included in a retrospective study. A D2 lymphadenectomy was performed for antropyloric tumors, and a modified D2 for upper tumors. SRC adenocarcinoma was diagnosed based on the presence of isolated carcinoma cells containing mucin.

Results

A total gastrectomy was performed in 979 (54.4 %) patients. SRC adenocarcinoma was diagnosed in 899 (50 %) patients. Patients with an SRC tumor were more frequently female, younger, and malnourished, had lower ASA scores, and had larger tumors than non-SRC patients. Median survival in patients with non-SRC carcinoma was 51 months, as compared to 26 months in patients with SRC carcinoma (p < 0.001). At multivariate analysis, SRC type remained an independent adverse prognostic factor (HR = 1.182). Factors that were prognostic in the SRC subgroup but not in the non-SRC subgroup were age >60 years, linitis, and involvement of adjacent organs. In contrast to non-SRC tumors, pre- and postoperative chemotherapy did not significantly impact on survival following resection of SRC adenocarcinoma.

Conclusion

In comparison to non-SRC adenocarcinoma, the SRC type has a worse prognosis, different prognostic factors, and is only poorly sensitive to perioperative chemotherapy. Non-SRC and SRC adenocarcinomas should be considered different entities in future therapeutic trials.

     

Long-term outcomes and prognostic factors of patients with advanced gastric cancer treated with S-1 plus cisplatin combination chemotherapy as a first-line treatment

Background

The long-term outcomes of advanced gastric cancer (AGC) patients treated with S-1 plus cisplatin (SP) combination chemotherapy remain unclear. Therefore, we sought to evaluate these outcomes to identify the prognostic factors affecting patient survival.

Methods

We retrospectively analyzed 153 AGC patients treated with SP at a single institution between January 2005 and July 2011.

Results

Median overall survival (OS) was 15.0 months [95 % confidence interval (CI), 12.5–17.9 months]. Three independent prognostic factors affecting poor survival were identified: performance status (PS) ≥ 1 [hazard ratio (HR) = 2.39, 95 % CI, 1.58–3.62); >1 metastatic site (HR = 1.57, 95 % CI, 1.10–2.26], and elevated alkaline phosphatase levels (HR = 1.70, 95 % CI, 1.16–2.49). A simple prognostic index was generated using three risk groups: good (no risk factor), moderate (one or two risk factors), and poor (three risk factors). The median OS for good-, moderate-, and poor-risk groups was 28.6, 14.8, and 7.3 months, respectively (log-rank test; P < 0.0001). Among the twelve 3-year survivors, 9 (75 %) had a PS of 0 and 8 (67 %) had only one metastatic site.

Conclusions

Three prognostic factors were identified in AGC patients treated with SP. Using a simple prognostic index, the patients were divided into three risk groups, in which the survival differences were markedly significant, suggesting that patients with good PS and only one metastatic site may have a higher chance of long-term survival than those with poor PS and multiple metastatic sites.     

Endoscopic submucosal dissection for early gastric cancer in anastomosis site after distal gastrectomy

Background

Detection of early gastric cancer (EGC) in the remnant stomach is increasing because of follow-up endoscopic surveillance programs. Endoscopic treatment appears to be desirable for EGC in the remnant stomach because it is less invasive than surgical resection.

Methods

In this retrospective study, to evaluate the feasibility of endoscopic submucosal dissection (ESD) for EGC in an anastomotic site, treatment results of ESD for EGC in an anastomotic site and in remnant stomach not involving an anastomotic site were compared. In total, 11 EGC lesions of anastomotic sites in 11 patients and 22 EGC lesions of remnant stomach not involving an anastomotic site in 21 patients were treated by ESD.

Results

All lesions were successfully treated by en bloc resection. There were three patients with perforations in the anastomotic site group. Although resected specimen size and tumor size were larger in the anastomotic site group than in the non-anastomotic site group (P < 0.01), the procedure duration was far longer in the anastomotic site group than in the non-anastomotic site group (P < 0.01). The speed of the procedure was faster in the non-anastomotic site group than in the anastomotic site group (P < 0.05).

Conclusions

Although ESD for EGC in an anastomotic site is a time-consuming procedure and requires advanced techniques compared with ESD for EGC not involving an anastomotic site, a high en bloc resection rate was achieved. ESD by endoscopists with sufficient experience appears to be a feasible treatment for EGC in an anastomotic site.     

A randomized phase II study of weekly docetaxel/cisplatin versus weekly docetaxel/oxaliplatin as first-line therapy for patients with advanced gastric cancer

Background

Docetaxel, in combination with cisplatin or oxaliplatin, has demonstrated efficacy in advanced gastric cancer (AGC). This randomized, non-comparative phase II trial evaluated two weekly docetaxel-based regimens to determine which is the most promising in terms of efficacy and safety as a front-line therapy in AGC.

Methods

Chemotherapy-naïve patients with measurable unresectable and/or metastatic gastric adenocarcinoma were randomly assigned to receive docetaxel (35 mg/m²) weekly on days 1 and 8 of a 21-day cycle plus either cisplatin (60 mg/m² on day 1) (wDP) or oxaliplatin (120 mg/m² on day 1) (wDO).

Results

Of the 77 randomly assigned patients, 76 patients (38 per arm) received one of the study treatments. Overall, response rate (ORR) was 37 % for wDP and 41 % for wDO. Median progression-free survival (PFS) was 4.9 and 4.4 months for wDP and wDO, respectively, and median overall survival (OS) was 9.7 and 12.3 months, respectively. Exploratory analyses showed no significant difference between wDP and wDO in terms of ORR (P = 0.707), PFS (P = 0.324), or OS (P = 0.581). The main grade 3 or 4 toxicity in the wDP and wDO groups was neutropenia (47 % in both groups). wDO was less associated with nausea (66 vs. 82 %) and vomiting (39 vs. 63 %), but more associated with peripheral neuropathy (68 vs. 39 %) than wDP. Rates of overall grade 3 or 4 adverse events were similar (wDP 66 vs. wDO 68 %).

Conclusions

wDP and wDO were found to be equally active and tolerable as front-line treatments in AGC.     

Frequent microsatellite instability in papillary and solid-type, poorly differentiated adenocarcinomas of the stomach

Background

Microsatellite instability (MSI) has been observed in 8–39 % of sporadic gastric cancers. However, despite numerous reports indicating a significant relationship between intestinal-type histology and MSI, detailed correlation between histological subtypes and MSI remains obscure. The purpose of the present study is to clarify the relationship between histological subtype and microsatellite status in gastric carcinomas.

Methods

Microsatellite status was examined for 464 consecutive gastric carcinomas from 420 patients as well as histological subtypes and other clinicopathological findings.

Results

MSI was observed in 82 carcinomas (17.7 %), and the greatest proportions were observed in solid-type, poorly differentiated adenocarcinoma (43.0 %) and papillary adenocarcinoma (32.5 %), both being significantly higher than those of other subtypes. The proportion increased with advancing age (0 % at 51–64 years, 8.5 % at 65–74 years, 18.4 % at 75–84 years, 35.3 % at 85–96 years). Compared with microsatellite-stable carcinomas, microsatellite-unstable carcinomas were significantly related with older age, female gender, antral location, and predominant papillary adenocarcinoma and solid-type, poorly differentiated adenocarcinoma. Poorly differentiated type carcinoma was significantly less frequent than differentiated type in microsatellite-unstable cancer at the early stage, whereas no significant difference existed at the advanced stage.

Conclusions

These results suggest that there are specific histological subtypes with highly frequent MSI and that gastric carcinoma with MSI originates from differentiated-type carcinomas, indicating histological diversity during tumor growth.     

Biweekly docetaxel,fluorouracil, leucovorin,oxaliplatin (TEF) as first-line treatment for advanced gastric cancer and adenocarcinoma of the gastroesophageal junction: safety and efficacy in a multicenter cohort

Background

Docetaxel–cisplatin-5-FU chemotherapy is superior to 5-FU-cisplatin in terms of response rate and survival in advanced gastric cancer (AGC), but is more toxic. Oxaliplatin is better tolerated than cisplatin, which it can effectively replace in this setting. We hypothesize that incorporating docetaxel into a simplified FOLFOX regimen should be a tolerable and effective option in first-line treatment of AGC.

Methods

Data were collected at six  French centers from patients with metastatic or local AGC who received docetaxel, fluorouracil, leucovorin, or oxaliplatin (TEF) as first-line treatment. TEF was administered as follows: docetaxel (50 mg/m²), oxaliplatin (85 mg/m²), and leucovorin (40 mg/m²) on day 1, and 5-FU continuous infusion for 48 h (2400 mg/m²) every 2 weeks.

Results

Forty-one patients were enrolled. Performance status was grade 0 and 1 in respectively 27 and 58 % of patients; 17 patients had adenocarcinoma of the gastroesophageal junction; 37 patients had metastatic disease, 22 had a poorly differentiated or diffuse type. Objective response rate was 66 %, with a complete response in two patients (5 %). Median progression-free survival and overall survival were respectively 6.3 and 12.1 months. Tolerability was acceptable with no treatment-related deaths. The most frequent grade 3–4 toxicities were neutropenia (30 %) and neuropathy (12.5 %). Curative intent surgery after response to TEF was performed in seven patients (17 %).

Conclusion

TEF is an effective first-line treatment with an acceptable toxicity profile for patients with AGC. It may allow curative resection in initially unresectable patients. TEF should now be evaluated in prospective randomized trials.     

Factors predicting peritoneal recurrence in advanced gastric cancer: implication for adjuvant intraperitoneal chemotherapy

Background

Despite adjuvant chemotherapy, patients with advanced gastric cancer (AGC) often develop recurrence, and the peritoneum is the most common site of recurrence. Therefore, intraperitoneal chemotherapy (IPC) has been proposed as a treatment option. The aim of this study was to select the eligible patients for application of IPC.

Methods

A total of 805 patients with AGC who underwent curative D2 gastrectomy between May 2003 and December 2009 were included in this study. Risk factors for peritoneal recurrence were analyzed.

Results

Recurrence developed in 245 patients (30.4 %). The first site of recurrence was the peritoneum in 144 patients (58.8 %), and the 5-year peritoneal recurrence-free survival was 79.3 %. Depth of tumor invasion ≥T3, extensive lymph node metastasis (N3), Bormann type 4, infiltrative type (Ming’s classification), and venous invasion were independent risk factors for peritoneal recurrence. In subgroup analysis with patients who had received adjuvant chemotherapy (n = 481), depth of tumor invasion ≥T3, Bormann type 4, infiltrative type (Ming’s classification), and venous invasion were independent risk factors for peritoneal recurrence. When a peritoneal recurrence risk index was made with each risk factor assigned 1 point (2 points for T4 stage), peritoneal recurrence rates with 0, 1, 2, 3, 4, or 5 points were 0 %, 3.9 %, 13.1 %, 33.3 %, 44.0 %, and 72.0 %, respectively, in those patients.

Conclusions

Patients at higher risk for peritoneal recurrence can be identified from the findings of this study. Further prospective studies are required to evaluate the usefulness of IPC for these patients.     

Long-term outcomes of endoscopic submucosal dissection versus surgery in early gastric cancer meeting expanded indication including undifferentiated-type tumors: a criteria-based analysis

Background

Endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) meeting the expanded indication is considered investigational. We aimed to compare long-term outcomes of ESD and surgery for EGC in the expanded indication based on each criterion.

Methods

This study included 1823 consecutive EGC patients meeting expanded indication conditions and treated at a tertiary referral center: 916 and 907 patients underwent surgery or ESD, respectively. The expanded indication included four discrete criteria: (I) intramucosal differentiated tumor, without ulcers, size >2 cm; (II) intramucosal differentiated tumor, with ulcers, size ≤3 cm; (III) intramucosal undifferentiated tumor, without ulcers, size ≤2 cm; and (IV) submucosal invasion <500 μm (sm1), differentiated tumor, size ≤3 cm. We selected 522 patients in each group by propensity score matching and retrospectively evaluated each group. The primary outcome was overall survival (OS); the secondary outcomes were disease-specific survival (DSS), recurrence-free survival (RFS), and treatment-related complications.

Results

In all patients and subgroups meeting each criterion, OS and DSS were not significantly different between groups (OS and DSS, all patients: p = 0.354 and p = 0.930; criteria I: p = 0.558 and p = 0.688; criterion II: p = 1.000 and p = 1.000; criterion III: p = 0.750 and p = 0.799; and criterion IV: p = 0.599 and p = 0.871). RFS, in all patients and criterion I, was significantly shorter in the ESD group than in the surgery group (p < 0.001 and p < 0.003, respectively). The surgery group showed higher rates of late and severe treatment-related complications than the ESD group.

Conclusions

ESD may be an alternative treatment option to surgery for EGCs meeting expanded indications, including undifferentiated-type tumors.

     

Randomized phase II study comparing paclitaxel with S-1 vs. S-1 as first-line treatment in patients with advanced gastric cancer

Purpose

This randomized phase II study was conducted to compare the efficacy and safety of paclitaxel with S-1 (PS) vs. S-1 in patients with advanced gastric cancer (AGC).

Methods

Eighty-two (82) patients were 1:1 randomly assigned to oral S-1 (daily for 2 weeks, every 4 weeks’ cycle) or S-1 (daily for 2 weeks, every 4 weeks’ cycle) plus paclitaxel (on day 1, 8 and 15 of a 4 weeks’ cycle). S-1 was orally administered with a fixed quantity according to body surface area (BSA), while paclitaxel was given 60 mg/m² i.v. daily through an implanted catheter. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), overall responsible rates and safety.

Results

The median OS with PS versus S-1 monotherapy was 14.0 versus 11.0 months (P = 0.02), survival at 12 months was 61.0 % in the PS group and 46.3 % in the S-1 group. Median PFS was also significantly longer in the PS group (6.0 months) than in the S-1 group (4.0 months). The overall response rate was determined in 82 evaluable patients, and was significantly higher (P = 0.04) with PS (19 patients, 46.3 %) than with S-1 monotherapy (10 patients, 24.4 %). PS was well tolerated with no treatment-related deaths, all were grade 3–4 gastrointestinal toxicities, including anorexia, nausea, and diarrhea developed in less than 10 % of the patients.

Conclusions

Combination chemotherapy of paclitaxel with S-1 is well tolerated and active in AGC patients. Further investigation with comparative trials is needed for confirmation.