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Aim: Despite the significant advances in chemotherapy, the prognosis of unresectable or recurrent gastric cancer is still very poor. Given that older adults are likely to have a number of concomitant diseases and an impaired major organ function, cancer chemotherapy in elderly patients requires particular caution. We examined what factors are associated with the overall survival of gastric cancer patients undergoing chemotherapy., Methods: A retrospective chart review of gastric cancer patients receiving oral fluoropyrimidines (N=130) was performed at Nagoya Memorial Hospital over 9 years. The overall survival was calculated from the beginning of chemotherapy until death or the most recent date of follow-up. The Kaplan-Meier method was used to plot survival curves, which were compared using the log-rank test. A multivariate analysis was performed using stepwise Cox proportional hazards models. A comprehensive geriatric assessment was conducted for the elderly patients. The chart review was approved by the ethics committee of Nagoya Memorial Hospital., Results: The objective response rate and overall survival did not differ markedly between the patients < 75 years (N=64) and those ≥ 75 years of age (N=28). The addition of lentinan significantly prolonged the survival of the stage 4 gastric cancer patients. In a multivariate analysis of those ≥ 75 years of age, the only independent prognostic factor for the survival was the functional capacity, as measured by the TMIG Index of Competence., Conclusions: This comprehensive geriatric assessment was useful for predicting the longevity of patients with stage 4 gastric cancer ≥ 75 years of age.

Severe oral mucositis induced by cancer chemotherapy can cause intolerable pain and increase the risk of systemic infections, necessitating dose reduction and discontinuation of antineoplastic agents. Moreover, this adverse effect may have an impact on patient nutrition and quality of life. An effective and prophylactic intervention should be useful for alleviating this complication. Because Nagoya Memorial Hospital has neither a dentistry nor an oral surgery department, we collaborated with dental associations near the hospital. First, we performed a questionnaire survey on the present status of the members of the local dental associations. The survey showed that 86% of the community dentists were interested in communicating with our hospital. In addition, they agreed to provide us with information on their specialty and status of amenities. In discussion with the community dentists, we decided on fax-based communication for collaboration to improve the quality of oral management in cancer patients. Three seminar series were conducted to share updated information on cancer treatment and enhance communication between the medical doctors and the dentists. Our hospital has registered 129 community dentists and enrolled 81 cancer patients in this medical and dental cooperation initiative.

Natural compounds containing fungal β-glucans have been used to improve general health for thousands of years in China and Japan. Lentinan, the backbone of β-(1, 3)-glucan with β-(1, 6) branches, is one of the active ingredients purified from Shiitake mushrooms and has been approved as a biological response modifier for the treatment of gastric cancer in Japan. Despite recent advances in chemotherapeutic agents, unresectable or recurrent gastric cancer remains an incurable disease, with survival rates being far from satisfactory. Recent clinical studies have shown that chemo-immunotherapy using lentinan prolongs the survival of patients with advanced gastric cancer, as compared to chemotherapy alone. In addition, trastuzumab, an antibody against HER2/neu growth factor receptor, has been used for the treatment of gastric cancer in combination with cytotoxic chemotherapeutic agents. Lentinan may exert a synergistic action with anti-cancer monoclonal antibodies to activate complement systems through the mechanism of antibody-dependent cellular cytotoxicity and complement dependent cytotoxicity. Because a better understanding of its biological activities should enable us to use lentinan more efficiently in the treatment of gastric cancer, immunological effects provided by β-glucans, a possible mode of action of lentinan, and its clinical application including future potential uses are discussed in the present review.

Objectives: To carry out a phase II multi-center study on the efficacy and safety of triple combination therapy with paclitaxel, S-1, and cisplatin in patients with unresectable/metastatic gastric cancer., Methods: A total of 63 patients from 8 institutions were included in this study. Paclitaxel (160 mg/m²) was administered by infusion for 3 h on the first day. S-1 (70 mg/m²/day) was administered orally for 14 consecutive days from the first day. Cisplatin (60 mg/m²) was administered intravenously over 24 h on day 14 of every 28-day cycle., Results: All 63 patients were assessed for clinical efficacy and safety. A total of 259 cycles of treatment were administered (median 4, range 1-10). Grade 3-4 toxicities included neutropenia in 30.2%, thrombocytopenia in 12.7%, and anemia in 11.1%. There was no grade 3-4 non-hematological toxicity or treatment-related death. Complete response was observed in 6 patients and partial response in 34 patients. The overall response rate was 63.5%. The median progression-free survival and response duration were 8.0 and 8.8 months, respectively, and median survival time was 15 months., Conclusions: Triple combination therapy with paclitaxel, S-1, and cisplatin showed promising safety and efficacy profiles with the potential to become a standard regimen for unresectable/metastatic gastric cancer., (Copyright © 2011 S. Karger AG, Basel.)

The prevalence of depression has been reported to be higher in cancer patients, especially those of advanced stage, compared to normal controls. However, depression is often under-recognized in clinical oncology settings. And this psychological problem is not routinely assessed even in patients with inoperable metastatic cancer who often have psychological disorders. Psychological distress including depression, is affected by physical, psychosocial, and clinical factors. In order to detect psychiatric problems at the early stage, we assessed the mental conditions of 47 inpatients with metastatic gastric and colorectal cancerusing the Japanese version of Zung's Self Rating Depression Scale(SDS)and analyzed the relationships between these factors and SDS scores. While SDS scores of our patients did not differ according to their gender, age, performance status (PS), ortypes of patients' character, they were significantly higher in Group B(cancer patients with palliative care alone), compared to Group A(those receiving chemotherapy)(p<0. 001). As the disease in the four identical patients progressed to the terminal stage, their scores were significantly increased, respectively(p<0. 05). These results suggest that psychological intervention should be more critical for terminally ill patients without any indication of chemotherapy.

We prospectively analyzed the adverse effects and outcomes of 15 patients with stage IV gastric cancer who underwent palliative gastrectomy from December, 2002 to May, 2008 and subsequently received combination therapy of S-1 and 4-h infusion of cisplatin. The National Cancer Institute common toxicity criteria (version 3. 0) were applied to evaluate the adverse effects of this therapy, and the Kaplan-Meier method was used to plot the survival curve. The side effects most frequently observed were anorexia (grade 3; 33%), although one case of grade 4 who was easily fatigued was noted during the first course and could not receive further courses of this therapy. The 2-year survival rate was 33% and median survival time was 31 months. It has been suggested that 24-h infusion of cisplatin combined with oral S-1 after reduction surgery might improve survival in patients with stage IV gastric cancer.

From July, 2007 to June, 2008, we prospectively investigated the influence of Hange-shashin-to on the therapeutic and adverse effects of chemotherapy and the changes in quality of life(QOL)scores of the patients with metastatic gastric and colorectal cancer. Twenty patients receiving S-1/Irinotecan (CPT-11) therapy were randomly allocated into group A (with Hange-shashin-to) and B (without Hange-shashin-to). While the anti-tumor effects did not differ significantly between these two groups, severe side effects of more than grade 3 occurred less frequently in group A. Our results suggested that the decrease in QOL scores on day 15 might be alleviated in group A, compared to group B. Therefore, Hange-shashin-to can be one of the useful supportive medicines in the combination therapy of S-1/CPT- 11.

Two unresectable advanced gastric cancer cases with peritoneal metastases were successfully treated by the combination therapy of S-1 and paclitaxel. S-1 (1.25m(2): 80 mg/day, 1.25m(2)-1.50m(2)<:120 mg/day) was administered orally for 14 consecutive days followed by 14 days rest and a 2-hour infusion of paclitaxel (50 mg/m(2)) was administered on day 1 and 15 of each course. Treatment was repeated every 4 weeks unless disease progression or severe adverse effects were observed. Case 1: 65-year-old male (performance status: PS 3) with type 1 gastric cancer with malignant ascites. Case 2: 66-year-old male (PS3) with peritoneal metastases whose primary gastric lesion was surgically resected. Partial response was obtained in the former and complete response in the latter. Combination therapy of S-1 and paclitaxel can be highly recommended for patients with inoperable gastric cancer with poor PS.

We report on two patients, successfully treated by the combination therapy of S-1 and 24-h infusion of cisplatin (CDDP), who were initially diagnosed with unresectable stage 4 advanced gastric cancer. Each patient had a very good clinical response and underwent curative gastrectomy after completion of 14 and 10 courses of S-1/CDDP chemotherapy, respectively. A microscopically detailed examination of surgically obtained specimens showed the complete disappearance of malignant cells in the two cases. S-1/CDDP combination therapy can, therefore, be highly active in incurable advanced gastric carcinoma.

Three cases with unresectable advanced gastric cancer with liver metastases were successfully treated by the combination therapy of TS-1 and cisplatin( CDDP). TS-1 (1.25 m2>: 80 mg/day, 1.25 m2-1.50 m2: 100 mg/day, > or =1.50 m2: 120 mg/day) was administered orally for 14 consecutive days followed by 14 days rest,and a 24-h infusion of CDDP (70 mg/m2) was administered on day 8 of each course. Treatment was repeated every 4 weeks unless disease progression was observed. Partial response was obtained in all of the following three advanced gastric cancer cases with liver metastases. Case 1: 67-year-old male with Borrmann type I gastric cancer with multiple liver metastases. Case 2: 55-year-old female with multiple liver and lymph node metastases whose primary gastric lesion was surgically resected. Case 3: 53-year-old-male with Borrmann type III gastric cancer with liver and lymph node metastases. TS-1/CDDP therapy can be highly recommended for the treatment of advanced gastric cancer with liver metastases.

Background: The aim of this multicentric trial was to determine the clinical toxicities and antitumor effects of a chemotherapy regimen of S-1 combined with cisplatin in patients with inoperable locally or metastatic advanced gastric cancer., Patients and Methods: Forty-two patients were entered into the study. S-1 (80 mg/m2) was administered orally daily for 14 consecutive days and 24-h infusion of cisplatin (70 mg/m2) was administered on day 8 of every 28-day cycle., Results: The overall response rate was 50% and complete response rate was 5%. The most common adverse event was leucopenia, which occurred with grade 3 in 7 patients (16.6%) and grade 4 in 2 patients (4.8%). Non-hematological adverse events were generally mild. The median survival time was 342 days. The 2-year survival rate was 22.9%., Conclusion: This combination chemotherapy is active, convenient and well tolerated in patients with high-grade advanced gastric cancer.

A 54-year-old patient with scirrhous type 3 gastric cancer having bulky N2 and para-aorta lymph node metastases was treated by combined chemotherapy of TS-1 and CDDP. Before treatment, CEA was 28.4 mg/ml. TS-1 (120 mg/day) administered for 14 days followed by 14 days rest was one course. CDDP (80 mg/m2) was administered by 24 hour continuous intravenous infusion at day 8 after the start of TS-1. After 2 courses of treatment, the level of CEA decreased to 1.4 mg/ml and the primary legion with lymph node metastases had decreased significantly. After 5 courses, endoscopic examination revealed complete disappearance of the primary tumor with no cancer cells detected by endoscopic biopsy. A CT scan also showed complete disappearance of all lymph node metastases. No severe adverse effects (NCI-CTC grade 3 of 4) were observed with this therapy. TS-1/CDDP chemotherapy is considered very effective for scirrhous gastric cancer with far advanced lymph node metastases.

TS-1 is a novel oral fluoropyrimidine anticancer agent and show synergism with CDDP. The objectives of this study were to determine the clinical toxicities, antitumor effect, survival duration, and a recommended dosage schedule in combination with TS-1 and CDDP. Patients with measurable, locally advanced or metastatic gastric cancer were candidates for the study. Three patients were assigned to one of four levels of treatment, as follows. At first, TS-1 was administered orally twice a day for 14 consecutive days followed by 14 days rest and a 24-h infusion of CDDP (70 mg/m2) was administered on day 8 of 28 every 4 weeks. Next, duration of S1 administration was increased in increments of 25% and in increments of 50%. At last, only the dose of CDDP was increased in increments of 10 mg/m2. The first three patients did not have over grade 3 hematologic and nonhematological toxicity during any course. Grade 4 neutropenia occurred during the second course in two patients consecutively in increments of 50% of TS-1. Neutropenia was considered as a dose limiting toxicity. Nonhematologic side effects generally were mild. The overall response rate including all levels was 90.9%. Three complete responses (27.3%) and 8 partial responses (63.6%) were observed among the 11 patients. At first schedule, CR was two of three patients, and PR by the other (overall response rate, 100%). Survival rate of all cases in eight months were 100%. In conclusion, a combination of TS-1 and CDDP chemotherapy showed favorable antitumor activity and less adverse reaction compared to results reported with other chemotherapy. Administration of TS-1 for 14 days followed by 14 days rest, plus CDDP (70 mg/m2) on day 8 every 4 weeks would be recommended in the view of high responsibility and low adverse reaction.

A 68-year-old man was diagnosed as having a scirrhous cancer of the stomach. Carcinomatous peritonitis was suspected on abdominal CT examination. Three courses of uracil and tegafur (UFT)/cisplatin (CDDP) chemotherapy were administered. The primary foci were reduced in size, then total gastrectomy was performed. Histological findings revealed a poorly differentiated adenocarcinoma with scirrhous invasion into the subserosa. Histological efficacy of the chemotherapy was judged to be grade 2. The patient has been alive without disease for more than five years after total gastrectomy. Neoadjuvant chemotherapy with UFT and CDDP may have contributed to the favorable clinical outcome in this patient.

The growth of a tumour can be determined by an interplay between cell proliferation and loss. The expression of apoptosis-related proteins (Bcl-2 and p53), cell proliferation (Ki-67), and apoptotic cell death were investigated using immunohistochemistry and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling in gastric neoplams, to evaluate whether they correlate with the morphology of the tumour. The materials included ten cases of gastric adenoma and 40 cases of early gastric carcinoma consisting of differentiated adenocarcinomas (n = 20) and undifferentiated carcinomas (n = 20). All cases of adenoma and eight cases of differentiated adenocarcinoma were of the elevated type, while 12 differentiated adenocarcinomas and all of the undifferentiated carcinomas were of the depressed type. The diffuse expression of Bcl-2 was observed in all cases of adenoma and seven out of eight (88 per cent) of elevated-type differentiated adenocarcinoma. In contrast, Bcl-2 expression was absent or focal in the depressed type of carcinoma. Overexpression of p53 was found exclusively in the depressed type of carcinoma. Thus, Bcl-2 and p53 expression was associated with tumour morphology. It seemed unlikely that Bcl-2 and p53 expression was involved in the morphogenesis of the gastric tumours through inhibiting apoptotic cell death, since the degree of apoptosis in Bcl-2-positive gastric tumours was rather higher than that in Bcl-2-negative ones and it did not differ significantly between p53-positive and p53-negative tumours. Instead, the diffuse distribution of Bcl-2 correlated with the superficial distribution of Ki-67-positive proliferating cells, and the overexpression of p53 had a tendency to correlate with the diffuse distribution of proliferating cells. These results suggest that diffuse Bcl-2 expression and a superficial distribution of proliferating cells may contribute to the elevated configuration, and that overexpression of p53 and a diffuse distribution of proliferating cells may result in the depressed configuration in the relatively early stages of gastric tumourigenesis.

Forty-eight patients with unresectable gastric cancer were enrolled for a randomized trial of FP (n = 24) vs FEP (n = 24) combination chemotherapy with respect to their effects on survival period. Of these, excluding 7 patients, 21 in FP group were treated with 400 mg/m2 UFT po daily and 50 mg/m2 CDDP i.v. on days 1 and 8 every 4 weeks, and 20 in FEP group were treated with 400 mg/m2 UFT po daily, 50 mg/m2 etoposide iv and 50 mg/m2 CDDP i.v. on days 1 and 8 every 4 weeks. In FP group, 10 PR in primary lesions were observed with an overall response rate of 52.4%. In FEP group, 5 PR in primary lesions were observed with an overall response rate of 35.0%. Toxicities over Grade 3 were anorexia (35%), vomiting (25%), and leukopenia (12%), which were manageable. The 50% survival time in FP and FEP group was 233 and 176 days, respectively. Because of the high response rate and prolongation of the survival period, combination chemotherapy with FP seemed to be useful for the treatment of patients with advanced gastric cancer.

The interleukin 2 (IL-2) and interferon-gamma (IFN-gamma) activities of regional lymph node mononuclear cells (LNMC) were studied in 22 patients with gastric cancer. Regional LNMC could produce high levels of IL-2 and IFN-gamma independent of the disease extension or the location of the lymph nodes. The activities of peripheral blood mononuclear cells (PBMC) from cancer patients were decreased especially in advanced disease compared to controls. The lymph node CD4+ cells were responsible for the bulk of IL-2 activity, whereas both CD4+ and CD8+ cells were equally capable of producing IFN-gamma. The proportion of T cells in LNMC was similar to that seen in PBMC, however, CD4+ cells predominated over CD8+ cells in the lymph nodes, contributing to higher activities of IL-2 and IFN-gamma in LNMC. Furthermore, significant cytotoxic activity could be induced from PBMC using the culture supernatant derived from autologous LNMC in cancer patients. This study suggests that regional lymph nodes are strategically located near the tumor and the local cells are capable of producing high levels of IL-2 and IFN-gamma.

A 69-year-old male visited our hospital in December, 1983, complaining of dysphasia. X-ray and endoscopic examination of the stomach revealed Borrmann's type 3 of the cardia. A biopsy specimen revealed typical features of adenocarcinoma. Because the tumor could not be resected, chemotherapy was started in February, 1984 with a combination of UFT (600 mg/day) and mitomycin (6 mg/week). After five courses of the combination chemotherapy, UFT therapy was continued. Follow-up endoscopy in August, 1985, showed a discolored area of the cardia. A biopsy specimen revealed no evidence of carcinoma. UFT-M therapy is a useful chemotherapy for gastric cancer.

It became increasingly evident that UFTM chemotherapy, a combination of UFT and mitomycin C is one of the most recommendable therapy for advanced gastric cancer, especially for the treatment of Borrmann type 4 gastric cancer. Objective responses were achieved in 18 out of 26 (69.2%) patients with Borrmann type 4 gastric cancer. Moreover, UFTM-Dpc treatment, a combination therapy of UFTM plus D-penicillamine (suppressor of collagen synthesis), is proposed for the treatment of Borrmann type 4 gastric cancer from the point of view of collagen synthesis inhibition. It is likely that D-penicillamine might inhibit the peritoneal metastatic involvements, which is lethal to the patients finally.

Investigations were made in human on the metabolism of Futraful (FT) and UFT (combination of uracil and FT), both of which are anticancer agents of pyrimidine metabolism antagonist. As a result, it was demonstrated that from the metabolic view point, those drugs essentially have a tumor-selective toxicity. Next, the mechanism of the superior clinical anticancer effect of UFT, compared to FT, was investigated enzymatically, showing the inhibitory effect of uracil on the degradation of 5-fluorouracil generated from FT in the organs and tumor tissues. Discussions were also made for the further development of fluoropyrimidines.

In brief, the clinical course of patients with Borrmann type 4 gastric cancer is characterized by its marked tendency for peritoneal metastasis (P-factor). This paper dealt with the treatment of Borrmann type 4 gastric cancer from the viewpoint of the disease P-factor, and included the following topics; UFTM chemotherapy, pharmacokinetics of mitomycin C (i.v. vs i.p. use), case presentation, Port-A-catheter (implantable drug delivery system), suppression of collagen biosynthesis, prevention of the adverse effects of mitomycin C, neochemotherapy, and autopsy findings.