Ken Kondo

Duodenogastric reflux and gastric stump carcinoma.

Abstract.Gastric stump carcinoma after gastric surgery for benign disease is now widely recognized as a distinct clinical entity. The stump carcinoma was often found to be localized to the anastomosis, known to be the site with severe duodenogastric reflux. For this reason, duodenogastric reflux, including the reflux of bile and pancreatic juice, after a Billroth II procedure for benign disease is frequently discussed as an important factor related to the development of stump carcinoma. Many experiments have implicated bile acids, the main component of the duodenal juice, in gastric carcinogenesis. In particular, rat models without the use of the carcinogen, N-methyl-N′-nitro-N-nitrosoguanidine (MNNG), showed adenocarcinoma in the remnant stomach that was related to the severity of duodenogastric reflux. However, human data are, inevitably, much less consistent. Whether the incidence of stump carcinoma is higher than that of gastric carcinoma in general is still controversial. Concerning the histogenesis of stump carcinoma after benign disease, a relationship between gastritis cystica polyposa (GCP) and gastric type adenocarcinoma has been suggested. Recently, the population at risk of gastric stump carcinoma for benign disease has been diminishing significantly, and the incidence of gastric stump carcinoma after surgery for malignant disease has been increasing. The influence of duodenogastric reflux in the gastric remnant after malignant disease may differ from its influence in the gastric remnant after benign disease. Further clinical study is needed to elucidate the pathogenetic factors involved in gastric stump carcinoma.

Preoperative embolization of gastric arteries for esophageal cancer

BACKGROUND We developed a novel treatment of preoperative embolization therapy in an attempt to prevent anastomotic leakage after esophageal resection. We report the results of this new treatment. METHODS Preoperative embolization therapy (PET) was performed in 24 cases of esophageal carcinoma. The femoral artery was punctured, and celiac angiography was performed. The left gastric artery and splenic artery underwent embolization. The right gastric artery then underwent embolization at a site beyond the second or third branch to the gastric wall. With a laser flow meter the stomach tissue blood flow was measured before and after construction of the gastric tube, and the change in blood flow was compared. RESULTS The average decrease in gastric blood flow was 23% in patients with PET and 65% in patients without PET. Twenty-one (88%) of 24 cases maintained more than 50% tissue blood flow in patients with PET and in 1 (8%) of 12 in patients without PET (p < 0.001 by t test). No serious complications occurred. CONCLUSIONS Preoperative embolization therapy is a safe and uncomplicated technique, and tissue blood flow in the stomach was better preserved. This new technique is expected to reduce the frequency of anastomotic leakage after esophageal operation.

Phase II study of a 4-week capecitabine regimen in advanced or recurrent gastric cancer.

Our objective was to evaluate the efficacy and safety of capecitabine in chemotherapy-naive patients with unresectable advanced or metastatic gastric cancer. An open-label multicenter phase II study was conducted for previously untreated patients with advanced or metastatic gastric cancer. Oral capecitabine 828 mg/m2 twice daily was given on days 1–21 every 4 weeks. Baseline characteristics of 60 enrolled patients were: male/female 49/11, median age 64 years (range 28–74), good performance status (ECOG 0–1) in 98% of patients and 27 patients had prior gastrectomy (45%). A median of 4 treatment cycles were administered (range 1–37). Five patients were excluded from the efficacy analysis because they did not meet eligibility criteria. The overall response rate (RR) in the evaluable patient population (n=55) was 26% [95% confidence interval (95% CI) 15–39%] and a further 29% of patients had stable disease. The overall RR in the intent-to-treat population (n=60) was 23% (95% CI 13–36.0%). Median time to progression in the evaluable patient population was 3.4 months (95% CI 1.8–6.1) and overall survival time in the intent-to-treat population was 10.0 months (95% CI 6.4–13.6). The most frequent grade 3/4 drug-related adverse event was hand–foot syndrome (13%), but this was readily managed by treatment interruption and dose reduction. No patients developed grade 3/4 drug-related diarrhea, vomiting, leukopenia or thrombocytopenia. We conclude that this 4-week regimen of capecitabine showed promising activity and was well tolerated as first-line therapy for advanced/metastatic gastric cancer. Further investigation of this regimen is warranted.

Preoperative embolization therapy for esophageal operation.

Since 1993, we have performed preoperative embolization therapy (PET) in an attempt to augment the blood flow of the gastric tube and prevent anastomotic leakage after esophageal resection. The clinical effects and complications associated with PET are reported.

A phase II study of radical surgery followed by postoperative chemotherapy with S-1 for gastric carcinoma with free cancer cells in the peritoneal cavity (CCOG0301 study)

BACKGROUND Patients with gastric cancer who have positive cytologic results for cancer cells in peritoneal washings (CY1) have poor outcomes, even in the absence of other distant metastases. A standard treatment for such patients remains to be established. METHODS We conducted a phase II trial with the 2-year survival rate as the primary endpoint. Patients who had gastric cancer with CY1 status but no other residual disease received postoperative chemotherapy with S-1 (1M tegafur-0.4M gimestat-1M otastat potassium) at a daily dose of 80mg/m(2) for 4 weeks, followed by 2 weeks of rest. This cycle was continued until disease progression or intolerable adverse events. D2 dissection was the recommended surgical procedure; splenectomy could be omitted at the discretion of the surgeon. Accrual of 50 patients was planned, and a 2-year survival rate of more than 36% was needed to exceed the historical control. RESULTS Forty-eight patients were enrolled, among whom 47 were assessable for survival and 46 for adverse reactions. Median overall survival was 705 days, and progression-free survival was 376 days. The 2-year survival rate was 47%. Median time to treatment failure was 288 days. Neutropenia was the commonest > or = grade 3 toxicity (6 patients), and anorexia was the most frequent > or = grade 2 non-hematologic toxicity (10 patients). CONCLUSIONS Gastrectomy followed by S-1 monotherapy resulted in survival that surpassed historical data and can serve as an active control treatment for future trials in patients who have gastric cancer with CY1 status in the Far East.

Feasibility Study on Protracted Infusional 5-Fluorouracil and Consecutive Low-Dose Cisplatin for Advanced Gastric Cancer

In this phase II trial 31 patients with advanced gastric cancer (21 with metastatic cancer and 10 with locally advanced cancer) were treated with a continuous 24-hour infusion of 5-fluorouracil (5-FU) 330 mg/m2/day plus low-dose cisplatin (CDDP) 6 mg/m2/day by bolus infusion on days 1-5. The regimen with a combination of 5-FU and low-dose CDDP (FLDP) was repeated weekly for two to four courses according to response and tolerance. In 24 (77%) of the 31 patients, four courses of this regimen were administered. The overall response rate was in 14/31 (45%) patients with measurable disease, including one complete response and 13 partial responses. An especially high response rate of 60% was seen in 10 patients with liver metastasis. Median survival time was 11 months (range 6-27+) in the 10 cases of locally advanced cancer and 11 months (range 6-24+) in the 21 cases of metastatic cancer. Toxicity was primarily hematologic. Leukopenia and thrombocytopenia of World Health Organization (WHO) grade 3 or 4 occurred in 4/31 (13%) and 4/31 (13%) of patients, respectively. Renal dysfunction, which is a major toxicity associated with CDDP, was not observed without hydration. The patients were able to eat during therapy and preserved a good quality of life. A randomized trial including the FLDP regimen is needed to compare it with other active regimens, particularly the use of high-dose CDDP.

Frequent Genetic Instability in Small Intestinal Carcinomas

To determine whether genetic instability plays a part in the development of digestive tract carcinomas, we analyzed 3 microsatellite loci isolated from tumors and surrounding normal tissue samples obtained during surgery. The polymerase chain reaction (PCR) technique was used to assess differences between tumor and matched normal DNAs. Replication errors (RERs) were observed in 3 of the 29 cases (10%) of gastric carcinoma and in 11 of the 72 cases (15%) of colorectal carcinoma. None of the 13 (0%) esophageal carcinoma cases showed any RER, but 5 of the 11 cases of small intestinal carcinoma (45%) had RERs, a significantly frequent finding. These results suggest that genetic instability plays an important role in the pathogenesis of small intestinal carcinomas.

Experission of glutathione-S-transferases α and π in gastric cancer: a correlation with cisplatin resistance

Glutathione-S-transferase (GST) in one of several factors that are proposed to affect tumor sensitivity to anticancer drugs, including cisplatin (CDDP). Attempts are made herein to evaluate the significance of the enzymes in resistance to CDDP in clinical samples of gastric cancer. A total of 22 gastric cancer specimens, 16 of which were obtained with matching normal mucosae, underwent immunoblotting with polyclonal antibodies against GST-α and GST-π. At the same time, the chemosensitivity of 15 gastric cancer specimens to CDDP was evaluated by the succinic dehydrogenase inhibition (SDI) test. The expression of GST-π was detected in all the specimens, and its content in the neoplasms exhibited a significant positive correlation with that in the matched normal mucosae. The expression of GST-α was detected in 18 of 22 cancer specimens (82%), but its content in the neoplasms did not correlate with that in the matched mucosae. A comparison of the drug-sensitivity findings with the results of immunoblotting revealed a weak but interesting correlation between the protein levels of GST-α and CDDP resistance. The cellular content of GST-α correlated weakly with CDDP resistance in gastric cancer, and its quantification could contribute to prediction of the clinical effects of CDDP in patients with gastric cancer.

Phase II Trial of 5-Fluorouracil and Low-Dose Cisplatin in Patients with Squamous Cell Carcinoma of the Esophagus

A phase II study was conducted to determine the clinical efficacy and toxicity of 5-fluorouracil (5-FU) and low-dose cisplatin (CDDP) in patients with squamous cell carcinoma of the esophagus. Chemotherapy consisted of 5-FU at a dose of 330 mg/m2 per day, given as a 24-h infusion on days 1–7, and CDDP at a dose of 6 mg/m2 per day, given as a 2-h infusion on days 1–5. Either two or four cycles of chemotherapy were administered to 20 patients with stage III advanced esophageal carcinoma. All 20 patients were then assessed for response and toxicity. An objective response was demonstrated by 11 of the 20 patients, with one complete response (CR) and ten partial responses (PR), bringing the response rate to 55%, with a 95% confidence interval of 27% to 83%. Surgical resection of the tumor was performed in all 20 patients. One patient was found to have a grade 3 histological CR. The median survival of all the patients was 20.5 months, with a range of 4.5 to 48.0 months. Neutropenia and thrombocytopenia developed in five (25%) and two (10%) patients, respectively, and the nonhematologic toxicities were insignificant. The findings of this phase II study indicate that preoperative treatment using 5-FU and low-dose CDDP chemotherapy for patients with advanced esophageal carcinoma appears to achieve a high response rate after shortterm administration without affecting the quality of sophisticated lymph node dissection.

Pharmacokinetic study of weekly administration dose of paclitaxel in patients with advanced or recurrent gastric cancer in Japan

BackgroundWe aimed to clarify the relationship between the maximum tolerated dose and plasma concentration of paclitaxel in Japanese patients with gastric cancer on a weekly paclitaxel administration regimen.MethodsThirty-three patients with advanced or recurrent gastric cancer were treated with escalating doses of paclitaxel, administered weekly, along with a fixed dose of 5-fluorouracil or cisplatin.ResultsThe plasma concentration of paclitaxel remained above 8.5 ng/ml for 24 h after administration. The mean area under the curve increased significantly with escalating dosage levels (R = 0.63; P 0.001). At level 4, patients showing dose-limiting toxicity had a significantly higher plasma paclitaxel concentration than patients without it.ConclusionThe weekly administration of paclitaxel, for which a single dose is about one-third of the dose for a tri-weekly treatment regimen, is clinically feasible and appropriate in terms of toxicity and the maintenance of an effective plasma concentration.