Randomized controlled trial of adjuvant uracil-tegafur versus surgery alone for serosa-negative, locally advanced gastric cancer.

BACKGROUND: This prospective randomized study compared the survival of patients with tumour node metastasis (TNM) stage T2 N1-2 gastric cancer treated by gastrectomy alone or gastrectomy followed by uracil-tegafur. METHODS: Patients were randomly assigned to surgery alone or to surgery and postoperative uracil-tegafur 360 mg per m(2) per day orally for 16 months. The primary endpoint was overall survival. Relapse-free survival and site of recurrence were secondary endpoints. RESULTS: Of 190 registered patients, 95 were randomized to each group; two patients with early cancer were subsequently excluded from the chemotherapy group. The trial was terminated before the target number of patients was reached because accrual was slower than expected. Drug-related adverse effects were mild, with no treatment-related deaths. At a median follow-up of 6.2 years, overall and relapse-free survival rates were significantly higher in the chemotherapy group (hazard ratio for overall survival 0.48, P = 0.017; hazard ratio for relapse-free survival 0.44, P = 0.005), confirming the survival benefit shown in an interim analysis performed 2 years earlier. CONCLUSION: Interim and final analyses revealed a significant survival benefit for postoperative adjuvant chemotherapy with uracil-tegafur in patients with serosa-negative, node-positive gastric cancer. REGISTRATION NUMBER: NCT00152243 (http://www.clinicaltrials.gov).

Plasma concentrations of VEGF and bFGF in patients with gastric carcinoma.

We examined plasma levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in 54 patients with gastric carcinoma. Postoperative survival was significantly poorer in patients with plasma VEGF levels more than 10.0 pg/ml at the time of surgery. By an univariate analysis of the factors affecting survival, serosal invasion, lymph node metastasis, peritoneal dissemination, lymphatic vessel invasion, curability, and VEGF proteins were significant. By a multivariate analysis only VEGF levels and curability remained significant. Patients with recurrent disease, including liver metastasis, had significantly higher plasma VEGF concentrations than those with resectable primary tumors. VEGF, not bFGF, may serve as an independent prognosticator and a sensitive indicator for liver recurrence in patients with gastric carcinoma.

Prognostic value of tissue inhibitor of matrix metalloproteinase-1 in plasma of patients with gastric cancer.

Tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in plasma has been reported to be related to disease progression in patients with gastric cancer. However, the prognostic significance of plasma TIMP-1 concentrations has not been clarified. Concentrations of TIMP-1 protein were measured by enzyme-linked immuno-sorbent assay in plasma samples of 147 preoperative patients who subsequently underwent gastric resection, and prognosis was compared. The cut-off value of plasma TIMP-1 concentrations was defined as 112.5 ng/ml, referring to the TIMP-1 levels in patients with intramucosal gastric cancer. Twenty-nine out of 147 patients had higher plasma TIMP-1 levels than the cut off value. When the patients were divided into those with elevated values and those with normal TIMP-1, such parameters as age, serosal invasion, metastases to lymph nodes, peritoneum, and liver, lymphatic invasion, curability, and stage were significantly different between the two. By univariate analysis of the factors affecting survival, macroscopic type, histology, serosal invasion, metastasis to lymph node, peritoneum, and liver, vessel invasions, curability, and plasma TIMP-1 were significant. However, multivariate analysis revealed that TIMP-1 was the only significant factor. In patients with gastric cancer, plasma TIMP-1 seem to be an independent and most powerful prognosticator for the survival.

Clinicopathologic differences between gastric remnant cancer and primary cancer in the upper third of the stomach.

BACKGROUND: The prognosis of gastric remnant cancer is considered to be poor compared with that of primary cancer. MATERIALS AND METHODS: This study was conducted to elucidate the differences of clinicopathologic findings and treatment results between 59 patients with gastric remnant cancer (GRC) and 579 patients with primary proximal gastric cancer (PGC). RESULTS: There was no significant difference in the incidence of lymph node metastasis between GRC and PGC. However, changes in the metastatic pattern to lymph nodes were observed in GRC. In GRC, the tumor easily invaded the neighboring organs due to the adhesions around the remnant stomach, resulting in a low resectability with curative intent. The 5-year survival rate after curative resection for advanced GRC was 50.9%. GRC patients without serosal invasion had a good prognosis. CONCLUSION: Although the survival rate after curative resection for GRC patients was similar to that of PGC, GRC patients without serosal invasion had a better prognosis. Therefore, early detection is an important way to improve overall survival in GRC.

Neoadjuvant chemotherapy with a combination of irinotecan and cisplatin in advanced gastric cancer--a case report.

We report a case of advanced gastric carcinoma successfully treated with a combination of irinotecan and cisplatin as neoadjuvant chemotherapy. The patient, a 78-year-old man, had type 2 gastric cancer, which had metastasized to the paraaortic lymph nodes. He was treated with irinotecan, 70 mg on day 1 and day 15, and cisplatin, 80 mg on day 1. The course was repeated every 4 weeks. Two courses of treatment resulted in a marked reduction of both the primary tumor and lymph nodes. Subsequently, the patient underwent curative surgery consisting of total gastrectomy, splenectomy, and D3 lymph node dissection. No surgical complications were observed. On microscopic examination, only a few tumor cells were detected in the granulation tissues of the resected stomach and in the lymph nodes. This would be the first case to demonstrate the effectiveness and the safety of irinotecan and cisplatin used in the neoadjuvant setting for treatment of advanced gastric carcinoma.

A combination chemotherapy of 5-fluorouracil and cisplatin against advanced gastric cancer.

BACKGROUND/AIMS: This study was designed to clarify the effects of treatment and toxicity between 5-fluorouracil (5-FU) plus bolus infusion of Cisplatin (CDDP) and 5-FU plus continuous infusion of low-dose CDDP in advanced gastric cancer. METHODOLOGY: Seventy-three patients with advanced gastric cancer were enrolled in this study to compare the antitumor effect and toxicity between the bolus infusion of CDDP and the continuous infusion of low-dose CDDP in combination with the continuous infusion of 5-FU. Sixty-five eligible patients were divided into two groups: group A: curative resection cases; and, group B: non-curative, recurrent or inoperable cases. Patients were classified into two arms in each group. One arm of treatment regimen is 5-FU and bolus infusion of CDDP (A-1, B-1) and the other arm is 5-FU and continuous infusion of low-dose CDDP (A-2, B-2). RESULTS: Response rates were 9.1% and 38.5% in arm B-1 and arm B-2, respectively, although the difference between the two was not at a significant level. Frequently observed toxicities during the treatment were gastrointestinal symptoms such as nausea, vomiting, and anorexia. The incidence of side effects in arm A-2 and arm B-2 was almost the same as that in arm A-1 and arm B-1. CONCLUSIONS: These results revealed that there was no advantage of low-dose continuous infusion of CDDP with 5-FU in terms of response rate and clinical toxicity in our present study.

Should scirrhous gastric carcinoma be treated surgically? Clinical experiences with 233 cases and a retrospective analysis of prognosticators.

BACKGROUND/AIMS: The prognosis of patients with scirrhous gastric carcinoma has been poorest. METHODOLOGY: To clarify the role of surgical treatment, 233 patients with a primary scirrhous gastric carcinoma were retrospectively analyzed. RESULTS: Of the 233 patients, 182 underwent surgical resection, while the other 51 did not. The median survival time of those with unresectable tumors was 88.0 +/- 15.3 days and that of those who underwent resection was 380.0 +/- 41.8 days. In the 182 patients who underwent resection, multivariate analysis revealed four significant factors; lymphatic invasion, serosal invasion, curability, and lymph node dissection. Of these, curability was the most significant. The median survival time of patients whose tumor were curatively resected was 727.0 +/- 116.3 days, significantly longer than 272 +/- 34.9 days for those whose resection ended noncuratively. In 65 patients whose tumor was curatively resected, subset analyses of factors by multivariate analyses revealed an absence of serosal invasion as the single significant prognosticator. The 5-year survival rate was 55.6% in patients with scirrhous cancer without serosal invasion. CONCLUSIONS: For patients with scirrhous gastric carcinoma, palliative resection should not be attempted for poor outcome. However, if curative resection seems feasible, radical surgery would be justified, especially for tumors without serosal exposure.

Angiogenesis inhibitor, TNP-470, suppresses growth of peritoneal disseminating foci.

BACKGROUND/AIMS: Angiogenesis is critical not only for growth of primary tumors but also for cells established at distant organs. We investigated the effects of angiogenesis inhibitor, TNP-470, on the establishment and growth of intraperitoneally inoculated human gastric cancer cell line, MKN-45, and survival of nude mice with this tumor. METHODOLOGY: Human gastric cancer cell line, MKN-45, were injected into the peritoneal cavity of an ICR nude mouse and a model of peritoneal dissemination was developed. TNP-470 was injected subcutaneously every other day from day 1 until sacrifice or death. The effects of TNP-470 on MKN-45 cells were also examined in vitro. RESULTS: Although the number of disseminated foci was not significantly different, the maximum size was significantly smaller in a TNP-treated group than those of a control. Survival time was significantly longer in a TNP-treated group. TNP-470 demonstrated no growth inhibition of MKN45 cells in vitro. CONCLUSIONS: Those results suggested that anti-angiogenic agent, TNP-470, might be effective in treating peritoneal dissemination of gastric cancer by inhibiting growth of the seeded tumor cells on the peritoneum.

Clinicopathologic differences between early gastric remnant cancer and early primary gastric cancer in the upper third of the stomach.

BACKGROUND/AIMS: This study was designed to clarify the clinicopathologic characteristics and survival in early gastric remnant cancer and compare with early primary cancer in the upper third of the stomach. METHODOLOGY: Twenty-five patients with early gastric remnant cancer, who underwent resection at Kanagawa Cancer Center and First Department of Surgery, Yokohama City University between 1974 and 1996 were evaluated in this study. Various clinicopathologic characteristics, such as age, sex, symptoms, size of tumor, depth of invasion, lymph node metastasis, cell differentiation, and survival were investigated and early gastric remnant cancer was compared with early primary cancer in the upper third of the stomach. RESULTS: According to the macroscopic type, protruded type such as I or II type accounted for a great majority in early gastric remnant cancer, while II c depressed type was common in early primary cancer in the upper third of the stomach, comprising 64.2% of all cases. Pathological examination disclosed that well-differentiated carcinoma and mucosal carcinoma were more frequently observed in early gastric remnant cancer than in early primary cancer in the upper-third of the stomach. The 5-year survival rate was 83.5% for early primary cancer in the upper-third of the stomach. In contrast, no patients experienced recurrence after operation for early gastric remnant cancer. CONCLUSIONS: From the view point of clinicopathological evaluation, gastric remnant cancer is a special from of gastric cancer. A follow-up program is important in order to detect early gastric remnant cancer. A low incidence of lymph node metastasis suggests that endoscopic mucosal resection of the tumor or limited operation could be performed under strict indication.

[Portal and peripheral blood immunoreactive insulin concentrations after glucose infusion during gastrectomy].

We evaluated portal and peripheral blood immunoreactive insulin concentrations (IRI) after glucose infusion in patients undergoing gastrectomy. Seventy-four patients were divided into following two groups: 68 received 25g glucose infusion in an hour (glucose group), and the remainder received no glucose (control group). Portal blood IRI level in glucose group was about thirty-fold higher than that in control group. However, peripheral blood IRI did not correlate with portal blood IRI in glucose group. In addition, significant negative correlation between portal blood IRI and blood glucose was observed in glucose group. Our results reveal that adequate pancreatic insulin secretion occurs after glucose infusion during gastrectomy, but peripheral blood IRI does not reflect this pancreatic insulin secretion. The results also suggest that blood glucose may be regulated by the liver under these conditions.

[Portal blood immunoreactive insulin concentration after glucose infusion in elderly patients during gastrectomy compared with younger patients].

We evaluated the effect of aging on portal blood immunoreactive insulin concentration, AKBR, and keton body concentration (acetoacetate + beta-hydroxybutyrate) after glucose infusion (25 g glucose in an hour) in patients undergoing gastrectomy. Twenty-seven patients studied were elderly (above 65 years) and twenty-eight were younger (below 60 years). There was no significant difference in portal blood immunoreactive insulin concentration after glucose infusion between the two groups of patients. In elderly patients, however, AKBR was significantly lower and keton body concentration was significantly higher than those in younger patients, and these imply that suppression of ketogenesis and activation of hepatic mitochondrial function due to insulin may be reduced in elderly patients. These findings suggest that, during gastrectomy, pancreatic insulin secretion may not be impaired in elderly patients, but insulin action may be attenuated with aging.

[Portal and peripheral blood insulin concentrations and arterial ketone body ratio before and after glucose infusion during gastrectomy].

The effect of glucose infusion on portal and peripheral blood immunoreactive insulin (IRI) concentrations and arterial ketone body ratio (AKBR) during gastrectomy were evaluated on twenty patients divided into two groups. Portal and peripheral blood IRI concentrations, AKBR, total ketone body concentration (TKB: acetoacetate + beta-hydroxybutyrate), and blood glucose were determined before and 30, 60, and 120 minutes after 25g glucose infusion in 30 minutes in ten patients (group 1) and 50 g glucose infusion in 30 minutes in ten patients (group 2). In both groups, the rate of increase in the portal blood IRI concentration was markedly higher than that in the peripheral blood IRI concentration after glucose infusion and AKBR increased and TKB decreased with the increase of the portal blood IRI concentration. These findings suggest that the peripheral blood IRI concentration does not reflect the pancreatic insulin secretion after glucose infusion during surgery and that portal insulin plays an important role for elevating and maintaining AKBR at higher levels. On the other hand, in both groups, the blood glucose had its peak just after completion of glucose infusion and then decreased gradually. After glucose infusion, however, the blood glucose in group 2 increased markedly and was significantly higher than that in group 1. It is suggested that, during surgery, glucose infusion rate of 50 g in 30 minutes may be too rapid.

[Translumbar local injection of OK-432 on para-aortic lymph nodes for recurrence of gastric carcinoma].

CDDP, 5-FU and LCV are administrated for recurrent gastric carcinoma in our hospital. We have been attempting translumbar local injection of a suspension of OK-432 and Lipiodol into the para-aortic lymph nodes or their surrounding areas for patients with para-aortic lymph node metastases when it was confirmed that the patient had a recurrence. This emulsion gradually degraded successively in the body. In this paper, we report the translumbar local injection method and its effective use in a case with para-aortic lymph node recurrence of gastric carcinoma.

[Effects of combination chemotherapy using 5-FU, leucovorin, and CDDP (FLP therapy) for noncurative resected or recurrent stomach cancer in outpatients].

We performed combination chemotherapy consisting of 5-FU, leucovorin, and CDDP (FLP therapy) against noncurative resected or recurrent stomach cancer in outpatients as of August 1991. Seventeen outpatients patients underwent FLP therapy until February 1993. Therapeutic responses, survival time after the operation or recurrence, rate at home, and the improvement of performance status (PS) were studied. The response rate was 54.5%, median survival time was 410 days, the rate at home was 75.5 +/- 14.7%, and the rate of improvement of PS was 82.4%. Toxicities were observed in 70.6%. Thrombocytopenia must be followed carefully, but it was encountered in only a few patients. FLP therapy for advanced or recurrent stomach cancer in outpatients was expected to improve the QOL.

[Clinical significance of matrix metalloproteinase-9 and tissue inhibitor of matrix metalloproteinase-1 in peripheral blood of patients with gastric carcinoma].

Matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in peripheral blood were measured in 54 patients with gastric carcinoma; 46 were primary and 8 were recurrent cases. There were no significant associations between MMP-9 concentrations and clinicopathological factors. TIMP-1 levels were significantly increased in advanced and recurrent cases, and in cases with peritoneal dissemination and lymph node metastasis, suggesting that TIMP-1 concentration in the peripheral blood could be a new tumor marker for the recurrence of gastric carcinoma.

[Significance of laparoscopy for response assessment of chemotherapy in gastric cancer].

UNLABELLED: We performed laparoscopy before and after chemotherapy in two patients with relapsed and advanced gastric cancer, whose major metastatic sites had been diagnosed as being in the peritoneum. A change in tumor responses when assessed by laparoscopy was found. Case 1: A 63-year-old man presented with an umbilical metastasis and suspected peritoneal metastases after gastrectomy. Laparoscopy revealed peritoneal metastases before chemotherapy. After one course of chemotherapy the umbilical tumor disappeared (CR). Laparoscopy after two courses of chemotherapy revealed increasing peritoneal metastases (PD). The overall response was PD. Case 2: A 67-year-old woman was referred to our hospital with a diagnosis of type 4 gastric cancer. Staging laparoscopy revealed massive lymph node metastases and the patient was positive in peritoneal washing cytology. After four courses of chemotherapy, the primary tumor and the metastatic lymph nodes had decreased in size (PR). In contrast, laparoscopy revealed increasing peritoneal metastases (PD). The overall response was PD. CONCLUSION: In patients with peritoneal and other modes of metastasis, tumor response to chemotherapy may be misjudged by conventional imaging alone. Intraperitoneal examination by laparoscopy provides accurate information, including the tumor response to chemotherapy.

[Significance of radical recurrent tumor resection for recurrent gastric cancer as assessed by prognosis].

To evaluate the relationship between radical surgery of recurrent tumor and prognosis in cases of recurrent gastric cancer, we analyzed data on 202 patients with relapsed gastric cancer, focusing on surgical recurrent tumor removal. In our series, 18 of the 202 patients underwent radical recurrent tumor resection. Resected tumors were located in the ovarium (n = 4), colorectum (n = 3), liver (n = 3), lymph node (n = 2), locoregional stoma (n = 2), and peritoneum, adrenal gland, brain, and lung (n = 1 each). No surgery-related mortality occurred. One patient remains alive over 5 years after hepatectomy without recurrence, and 17 died within 3 years: 7 patients from primary recurrence and 10 from multiple modes of recurrence. Median survival after recurrence (MSTAR) in the 18 radical surgery patients was 14 months, against 5 months in those treated palliatively (p = 0.0001). MSTAR for the ovary and the liver were 30 months and 15 months in the radical surgery cases, and 2.5 months for the ovary and 5 months for the liver in the palliative cases. Significant differences were thus seen between radical and palliative cases in the ovary (p = 0.010) and in the liver (p = 0.036). Median survival after gastrectomy was 45 months in the radical surgery cases, and 28 months in the palliative cases (p = 0.024). In postoperative gastric cancer follow-up, early detection of recurrence and radical surgery may well benefit patients with relapse, especially in the liver and ovary, in terms of survival.

[Prolonging home residence and treatment of cancer in patients with recurrent stomach cancer].

A study was conducted on 27 patients with cancer of the stomach who died from a postoperative recurrence of the cancer, 26 of whom died in the hospital and one of whom died at home. The period from the manifestation of initial symptoms of the recurrence to confirmed diagnosis was less than two months in 20 of the 26 cases (77%). The period from confirmed diagnosis to terminal hospitalization was in excess of three months in 11 of the 26 cases (42%). Of these cases, there were some in which it appeared that the time spent at home could have been extended through means such as another operation, insertion of an intraperitoneal access apparatus, or insertion of a subselective movable catheter. Forty-six percent (46%) of the patients were notified of their diagnosis, but none of them were notified of the recurrence of the cancer, suggesting the difficulty of notifying a patient of a diagnosis of cancer recurrence. A private home-care medical system was used in the case of the patient who had died at home of terminal stomach cancer. There were no major problems with this system other than the complaint that it placed a great financial burden on the family.

[A patient with stage IV gastric cancer responding to combination chemotherapy with 5-FU, leucovorin and CDDP].

The patient was a 44-year-old male with gastric cancer accompanied by pancreatic invasion and metastasis to the periaortic lymph nodes. Combination chemotherapy with 5-FU, leucovorin (LCV) and CDDP (FLP therapy) was preoperatively given. Pancreaticoduodenectomy was carried out as absolutely noncurative resection. FLP therapy was continued postoperatively, and resulted in disappearance of the metastases in the periaortic lymph nodes on CT. As there were no findings of recurrence, the patient was regarded as being in complete response. In addition, the performance status improved from Grade 2 to Grade 0. Since the three-drug combination therapy induced only slight adverse reactions (Grades 1-2), it could be safely carried out at the outpatient department. Thus, combination therapy with 5-FU, LCV and CDDP is thought to be effective against gastric cancer.

[Distribution of lymphocytes to tumor tissue and regional lymph nodes in patients with gastric cancer--the effects of oral administration of OK-432].

We attempted to clarify the accumulation of radiolabeled lymphocytes to tumors and regional lymph nodes in patients with gastric carcinoma. The effects of oral administration of OK-432 were also studied. Five patients with gastric cancer and one who underwent endoscopic mucosal resection, were entered in the study. Prior to the tracer study in 3 patients with gastric cancer, 5 KE of OK-432 was administered for 2 days. Peripheral mononuclear cells were separated and labeled with [111] In-tropolone. After the resection of stomach, tumor tissue, normal gastric mucosa, regional lymph nodes, and non-regional lymph nodes were dissected and radioactivity was measured by a gamma-counter. Accumulation of lymphocytes to the tumor tissue and n1 lymph node station was more than two times that in the normal gastric mucosa and ten times that in non-regional lymph nodes. Accumulation of lymphocytes to the n2 station was strongly enhanced by oral administration of OK-432.