Effect of carboxylesterase inhibition on the anti-tumour effects of irinotecan.

Irinotecan (CPT-11) is an important anti-cancer agent activated by carboxylesterase (CE). Treatment with CPT-11 may be associated with severe adverse effects, however, so determining the optimal dose would greatly benefit patients. We investigated the relationship between the anti-tumour effects of CPT-11 and CE concentration using bis-p-nitrophenylphosphate (BNPP), a specific inhibitor of CE, in nude mice with xenograft tumours. Initial experiments showed that the optimal dose of CPT-11 was 100 mg/kg. This dose was then used to study the anti-tumour effects of CPT-11 with and without BNPP. A direct correlation was found between the dose of administered BNPP and the growth rate of the tumour, demonstrating that the anti-tumour effects of CPT-11 were related to the CE concentration. Measuring the concentration of CE may allow the optimum dose of CPT-11 to be determined, opening up the possibility of individualized chemotherapy programmes.

[FLEP therapy for advanced and recurrent gastric cancer].

The FLEP regimen (5-FU, LV, ETP and CDDP) is a combination chemotherapy administered regionally and systemically for the control of both local and disseminated disease in intra- and extra-abdominal regions in patients with advanced and recurrent gastric cancer. Sixty-one patients with advanced and recurrent gastric cancer were entered into this study. The treatment regimen consisted of 5-FU at 370 mg/m2 (days 1 to 5, i.v. 24 h); LV at a dose of 30 mg (days 1 to 5, i.v. bolus); and ETP and CDDP each at 70 mg/m2 (days 7 and 21, ia 2 h). This regimen was repeated every four weeks. The overall response rate was 36.1% (22/61) and the 50% and median survival times were 10.23 and 11.80 months, respectively. The adverse events were Grade 3/4 leukocytopenia (18.0%), Grade 3/4 thrombocytopenia (4.9%), Grade 3 nausea and/or vomiting (3.3%) and Grade 3 stomatitis (1.6%). Of the 17 NAC patients, the six curability B patients showed a statistically higher survival rate than the curability C and unresected patients. Based on the encouraging response rate and the improvement in prognosis, we recommend the FLEP regimen for patients with primary gastric cancer. Neoadjuvant chemotherapy using the FLEP regimen should be performed with curative resection as an objective.

Clinicopathological analyses of advanced colorectal cancers of different sizes--especially those of 20 mm or less in diameter.

BACKGROUND/AIMS: Many small cancers of the flat type can now be detected, and many advanced cancers of the flat type have been discovered. In this study, to clarify the clinicopathological characteristics of small advanced cancers, advanced cancers of 20 mm or less in diameter were compared with those of other sizes. METHODOLOGY: Patients with advanced colorectal cancer (n = 865) were divided into four groups on the basis of cancer diameter as follows: Group A (20 mm or less), 21 patients; Group B (21-60 mm), 581 patients; Group C (61-100 mm), 215 patients; and Group D (101 mm or more), 48 patients. These groups were compared for various clinicopathological findings. RESULTS: The depth of invasion was muscularis propria in 14 cases and subserosa in 7 cases. In Group A, cancer was histologically well-differentiated in 8 cases, moderately differentiated in 12 cases, and mucinous in one case. Six cases (28.6%) in Group A had lymph node metastasis (N1). In Group A, one patient had multiple liver metastasis and all of the other cases were assessed as R0 resection. CONCLUSIONS: Most small advanced colorectal cancers of 20 mm or less in diameter can be regarded as quasi-early cancers, but some have the potential for high malignancy, and for these, reduction surgery cannot be used.

[Curative resection of advanced gastric cancer responding to preoperative chemotherapy--a case report].

A 56-year-old male was admitted for treatment of advanced gastric cancer. The patient was diagnosed as having an unresectable advanced gastric cancer because cancer cells had invaded the pancreas head and there were metastatic lymph nodes. The patient underwent preoperative chemotherapy (FLEP: intra-arterial infusion of CDDP, ETP and intravenous infusion of 5-FU, LV). The primary tumor and metastatic lymph nodes were reduced by three course of chemotherapy. The patient underwent curative resection and survived without recurrence for 14 months after operation. Preoperative chemotherapy using FLEP was performed in 15 patients with unresectable primary advanced gastric cancer. This therapy resulted in significantly higher survival times. In conclusion, FLEP has been shown to be effective for unresectable advanced gastric cancer.

Gastrectomy with D2 lymph node dissection in gastric cancer: a retrospective study at a single institution.

The purpose of this study was to clarify the clinicopathological characteristics of gastric cancer with lymph node (LN) dissection and the significance of D2 dissection by investigating surgical techniques and prognosis. Three hundred ninety patients with early cancer and 310 with advanced cancer underwent gastrectomy with D1 or D2 dissection, based on the presence or absence of LN metastasis determined pre- and intraoperatively. LN metastasis occurred in 10.5% of early gastric cancer patients, and several cases of advanced cancer were found to have N2 or more advanced metastasis. The pre- and intraoperative macroscopic findings accorded with histological grade of LN metastasis in 69.5% of early cancers and in 56.5% of advanced cancer patients. The false negativity rate was 6.8% in early cancer, 19.4% in advanced cancer, and 8.4% as a whole. Death was operation-related in only two cases and the operative mortality rate was low (0.29%). The 5-year survival rates in early and advanced gastric cancer were 95.8% and 67.6% in the D1 groups, respectively, and 100% and 89.5% in the D2 groups, respectively. Survival was better in the D2 groups than in the D1 groups (P < 0.0001 for early cancer, P = 0.0279 for advanced cancer). D2 dissection should be conducted positively for patients with LN metastasis.

[Neoadjuvant chemotherapy for advanced gastric cancer using FLEP therapy].

Combination chemotherapy with 5-FU, LV, ETP and CDDP (FLEP) for advanced gastric cancer uses a combination of regional and systemic delivery for the control of both local and disseminated disease in the intra- and extra-abdominal regions. We performed this regimen as neoadjuvant chemotherapy (NAC). Fifteen patients with unresectable primary advanced gastric cancer underwent FLEP. The treatment regimen was 5-FU at 370 mg/m2, LV at 30 mg/body (days 1 to 5, i.v. 24 h) and ETP and CDDP each at 70 mg/m2 (days 7 and 21, ia 2 h). This regimen was repeated every four weeks. The overall response rate was 46.7% (7/15), and the 50% and median survival times were 11.43 and 12.35 months, respectively. The adverse events were Grade 3 leukocytopenia, Grade 3 thrombocytopenia, and Grade 3 stomatitis in 20.0%, 13.3%, and 6.7% of the patients, respectively. The 50% and median survival time overall were 11.43 and 12.35 months, respectively. Of the 15 NAC patients, curability B patients showed a statistically higher survival rate than curability C and unresected patients. In conclusion, FLEP was effective for unresectable advanced gastric cancer.

Clinicopathological study of brain metastasis in gastric cancer patients.

Brain metastasis from cancers of the gastrointestinal tract is uncommon; brain metastasis from gastric cancer is rare and its incidence is low. Brain metastasis of gastric cancer is often difficult to treat and is resectable in only a few cases. We have treated three patients who had a solitary brain metastasis after a gastrectomy. These three cases are reviewed along with eight other previously reported cases of brain metastasis to clarify the clinicopathological features and to suggest guidelines for patients with metastatic brain tumors. The clinicopathological features of 11 cases of brain metastasis were analyzed. For comparison purposes, the 11 cases were classified into three groups as follows: a resection group, a chemoradiotherapy group, and a nontreatment group. All the patients had advanced gastric cancer of stage III or more. The resection group had the most survivors, and survival rates decreased in the order of the resection group, the chemoradiotherapy group, and the nontreatment group. There was a statistically significant difference between the resection group and the nontreatment group (P = 0.0177). Aggressive multidisciplinary treatment, including a resection, for brain metastasis should improve the quality of life and prolong life expectancy.

Is there a benefit of pancreaticosplenectomy with gastrectomy for advanced gastric cancer?

BACKGROUND: In Japan, wide resection with extended lymph node dissection has been performed for advanced cancer with good prognosis. Pancreaticosplenectomy with gastrectomy is performed to facilitate dissection of the lymph nodes around the splenic artery. We attempted to evaluate the effects of pancreaticosplenectomy and splenectomy with gastrectomy for advanced gastric cancer. METHODS: Gastric cancer patients underwent splenectomy with gastrectomy (78 cases), pancreaticosplenectomy with gastrectomy (105 cases), or gastrectomy alone (1,755 cases). Survival rates were compared among the three groups for each factor of the depth of invasion, stage, and curability. RESULTS: There were no significant differences among the three groups. Pancreaticosplenectomy or splenectomy with gastrectomy to dissect lymph nodes does not improve survival but is associated with severe complications. CONCLUSIONS: The spleen should be resected when a patient has clearly positive node metastasis around the splenic hilus and artery, and pancreaticosplenectomy be performed when the cancer lesion invades the pancreas.

[Two patients with obstructive jaundice due to intra-abdominal lymph-node metastases of gastric cancer responding to combination chemotherapy with 5-FU and CDDP].

Combination chemotherapy with 5-FU and CDDP was given to two patients with obstructive jaundice due to intra-abdominal lymph-node metastases of advanced and recurrent gastric cancer. One patient was a primary case associated with lymph-node metastases of portal fissure and periaorta, and the other was a recurrent case associated with lymph-node metastases of hepatoduodenal ligament and periaorta. The regimen consisted of 5-FU 1,000 mg/ m2 (day 1-5, continuous infusion) and CDDP 100 mg/m2 (day 3, 1 hr drip infusion). The interval was from the 6th to 21st day. The response to chemotherapy showed shrinking of intra-abdominal lymph-nodes and reopening of the biliary tract. The patients could be discharged from the hospital without PTBD tube and enjoyed a better quality of life (QOL). This therapy is thought to be effective against obstructive jaundice due to intra-abdominal lymph-node metastases of advanced and recurrent gastric cancer.

[The optimal period for orally administered fluoropyrimidines as an adjuvant chemotherapy for gastric cancer--a pilot study using 5-FU tablets compared with surgical operation alone].

Long-term oral administration of fluoropyrimidines such as 5-fluorouracil (5-FU) or tegafur is commonly used as an adjuvant chemotherapy for gastric cancer, but the optimal period or optimal total doses of fluoropyrimidines have not been studied. Two hundred cases of macroscopical Stage II and III curatively resected gastric cancer patients were entered in this study, and divided into three groups (6 months group: mitomycin C was given i.v. at day 0 and day 1 and 5-FU tablets were orally administered at a dose of 200 mg/day for 6 months. 12 months group: MMC was given the same as for the 6 months group and 5-FU tablets were administered for 12 months. Surgery alone group: No chemotherapy, operation only). As the result, 185 cases were eligible. There was no significant difference between the 6 months group and the 12 months group among Stage II patients. Although there was also no significant difference between the 2 groups in Stage III patients, the survival curve of 12 months group was always higher than in the 6 months group. When comparing with surgery alone group, 5-year survival of the 12 months group was always higher than in the surgery alone group of Stage III patients; however, the survival rate in the 6 months group was worse than in the surgery alone group at Stage II and III. These results suggest that MMC i.v. and 12 months or over administration of 5-FU tablets is useful for Stage III gastric cancer patients, and that cooperative study is required comparing with surgery alone in Stage II patients.