Adjuvant chemotherapy for gastric cancer--relation between long-term administration of FT-207 and prognosis

The effect of adjuvant chemotherapy with FT-207 on survival rates in gastric cancer patients was evaluated. Patients who underwent curative gastrectomy in our Department were classified into the four groups: (A) short-term chemotherapy; total doses of 5 g 5-fluorouracil, or 1/2 MF (F') C alone (futraful 400mg/day, or 5-fluorouracil 250 mg/day for 3 weeks, mitomycin C 2 mg and cytosine arabinoside 20 mg twice a week for 3 weeks; (B) intermediate term chemotherapy; 1/2 MF (F') C followed by the oral administration of futraful 0.6g/day for less than 6 months; (C) long-term chemotherapy; 1/2 MF (F') C followed by futraful 10.6g/day longer than 6 months (D) control; no chemotherapy No significant difference back ground factors among four groups was found. Patients who recurred during the administration of drugs were excluded from this study. The survival rate of Group (C) in stage III was significantly higher than that of Group (A), (B) and (D) (generalized Wilcoxon test, p less than 0.03). There was no difference between (B) and (D). The survival rate of Group (A) was lower than Group (D). The effectiveness of chemo- therapy was not observed in patients with stage I and II. Survival rates of patients receiving futraful longer than 3 months continuously were significantly higher compared to patients who had to discontinue the drugs due to side effects. These results suggested that the adjuvant chemotherapy with futraful lasting more than 6 months prolonged the survival time, but short-term chemotherapy decreased the survival rate when compared with no chemotherapy group.     

Intraperitoneal administration of FT-207 for mouse peritonitis carcinomatosa

The peritoneal surface of the lesion was observed after treatment by scanning electron microscopy to evaluate the anticancer effect of FT-207. FT-207 (1.0 mg/day) was injected intraperitoneally to the DDN mice in which 3 X 10(7) MM2 tumor cells were inoculated the day before treatment. The anticancer effect was examined from 2nd to 7th consecutive day after tumor cell implantation, and the following results were obtained. 1) In the early phase after injection of FT-207, many macrophage-like cells were observed on the peritoneal surface. 2) Each MM2 tumor cell was covered by many macrophage-like cells, and these tumor cells were destroyed. 3) In the late phase after injection of FT-207, tumor cells were hyperplastic on the peritoneal surface, but less prominent than in the control group. 4) Effusion and adhesion in peritonitis carcinomatosa of FT-207 group were less than in the control group.     

Effect of FT-207 on bladder cancer in rats induced by BBN. II: The effect of oral administration of FT-207 during oncogenesis of bladder cancer

The effect of Tegafur (FT-207) by oral administration on the development of urinary bladder tumors in Wistar strain male rats induced by N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) was studied. Urinary bladder tumors were induced in 18 of 20 rats (90.0%) when rats were given 0.05% BBN in the drinking water for 8 weeks and then given water without BBN for 12 weeks. When FT-207 100mg/kg B. W./day was given in their diet after treatment with 0.05% BBN for 8 weeks, tumors developed in the urinary bladder with low incidence (9 of 16 rats: 56.3%). Hematotoxicity was not observed in all animals treated with FT-207. These results shows that FT-207 also inhibited the development of urinary bladder tumors treated with BBN in rats by oral administration, which were similar those our previous results showed by intraperitoneal administration of FT-207.     

5-FU concentration in tissues of gastric cancer patients with preoperative administration of UFT--especially in comparison with FT-207

FT-207 or UFT was administered preoperatively to 74 patients with gastric cancer. The 5-FU and FT-207 concentrations in the serum and various tissues were investigated. The 5-FU concentration in various tissues was higher than in the serum after the administration of FT-207 or UFT. Especially it showed that 5-FU concentration in tumor was highest in other normal tissues. The 5-FU concentration in the tumor for the UFT group was higher than for the FT-207 group. There was a significant difference between the UFT and FT-207 groups (P less than 0.05). Levamisole had no influence on the concentration of 5-FU.     

FT-207 maintenance therapy of malignant gynecologic cancer

Maintenance treatment with FT-207 was applied to 92 patients with uterine cancers after initial treatments were performed. Daily dosage of FT-207 was either 600 or 800 mg and the drug was administered orally. The duration of 6 months and the total dosage of 100 g were proposed as administration schedule and 34 patients (37%) received this regimen. Side effects during the treatment were observed in 35 cases (38%). Gastrointestinal disturbance was most frequently observed and other side effects included myelosuppression, general fatigue, hepatic dysfunction and skin toxicities. There were no serious side effects, the treatment was continued in most patients and was interrupted only in 7 cases (8%). In the cases of recurrence or advanced cancer, however, the side effect was the predominant cause for interruption of administration. As for the antitumor effect of the treatment, a survival rate of the patients with cervical cancer of early stages was evaluated. Three-year survival rate in the treatment group was higher comparing to the one reported hitherto.     

Serum concentration of 5-FU and tegafur (FT-207) after administration of tegafur (FT-207) suppository with the colostomy

Tegafur (FT-207) suppositories were administered at a rate of 750 mg via the artificial anus (ST Group) following surgery of rectal cancer. Comparative studies were conducted of changes in blood concentrations of 5-FU and tegafur at the time of initial administration and following one week of continuous use for the low-anterior resection cases (LA Group) and the rectal administration cases (RE Group). FT-207 concentration at initial administration was low in the ST group compared to those for both LA and RE groups which received anal administration of the drug, but only little changes were noted. Blood concentration one hour after administration was 11.1 micrograms/ml, elevated to 14.3 micrograms/ml at two hours, and remained at 10 micrograms/ml and above for six hours following administration. The ST group 5-FU concentrations at two, four and six hours after administration were significantly lower than those in the RE group but the changes were little. Blood concentrations were 0.015 microgram/ml at one hour after administration, 0.017 micrograms/ml at two hours and maintained virtually the same level thereafter. An effective concentration of 0.012 microgram/ml was maintained even at ten hours following administration. After one week of administration of the suppositories, the ST group showed the lowest concentration among three groups, but it was approximately double compared to the initial concentration; FT-207 showed nearly the same concentration in the LA group and 5-FU blood concentration was 0.025 microgram/ml at one hour after administration, reached to a maximum of 0.030 microgram/ml at two hours and maintained 0.020 microgram/ml and higher at ten hours. 5-FU concentration in the LA and RE groups after one week of continuous administration showed a dual-peaked pattern. No patient with an abnormal artificial anus was involved in this study. The artificial anus is thought to be an adequate and effective administration route of FT-207 suppositories.     

An advanced gastric carcinoma which responded to combined administration of mitomycin C, FT-207, and lentinan immunochemotherapy

A 59-year-old man with a gastric cancer underwent a laparotomy and was found to have an unresectable tumor that formed a large mass with metastatic lymph nodes around the aorta. He therefore was treated by a combined administration of Mitomycin C, FT-207, and Lentinan for 3 months. Remarkable tumor reduction was observed endoscopically, and a subtotal gastrectomy was performed. The immunochemotherapy then was resumed, and the patient has survived for 16 months despite the remnant lymph node metastases. A histological examination of the resected stomach revealed a marked degeneration of the tumor.     

Preoperative treatment of FT-207 suppository in cervical cancer-- serum and tumor tissue content of FT-207

A 750 mg FT suppository was inserted daily for seven days prior to surgery of uterine cervical carcinoma. The concentrations of FT and 5-FU in the serum, tumor tissue, adjacent normal tissues and regional lymph nodes were then measured. In addition, the concentrations of FT and 5-FU in the serum of patients who had been receiving chemotherapy for long term (an average of 15 months) after the initial remission were measured. The results are as follows: The 5-FU concentration in the serum of patients following short duration of administration was 0.014 +/- 0.006 micrograms/micromilligram. The 5-FU concentration in the tumor tissue was 0.209 +/- 0.132 microgram/g. This was approximately 3.2 times higher than the concentration in the normal tissue which was 0.065 +/- 0.017 microgram/g, and approximately 2.4 times higher than in the regional lymph nodes of 0.088 +/- 0.055 microgram/g. Relatively higher concentrations of 5-FU were seen in the non-keratinizing type than in the keratinizing type suggesting. The correlation between the concentration in the tumor tissue and the histologic findings of the carcinoma tissue. The 5-FU concentration in the serum of patients receiving long-term chemotherapy was 0.019 +/- 0.015 microgram/micromilligram, showing no significant difference from the patients receiving short-term chemotherapy.     

Long-term chemotherapy in patients with stage IV gastric cancer after surgical treatment--a randomized comparative study of FT-207 and UFT

A prospective randomized and comparative study of FT-207 and UFT was performed for cases of Stage IV gastric cancer involving long-term cancer chemotherapy after surgery. Immediately after the surgery, the subjects were randomly divided into two groups: A group treated by MMC and FT-207: and B group treated by MMC and UFT. From a total of 54 cases, 8 cases were excluded, so that A group consisted of 24 subjects and B group of 22 subjects. There were no differences in background factors between the two groups. In a comparison of all the cases, B group revealed a significantly higher survival rate than A group. These results indicated that the simultaneous use of MMC and UFT was effective as a long-term cancer chemotherapy after surgery for patients with Stage IV gastric cancer.     

Clinical study of serum and tissue concentrations of FT-207 and 5-FU in patients with cancer of the large intestine following preoperative application of FT-207 suppositories

1.5 g/day of FT-207 suppository was administered for two weeks prior to operation to twenty patients with large bowel carcinoma of familiar poliposis coli. The level of FT-207 and 5-FU in serum, lymph node, tumor and normal colonic mucosa were determined by bioassay. The levels of FT-207 in the rectum, sigmoid colon and tumor were higher than that in serum. The levels of 5-FU in the rectum, sigmoid colon, tumor and lymph node were also higher than that in serum. The levels of FT-207 and 5-FU in carcinoma of the rectum was higher than those in serum. Compared with the level in normal rectal mucosa, only the level of 5-FU in rectal carcinoma was higher. From the histological point of view, the highest levels of FT-207 and 5-FU was observed in well-differentiated adenocarcinoma. There was no side effect experienced in our series, therefore, FT-207 suppository seems to be one of the safe promising preoperative chemotherapies.     

Pre- and intra-operative chemotherapy using FT-207 suppositories--with special reference to lung cancer

This study was conducted to determine efficacy of FT-207 to prevent hematogenous peri-operative metastasis of lung cancer. A total of 16 patients consisting of 10 with squamous cell cancer, 6 with adenocarcinoma were evaluated in this study. The protocol of this study consisted of the pre-and peri-operative chemotherapy, giving 1000 mg of FT-207 suppository daily for 10 days. 5-FU plasma concentration in the systemic circulation during surgery was 0.01 mcg/ml. 5-FU tissue concentration of the normal lung was 0.07 mcg/g, and cancerous tissue (squamous cell ca 0.11 mcg/g, adenocarcinoma 0.12 mcg/g), and lymph nodes 0.15 mcg/g. It was found in this study that the pre-and peri-operative adjuvant chemotherapy with FT-207 was effective to prevent operation-induced hematogenous metastasis of lung cancer.     

Clinical study on concentration of FT-207 and 5-FU in serum, lymph nodes and tissues after rectal administration of FT-207 suppositories for malignant diseases of the liver, biliary tract and pancreas

In order to study the antitumor effect of FT-207 in a solid tumor, it is necessary to determine the concentration of 5-FU and FT-207 in a tissue. This has only been done so far for gastric cancer and colon cancer, but these has been practically no research carried out regarding cancers of the liver, biliary tract and pancreas. A study was therefore made of lymph nodes and tissues after rectal administration of FT-207 suppositories to 12 patients with cancers of the liver, biliary tract and pancreas. These included 7 cases of pancreatic cancer, 2 cases of gall bladder cancer with infiltration to the liver, and 3 cases of hepatoma. In serum, the concentration of 5-FU reached 0.018 +/- 0.006 micrograms/ml at one hour after administration, 0.019 +/- 0.004 micrograms/ml at three hours after administration, and 0.023 +/- 0.008 micrograms/ml at six hours after administration. These concentrations would be expected to maintain a clinically sufficient dose. The concentration of 5-FU in metastatic lymph nodes was high compared with normal lymph nodes (p less than 0.05), its concentration in liver tumors was high while compared with normal liver tissues (p less than 0.05).     

5-FU, FT-207 and uracil concentrations in the serum and tissues of patients with cervical cancer after UFT oral administration

The concentrations of 5-FU, FT-207 and uracil were estimated in blood serum, cancer tissue and normal tissue of patients with uterine cervical cancer. A daily dose of 600 mg of UFT was administrated for 7 days to cervical cancer patients, and they received radical hysterectomy and pelvic lymphadenectomy. After single administration of UFT, the serum concentration of 5-FU was highest at 60 minutes (0.094 micrograms/ml) and became reduced with time. On the other hand, when UFT was administered for 7 consecutive days, the serum concentration of 5-FU was found to reach a plateau between 60 minutes (0.215 micrograms/ml) and 120 minutes (0.222 micrograms/ml) with gradual decline thereafter. Significantly higher levels of 5-FU were achieved at 60 min. and 120 min. and apparent accumulation of 5-FU in serum was observed following continuous administration of UFT. Similar results were observed regarding the change of serum concentration of uracil, while FT-207 was observed to remain in serum for a longer time than 5-FU. In the uterine cervix, the concentration of 5-FU cancer tissue was 0.087 micrograms/ml, approximately 3 times that of normal tissue, and approximately 5.1 times that of the preoperative serum concentration of 5-FU, indicating a tendency to accumulate in cancer tissue. Although a higher concentration of 5-FU was detected in pelvic lymph nodes and ovaries, no significant differences were recognized between metastatic nodes and metastasis-free nodes.     

A sensitivity test of UFT and FT-207 against human pulmonary cancer using nude mice

Transplanted tumors of human pulmonary adenocarcinoma subcutaneously into nude mice were used, to investigate the effect UFT and FT-207. Concentration of 5-FU and uracil in tumors, measured by the gas chromatographic-mass fragment graphic method, was followed. 5-FU concentration in UFT group were higher than other group, and uracil concentration show no significant difference. In one of the lines, tumor growth was stopped in UFT group and regression rate was 68% in comparison with control group, pathologically revealed grade II b in classification of Simosato-Oohoshi. It was also indicated in this experiment, anticancer effect is related with specific anticancer drug sensitivity.     

Clinical study on the permeability of FT-207 and 5-FU in primary lung cancer

Distribution of the FT-207 and 5-FU between plasma and lung tissue as well as tumor tissue was studied in 28 patients with lung cancer after administration of FT-207 preoperatively. Two methods of administration were employed, one is intravenous drip infusion (IV Group) (800 mg/day for three days) and the other is suppository (Supp Group) (750 mg 2/day for three days). The level of FT-207 was higher in plasma than in normal lung tissue or tumor tissue in IV Group. There was no difference in the level of FT-207 between plasma, normal lung tissue and tumor tissue in Supp Group. The level of 5-FU was higher in tumor tissue than in plasma both in IV Group and Supp Group. Furthermore, intravenous drip infusion was more effective method to give FT-207 because of higher level of 5-FU in tumor tissue than in normal tissue. Comparison of the tissue level in IV Group between two histologic types of tumor, i.e. squamous cell carcinoma and adenocarcinoma, disclosed that there was no significant difference in the concentration of FT-207 and 5-FU both in normal lung tissue and in tumor tissue.     

In vivo chemosensitivity test for UFT and FT-207. I--Subrenal capsule assay

A chemosensitivity test for UFT and FT-207, which are used in long-term administration clinically, was investigated for prediction of clinical response. Five transplantation-established human tumor xenograft systems were examined using subrenal capsule assay. Both anticancer agents showed antiproliferative effects according to the total administered dose. Two of 5 tumors were determined to be sensitive to UFT using microscopic measurements following intragastric administration of 1/2 of the LD50 value, while they were shown to be resistant to 5-FU. In these two cases, prolongation of life span by long-term administration of UFT was shown clinically. All these experiments could be performed on condition that the loss of body weight in mice was less than 20%. These results suggest that in the 4-day subrenal capsule assay, clinical responses to long-term administration of UFT or FT-207 are predictable using intragastric high-dose administration which does not induce more than 20% body weight loss in experimental mice.     

Clinical study on preoperative chemotherapy of primary breast cancer. 2--A comparative study of CPA + FT-207 (5-FUDS) and CPA + FT-207 (5-FUDS) + MMC

In 41 cases of primary breast cancer preoperative treatment was performed using 2 methods consisting CPA + FT-207 (5-FUDS) (for Group I) and CPA + FT-207 (5-FUDS) + MMC (for Group II) to determine clinical and histological efficacies. A daily dose of each anticancer drug was: CPA 50-200 mg, FT-207 200-600 mg, and 5-FUDS 200 mg orally, and MMC 4-20 mg intravenously. The mean total doses were 1.8 g, 6.3 g, 3.4 g and 26.3 mg, respectively. Reduction in tumor size was obtained in 11 cases (37.9%) in Group I and 6 cases (50.0%) in Group II. According to Ohboshi's criteria, histological efficacy as defined over Grade II a was seen in 5 cases (17.2%) in Group I and 6 cases (50.0%) in Group II, while the efficacy classified as Grade III was not seen in any of the cases. Although the clinical effect was not always consistent with the histological effect, there was a tendency of agreement between them in Group II. As to the dosages of anticancer drugs, more effective cases were seen when dosages of more than 25 mg/kg of CPA, 80 mg/kg of FT-207 (5-FUDS) or 0.5 mg/kg of MMC were used. Reduction in tumor size began to appear at 2 to 3 weeks after the initiation of treatment.     

Evaluation of preoperative administration of N1-(2-tetrahydrofuryl)-5-fluorouracil (FT-207) suppository in surgical adjuvant chemotherapy for large bowel cancer

A prospective randomized study was performed for 72 patients with large bowel cancer, and 36 cases each of rectal cancer and colonic cancer, who had received curative resection respectively. The regimen consisted of two adjuvant chemotherapies: group A, postoperative administration of FT-207 suppository; group B; preoperative and postoperative administration of the same suppository. A follow-up study was then done. The results revealed the 5-year survival rate to be 65.1% for group A and 72.4% for group, B respectively. With rectal cancer, 5-year survival was 57.8% for group A and 70.5% for group B respectively. In colonic cancer the figures were 70.8% for group A and 75.0% for group B. Thus, there was no significant difference but a somewhat higher survival rate was observed in the preoperative plus postoperative administration group. Comparison of in the prognosis two groups classified according to the degree of nodal metastasis and invasion revealed good results in group B. The above-mentioned facts suggest that pre- and post-operative administration of FT-207 suppositories as adjuvant chemotherapy for colorectal cancer is superior to postoperative use alone.