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.     

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.     

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.     

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).     

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.     

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.     

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.     

Study on the concentration of FT-207 and 5-FU in serum and tissues of bladder tumor and prostatic carcinoma

Serum and tissue concentrations of 5-FU and FT-207 were estimated in 26 patients with bladder tumor or prostatic carcinoma after administration of FT-207 suppositories. The 5-FU concentration in bladder tumor was higher than in normal mucosal bladder tissue. The 5-FU concentration of prostatic cancer was almost equal to that of normal prostatic tissue. Relatively higher concentrations of 5-FU were recognized in bladder tumor of a high stage than of a low stage. There were no differences of serum and tissue 5-FU concentration in bladder tumor between patients more than 65 years old and those under 65 years old. No side-effects occurred in any case during suppository administration.     

Clinical study of preoperative chemotherapy of primary breast cancer. 1. Efficacy of a combined use of CPA (endoxan) and FT-207 (or 5-FU dry syrup)

In twenty-nine cases of primary breast cancer preoperative treatment using CPA and FT-207 (or 5-FUDS) was performed to determine their efficacy. Daily dose of each anticancer drugs was as follows: CPA 50-200 mg, FT-207 200-600 mg, 5-FUDS 200 mg, p.o.. The total doses were CPA 1.8 g, FT-207 5.0g, 5-FUDS 3.4 g in average. In 11 cases (37.9%) reduction in tumor size was obtained. According to Ohboshi's criteria, over Grade II a effect was seen in 5 cases (17.2%), while Grade III effect was not seen in any of the cases. Effective cases were more frequently observed among those which received CPA at 25 mg/kg or more, or FT-207 (5-FUDS) at 80 mg/kg or more. Main side effects were G. I tract symptoms such as anorexia and nausea. To obtain definitive conclusion on the clinical significance of use of CPA and FT-207 (5-FUDS) as preoperative chemotherapy for breast cancer, further studies are required.     

Comparison of continuous venous infusion of 5-FU and FT-207 under total parenteral nutrition

Yoshida sarcoma-bearing rats were continuously infused with 5-FU at a dose of 20 mg/kg/day, and FT-207 at a dose of 40 mg/kg/day, 100 mg/kg/day or 140 mg/kg/day under TPN. After 4 days, rats were sacrificed and the 5-FU and FT-207 concentrations in their organs were measured. The 5-FU level in the tumor was almost the same at when 5-FU was injected at 20 mg/kg/day and FT-207 at 140 mg/kg/day. This 5-FU level in the tumor was twice and four times higher than that of the group injected with FT-207 at 100 mg/kg/day and 40 mg/kg/day. The 5-FU level in the tumor in all four groups was almost twice as high as that in the stomach, intestine and kidney, 7-10 times higher than that in the liver, and 10-30 times higher than that in serum. The FT-207 levels in the alimentary tract, kidney, tumor and serum were almost the same. The conclusion of our preliminary research is that FT-207 is recommended for use in continuous infusion at 7 times the dose of 5-FU when injected under TPN.     

Studies of 5-FU concentrations associated with microangiography in colorectal cancer tissue

In order to elucidate the effect of supplying vessels on 5-FU distribution within a tumor, the correlation between 5-FU tissue concentration and tumor microangiography was examined in 31 patients with colorectal cancer after administration of 5-FU (500 mg/day for 3 days). The 5-FU concentration at the tumor margin was significantly higher than that in the other two tissue areas (p less than 0.05). A low 5-FU concentration was noted in the central region of ulcerative cancer showing vertical invasion with vascular disarray and/or histological necrotic foci. This type of tumor also showed a low RNA index by flow cytometry. The present study indicates that the vascular change and vascular pattern of a tumor may be a major contributing factor to 5-FU transfer from the blood circulation into a tumor.     

Enterosorption in the preoperative period in patients with cancer of the large intestine

Polifepan was used for preoperative detoxication by enterosorption in 40 cases of cancer of the large bowel. The results were compared in the study group and controls who had received standard premedication. Postoperative complication frequency dropped 35-10% and postoperative inpatient stay duration--28.3-17.8 days.     

Tegafur and 5-fluorouracil pelvic tissue concentrations in rectal cancer patients receiving preoperative chemoradiation

Background and purpose To investigate the presence of 5-Fluorouracil (5-FU) in pelvic tissue after oral administration of tegafur. To measure tegafur and 5-FU concentrations in normal rectal mucosa, perirectal fat and residual tumor in rectal cancer patients receiving preoperative chemoradiation. To correlate drug concentrations with cancer down-staging effects. Patients and methods Three tissue samples taken from 16 surgical specimens after recto-sigmoid resection were analyzed. Tegafur and 5-FU concentrations were measured using high-performance liquid chromatography. 16 patients with locally advanced rectal cancer were treated with preoperative pelvic irradiation (45–50 Gy) sensitized with oral tegafur (400 mg for every 8 hours daily). Seven patients received a precharge dose of tegafur (400 mg oral every 8 hours) 24 hours before surgery. Results In 8 of the 9 patients who did not receive a precharge dose, detectable levels of tegafur were observed in fat tissue, normal mucosa and tumor, but detectable 5-FU levels were only observed in one patient. Mean concentrations (ranges) for tegafur in fat, normal mucosa and tumor in patients without the precharge dose were 72.19 (12.1–205.6), 179.53 (11.30–727.7) and 252.35 (27.9–874.6) ng/g, respectively; mean concentrations for 5-FU in the same samples were 0.95, 1.92 and 2.68 ng/g (1 patient), respectively. In patients receiving a tegafur precharge, both tegafur and 5-FU were present in all tissue samples with the exception of 2 fat samples, in which drug concentrations were undetectable. 5-FU levels were higher in tumor than other sites, with a median value of 68.24 ng/g (range 3.8–283.05 ng/g). Tegafur levels were also higher in tumor samples than other sites (mean 3446.53 ng/g, range 1044.5–7847.0 ng/g), except in 2 patients who had higher levels of tegafur in normal mucosa. Conclusions Tegafur and 5-FU are not always present in pelvic tissues 5 to 6 weeks after oral administration of tegafur. Both drugs were present in the tissues analyzed, in relevant concentrations, 24 hours after oral administration of tegafur. The data obtained suggest a tendency (not significant) toward a correlation between levels of 5-FU present in the residual tumor and cancer down staging. Scientifically supervised by GICOR (Grupo de Investigación Clínica en Oncología Radioterápica).     

Experience of a combination chemotherapy consisting of 5-FU, MMC, and FT-207--side effects against kidney

We are using 5-FU, MMC, and FT-207 in combination for the treatment of the patients with gastric cancer for a long term, and the renal dysfunction was found in two cases. The 1st case was a 69 years old male, suffering from gastric cancer which was unresectable. He was treated with the anticancer drugs for 2.5 years after exploratory laparotomy and no development of gastric cancer was detected endoscopically. But renal function of the patient was damaged. The 2nd case was a 58 years old male, also suffering from gastric cancer. The chemotherapy lasting for 1.5 years after gastrectomy resulted also in renal dysfunction.     

The concentration in the tissue and antitumor effect of anticancer drug--assessment of breast cancer with UFT or FT-207

The correlation between intralesional 5-FU concentrations and the extent of antitumor effect with particular attention to histopathology was assessed in 30 patients with breast cancer. Therapy consisted of either UFT or FT-207 given preoperatively. Although the UFT-treated group showed a significantly higher intratumoral concentration of 5-FU, there was no intergroup difference in 5-FU levels in normal tissue. In addition, this greater concentration of intratumoral drug had no significant effect on therapeutic response; for both UFT and FT-207 treated groups, the histologic interpretation was rated as grade IIa. Regardless of which drug was used, when tumors were stratified according to histologic type, papillotubular carcinomas revealed the greatest tissue 5-FU levels. However the greatest histologic antitumoral responses were seen in scirrhous carcinomas; hence no correlation was seen here either. The results suggest that attainment of a high intratumoral 5-FU concentration is not reflected in a better histologic tumor response in patients receiving the above drug regimens.     

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.     

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.     

奥沙利铂联合甲酰四氢叶酸和氟尿嘧啶治疗晚期结直肠癌的临床观察

目的:评价奥沙利铂(LOHP)联合氟尿嘧啶(5FU)、甲酰四氢叶酸(CF)治疗晚期结直肠癌的近期疗效和不良反应。方法:采用LOHP85mg/m2,静脉滴入,持续2h,d1;CF300mg,静脉滴入,持续1h,d1～d5;5FU500mg,静脉滴入,持续4h,d1～d5。21d为1个周期,治疗3个周期后评价疗效。结果:共治32例,CR0例,PR12例,MR10例,SD6例,PD4例,总有效率37.5%(12/32)。不良反应主要为轻度的感觉神经毒性,轻度骨髓抑制及恶心、呕吐。结论:LOHP、5FU和CF联合应用治疗复治晚期结直肠癌患者有一定的疗效,不良反应较轻。     

奥沙利铂联合亚叶酸钙及5-氟尿嘧啶治疗晚期大肠癌的临床观察

目的观察奥沙利铂(L-OHP)联合亚叶酸钙(CF)及5-氟尿嘧啶(5-Fu)治疗晚期大肠癌的疗效及不良反应。方法将我院2002年10月~2005年10月收治的65例晚期大肠癌,随机分为A组和B组,A组奥沙利铂130mg/m2静脉滴注2小时,第1天;亚叶酸钙200mg/m2持续静滴24小时,第1~5天;5-氟尿嘧啶500mg/m2持续静滴24小时,第1~5天;每3周重复。B组羟基喜树碱(HCPT)8mg/m2静脉滴注,第1~5天;亚叶酸钙200mg/m2,静脉滴注2小时,第1~5天;5-氟尿嘧啶500mg/m2持续静滴24小时,第1~5天,每3周重复。所有病例均接受2周期化疗。结果A组CR2例,PR12例,SD11例,DD8例,总有效率42.4%,B组CR1例,PR5例,SD16例,PD10例,总有效率18.8%,A组的主要不良反应是周围神经炎及恶心呕吐、骨髓抑制。结论奥沙利铂联合亚叶酸钙及5-氟尿嘧啶疗效优于羟基喜树碱、亚叶酸钙、5-氟尿嘧啶联合化疗,不良反应轻,值得临床推广。