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.     

Joint clinical Phase II study of SF-SP

A clinical Phase II study on a new type of anti-malignant tumor agent 1-(2-tetrahydrofuryl) 5-fluorouracil (SF-SP) encapsulated with slow releasing granules has been performed by the Tokyo cancer chemotherapy joint study group. Sixty-five patients out of 81 were evaluable for response by criteria of Saito and Koyama 's clinical evaluation. The partial response rate was obtained in 21.5% of evaluable patients and better than that of FT-207 observed by the same group. More effective rates in colon and breast cancer were obtained by SF-SP as compared with FT-207. The optimal dosage was considered to be between 17 mg/kg and 24 mg/kg. The side effects of this therapy were encountered in 33.3% (27 of 81 cases) of patients and were less gastrointestinal disturbance and bone marrow depression than in FT-207 treatment. The effective responses were demonstrated even in patients with previous therapy by 5-FU, FT-207, or HCFU.     

Clinical studies on chemo-immunotherapy for advanced and recurrent carcinoma of the breast

The effectiveness of combination chemo-immunotherapy with ADM, CPA, FT-207 plus OK-432 for advanced and/or recurrent carcinoma of the breast was investigated in a prospective randomized and controlled study. Fifty-seven patients from 10 major hospitals in the Tohoku area were grouped into the following protocols: protocol I (ADM 40-60 mg/body on the first day, CPA 150mg p.o./body/from the 5th to the 9th day, FT-207 600mg p.o./body/from the 10th to the 30th day, OK-432 total dose 30KE and over) and protocol II(ADM, CPA, FT-207). These protocols were performed repeatedly two or more times. Forty-five cases from the total of 57 were available for this randomized study. Twenty-three of these cases were treated with protocol I (OK-432 group), while the remaining 22 were treated with protocol II (non-OK-432 group). The OK-432 group and the non-OK-432 group were compared for prognostic factors, and no difference could be observed between the two groups. Seven cases from each group were interpreted as effective clinically by Koyama-Saito's criteria of PR or better. Eight cases from the OK-432 group and 4 from the non-OK-432 group were interpreted as effective by Karnofsky's criteria of I-A and better, but no statistical difference was recognized between the two groups. The survival curve obtained by the Cox-Mantel test for the OK-432 group was better than that for the non-OK-432 group (U = 1.943, p less than 0.1).     

Antineoplastic effect of UFT therapy (uracil-FT-207 combination therapy) on experimental pancreatic cancer transplanted in the pancreas and subcutaneous region

The pancreatic duct cell adenocarcinoma induced by di-isopropanol nitrosamine could be easily and repeatedly transplanted into the subcutaneous or pancreatic tissues of the homologous animals. We established a tumor bearing animal design in which tumor tissues were transplanted simultaneously into subcutaneous and pancreatic tissues. At the first week after the transplantation, the animals were divided into three groups: In FT group FT-207 was given at a dose of 15 mg/kg/day, in UFT group FT-207 and uracil were given at a dose of 3 mg/kg/day and; 6.7 mg/kg/day (molar ratio; 1:4), respectively and in control group a solvent of FT-207 was given. In all groups the drugs were administrated orally for ten days. The size of tumors transplanted in subcutaneous and pancreatic tissues increased more slowly in FT and UFT groups, as compared with that of control group. The inhibitory effect on tumor growth observed in UFT group was more striking than that in FT group. No major side effects were observed in all groups. At the fourth weeks after subcutaneous and intrapancreatic transplantation, the animals were divided into two groups: In FT group FT-207 was given at a dose of 30 mg/kg and in UFT group FT-207 and uracil were given at a dose of 30 mg/kg and 67.2 mg/kg, respectively. In both groups the drugs were given orally, and at one hour after the administration all the animals were killed to determine 5-FU concentration in various tissues. The 5-FU concentrations of subcutaneous and intrapancreatic transplanted tumor tissues were significantly higher in UFT group than those in FT group. UFT therapy, therefore, seems to be hopeful for the treatment of human pancreatic cancer.     

方克联合顺铂治疗头颈部肿瘤的疗效观察

目的 评价方克联合顺铂治疗复发转移性头颈部肿瘤的疗效和毒性。方法 将46例复发转移性头颈部肿瘤患者随机分为两组,治疗组：亚叶酸钙200mg静滴d1～5,方克600mg／m^2静滴d1-5,顺铂30mg／m^2静滴d1-3,21d为1周期;对照组：亚叶酸钙200mg静滴d1,5,5-Fu500mg／m^2静滴4～6hd1～5,顺铂30mg／m^2静滴d1～3,21d为1周期。结果 治疗组有效率为43％,中位生存期为7个月,1年生存率为30.4％;对照组有效率为34％,中位生存期为6个月,1年生存率为26．1％。两组有效率差异无统计学意义（P〉0．05）,治疗组不良反应明显轻于对照组（P〈0.01）。结论 方克联合顺铂是治疗复发转移性头颈部肿瘤患者的一种安全、有效的化疗方案。     

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.     

N1-(2 tetrahydrofuryl)-5-fluorouracil (FT-207) in the postoperative adjuvant chemotherapy of gastric cancer. Delivery of a fat-emulsified agent to the lymph

The influence of fat emulsification of N1-(2-tetrahydrofuryl)-5-fluorouracil (FT-207) on lymphatic transport was studied in seven postoperative gastric cancer patients. The water-in-oil-type of emulsion of FT-207 (FT-w/o), the oil-in-water-type emulsion of FT-207 (FT-o/w) and an enteric-coated granule of FT-207 (FT-G) each in 1-g doses, calculated in terms of FT-207, were administered orally. Lymph from a thoracic duct fistula, prepared in advance, and from the blood of a peripheral vein was collected simultaneously along a time course after administration to measure the concentrations of FT-207 and 5-fluorouracil (5-FU). For FT-w/o, FT-207, and 5-FU, concentrations were significantly higher, both in the lymph and in the blood, than those for FT-G and FT-o/w. However, no significant differences in FT-207 and 5-FU concentrations were observed between FT-o/w and FT-G. It was concluded that FT-w/o can be useful as an adjuvant chemotherapeutic drug in the postoperative treatment of gastric cancer.     

5-FU concentration in the tissues (tumor and lymph node) of breast cancer patients given preoperative administration of UFT and FT

In 16 patients with breast cancer who were administered UFT or FT-207 (UFT: 9 cases, FT-207: 7 cases) for a were prior to surgery, we studied the concentrations of 5-FU in the blood and tumor tissues, and in normal and metastatic lymph nodes sampled during surgery. As a result, a high level of 5-FU was found in tumors, especially in metastatic lymph nodes, in the patients who were administered UFT. On the other hand, no significant difference was found between the 5-FU levels of blood in UFT- and FT-treated patients. These facts suggest that UFT can be expected to increase antitumor activity without side effects, especially in cases of metastatic lymph nodes.     

Effect of UFT on urinary bladder tumors in rats induced by N-butyl-N-(4-hydroxybutyl)nitrosamine

The effect of combined tegafur and uracil (UFT) on the development of rat urinary bladder tumors induced by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) was studied. Two hundred F344 male rats were divided into 10 groups. Groups 1 to 5 were given 0.05% BBN in drinking water for the initial 8 weeks of the experiment, and Groups 6 to 10 were the controls of the prior 5 groups treated with BBN. UFT in commercial diet was administered at daily doses of 100mg (30.9 mg as FT-207) per kg of body weight in Groups 2 and 4 and 200 mg (61.7 mg as FT-207) per kg of body weight in Groups 3 and 5. Groups 2 and 3 received UFT throughout the period of the experiment, and Groups 4 and 5 for 12 weeks after 8 week treatment with BBN. All animals were sacrificed at 20 weeks, and studied histopathologically. In Groups 1 to 5, urinary bladder tumors developed in 20 of 20, 13 of 20, 6 of 20, 14 of 20 and 6 of 20, respectively. Incidences of tumors in the 4 groups treated with UFT were significantly lower than that in Group 1 treated with BBN alone. This result shows that UFT inhibits the development of urinary bladder tumors in rats induced by BBN.     

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.     

Effect of intravenous administration of FT-207 for gastric cancer

FT-207, 800mg per day, was administered intravenously 2 hours per day for 6 days to 15 patients with gastric cancer. By chemical assay, FT-207 and 5-FU concentrations in the blood and tissues were determined. The FT-207 levels in cancerous tissue, metastatic lymph nodes and normal gastric mucosa were almost equal. The mean 5-FU level in cancerous lesions was 0.110 +/- 0.075mcg/g, and was 0.124 +/- 0.080mcg/g in lymph nodes, and 0.043 +/- 0.021mcg/g in normal mucosa. This showed that 5-FU levels were significantly higher in tumors and lymph nodes than in normal mucosa. (p less than 0.05, p less than 0.01 respectively). The mean blood level of 5-FU was low at 4 hours after FT-207 infusion. In conclusion, intravenous drip administration of FT-207 was considered to be effective for gastric cancer because of the high tumor affinity of 5-FU.     

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.     

Pharmacokinetics of FT-207 rectum suppository in squamous cell carcinoma of the uterine cervix. (I) Pharmacokinetics in single administration at a dose of 1 gram

In order to use FT-207 rectum suppository for a long-term maintenance chemotherapy of squamous cell carcinoma of the uterine cervix, we examined its pharmacokinetics by single administration at a dose of 1 g employing chemical assay. The results were as follows: 1. The blood level of FT-207 showed its peak of 30 mcg/ml at 2 hours after administration, of which half-time was 9 hours. Inter-individual differences were few in changes in the curve. 2. The blood level of 5-FU showed two peaks, 0.25 mcg/ml at 4 hours and 0.017 mcg/ml at 36 hours after administration. There were large inter-individual differences in its alteration. 3. At the time of operation, both FT-207 and 5-FU showed low concentrations in blood. 4. The level of 5-FU in cervical focus was 0.068 mcg/g which was the highest among those in all genital organs, and 2.7 times higher than the level of 5-FU in blood. 5. There was a significantly positive correlation at r = 0.174 (p less than 0.1) between the level of 5-FU in the focus of cervical cancer and the level of FT-207 in blood.     

The efficacy of combination chemotherapy of 5'-deoxy-5-fluorouridine (5'-DFUR), cyclophosphamide (CPA) and medroxyprogesterone acetate (MPA) for bone metastasis in breast cancer patients

5'-DFUR is a pro drug of 5-FU, which is known to be converted by thymidine phosphorylase (dThdPase). A recent pre-clinical study revealed that CPA upregulates dThdPase activity specifically in tumor cells. Furthermore, clinical trials have shown significant response rates in breast cancer patients, when using the chemotherapy combination of 5'-DFUR, CPA and MPA. The purpose of this study was to examine the efficacy of this regimen as a pain reduction therapy for breast cancer patients with bone metastasis. Ten patients who had bone metastasis with restricted ADL were included in the study. All of the patients had had previous exposure to such standard chemotherapy as CAF, CMF, taxol and oral 5-FU administration. The patients were administered daily oral doses of 5'-DFUR at 800-1,200 mg, CPA at 200 mg and MPA at 400-800 mg for two weeks as induction therapy, followed by two weeks rest (one to two cycles). Daily dose of 800 mg of 5'-DFUR, 100 mg of CPA, 400-800 mg of MPA was continuously administered thereafter. The main findings included a significant decrease in pain in eight patients, which continued for more than 6 months. In five patients, the effect lasted more than one year. As the pain decreased, the patients' QOL was improved. Hematological toxicity of more than grade 3 was observed in three patients but only during the induction therapy. One patient had pulmonary thrombosis and required hospitalization. In conclusion, oral administration of 5'-DFUR/CPA/MPA is well tolerated and useful in reducing pain.     

A phase II study of Futraful suppository in head and neck cancer

A phase II study of FT-207 suppository (Futraful Suppository) for head and neck cancer was conducted at the Kagoshima University Hospital Dept. of Otorhinolaryngology and its 6 affiliated hospitals. Forty cases with head and neck cancer were entered in the trial, of which 37 were perfectly evaluable. Partial response (PR) (16.7%) was achieved in one of 6 patients with maxillary cancer, in 2 of 9 cases with oral cancer (22.2%), in one of 7 with laryngeal cancer (14.3%), in 3 of 13 with pharyngeal cancer, while 2 of the same 13 achieved a complete response (CR) (38.5%), for a total response rate of 24.3%. FT-207 suppository was continuously administered as standard, at a dose of 750 mg each twice daily, or 1,500 mg/day. The response rate was dose-dependent; 2 CR cases with a total dose of 105 g for administration over a total period of more than 150 days. Adverse effects appearing in 35.0% of the overall were mainly anorexia, nausea and vomiting; none of them, however, were serious.     

Metabolism of 1,3-bis(tetrahydro-2-furanyl)-5-fluorouracil in mice.

1,3-Bis(tetrahydro-2-furanyl)-5-fluorouracil (FD-1) is a new masked compound of fluorinated pyrimidine and a derivative of 1-(tetrahydro-2-furanyl)-5-fluorouracil (FT-207). The pharmacokinetics of FD-1 and FT-207 were compared in the livers and kidneys of control mice and in mice (DD males) pretreated with phenobarbital. The half-time in the liver of FD-1 orally administered was about 40 minutes, whereas that of FT-207 in the liver was about 3 hours. Hepatic concentrations of 5-fluorouracil (FUra) originating from FD-1 were three to five times as much as those originating from FT-207. FD-1 formed 3-(tetrahydro-2-furanyl)-5-fluorouracil (3-T-F-FU) and FT-207 by a ratio of about 3 to 10, respectively. Although FD-1 had a short period of half reduction, FT-207 and 3-T-F-FU had a half-time lasting for 3--4 hours. In contrast, the renal concentration of FD-1 was one-third that of FT-207. Oral administration of FD-1 to the mice pretreated with phenobarbital elevated the FT-207 and 3-T-F-FU levels in the livers to twice the levels in the control mice and further elevated the FUra levels in the livers to twice the levels in the controls. These results indicate that FD-1 is catabolized in the liver by microsomal enzymes (including cytochrome P450) faster than is FT-207, which consequently enlarges the hepatic pool of the intermediates on the way to FUra formation.     

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.     

Combination therapy of doxifluridine (5'-DFUR) + cyclophosphamide (CPA) + tamoxifen (TAM) for advanced or recurrent breast cancer. Joint Research Group in the Osaka Area for Combination Therapy of 5'-DFUR with Other Drugs]

Outpatients with advanced and recurrent breast cancer were treated by a combination therapy of the following drugs: doxifluridine (5'-DFUR) orally administered at a dose of 1200 mg/day; cyclophosphamide (CPA) orally given at dose of 100 mg/day; and tamoxifen (TAM) orally given at dose of 20 mg daily. 5'-DFUR and CPA were administered on consecutive days 1-14, then discontinued for 14 days. The response rate was 44.8% including five CR and eight PR out of 29 complete cases. As for response cases in terms of the subject lesions, corresponding cases were chiefly found in soft tissue and the lung. As for the response rate with or without pretreatment, cases previously treated showed a higher response rate such as 42.9% indicating that the present therapy was effective in pretreatment cases. The main side effect was leukopenia, but not so severe. Few cases with diarrhea were found. Based on the above findings, the present treatment is conceivably a highly useful therapy, on an outpatient basis, for advanced and recurrent breast cancer, especially metastatic lesions of soft tissue and the lung.     

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.     

Serum and tissue concentrations of UFT in patients with lung cancer

Postoperative serum and tissue concentrations of 5-FU, FT-207 and uracil were measured in 36 patients with lung cancer who were administered UFT for seven days preoperatively. The concentration of 5-FU was high in tumor tissue and lymph nodes, but very low in serum. Such differences were not observed in the FT-207 levels. Tumor concentration of 5-FU in patients administered daily doses of 600 mg was 0.151 +/- 0.099 microgram/g which was three times higher than the minimum inhibitory concentration, and higher than that seen with other doses. The histological type and T factor were not related to the tissue concentration of 5-FU. Lymph node metastasis was not related to the concentration of 5-FU in the lymph nodes. The optimal daily dose of UFT for patients with lung cancer was considered to be 600 mg.