A case of advanced gastric cancer (type 3) with pyloric stenosis, multiple liver and lymph node metastases responding to UFT-E granules and lentinan

The patient was a 80-year-old male with advanced gastric cancer (Type 3) accompanied by multiple liver and lymph node metastases. Histological findings in the stomach showed poorly differentiated adenocarcinoma. He had nausea, vomiting and anorexia due to pyloric stenosis, and was treated with 600 mg of UFT E granules/day orally for 5 consecutive days followed by 2 drug-free days (weekly-5 method), and 2 mg of lentinan intravenously twice a week. After 4 weeks of treatment, the primary tumor and metastatic lesions of the liver and lymph nodes were markedly reduced. His symptoms had completely disappeared along with lessening of the pyloric stenosis after 6 weeks of treatment. The patient survived for 7 months in a state of CR and PR. The adverse effects were very mild and negligible. A weekly-5 method of UFT, in comparison with conventional daily administration, may induce maximal antitumor effects with minimal adverse effects.     

Feasibility of weekday-on/weekend-off oral UFT/Leucovorin schedule as postoperative adjuvant chemotherapy for colorectal cancer

Two phase III studies revealed an oral UFT/Leucovorin (LV) regimen, in which the drugs are taken for 28 consecutive days every 35 days, which proved to be equivalent to an infusional 5-fluorouracil/LV regimen for metastatic colorectal cancer (CRC). The weekday-on/weekend-off schedule for UFT, which is taken for 5 consecutive days followed by 2 drug-free days,has been reported to be safe and to have good feasibility. In the present study, we investigated the weekday-on/weekend-off schedule for UFT/LV in 54 patients with CRC. The median administration period was 8 months. Ten patients (19%) showed grade 2 or more severe adverse reactions. One of them had grade 3 diarrhea and anorexia. Grade 2 anemia was observed in 9 cases (19%) and grade 2 leucopenia was in 2 cases (4%). Myelotoxicity was mild. These results suggested that the adverse reactions in the weekday-on/weekend-off schedule for UFT/LV are less severe than the conventional UFT/LV schedule reported previously. Antitumor effects and survival benefits of the two schedules should be evaluated by a phase III study.     

Timing of UFT administration combined with surgical operation in pulmonary metastasis of rat mammary carcinoma

We investigated the effective timing of UFT administration combined with surgical operation for inhibiting pulmonary metastasis of spontaneously developed mammary carcinoma (SST-2) which produces 100% pulmonary metastasis in syngeneic rats after s.c. transplantation. Rats (5 rats per group) were inoculated s.c. with 1 X 10(6) SST-2 cells and administered orally with UFT (15, 30 and 60 mg/kg/day) starting 21 days after the tumor inoculation for 2 weeks. UFT at the dose of 30 mg/kg/day was found to be most effective in inhibiting pulmonary metastasis in SHR rats without any noticeable side effects. The rats inoculated s.c. with 5 X 10(4) SST-2 cells were divided into 3 groups: The 1st group was given oral administration of UFT (30 mg/kg/day) starting 7 days before surgical excision of the primary tumor for 2 weeks; 2nd group was treated with UFT starting one day after surgical operation for 2 weeks; and 3rd group was treated with UFT starting 7 days after surgical operation for 2 weeks. The number of lung colonies and survival time were compared among these 3 groups. The results clearly showed that combination of UFT and surgical operation was most effective on the 1st group when compared with the other two groups. UFT therapy, therefore, should be started prior to surgical operation for inhibiting cancer metastasis.     

Metronomic chemotherapy using weekly low-dosage CPT-11 and UFT as postoperative adjuvant therapy in colorectal cancer at high risk to recurrence

This study was designed to evaluate the antitumor efficacy and feasibility of postoperative adjuvant metronomic chemotherapy using weekly low-dosage CPT-11 and UFT in colorectal cancer at high risk to recurrence. A total of 49 patients (24 stage IIIb and 25 distant metastasis) who underwent a R0 operation were enrolled in this prospective study. Forty mg/m2 of CPT-11 were administered on day 1, day 8, and on day 15 in 28-day cycles. A dosage of 335 mg/m2/day of UFT was given perorally on daily schedule. Cycles were repeated for 6 months, and were followed by UFT alone for further 6 months. One or more adverse effects were seen in 43 of the 49 patients. However, most of these effects were mild at grade 1 or 2: with only nausea in 3 patients, vomiting in 2, leucopenia in 2 and neutropenia in 2 at grade 3. The overall survival rates were favorable both in the stage IIIb group (5-year: 73%) and in the distant metastases group (5-year: 62%). Postoperative adjuvant metronomic chemotherapy using weekly low-dosage CPT-11 and UFT might be safe and feasible and prolong survival time in colorectal cancer at high risk to recurrence.     

GEM 231, a second-generation antisense agent complementary to protein kinase A RIalpha subunit,potentiates antitumor activity of irinotecan in human colon,pancreas, prostate and lung cancer xenografts

GEM 231, a second-generation antisense oligonucleotide targeted against the RIalpha subunit of protein kinase A (PKA) was co-administered with the chemotherapeutic agent irinotecan, a topoisomerase-I inhibitor, to study the antitumor efficacy of the combination in nude mice bearing various human tumor xenografts. The combination treatment of GEM 231 and irinotecan produced enhanced and prolonged tumor-growth inhibition, compared with irinotecan monotherapy, against human colon (HCT-116), pancreas (Panc-1), prostate (PC3) and lung (SKMES) tumors in mice. The extent of tumor-growth inhibition, however, varied among the different tumor models studied. The tumor-growth inhibition depended on the dose of GEM 231 co-administered with irinotecan. The combination of GEM 231 (20 mg/kg, i.p., 5 days on 2 days off x 7) and irinotecan (50 mg/kg, i.v., qwk x 3) produced significantly longer tumor-growth delay than did irinotecan administered alone. Importantly, the co-administration of irinotecan and GEM 231 did not result in higher toxicity compared with monotherapies in the several tumor models tested. These results suggest that the use of irinotecan in combination with GEM 231 may increase the therapeutic index of irinotecan in cancer patients.     

Effects of OK-432 on UFT activation

An experiment to gauge the effect of OK-432 on UFT activation under a combined administration of UFT and OK-432 at a therapeutic dose has been pursued clinically by determining the blood and intratumoral 5-FU concentrations after administration of UFT. UFT was administered orally to a group of AH-130-bearing rats at a dose of 12 mg/kg or 8 mg/kg. In another group that was given combined treatment with OK-432, the OK-432 was administered subcutaneously at a dose of 0.1 KE/kg together with UFT. The intratumoral 5-FU concentration at 4 hours after UFT 12 mg/kg administration showed higher values in th single UFT treated group than in the combined treated group, but at 8 hours no significant difference was found between these two groups as the concentrations were 0.133 +/- 0.027 microgram/g and 0.128 +/- 0.021 microgram/g, respectively. Further, no significant differences were noticed in the blood and intratumoral 5-FU concentrations between both groups after administration of UFT at a dose of 8 mg/kg. Clinically, the blood FT-207 and 5-FU concentrations after UFT administration showed no significant difference between the single UFT treated group and the combined OK-432 treated group, nor was there a significant difference in the intratumoral concentration. In summary, it is considered that OK-432 has little effect on UFT activation when UFT and OK-432 are administered in combination.     

5-FU concentration in the blood and tissue of patients with gastric and colorectal cancer after administration of UFT or tegafur

UFT or tegafur (5, 7.5 and 15 mg/kg, respectively) were given to Donryu rats with AH-130 cancer twice a day for 3 days, and 5-FU concentrations in the blood, tumor, normal stomach and large bowel tissues were measured by chemical assay and compared. The 5-FU concentrations in the tumor were higher than those of normal tissues and still remained 12 hours after the final dosage. According to increased UFT dosage, there were significantly higher levels of 5-FU concentration in tumor tissues but blood levels of 5-FU were low. The peak of concentration occurred at one to two hours after the final dosage. However, increase in tegafur dosage volume did not correlate with 5-FU levels. Clinical cases (74 patients) of gastric and colorectal cancer were orally administered UFT or tegafur at 300 mg twice a day for 3 days preoperatively. Materials were obtained at surgery at 5.5 hours on average after the final dosage and 5-FU levels in tissues were measured by chemical assay. Concentrations of 5-FU in cancerous tissues after UFT administration were 0.177 +/- 0.131 micrograms/g in gastric cancer and 0.130 +/- 0.051 micrograms/g in colorectal cancer, while in patients to whom tegafur had been administered, the concentrations were 0.194 +/- 0.124 micrograms/g and 0.119 +/- 0.075 micrograms/g, respectively. There was no significant difference in 5-FU levels between the UFT-administered group and the tegafur group.     

5-Fluorouracil incorporated into the tissue RNA of human and rat bladder carcinoma after administration of 1-(2-tetrahydrofuryl)-5-fluorouracil combined with uracil

Background UFT is an anticancer agent consisting of 1-(2-tetrahydrofuryl)-5-fluorouracil (5-FU) combined with uracil in a molar ratio of 1: 4. Its mechanisms of action are, presumably, inhibition of deoxyribonucleic acid (DNA) synthesis by thymidylate synthetase (TS) and impairment of ribonucleic acid (RNA) function by the incorporation of 5-fluorouridine-5′-triphosphate into RNA. This study was conducted to examine the TS inhibition rate (TS-IR) and the concentration of 5-FU incorporated in RNA per milligram of tissue treated with UFT (F-RNA). Methods We administered UFT to 12 patients with bladder cancer. We also administered UFT to 20 rats bearing bladder tumors induced by N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN), and to 10 BBN-untreated control rats. We then determined the total TS concentration, TS-IR, and F-RNA in the human bladder tumor and normal tissues and in the BBN-treated and BBN-untreated rat organs, including the urinary bladder. Results In the bladder cancer patients, the mean F-RNAs in the bladder tumor and normal tissue were 0.133 ± 0.137 and 0.056 ± 0.062 ng/mg, respectively, without a significant difference (P < 0.1). The mean TS-IR was 35.3 ± 19.6% in the tumor tissue and 38.0 ± 16.6% in the normal bladder tissue, and this difference was also not significant. In the rat bladder cancer model, the total TS concentration and F-RNA in the tumor after the administration of UFT were 15.32 pmol/g and 0.780 ng/mg, respectively, being markedly higher than the corresponding values (1.22 pmol/g and 0.129 ng/mg) in the control normal bladder tissue. Conclusion The impairment of RNA metabolism by F-RNA incorporated in RNA did not seem to be the critical mechanism of the antitumor effect of UFT at the usual clinical dose, as neither TS-IR nor F-RNA (as antitumor parameters) seemed to increase significantly after a clinical dose of UFT. However, the inhibition of DNA synthesis and the impairment of RNA were independent mechanisms of the action of high-dose UFT in the experimental rat bladder tumors, as both total is consentration and F-RNA were increased significantly.     

Dose-intensive,Time-compressed Procarbazine,CCNU, Vincristine (PCV) with Peripheral Blood Stem Cell Support and Concurrent Radiation in Patients with Newly Diagnosed High-grade Gliomas

The dose intensity of the PCV regimen can be doubled using peripheral blood stem cell (PBSC) support. This study sought to determine the feasibility of giving dose-intensive PCV concurrently with radiation therapy. Twelve patients, age 3.2–22.7 years, median 7.5 years, with newly diagnosed high grade gliomas were enrolled. Diagnoses included diffuse intrinsic brainstem gliomas (BSG) (n=6), glioblastoma (n=4), anaplastic astrocytoma (n=2). PBSCs were harvested prior to chemotherapy with G-CSF priming. Chemotherapy consisted of CCNU 130 mg/m² and vincristine 1.5 mg/m² on day 0, and procarbazine 150 mg/m² on days 1–7. PBSCs were reinfused on day 9 of each course. Four courses of chemotherapy were administered every 28 days or when blood counts recovered. The first course was administered the week prior to RT, the second course began on week 3 of RT and the third and fourth course were given after RT. Hematologic toxicity was mild and the majority of courses were given on schedule. Five of six patients with diffuse BSG showed clinical improvement and three showed a radiographic response; however, only one remains alive 12+ months from diagnosis. All four patients with non-brainstem large-volume tumors showed clinical deterioration and radiographic progression during or shortly after RT. MRI scans showed massive edema and enhancement. Median time to radiographic progression was five months. Median overall survival was 11 months. We conclude that dose-intensive, time-compressed PCV given concurrently with large-volume RT appears to result in unacceptable toxicity in patients with large residual tumors.     

Inhibitory effect of UFT on postoperative lung metastasis of mammary adenocarcinoma in SHR rats

It is well known that UFT has significant therapeutic effects against experimental and clinical cancers at the primary sites. In this experiment, we studied the inhibitory effect of UFT on the lung metastasis of spontaneously developed rat mammary carcinoma (SST-2) after surgical excision of the primary site. In comparison of UFT-treated (15 or 30 mg/kg/day) with 5-FU-treated (9.7 or 19.5 mg/kg/day) groups, UFT was more effective than 5-FU in the antitumor activity and the inhibitory effect of lung metastasis with/without surgical excision of the primary sites. Rats (5-10 rats per group) were inoculated s.c. with 1 x 10(6) SST-2 cells and administered with UFT orally (15, 30 or 60 mg/kg/day) starting the day after tumor inoculation for 30 days. The therapeutic effect of UFT was studied by the growth rate of primary tumor and the numbers of metastatic colonies in the lung 35 days after tumor inoculation, comparing the UFT-treated with control groups. UFT administration at the doses of 30 or 60 mg/kg/day markedly inhibited the growth of the primary tumors and the number of metastatic lung colonies decreased, compared with that of the control group. However, in the group of rats treated at the dose of 60 mg/kg/day, 60% of rats died from the side effects of UFT such as weight loss, hemorrhage etc. In all groups in which the primary tumors were surgically excised 20 days after tumor inoculation and then treated with UFT (15, 20 or 30 mg/kg/day), we observed marked prolongation of survival period and inhibition of lung metastasis as well. Furthermore, we studied the effect of combination therapy of UFT and lentinan (1 mg/kg/day i.p.) on the metastasis of SST-2 cells after surgical excision of the primary sites. It was more effective than UFT alone. Thus, it is clear that UFT is an effective anticancer drug to inhibit metastasis of tumors in the lung after surgical excision of primary tumor.     

Report on nationwide pooled data and cohort investigation in UFT phase II study

Summary UFT is a compound in which futraful (FT) and uracil are combined at a ratio of 1:4. UFT was given orally at a daily dose of 300–600 mg in a phase II study. Pooled data on a UFT phase II study of 438 evaluable patients, at 104 institutions revealed a response in carcinoma of the stomach (27.7%), pancreas (25.0%), gallbladder and bile duct (25.0%), liver (19.2%), colon and rectum (25.0%), breast (32.0%), and lung (7.0%). The mainly gastrointestinal toxicity resulted in anorexia (24.3%), nausea and vomiting (12.5%), and diarrhea (11.8%). On the other hand, hematological toxicity was rare and mild. To analyze the lifeprolonging effect of the therapy, a cohort study was carried out in 438 cases collected in the UFT phase II study 5 years after the commencement of the therapy. The 50% survival time for 185 patients with gastric cancer was 185 days. The corresponding times in 54 patients with colorectal cancer and 49 with breast cancer were 227 and 505 days, respectively. A historical comparative study of UFT and FT, which was administered in the same institutions for equal evaluation, revealed that UFT had a significantly better effect than FT without more pronounced side effects with the equivalent dose schedule. In conclusion, UFT can be considered a useful agent against cancers over a broad spectrum, especially in gastrointestinal cancer.     

Adjuvant chemotherapy with vinblastine, adriamycin and UFT (VAU) for renal cell carcinoma

We tried adjuvant chemotherapy with vinblastine, adriamycin, and UFT on thirty-one renal cell carcinoma patients in stage I, II or III to determine whether or not it might improve their survival rate. The patients were started on adjuvant chemotherapy with vinblastine 5 mg/m2 i.v. and adriamycin 30/m2 i.v. 7 to 14 days after surgery, and drugs were administered every 4 weeks for a total of 5 times. UFT was administered orally in a dose of 3 capsules (300 mg as tegafur) daily for 2 to 3 years. The postoperative period averaged 4 years and 2 months with a range of 2 years and 6 months to 7 years and 1 month. The 1-year survival rate for the 31 patients was 100%, and 3- and 5-year survival rates were 96%. These results were encouraging, compared to the 1-, 3-, and 5-year survival rates of 81%, 72% and 60% achieved in a series of 60 renal cell carcinoma patients in stage I, II or III without adjuvant chemotherapy. Side effects such as alopecia, gastrointestinal symptoms, and myelosuppression were observed, but all symptoms were so mild or transient that the treatment could be continued in the patients.     

A pharmacological study of the weekday-on/weekend-off oral UFT schedule in colorectal cancer patients

PURPOSE: The new weekday-on/weekend-off schedule for oral UFT administration consists of its administration for 5 consecutive days followed by 2 days off the drug. The intratumor 5-FU (5-fluorouracil) concentration has been reported to be correlated to the tumor response in patients treated with intravenous 5-FU. The aim of this study was to investigate the pharmacokinetics during the 2 days off the drug in cancer patients treated with the weekday-on/weekend-off schedule for oral UFT. METHODS: The subjects were 24 colorectal cancer patients. They were divided into three groups, and were all given UFT, 600 mg/day, for 5 days before surgery. Surgery was performed 2, 24, or 48 h after the final dose of UFT. The 5-FU concentrations in the serum, tumor, and in the normal mucosa were measured. RESULTS: The serum 5-FU concentrations after the final dose of UFT were: 23 +/- 12 ng/ml (mean +/- SD) at 2 h, 7 +/- 3 ng/ml at 24 h, and 6 +/- 3 ng/ml at 48 h. The intratumor 5-FU concentrations were: 113 +/- 45 ng/g at 2 h, 54 +/- 20 ng/ml at 24 h, and 54 +/- 35 ng/ml at 48 h, and the concentrations in the normal mucosa were: 36 +/- 15 ng/g (mean +/- SD) at 2 h, 17 +/- 6 ng/ml at 24 h, and 18 +/- 6 ng/ml at 48 h after the final dose. While the serum 5-FU concentration decreased to very low levels by 24 h after the final dose of UFT, the intratumor 5-FU concentrations were maintained at more than 50 ng/g at least until 48 h after the final dose. The 5-FU concentrations in the normal mucosa were maintained at about one third of the intratumor concentrations at all time points. CONCLUSION: Although the weekday-on/weekend-off schedule for UFT administration included intermittent 2-day drug-off periods, this pharmacokinetic study revealed that the 5-FU concentrations in the tumor were maintained at much higher levels than in the serum throughout these periods.     

Phase I Trial ofU racil-Tegafur (UFT) plus Oral Leucovorin: 28-Day Schedule

UFT [Taiho Pharmaceutical Co. Ltd., Tokyo, Japan; (BMS-200604), Bristol-Myers Squibb, Princeton, NJ], a fluorouracil prodrug, is an oral 4:1 molar concentration of uracil plus tegafur. This study examined the dose-limiting toxic effects and maximum tolerated dose of UFT plus leucovorin administered for 28 consecutive days followed by a 7-day rest period. A course of therapy was repeated every 35 days. UFT dose levels examined were 200 mg/m²/day, with planned escalations to 250, 300, 350, and 400 mg/m²/day; the leucovorin dose remained at 150 mg/day. Three patients were initially enrolled at each UFT dose level. The total daily doses of both UFT and leucovorin were divided into three doses administered every 8 hr. Diarrhea became the dose-limiting toxicity at 400 mg/m²/day UFT, with grade 3 diarrhea noted in 2 of the 3 patients receiving that dose. To further define a phase II UFT starting dose, 3 additional patients were entered at the 350 mg/m² level; 3 of the 6 patients treated at this level developed grade 3 nonhematological toxic effects. No partial or complete responses were observed. The recommended phase II UFT starting dose is 300 mg/m²/day plus 150 mg/day leucovorin. Since neutropenia, significant mucositis, and “hand-foot syndrome“ were not observed with UFT plus leucovorin, the toxicity profile of this regimen appears favorable compared with that of intravenous regimens of fluorouracil plus leucovorin. This phase I trial of UFT served as the basis for a phase II trial, current phase III trials, and a national adjuvant therapy trial of UFT for high-risk colon cancer patients.     

Relationship between the anti-metastatic effect of UFT and in vitro chemosensitivity to 5-FU in metastatic tumors from orthotopic implanted colon cancer in nude rats

We have investigated the correlation between the in vitro chemosensitivity to 5-FU, measured using the collagen gel droplet embedded culture drug sensitivity test (CD-DST), and the anti-tumor effect of UFT, a prodrug of 5-FU, in metastatic tumors from orthotopic implanted colon cancer in nude rats. Human colon cancer cells (KM12SM) were injected into the cecal wall of the nude rats. Five weeks later, the implanted cecal tumors were removed. Oral UFT (a daily dose of 30 mg/kg) was administered postoperatively for four weeks. After the UFT administration period, the lung and lymph nodes were analyzed macroscopically and microscopically. In vitro chemosensitivity to 5-FU in the lung and lymph node metastases was tested using CD-DST, and the enzymatic activities of thymidine synthetase (TS) and dihydropyrimidine dehydrogenase (DPD) in the lung and lymph node metastases were measured. A daily administration of UFT produced an inhibitory effect on lung metastasis compared with the control group. However, there was no difference in the frequency of lymph node metastasis. The inhibition rate produced by 5-FU in CD-DST was significantly higher for lung metastases than for lymph node metastases. There was no difference in the TS and DPD activities between the metastatic tumoral tissues. These results suggest that the organ specificity of the anti-tumor effects of UFT on colon metastases may be determined by CD-DST of 5-FU for individual tumors. The TS and DPD activity in the tumoral tissues may not affect the organ specificity of the anti-tumor effect of UFT on colon metastases.     

Phase II study of uracil-tegafur in patients with metastatic pancreatic cancer

OBJECTIVE: Uracil-tegafur (UFT) has been reported to have a broad anti-tumor activity in a variety of malignancies including colorectal cancer and breast cancer. However, its activity in pancreatic cancer has not been fully evaluated. The aim of the present study was to evaluate the anti-tumor activity and toxicity of UFT in patients with metastatic pancreatic cancer. METHODS: All patients were required to have a pathologic diagnosis of pancreatic adenocarcinoma with measurable metastatic lesions, and no prior chemotherapy. A dose of 360 mg/m2/day of UFT was administered orally until the appearance of disease progression or unacceptable toxicity. RESULTS: Twenty-two patients were entered into this study. Of 21 patients evaluable for response, no patient achieved an objective tumor response; one showed no change, and the remaining 20 showed progressive disease. The median survival time for all patients was 4.2 (range: 0.9-9.0) months. The most common toxicities were nausea/vomiting and anorexia. Five patients (23%) had to discontinue UFT treatment because of gastrointestinal toxicity. CONCLUSION: This schedule of UFT did not demonstrate a significant anti-tumor activity against metastatic pancreatic cancer.     

Phase I trial of UFT/leucovorin and irinotecan in patients with advanced cancer

UFT (BMS-200604, Uftoral) is an oral fluoropyrimidine that combines uracil and the 5-fluorouracil (5-FU) prodrug, ftorafur, in a 4:1 molar ratio with single-agent activity in breast and gastrointestinal cancers. In vitro studies have shown that irinotecan downregulates thymidylate synthase (TS) expression in tumour cells, leading to synergy between irinotecan and 5-FU that is maximal when irinotecan is given 24 h prior to 5-FU. Given this observed synergy and the confirmatory clinical activity of combination therapy with 5-FU, leucovorin (LV) and irinotecan, we performed a phase I trial to determine the maximum tolerated doses (MTD) of UFT, LV, and irinotecan. Treatment consisted of irinotecan administered as a 90-min intravenous (i.v.) infusion on day 1 followed by twice daily oral UFT/LV on days 2-15, repeated every 21 days. Initial doses were irinotecan 200 mg/m(2) and UFT 200 mg/m(2)/day, with LV dose fixed at 60 mg/day. 31 patients received a total of 130 cycles of UFT/LV and irinotecan. 3 of 9 patients experienced grade 3/4 diarrhoea at the highest dose level of irinotecan 310 mg/m(2) and UFT 300 mg/m(2)/day. Other toxicities included neutropenia, anaemia, alopecia, nausea/vomiting and fatigue. Further dose escalation was not pursued since this level of toxicity was appropriate for future phase II study. One patient with colorectal cancer experienced a partial response and 9 patients with non-small cell lung, colorectal and gastro-oesophageal junction carcinomas had disease stabilisation lasting 4-26 (median 6) cycles. Methylenetetrahydrofolate reductase (MTHFR) C677T genotype was analysed in peripheral mononuclear cells (PMNs) obtained from 24 patients. 2 patients had the homozygous TT polymorphism and 1 of them had grade 3 diarrhoea at the first dose level. Irinotecan on day 1 followed by a 14-day course of oral UFT/LV beginning on day 2 is well tolerated, and suitable for testing in several tumour types. Doses recommended for further study on this schedule are irinotecan 310 mg/m(2) and UFT 300 mg/m(2)/day, with LV 60 mg/day.     

Monthly 5-days 5-fluorouracil and low-dose leucovorin for adjuvant chemotherapy in colon cancer

We investigated the dose-related effect of the 5-fluorouracil (5-FU)/leucovorin regimen on survival in 139 colon cancer patients with Dukes' B2 and C2 stage disease. Chemotherapy consisted of 400 mg/m(2) of 5-FU and 20 mg/m(2) of leucovorin injected daily for 5 days in every 4 weeks for a maximum of 12 cycles. The total dose of 5-FU administered per body surface area had a significant effect on the 5-year disease-free survival and 5-year overall survival in stage B2 and C2 colon cancer patients (P=0.0018, P=0.0011). Analysis with reference to the median DSDI demonstrated that there was a significant difference in 5-year survival in Dukes' C2 (P=0.0016), but survival was not affected by the dose intensity. Multivariate analysis demonstrated that only the total dose of 5-FU administered per surface area affected the 5-year disease-free survival and 5-year overall survival (P=0.0016, P=0.0007, respectively). It can be concluded that the total dose of 5-FU administered is important in planned dosage schedule of adjuvant chemotherapy in colon cancer.     

A phase 2 study of a fixed combination of uracil and ftorafur (UFT) and leucovorin given orally in a 3‐times‐daily regimen to treat patients with recurrent metastatic breast cancer

BACKGROUND:

A combination of uracil and ftorafur (UFT) was developed to combine the cytotoxic effects of 5‐fluorouracil (5‐FU) with convenient oral dosing. Leucovorin was combined with UFT to further potentiate the effect of 5‐FU on tumor cells. Orally administered UFT and leucovorin provided higher peak plasma concentrations of 5‐FU and prolonged therapeutic 5‐FU concentrations compared with continuous infusion of 5‐FU.

METHODS:

Ninety‐one patients with metastatic breast cancer who had been previously treated with anthracyclines and/or taxanes were treated with UFT and leucovorin, given orally, for the first 28 days of a 35‐day cycle. The total daily dose of UFT was 300 mg/m², administered in 3 doses of 100 mg/m² each every 8 hours. The primary endpoint was time to disease progression (TTP). Secondary objectives included overall tumor response rate (overall response equals complete response plus partial response) and overall survival.

RESULTS:

Of the 91 patients enrolled, 70 were evaluable for efficacy. Although no complete responses were observed, 7 patients had partial responses, for an overall response rate of 10% in the evaluable population. The median TTP for the evaluable population was 10 weeks, and the proportion of patients who were free of disease progression at 6 months was 23%. The median overall survival was 59.4 weeks for all patients enrolled. Common, drug‐related ≥ grade 3 adverse events (graded according to National Cancer Institute Common Toxicity Criteria, version 2) included diarrhea, vomiting, abdominal pain, and nausea.

CONCLUSIONS:

The combination of UFT and leucovorin administered orally in a 3‐times‐daily regimen was found to have modest activity. Grade 3 toxicities were manageable with appropriate dose adjustments in patients with metastatic breast cancer previously treated with anthracyclines and/or taxanes. Cancer 2010. © 2010 American Cancer Society.     

Contrasting effects of extended low dose versus standard dose shorter course UFT chemotherapy on microscopic versus macroscopic established tumors: implications for optimal postoperative adjuvant chemotherapy

Given such differences as relative tumor burden, the optimal dose and schedule for postoperative adjuvant chemotherapy of microscopic disease might be expected to differ significantly from therapy of advanced higher volume disease. We investigated this hypothesis by determining the optimal dose and schedule of the 5-FU pro-drug, UFT, for treatment of early versus later stage disease models of the Lewis lung carcinoma (LLC). Postoperative adjuvant therapy of early stage disease was modeled by intravenous injection of LLC cells and initiating therapy one day later, thus simulating the presence of micrometastases at the time of surgery. As a model of 'late' stage disease, a LLC fragment was implanted subcutaneously and UFT therapy was initiated when the tumor was firmly established and had grown to >5 mm in size. A number of UFT dosing protocols were evaluated such as short-term (daily, for 7 days) maximum tolerated dosing (MTD), e.g. 31 mg/kg/day, or a much longer-term (e.g., daily, for up to 60 days) repetitive dosing using doses such as 24 mg/kg/day (the MTD) or lower. The long-term consecutive administration of UFT at relatively low minimally toxic dose levels is a superior dosing regimen in the postoperative adjuvant chemotherapy model; in contrast, the short-term higher dose protocols were superior for treatment of more advanced, established cancer. In addition, the efficacy of UFT in an adjuvant setting is more effective when drug administration is continued for longer periods and when treatment is initiated at progressively earlier time points, after disease establishment.