Retrospective analysis of tegafur/uracil (UFT) plus oral leucovorin (LV) regimen in patients with advanced colorectal cancer

The clinical efficacy and safety of tegafur/uracil (UFT) plus oral Leucovorin (LV) regimen for advanced or metastatic colorectal cancer were studied retrospectively. From September 2003 to March 2005, 82 patients were treated with UFT (300 mg/m(2)/day)/LV (75 mg/day) at our institute. The objective overall response rate was 14. 8% (95% confidence interval, 5.3 to 24.3%) in 54 evaluable patients. The response rate was 33.3% for previously untreated patients and 5.5% for previously treated patients, respectively. Grade 3 or more severe adverse reactions such as diarrhea or liver function abnormalities were only 7.3%. In 28 previously untreated patients,the median survival was 25.8 months with 1-and 2-year survival rates of 88.0% and 60.5%, respectively. This retrospective study demonstrated the reproducible activity and safety of UFT/LV for advanced or metastatic colorectal cancer in clinical practice.     

Clinical compliance with an oral uracil/tegafur (UFT) plus leucovorin (LV) regimen as adjuvant chemotherapy in Japanese colorectal cancer patients

Background  

The combination of oral uracil/tegafur (UFT) plus leucovorin (LV) is widely accepted as adjuvant chemotherapy for stages II and III of colorectal cancer. However, the clinical compliance of Japanese patients with this regimen has not been clearly elucidated to date.     

Efficacy of uracil/tegafur (UFT) plus oral Leucovorin (LV) therapy for colorectal cancer in elderly patients

BACKGROUND & AIMS: The uracil/tegafur (UFT) plus oral Leucovorin (LV) regimen is one of the standard chemotherapy modalities for colorectal cancer, and has been reported to have fewer side effects. In this study, we investigated the efficacy and toxicity of UFT/LV regimen in elderly patients. PATIENTS AND METHODS: The subjects were twelve patients older than 70 years (median age, 76 years), who received a UFT/LV regimen for colorectal cancer between January 2004 and June 2005. Chemotherapy was attempted for metastatic colorectal cancer in seven patients and for postoperative adjuvant chemotherapy in five patients. The response rate and toxicity were compared with those of patients younger than 70 years old. RESULTS: Four courses of chemotherapy, in median, were delivered. The regimen consisting of UFT 300 mg/m(2) was completed in all patients. One patient achieved a complete response and another patient a partial response, thus resulting in an overall response rate of 28.6%. Three patients experienced Grade 1 diarrhea, and seven patients had Grade 1 or 2 anemia. Grade 3 or 4 toxicity was not recognized in all patients. CONCLUSIONS: Treatment with UFT/LV regimen is effective and well tolerated in elderly as well as younger patients.     

A case of recurrent colon cancer responding completely to uracil/tegafur (UFT) plus oral leucovorin (LV) therapy

The patient was a 78-year-old woman who underwent right hemicolectomy with lymph node dissection (D 2) for cecal cancer in June 2003. Histological diagnosis was moderately differentiated adenocarcinoma, ss, n(-), P 0, H 0, M (-), stage II. Adjuvant chemotherapy was not conducted, and the patient was periodically observed after operation. In April 2004, the serum CEA level was elevated to 14.9 ng/ml. Abdominal CT examinations revealed a tumor, 50 x 35 x 50 mm in size, on the right iliopsoas muscle close to the anastomotic site. Systemic chemotherapy with UFT + Leucovorin was initiated under the diagnosis of local recurrence. Only grade 1 body weight loss,pigmentation, pruritus, and anorexia were recognized during chemotherapy. However, these complications did not require administration. After completion of 6 courses of this chemotherapeutic regimen,the serum CEA level was normalized at 3.1 ng/ml, and CT scan revealed the tumor had disappeared in November 2004. Currently, the patient is free from any signs of recurrence and has maintained a complete remission (CR).     

Efficacy of tegafur/uracil plus oral leucovorin therapy for advanced or recurrent colorectal cancer

The aim of this study was to evaluate the efficacy of tegafur/uracil (UFT) and oral Leucovorin(UZEL) in patients with advanced or recurrent colorectal cancer. Eight patients were treated with UFT/UZEL therapy as a first-line chemotherapy. UFT(300 mg/m(2)/day) and UZEL (75 mg/body/day) were administered orally for 28 consecutive days followed by a 7-day rest period, and this schedule was repeated every 5 weeks. The mean of treatment courses given to the patients was 7.6. Tumor response was evaluated in 7 patients who had assessable lesions, and the response rate was 86% (6 PR and 1 NC). Adverse reactions of grade 3 were observed in 2 patients (25%), but toxicity did not cause a discontinuance of treatment in any case. The UFT/UZEL therapy was considered to be a promising regimen for advanced or recurrent colorectal cancer from a standpoint of effect, safety and QOL of patients.     

Two cases of recurrent colorectal cancer treated successfully with folinate/tegafur/uracil (UFT/LV) chemotherapy on an outpatient basis

We report two cases of recurrent colorectal cancer in two patients who were treated successfully with a combined oral chemotherapeutic agent folinate/tegafur/uracil (UFT/LV) dosage. The first case was a 74-year-old woman who underwent Hartmann operation for colon cancer perforation. One year and 7 months after surgery, a local recurrence was found on the CT scan and endoscopy. It ended in exploratory laparotomy though we were operated on. Chemotherapy using 5-fluorouracil/Leucovorin (5-FU/LV) was performed six times. Sequentially, UFT/LV internal use was managed at our outpatient clinic. This patient has been living without side effects in the first three postoperative years, and without increase in tumors. The second case was a 65-year-old woman who underwent abdominoperineal resection of the rectum for rectal cancer. The histologic stage of disease aggravation of the patient was stageI. Post operatively, 2 years and 6 months later, we recognized a metastasis node on the lung upper right lobe of the patient and her CA19-9 value climbed dramatically. The patient took UFT/LV during outpatient visits to the hospital, the lung node shadow disappeared two months later, and CA19-9 decreased, too. The patient is living without a cancer recurrence now. UFT/LV treatment is one of the effective modalities against recurrence of colorectal cancer from outpatient treatment while maintaining QOL.     

Combination chemotherapy of biweekly irinotecan (CPT-11) plus tegafur/uracil (UFT) and leucovorin (LV) for patients with metastatic colorectal cancer: phase I/II study in Japanese patients

Purpose  We aimed to evaluate the safety and efficacy of combination chemotherapy with biweekly irinotecan (CPT-11) plus oral tegafur/uracil (UFT) and leucovorin (LV) in patients with previously untreated metastatic colorectal adenocarcinoma in phase I/II setting. Patients and methods  We recruited 37 patients with histologically proven metastatic colorectal adenocarcinoma. UFT (300 mg/m² per day) and LV (75 mg/day) were administered orally on days 1–21. CPT-11 was administered intravenously on day 1 and 15, at an initial dose of 60 mg/m², stepping up to 150 mg/m² in a traditional phase I fashion. The treatment was repeated every 4 weeks. After patients enrolled into a phase II portion, the efficacy and toxicity of this regimen were also assessed. Results  The recommended dose of CPT-11 was determined to be 150 mg/m². Although one patient had a pulmonary embolism after 60 mg/m² of CPT-11, the treatment was well tolerated in general. The overall objective response rate was 37.8% (14/37; 95% CI, 22.5–55.2) in all patients. Median progression-free survival was 226 days (95% CI, 133–276). Conclusions  Biweekly CPT-11 plus UFT and LV had a reasonable safety profile with manageable toxicity, and had a promising activity in patients with metastatic colorectal cancer. Further trials are indicated based on the promising results observed in this study.     

Clinical outcome of oral uracil/tegafur (UFT) therapy for patients with hormone refractory prostate cancer

There is no standard therapeutic strategy for advanced hormone refractory prostate cancer after the initial hormonal therapy fails. The objective of this study was to retrospectively evaluate the clinical outcome of the oral anticancer agent, uracil/tegafur (UFT) for patients with hormone refractory prostate cancer. This study included 68 patients with hormone refractory prostate cancer treated by oral administration of UFT (300-600 mg/day). All patients had previously received maximum androgen blockade (MAB) which failed. In this series, response was defined as more than 50% decrease from the baseline prostate specific antigen (PSA) value at the start of second line therapy. Upon initiating administration of UFT, a reduction in PSA value was observed in 41 of the 68 patients (60.3%), among whom 13 (19.1%) were regarded as responders; however, PSA value continued to increase in the remaining 27 (39.7%). Median duration of PSA response was 7 months (range 1-22 months). During the observation period, there were no severe side effects due to UFT administration, but 7 patients transiently presented appetite loss. Patients without bone metastasis at the initial diagnosis or whose serum PSA value at the start of UFT therapy was less than 2.0 ng/ml showed a significantly higher incidence of PSA response to UFT; however, other factors examined had no significant impact on PSA response to UFT. Furthermore, cause-specific survival in responders to UFT therapy was significantly better than that in non-responders. These findings suggest that administration of UFT after the failure of initial MAB therapy can achieve a comparatively favorable PSA response without severe side effects; therefore, it may be worthy to consider administering UFT to patients with hormone refractory prostate cancer.     

A phase I/II study of oral uracil/tegafur (UFT), leucovorin and irinotecan in patients with advanced colorectal cancer.

BACKGROUND: The aim of this study was to determine the maximum tolerated dose (MTD), toxicity profile and response rate of the oral 5-fluorouracil prodrug UFT (tegafur/uracil) and leucovorin (LV) in combination with irinotecan in patients with advanced or metastatic colorectal cancer. PATIENTS AND METHODS: Patients with histologically proven advanced or metastatic colorectal adenocarcinoma received first-line chemotherapy comprising UFT 250 mg/m(2)/day and LV 90 mg/day given on days 1 to 14, with escalating doses of irinotecan (200-300 mg/m(2)) administered intravenously on day 1 of a three-weekly cycle. Eligibility criteria were standard. The MTD was defined as the dose at which >33% of six patients experienced a dose-limiting toxicity (DLT) during cycle 1. RESULTS: A total of 32 patients were studied. Initially, six patients were treated at each of the irinotecan dose levels (200, 250 and 300 mg/m(2)) combined with UFT 250 mg/m(2)/day and LV 90 mg/day. DLTs consisting of grade 3 or 4 diarrhoea and febrile neutropenia were observed in one of 20 patients at 250 mg/m(2) and three of six patients at the 300 mg/m(2) irinotecan dose level. Having defined the MTD, the 250 mg/m(2) dose level was established as the recommended dose (RD) and expanded to 20 patients in whom treatment was generally well tolerated. The overall response rate was 19%, with five patients having a partial response (PR) and 18 stable disease (SD) out of 32 response-evaluable patients. CONCLUSION: UFT and LV can be safely combined with irinotecan. The RDs for future studies are UFT 250 mg/m(2)/day and LV 90 mg/day given on days 1-14, with irinotecan 250 mg/m(2) administered on day 1, every 3 weeks. This combination is well tolerated and active. Further investigation of UFT and LV in combination with irinotecan is warranted in patients with colorectal cancer.     

Complications related to hepatic arterial infusion chemotherapy for liver metastasis from colorectal cancer

We evaluated the complications of hepatic arterial infusion (HAI) chemotherapy in patients (pts) with hepatic metastasis from colorectal cancer. The subjects consisted of 61 pts with hepatic metastasis from colorectal cancer, who were treated by combined chemotherapy with 5-FU and CDDP weekly or continuously. Indwelling route of catheter: 30 via gastroduodenal artery (GDA) at the time of laparotomy ('LP'), 21 via femoral artery (FA) and catheter tip in PHA ('PHA'), 10 via FA and catheter tip is inserted with steel coil into the GDA ('GDA-coil'). Complications resulting in interruption of therapy occurred in 19 pts (31%), and the 'GDA-coil' method had a lower rate of complication than others. There was no difference in the incidence rate of complications between the two chemotherapy regimens. The complications of this therapy were: 8 (13%) cases of hepatic arterial occlusion, 3 (5%) cases of duodenal ulcer, 4 (7%) cases of catheter tip dislocation, 2 (3%) cases of catheter tip dislocation to the duodenal bulb, and 1 (2%) case of liver abscess. Hepatic arterial occlusion occurred frequently in LP. Up to 67% of patients with duodenal ulcer had hepatic arterial occlusion at the same time. All pts with catheter tip dislocation were 'PHA', and all pts with catheter tip dislocation to the duodenal bulb were 'LP'. In conclusion: 1. The best indwelling route for the catheter is by the 'GDA-coil' method. 2. To diagnose complications soon, regular CTA or DSA is necessary.     

Comparison of the efficacy, toxicity, and pharmacokinetics of a uracil/tegafur (UFT) plus oral leucovorin (LV) regimen between Japanese and American patients with advanced colorectal cancer: joint United States and Japan study of UFT/LV.

PURPOSE: To compare the efficacy, toxicities, and pharmacokinetics of an oral regimen consisting of uracil/tegafur (UFT) and leucovorin (LV) between Japanese patients and patients in the United States with previously untreated metastatic colorectal cancer. PATIENTS AND METHODS: Forty-four Japanese patients and 45 patients in the United States were enrolled in concurrent nonrandomized phase II trials. UFT 300 mg/m2/d and leucovorin 75 mg/d were administered orally for 28 days followed by a 7-day rest period. The total daily dose of each drug was divided into three equal doses. Treatment was repeated every 5 weeks until disease progression. Blood samples for the pharmacokinetic study were obtained after the initial dose on day 1 of the first course. RESULTS: The response rate for the Japanese patients and the patients in the United States was 36.4% (95% CI, 22.4% to 52.2%) and 34.1% (95% CI, 20.5% to 49.9%), respectively. The only major toxicity was diarrhea, and other toxicities were mild in both populations. The incidence of grade 3 or higher diarrhea in the Japanese and Americans was 9% and 22%, respectively. Although the area under the curve and maximum concentration of fluorouracil were found to be slightly higher in the Japanese patients than the patients in the United States, and area under the curve-adjusted body surface area appeared to be comparable between the two groups. CONCLUSION: The efficacy and pharmacokinetic parameters of UFT and LV are comparable in Japanese and American patients; however, a difference in toxicity profile, specifically diarrhea, was noted. This oral regimen of UFT and LV is considered to have similar activity against metastatic colorectal cancer and to have acceptable toxicity in patients in both countries.     

Hepatic arterial infusion (HAI) chemotherapy for liver metastases of colorectal cancer using 5-FU

Thirty-three patients with liver metastases of colorectal cancer were treated by intra-arterial 5-FU chemotherapy. The median survival time of all patients was 14 months. A partial remission could be observed in nine patients, and a further 15 patients had stable disease. Patients were treated on an outpatient basis and the toxicity of treatment was mild. We observed no case of sclerosing cholangitis or chemical hepatitis. Intra-arterial 5-FU chemotherapy provided treatment results similar to those reported for FUdR but with less hepatobiliary toxicity.     

Preliminary study on the optimal dosage schedule for oral tegafur/uracil (UFT) chemotherapy

Background We evaluated a new dose-intensive schedule for oral UFT (tegafur and uracil in a molar ratio of 1:4) administered for 5 consecutive days followed by 2 drug-free days (weekly-5-method), in comparison with conventional daily administration (weekly-7 method), in Yoshida-sarcoma-bearing rats. Methods The single dose of 20 mg/kg of UFT for rats corresponds to the human single dose when converted to dose per unit of body-surface area. The drug was administered 3 times a day for the weekly-5 method and twice a day for the weekly-7 method. A 7-day period was considered 1 course. The total doses per course were almost the same in both methods. Antitumor efficacy and survival effect were evaluated after 3 courses. Body weight changes and food consumption were also measured as indices of toxicity. The plasma pharmacokinetics were analyzed by simulating dosage patterns. Results Significant tumor-growth inhibition was seen with both the weekly-5 and the weekly-7 methods as compared to the control. Moreover, the weekly-5 method showed higher tumor-growth inhibition and a better survival effect than the weekly-7 method. These results appear to be related to the duration of plasma concentrations of 5-FU being maintained above a certain concentration for a longer time with the weekly-5 method. Food consumption with the weekly-5 method recovered to the control level after the drug-free period, and body weight gain was also favorable. Conclusion The results of this study suggest that the dose-intensive method of administering UFT orally for the weekly-5 method is a useful dosage schedule. Thus, this dosage schedule is recommended for use in clinical trials.     

Evaluation of intermittent hepatic arterial infusion chemotherapy for multiple liver metastasis of colorectal cancer

Five patients with synchronous multiple hepatic metastasis of colorectal cancer were treated with hepatic arterial infusion chemotherapy. All cases received intermittent 5-FU infusion (5-FU 250-1,000 mg/2-3 hrs/1-2 weeks) on an outpatient basis. In the evaluation of 5 cases, 3 PR and 1 NC were observed. One case administered arterial infusion for adjuvant chemotherapy has no recurrence in liver. In two patients, extra-hepatic metastases were found. In conclusion, this therapy was effective and useful for hepatic metastasis. Moreover, other forms of treatment for extra-hepatic metastasis must be used.     

Combination chemotherapy with orally administered UFT and leucovorin (LV)

We evaluated the efficacy of the combination therapy of UFT with Leucovorin (LV) against mouse colon adenocarcinomas and human colon adenocarcinoma. In vitro studies, it was shown that LV potentiated the cytotoxicity of FUra against 7 out of 9 cell lines used in this experiment. In vivo studies, the antitumor activity of UFT against mice bearing colon 38 adenocarcinoma was increased following administration of LV either before, after or at the time of treatment with UFT. Further studies were performed on the combination effect of UFT and LV against mouse colon 26 adenocarcinoma and human colon adenocarcinoma KM20C. Consequently, the combined treatment of UFT with LV was more effective than UFT alone against two cell lines. Our studies suggest that combination chemotherapy of UFT with LV is a promising approach for the treatment of a human colon cancer in clinical practice.     

Results of hepatic arterial infusion chemotherapy with 5-FU and leucovorin for unresectable liver metastases from colorectal cancer

PURPOSE: Hepaticarterial infusional(HAI)5-FU chemotherapy, which involves the use of interventional radiology technique, has matured technically in Japan in the 1990's. The antitumor effect of 5-FU is enhanced by combination with leucovorin. This study was performed to evaluate the efficacy and toxicity of HAI 5-FU and leucovorin chemotherapy for patients with unresectable liver metastases from colorectal cancer. METHODS: Treatment was given to 20 patients with unresectable liver metastases from colorectal cancer. The chemotherapy regimen consisted of weekly HAI of 5-FU(1,000 mg/body)and leucovorin(250 mg/body)over five hours. The survival and response rates to the therapy were assessed according to RECIST. Hematologic and non-hematologic toxicity was assessed according to CTCAE v3.0. RESULTS: Combined HAI 5-FU and leucovorin therapy was carried out an average of 27 times. The response rate for liver tumors was 75%, and the median survival time was 22 months. The applied regimen caused only mild adverse events. There was no evidence of myelosuppression except for platelet decrease(grade 3)in a patient with chronic renal failure. CONCLUSION: This HAI approach using 5-FU and leucovorin was effective and the therapy for unresectable liver metastases from colorectal cancer was tolerated well. Therefore the HAI approach should be reconsidered as an effective therapy against this disease in Japan.     

Alternating hepatic arterial infusion and systemic chemotherapy for stage IV colorectal cancer with synchronous liver metastasis

Among 41 patients with synchronous liver metastases of colorectal cancer, 15 patients underwent synchronous resection of their liver metastases and achieved a median survival time (MST) of 1,441 days (versus 748 days for the 26 patients without resection, p=0.038), a median relapse-free survival time of 652 days (MST not reached), and a recurrence rate in the residual liver of 20% (3/15 patients). The alternating hepatic arterial infusion and systemic chemotherapy showed partial response (PR) in 6 cases, stable disease (SD) in 8 cases, and progressive disease (PD) in 1 case (n=15/26). They had an objective response rate of 40% (6/15), tumor control rate (>/= SD) of 93.3% (14/15), one-year progression-free survival rate of 35.7%, 50% time to progression of 270 days, one-year survival rate of 76.2%, and two-year survival rate of 50.8% (MST not reached). Grade 3 leucopenia was observed in 2/15 patients (13.3%). These results suggest that the present alternating therapy may become a standard regimen for patients in whom synchronous resection of liver metastases is impossible and patients who have stage IV colorectal cancer with a risk of recurrence in the remnant liver and/or at extrahepatic sites such as the lungs.     

A case of unresectable colon cancer responding to oral leucovorin+oral tegafur/uracil

The patient was a 63-year-old man,who first visited our hospital with the chief complaints of left lower quadrant pain and abdominal distension that had developed around November 13, 2004. On close examination, he was diagnosed with sigmoid colon cancer, multiple liver metastasis, and subileus due to a lung metastasis. His operation took place on December 12 of the same year. Intraoperatively, the sigmoid colon was firmly fixed to the retroperitonium, there was a hard node in the pouch of Douglas, and that part of the jejunum was involved. The lesion was judged to be unresectable,and thus loop colostomy, partial jejunectomy and gastrojejunostomy were performed. After the surgery,the patient was treated with 4 courses of therapy with oral Leucovorin (LV, 75 mg) +oral tegafur/uracil (UFT, 400 mg). As a result, the tumor marker levels decreased markedly, the lung metastasis was no longer observed and the liver metastases became smaller. Therefore, a second-look operation was performed on May 30, 2005. This time it was relatively easy to free the sigmoid colon. The node in the pouch of Douglas was no longer observed, and there were only 2 metastatic lesions in the liver (1 each in S 2 and S 6). Sigmoidectomy and partial hepatectomy were performed, and the stoma was closed. The patient made good progress after the operation and was discharged on the 11 th POD. At present he is receiving chemotherapy with UFT+oral LV as an outpatient. As this therapy is relatively easy to perform and imposes only a small burden on patients,we think that it may be effective not only as adjuvant chemotherapy but also as neoadjuvant chemotherapy in some patients.     

Radiofrequency ablation therapy combined with intrahepatic arterial infusion chemotherapy for liver metastasis of colorectal cancer

We performed radiofrequency ablation (RFA) therapy combined with intrahepatic arterial infusion chemotherapy for 7 patients with liver metastasis from colorectal cancer. Synchronous metastasis accounted for 5 cases and metachronous for 2 cases. Two cases were H1, 2 cases H2, and 3 cases H3. Following the resection of colorectal primary lesion, we performed RFA for liver metastasis, using a Cool-tip electrode purchased from Radionics (Burlington, MA, USA). The mean number of sessions per patient was 5.1 (1-10). Ablation time of each session was changed according to tumor size, as follows: less than 1 cm in diameter: 2 min, 2 cm: 5 min, 2.5 cm: 10 min. By using intra-operative catheterization, weekly intrahepatic arterial infusion chemotherapy was performed for liver metastasis. Excellent ablation was achieved in all cases by CT evaluation and no significant side-effect was observed. Average observation period was 15 months (maximal survival period was 31 months) and 6 patients are alive. RFA therapy combined with intrahepatic arterial infusion chemotherapy achieved excellent therapeutic effect, and maintained good quality of life in patients.     

Oral uracil/ftorafur (UFT) plus leucovorin as first-line chemotherapy and salvage therapy with weekly high-dose 5-fluorouracil/leucovorin for the treatment of metastatic colorectal cancer

BACKGROUND: The purpose of this study was to determine the efficacy and toxicity of uracil/ftorafur (UFT) plus oral leucovorin (LV) as first-line chemotherapy for patients with metastatic colorectal cancer and salvage chemotherapy with weekly high-dose 5-fluorouracil (5-FU)/LV 24 h infusion. METHODS: Adult patients with no prior chemotherapy for metastatic diseases were enrolled to receive oral UFT 300 mg/m(2)/d plus LV 90 mg/d for 28 days. Treatment was given continuously for 28 days followed by a 7 day rest period from all treatment. For UFT failed patients, weekly 24 h infusion of 5-FU 2600 mg/m(2) plus LV 100 mg/m(2) was used as salvage therapy. RESULTS: Fifty-one patients with metastatic colorectal cancer were enrolled in the study. The objective response rate was 29.5% [95% confidence interval (CI), 16.8-45.2%] among the 44 evaluable patients and 25.5% in the intent-to-treat population. The median survival for all 51 patients was 16.6 months. The median time to progression was 5.9 months. Diarrhea was the major adverse effect of UFT/LV that made patients reduce dosage. Grade 3 or 4 diarrhea developed in 13.7% of patients. Twenty-six patients were treated with weekly 24 h infusional 5-FU/LV as salvage therapy and only two patients responded. CONCLUSION: Our results suggest that this 28 day schedule of UFT/LV regimen may offer a well-tolerated, full oral treatment option with efficacy that appears comparable to that of intravenous 5-FU/LV regimens. Parenteral 5-FU/LV as salvage therapy for UFT refractory patients is not recommended.