Feasibility of metronomic chemotherapy with tegafur-uracil, cisplatin, and dexamethasone for docetaxel-refractory prostate cancer / Journal of Rural Medicine

<p><b>Objectives:</b> To evaluate the efficacy of tegafur–uracil (UFT), a prodrug of 5-fluorouracil, plus cisplatin and dexamethasone in patients with docetaxel-refractory prostate cancers.</p><p><b>Methods:</b> Twenty-five patients with docetaxel-refractory prostate cancer were administered oral UFT plus intravenous cisplatin (UFT-P therapy) and dexamethasone. Treatment responses were assessed monthly via prostate-specific antigen (PSA) level measurements. Treatment-related adverse events and overall survival were also assessed.</p><p><b>Results:</b> UFT-P therapy resulted in decreased PSA levels in 14 (56%) patients and increased PSA levels in 11 (44%). In patients with increased PSA levels, 7 (64%) of the 11 patients displayed decreased PSA doubling times. The UFT-P therapy response rate was 84% (21/25 patients). Imaging studies revealed that tumor shrinkage during UFT-P therapy occurred in 1 patient in whom bilateral hydronephrosis caused by lymph node metastasis improved. The median survival time from docetaxel initiation was 36 months. In UFT-P-treated patients, the median PSA progression and overall survival times were 6 and 14 months, respectively. UFT-P treatment-related adverse events were mild diarrhea, general fatigue, and anorexia. Treatment was not discontinued for any of the patients. UFT-P therapy did not cause serious hepatic or renal dysfunction or pancytopenia.</p><p><b>Conclusions:</b> UFT-P therapy is a safe and effective treatment for patients with docetaxel-refractory prostate cancer, although large-scale, multicenter, prospective studies are needed to validate these findings.</p>

Oral fluoropyrimidine-induced severe hyperlipidemia.

Background: Severe hyperlipidemia secondary to capecitabine, an oral fluoropyrimidine, is a very rare condition. There are no reported cases of hyperlipidemia associated with Uracil/tegafur (UFT). Objective: Report UFT-induced severe hyperlipidemia. Method: A 71-year-old male patient with metastatic colorectal cancer receiving capecitabine treatment was hospitalized at the end of the eighth cycle with the complaint of fatigue. Capecitabine treatment was discontinued in the patient in whom severe hyperlipidemia was detected together with disease progression. Gemphibrozile 1200 mg/day was initiated; patient’s triglyceride level and serum cholesterol decreased from 1768 to 149 mg/dL and from 497 to 99 mg/dL, respectively, five weeks later. The patient started to receive UFT chemotherapy and after the second cycle, he presented to our hospital again with the complaints of fatigue, headache, and yellow vision. The investigations revealed a serum triglyceride level of 4115 mg/dL and a cholesterol level of 734 mg/dL. Results: UFT chemotherapy was discontinued and lipopheresis was administered for three consecutive days, and gemphibrozile was initiated again at a dose of 1200 mg/day. The clinical presentation might be due to oral fluoropyrimidine. Three weeks later, serum cholesterol and triglyceride levels decreased to 106 and 403 mg/dL, respectively. Conclusion: This case is a unique case of hyperlipidemia secondary to UFT. Monitoring of lipid levels, when using Fluoropyrimidine, as well as hemograms, liver and renal functions would be appropriate.

Discoid Lupus Erythematosus-like Eruption Induced by Tegafur - Uracil (UFT) / 대한피부과학회지

The second-generation oral anticancer agent UFT is a combination of uracil, which has fluorouracil's (5-FU) degradation-inhibitory effect, and tegafur, which is slowly converted to 5-FU in vivo, and UFT shows a higher 5-FU concentration in the tumor tissues than is achieved by tegafur alone or with comparable doses of intravenous 5-FU. Mucocutaneous side reactions induced by UFT are rare and these include photosensitivity of the lichenoid and eczematous types, acral erythema, hyperpigmentation, palmoplantar keratoderma and scleroderma-like reactions, and discoid lupus erythematosus (DLE)-like eruption. However, there has been no report in the Korean medical literature on patients presenting with a DLE-like eruption associated with UFT. So, we report here a case of DLE-like eruption induced by oral UFT.

Improving Conventional or Low Dose Metronomic Chemotherapy with Targeted Antiangiogenic Drugs / Journal of the Korean Cancer Association, 대한암학회지

One of the most significant developments in medical oncology practice has been the approval of various antiangiogenic drugs for the treatment of a number of different malignancies. These drugs include bevacizumab (Avastin(R)), the anti-VEGF monoclonal antibody. Thus far, bevacizumab appears to induce clinical benefit in patients who have advanced metastatic disease only or primarily when it is combined with conventional chemotherapy. The reasons for the chemo-enhancing effects of bevacizumab are unknown, and this is a subject that we have been actively studying along with additional ways that antiangiogenic drugs may be combined with chemotherapy. In this respect, we have focused much of our effort on metronomic low dose chemotherapy. We have been studying the hypothesis that some chemotherapy drugs at maximum tolerated doses or other cytotoxic-like drugs such as acute "vascular disrupting agents" (VDAs) can cause an acute mobilization of proangiogenic cells from the bone marrow which home to and colonize the treated tumors, thus accelerating their recovery. These cells include endothelial progenitor cells. This systemic process can be largely blocked by a targeted antiangiogenic drug, e.g. anti-VEGFR-2 antibodies. In addition, metronomic chemotherapy, i.e., close regular administration of chemotherapy drugs at low non-toxic doses with no breaks, over prolonged periods of time not only prevents the acute CEP bone marrow response, but can even target the cells. This potential antiangiogenic effect of metronomic chemotherapy can also be boosted by combination with a targeted antiangiogenic agent. Treatment combinations of metronomic chemotherapy and an antiangiogenic drug have moved into phase II clinical trial testing with particularly encouraging results thus far reported in metastatic breast and recurrent ovarian cancer. Oral chemotherapy drugs such as cyclophosphamide (CTX), methotrexate are the main chemotherapeutics used for such trials. Oral 5-FU prodrugs such as UFT would also appear to be highly suitable based on long term adjuvant therapy studies in patients. Recent preclinical results using metronomic cyclophosphamide and metronomic UFT in models of advanced metastatic breast cancer suggest that this type of combination might be particularly promising for metronomic chemotherapy in this indication, particularly when combined with a targeted antiangiogenic drug.

The Advantage of UFT in the Patients with Stage IA & IB Lung Cancer after Complete Resection

Despite complete resection of tumor and mediastinal lymph node dissection, the post-operative survival rate of early stage I non-small cell carcinoma is not so good due to increased recurrences. So, we tried to use one of the chemotherapeutic agents after complete resection of lung carcinoma even though the pathologic final diagnosis is stage IA or IB in order to improve post-operative survivals. One-hundred and eight male and 23 female patients (mean age: 62 years, range: 28~83 years) participated in this clinical study from January 1992 to April 2002 at the Department of Thoracic and Cardiovascular Surgery, Yongdong Severance Hospital, Yonsei University, College of Medicine, Seoul, Korea. Twenty-nine patients were in stage IA and 102 were in stage IB. Among them, 3 patients died from surgical problems and 3 patients died from non surgical problems. Fifty-six patients were placed in the UFT treated group and 61 patients were in the control group. The 5-year survival rate of the patients treated with UFT was 88.6% and the 5-year survival rate of the patients in control group was 72.3% (p=0.0596). The results of our trial indicate that even patients with stage IA and IB non-small cell lung carcinoma would be benefited from orall UFT after complete surgical resection of the tumor.

Pilot Study of Heptaplatin, UFT-E and Leucovorin in Advanced Gastric Carcinoma / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Heptaplatin (SKI-2053R, Sunpla ), a new platinum analogue which has a better toxicity profile than cisplatin, has been used with 5-fluorouracil (5-FU) continuous infusion for the treatment of advanced gastric carcinoma. However, continuous 5-FU infusion had a inconvenience to administration. The aim of this study was to evaluate the efficacy and toxicity of heptaplatin, UFT-E and leucovorin combination chemotherapy in advanced gastric cancer. MATERIALS AND METHODS: A total of 22 patients was enrolled in this study at Kyung Hee University and Korea University from September 1999 to May 2001. Heptaplatin 400 mg/m2 was given as intravenous infusion for 1 hour at day 1. Oral UFT-E 360 mg/m2 and leucovorin 45 mg/day were administered for 21 consecutive days followed by a 7-day drug free interval. This schedule was repeated every 4 weeks. RESULTS: The 22 enrolled patients received 81 courses of chemotherapy and the median number of course per patient was three with a range of one to six. Five of 21 patients achieved partial responses (23.8%; 95% confidence interval, 5.6% to 42%) without complete response. Out of the 5 responding patients, three had unresectable perigastric lymph-nodes, one patient had a ovarian metastasis, and one patient had a peritoneal metastasis respectively. Main toxicities were neutropenia and nausea/vomiting. Grade 3 and 4 neutropenia were observed in 4 patients (18%) and grade 3 nausea/vomiting were observed in 5 patients (22.7%). The median time to progression was 4 months (range, 0.5 to 13 months), and median survival duration was 7.5 months (range, 2.0 to 14 months). Median response duration was 5.0 months (range, 1.5 to 10 months). CONCLUSION: A combination chemotherapy of heptaplatin, UFT-E and leucovorin has a comparable efficacy with those of previously reported heptaplatin and intravenous regimen of 5-FU and controllable toxicity in advanced gastric carcinoma. Further study with large patient population is warranted to determine the usefulness of this regimen.

Phase II Trial of Gemcitabine, UFT-E, Leucovorin Combination Chemotherapy in Advanced Pancreatic Adenocarcinoma / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: To evaluate the efficacy and toxicity of a Gemcitabine, UFT-E, Leucovorin combination chemotherapy in the treatment of advanced pancreatic adenocarcinoma. PATIENTS AND METHODS: Patients <=70 years, with no prior chemotherapy and with bidimensionally measurable advanced pancreatic adenocarcinoma, ECOG performance status <=2, and adequate bone marrow, kidney, and liver function were eligible for this trial. Eligibility criteria for clinical benefit assessment were pain with at least a daily analgesic consumption of two nonsteroidal anti-inflammatory drugs or a Karnofsky performance status between 50 and 70. Treatment consisted of 1,000 mg/m2 of Gemcitabine on days 1, 8 and 15, repeated every 4 weeks, with UFT-E administered orally 500 mg-700 mg by body surface area (BSA). Leucovorin was administered 45 mg/day orally. Dosages of UFT-E and Leucovorin were divided and administered three times per day from day 1 to day 21. After 7 days of rest, UFT-E and Leucovorin were administered repeatedly. RESULTS: Twenty-three patients were enrolled between April 1999 to April 2000. Eighty two cycles (median, four cycles) were delivered to all patients. The objective response rate was 15.8% in 19 assessable patients and 13.0% in the intent-to-treat population. Twelve patients (57.9%) displayed stable disease. Grade 3 or 4 neutropenia occurred in 30.4% of patients, nausea/vomiting in 8.3%, diarrhea in 4.3%, and mucositis in 4.3%. The median time to progression was 8 months. The median survival was 8 months in the assessable population and 6 months in the intent-to-treat population Clinical benefit was achieved in 11 (57.9%) of 19 assessable patients. CONCLUSION: Gemcitabine, UFT-E, Leucovorin combination chemotherapy is a well-tolerated and safe regimen in cases of advanced pancreatic adenocarcinoma. Although the response rate is low, it shows a survival benefit and clinical benefit and deserves further evaluation in a phase III trial.

A Phase II Trial of UFT-E and Oral Leucovorin in Advanced Colorectal Cancer / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: To determine the efficacy and toxicity of UFT-E plus oral calcium leucovorin in the treatment of patients with advanced colorectal cancer. MATERIALS AND METHODS: Forty-three patients with advanced, bidimensionally measurable colorectal adenocarcinoma were enrolled in the trial. No patients had received prior palliative chemotherapy. The patients that had received previous adjuvant chemotherapy were enrolled when more than 6 months had elapsed after the completion of adjuvant therapy. Patients were treated with 300 mg/m2/day of UFT-E (tegafur-based) plus 90 mg/day of leucovorin administered orally in three divided daily doses, every 8 hours for 28 days followed by a 7-day rest period. Response was evaluated after two or three courses of therapy. RESULTS: Thirty-six of forty-three patients were evaluable for response; seven dropped out due to infection, toxicity and patients' refusal. Ten patients had partial responses and one patient complete response (response rate, 31%; 95% confidence interval, 16~46%). The median response duration for the UFT-E plus leucovorin regimen was 28 weeks. Grade III toxicity was seen in one case, with diarrhea. CONCLUSION: This oral regimen proved effective and well tolerated. This schema also avoided inconveniences, such as hospitalization and the use of infusion pumps, which are associated with 5-FU infusion regimens. The regimen used showed minimal toxicity, especially in the upper digestive tract, with good patient compliance.

Toxicity Evaluation of Oral Adjuvant Chemotherapeutic Drugs UFT Versus UFT-E in the Colorectal Cancer

PURPOSE: Oral UFT is known to be a safe and effective antineoplastic regimen for adjuvant chemotherapy of colorectal cancer. As it sometimes produces upper gastrointestinal symptoms such as anorexia, nausea, vomiting and abdominal pain, medication should be stopped transiently or dosage reduced. UFT-E, an enteric coated granule of UFT was introduced to reduce UGI toxicity. We analyzed the toxicity of UFT and UFT-E prospectively for the purpose of comparison between the two types. METHODS: The toxicity of UFT and UFT-E were evaluated in 83 patients (UFT; 45, UFT-E; 38) with colorectal cancer who underwent curative surgery according to the WHO toxicity criteria. All patients were selected consecutively with patients' approval and by the "Institutional Review Board, Asan Medical Center". RESULTS: The toxicity incidence in UFT-E group was slightly less than that in UFT group without statistical significance. The severity of toxicity seemed to be mild within grade 1 or 2 and most of them toxicity self-limiting. The regimen was completely interrupted in 9 patients (20%) in the UFT group, 3 patients (7.9%) in the UFT-E group due to severe UGI symptoms, prolonged leukopenia, derrangement of liver function and skin rash. CONCLUSIONS: Toxicity rate of UFT-E was not higher than that of UFT. But we cannot prove superiority of UFT-E on UGI toxicity. Oral UFT-E can be administered safely on an outpatient basis without lethal toxicity requiring hospitalization.

Effect of Epirubicin, Cisplatin, oral UFT, and Leucovorin Combination Chemotherapy in Advanced Stomach Cancer / 대한내과학회지

OBJECTIVE: UFT plus leucovorin treatment had favorable activity and tolerable toxicity in patients with advanced stomach cancer. Recently, high response rates have been reported in patients with advanced stomach cancer with a schedule of epirubicin, cisplatin, and protracted infusion of 5-fluorouracil (5-FU). The advantage of long term oral administration of UFT is that this treatment might be used to mimic protracted infusions of 5-FU. Instead of inconvenience of infusion pump and intravenous catheter for protracted infusion of 5-FU, we administered UFT plus leucovorin in this treatment. METHODS: Thirty-seven patients with locally advanced or metastatic stomach cancer received epirubicin, cisplatin, oral UFT plus leucovorin. Epirubicin 50 mg/m2 and cisplatin 60 mg/m2 were administered on day 1 by intravenous injection. UFT 360 mg/m2/day in conjunction with leucovorin administered at 25 mg/m2/day per os in divided daily doses for 21 days followed by a 7-day rest period. Courses were repeated every 4 weeks. The median age of the patients was 55 years with a median World Health Organization (WHO) performance status of 1. Patients received a median of four courses of treatment (range, 2 to 10). RESULTS: Among 37 evaluable patients, two patients achieved complete response, and eighteen had partial responses, for an overall response rate of 54% (95% confidence interval; 39% to 70%). Stable disease was reported in 12 patients (32.5%) and another 5 (13.5%) showed disease progression. The median duration of survival was 10 months (range, 2 to 15+). The main toxicity was nausea/vomiting, leukopenia, diarrhea and oral mucositis. Significant toxicity (WHO grade 3 or 4) included leukopenia in fourteen patients (39.8%), nausea/ vomiting in eleven (29.7%), oral mucositis in five (13.5%), and diarrhea in four (10.8%) patients. CONCLUSION: We conclude that epirubicin, cisplatin, oral UFT plus leucovorin, a convenient out-patient regimen, has a significant activity in patients with stomach cancer and has tolerable toxicities.

Oral mitomycin C and UFT concomitant with irradiation in carcinoma of the cervix, stage IIb and stage IIIb.

Mitomycin C and UFT were given orally, concomitant with irradiation to patients with squamous and adeno-squamous cell carcinoma of the cervix, stages IIb and IIIb, at Siriraj Hospital between June 1993 and June 1994. All patients had tumours larger than 5 cm in diameter. The result showed that the patients were 100 percent disease-free for carcinoma of the cervix stage IIb and 60 percent for stage IIIb.

A Case Diagnosed as Primary Progressive Liver Carcinoma with Lung Metastasis Based on diagnostic Imaging and Tumor Markers found to be Responsive to Combined Treatment using Shosaiko-to and IFT / 日本東洋医学雑誌

The subject of this study was a 64-year-old male. He had experienced a sensation of abdominal fullness during treatment for chronic hepatitis C at a neighborhood clinic. He was referred to our hospital for work-up upon discovery of elevated AFP.<br>Examination on admission revealed abdominal swelling, ascites and marked swelling of the liver. The AFP was 11, 535ng/m<i>l</i>. A tumor measuring 9 by 8 centimeters was revealed in the right lobe of the liver on the CT scan, and there were many metastatic lesion 1cm in diameter in both the lung field. Since the liver tumor was considered unresectable, in August 1992, MMC and ADM were administered intraarterially just once at doses of 10 and 20mg, respectively. At the end of August, oral administration of UFT at a dose of 600mg/day was started.<br>The patient was discharged after 3 weeks of treatment, but the administration of 300mg/day of UFT was continued, Since hepatic function tended to be aggravated, administration of Shosaiko-to (EK-9) was commenced at a dose of 6g/day. With the combination therapy, the symptoms were gradually relieved and the subjective symptoms disappeared. In September 1992 (8 months after initiation of Shosaiko-to administration), the shadows due to lung metastasis were absent on the chest x-ray examination, and the CT scan turned negative for the tumor in the right lobe. AFP and PIVKA-II decreased below 11.7ng/m<i>l</i> and 0.06AU/m<i>l</i>, respectively. As of December 1994, the patient is still on combination therapy consisting of Shosaiko-to and UFT. Neither adverse reactions such as weight loss have been induced nor has the tumor returned. The general condition of the patient is good.<br>The results obtained in this case suggest that Shosaiko-to and UFT in combination are effective in treating liver carcinoma.