The University of Texas M. D. Anderson Cancer Center Orzel/UFT Investigators’s Workshop and Consensus Conference

Supported by an unrestricted educational grant from Bristol-Myers SquibbOncology and Taiho Pharmaceutical Co., Ltd.

Beyond 5-Fluorouracil

Richard Pazdur, MDProfessor of Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

Because of the absence of severe toxicities, UFT plus oral leucovorin is an optimal candidate for combination chemotherapy regimens. Its excellent acceptance by patients and well-tolerated safety profile make it a potential therapy for patients with poor performance status or patients who have been extensively pretreated. This symposium brought investigators from the United States, Canada, Japan, Europe, and South America together to share their collective experiences. Most of the work has concentrated on the use of UFT plus oral leucovorin in colorectal cancer. In this disease setting, UFT plus oral leucovorin has been investigated as the first-line treatment of metastatic disease; combined with irinotecan (CPT-11; Camptosar) or oxaliplatin; studied in the adjuvant setting; and administered concurrently with pelvic irradiation to treat rectal cancers. Discussed in this supplement is the work of additional investigators examining UFT plus oral leucovorin alone or combined with other agents in the treatment of gastric, breast, lung, pancreas, and bladder carcinomas.

Clinical Implications of Dihydropyrimidine Dehydrogenase Inhibition

Robert B. Diasio, MDChairman, Department of Pharmacology/Toxicology, and Director, Division of Clinical Pharmacology, and Associate Director, University of Alabama Cancer Center, University of Alabama at Birmingham , Birmingham, Alabama

Dihydropyrimidine dehydrogenase (DPD) is the initial, rate-limiting enzyme in the catabolism of 5-fluorouracil (5-FU). DPD has an important role in regulating the availability of 5-FU for anabolism. It is now clear that DPD also accounts for much of the variability observed with the therapeutic use of 5-FU, including variable drug levels during 24-hour infusion, erratic pharmacokinetics, variable bioavailability, inconsistent toxicity, and variability in drug response (resistance). The use of DPD inhibitors has been explored as a means to improve 5-FU pharmacology. This article describes how drugs that modulate DPD activity have been used to develop a new class of orally administered fluoropyrimidines, now referred to as DPD-inhibiting fluoropyrimidine (DIF) drugs. The biochemical basis for using four DIF drugs—uracil and tegafur (UFT), ethynyluracil, S-1, and BOF-A2—currently in clinical evaluation in the United States, is hereby reviewed. Early clinical data suggest that these drugs may achieve antitumor efficacy equivalent to that of conventional intravenously administered 5-FU therapy, with the additional advantages of reduced toxicity, less expense, and improved quality of life.

Clinical Implications of Dihydropyrimidine Dehydrogenase Inhibition

Robert B. Diasio, MDChairman, Department of Pharmacology/Toxicology, and Director, Division of Clinical Pharmacology, and Associate Director, University of Alabama Cancer Center, University of Alabama at Birmingham , Birmingham, Alabama

Dihydropyrimidine dehydrogenase (DPD) is the initial, rate-limiting enzyme in the catabolism of 5-fluorouracil (5-FU). DPD has an important role in regulating the availability of 5-FU for anabolism. It is now clear that DPD also accounts for much of the variability observed with the therapeutic use of 5-FU, including variable drug levels during 24-hour infusion, erratic pharmacokinetics, variable bioavailability, inconsistent toxicity, and variability in drug response (resistance). The use of DPD inhibitors has been explored as a means to improve 5-FU pharmacology. This article describes how drugs that modulate DPD activity have been used to develop a new class of orally administered fluoropyrimidines, now referred to as DPD-inhibiting fluoropyrimidine (DIF) drugs. The biochemical basis for using four DIF drugs—uracil and tegafur (UFT), ethynyluracil, S-1, and BOF-A2—currently in clinical evaluation in the United States, is hereby reviewed. Early clinical data suggest that these drugs may achieve antitumor efficacy equivalent to that of conventional intravenously administered 5-FU therapy, with the additional advantages of reduced toxicity, less expense, and improved quality of life.

Clinical Implications of 5-FU Modulation

Youcef M. Rustum, PhDSenior Vice President for Scientific Affairs, and Professor of Molecular Pharmacology, Roswell Park Cancer Institute Buffalo, New York

In recent years, due to the advent of sensitive instrumentation and methodologies, it has been possible to identify parameters that predict the quality of response of individual patients to treatments for specific selected diseases, eg, colon carcinoma and breast carcinoma. Ongoing studies are attempting to identify sensitive patients in order to select treatment regimens suitable for the individual patient. The critical question that remains is whether the basis for drug resistance is due in part to insufficient delivery of drugs to target tumor cells or to the resistance of target tumor cells by various mechanisms, including, in the case of 5-fluorouracil (5-FU), drug transport, metabolism, expression of the target enzyme thymidylate synthase (dTMPS), depletion of folate cofactors, and/or level of competing substrate deoxyuridine monophosphate. Also in recent years, attempts have been made to delineate mechanisms of resistance to the fluoropyrimidines. On the basis of such studies, it may be possible to develop approaches aimed at the selective modulation of the therapeutic efficacy of these agents in tumor tissues with varying degrees of sensitivity to fluoropyrimidines, eg, patients with advanced colorectal cancer. One such approach is the use of calcium folinate to modulate the therapeutic efficacy of 5-FU.

Schedule Dependency of 5-Fluorouracil

Cynthia Gail Leichman, MDDepartment of Medicine, Roswell Park Cancer Institute, Buffalo, New York

5-Fluorouracil (5-FU) is cell-cycle specific for its cytotoxicity and has a pharmacokinetic profile characterized by a short, single-dose half-life of 10 to 20 minutes in plasma. Efforts to maximize its clinical efficacy have been directed at overcoming this short half-life. Strategies have included prolonging intracellular exposure by biochemical modulation or administration by infusional schedules, and more recently by chronic oral dosing. A number of clinical trials comparing routes of administration and biochemical modulation of 5-FU are presented in this article. Issues of dose intensity, differing toxicity profiles, and pharmacoeconomics are reviewed.

Toxicity of 5-Fluorouracil

John S. Macdonald, MDProfessor of Medicine, and Chief, Gastrointestinal Oncology Service, St. Vincents Comprehensive Cancer Center, New York, New York

Fluorouracil (5-FU) is a relatively unique drug in oncology because administration in different doses and schedules results in dramatically different patterns of qualitative toxicity. In the 41 years 5-FU has been available to the clinical oncologist, a wide variety of doses and schedules of this agent have been used. Infusional schedules are associated with less myelosuppression but may have more gastrointestinal and skin toxicity. Bolus schedules cause myelotoxicity, and bolus schedules including calcium folinate are associated with diarrhea, mucositis, and, in some schedules, myelosuppression. The availability of various doses and schedules of 5-FU for administration allows clinicians to choose a 5-FU regimen with the most acceptable pattern of toxicity for individual cases. Also, the study of 5-FU in various groups of patients has demonstrated that relatively increased drug toxicity may be expected in patients above the age of 70 years and in female patients.

UFT Plus or Minus Calcium Folinate for Metastatic Colorectal Cancer in Older Patients

Eduardo Díáz-Rubio, MD, PhD, and Javier Sastre, MD, PhDHospital Clinico San Carlos, Madrid, SpainAlbert Abad, MD, PhDHospital Germán Trias i Pujol, Badalona, SpainMatilde Navarro, MDInstituto Catalán de OncologiaEnrique Aranda, MD, PhDHospital Reina Sofia, Córdoba, SpainAlfredo Carrato, MD, PhDHospital Elche, Alicante, SpainManuel Gallén, MDHospital del Mar, Barcelona, SpainEugenio Marcuello, MDHospital Santa Cruz y San Pablo, Barcelona, SpainJjulio Rifá, MDHospital San Dureta, Palma Mallorca, SpainTomeu Massuti, MDHospital General, Alicante, SpainAndrés Cervantes, MD, PhDHospital Clínico, Valencia, SpainAntonio Antón, MD, PhDHospital Miguel Servet, Zaragoza, SpainCarlos Fernández Martos, MDInstituto Valenciano de Oncología, Valencia, Spain

Two studies were carried out to determine the activity and evaluate the toxicity of oral chemotherapy with uracil and tegafur in a 4:1 molar ratio (UFT) plus or minus calcium folinate in elderly patients with advanced colorectal cancer. In one study, 106 patients received a fixed dose of UFT 400 mg/day in two daily doses every 12 hours continuously, plus calcium folinate 45 mg/day administered in three divided doses every 8 hours continuously. In study 2, calcium folinate was omitted, and the dose of UFT was increased to 400 mg/m²/day in two daily doses administered every 12 hours continuously to 95 patients. Treatments for both studies were administered until grade 3 or grade 4 toxicity occurred or disease progressed. The response rate among the 96 available patients in study 1 was 17.7% (95% confidence interval [CI], 10% to 27%); 41 patients (43%) achieved an objective response or stable disease. Overall survival was 13.7 months with a statistically significant difference between patients with no progressive disease and patients with progressive disease (P < .01). In study 2, 62 of 95 patients have now been evaluated for response. The response rate was 21% (95% CI, 13% to 30%); 38 patients (61%) experienced an objective response or stable disease. The overall survival for study 2 has not yet been evaluated. Toxicity was generally mild, consisting of grade 3 nausea/vomiting (6% in study 1 and 2% in study 2), grade 3 or grade 4 diarrhea (11% in study 1 and 7% in study 2), plus one case of grade 3 mucositis in study 1. These findings suggest that chemotherapy with UFT (with or without modulation with calcium folinate) is feasible for elderly patients with advanced colorectal carcinoma.

Hospitalization for 5-FU Toxicity in Metastatic Colorectal Cancer: Incidence and Cost

Gerry Oster, PhDVice President, Policy Analysis Inc. (PAI), Brookline, Massachusetts

Although treatment with 5-fluorouracil (5-FU) plus calcium folinate has been reported to prolong survival in patients with metastatic colorectal cancer, it can also cause significant toxicity, potentially resulting in hospitalization. The incidence and cost of these admissions have not been fully documented. The purpose of this study was to document the incidence and cost of toxicity-related admissions among patients with newly diagnosed metastatic colorectal cancer who received 5-FU.

Impact of Uracil/Tegafur Plus Oral Calcium Folinate on Resource Utilization

Dan Ollendorf, MPHSenior Analyst, Policy Analysis Inc. (PAI), Brookline, Massachusetts

Data from a multinational phase III trial were analyzed to evaluate the use of in- and outpatient services for 373 patients with metastatic colorectal cancer being administered uracil/tegafur (in a molar ratio of 4:1 [UFT]) plus oral calcium folinate (Orzel) (N = 188) vs 5-fluorouracil (5-FU) plus oral calcium folinate (N= 185). Hospital and/or nursing home admissions were studied, including hospitalizations for febrile neutropenia, infection, tumor progression, drug toxicity, and transfusion. Chemotherapy hospitalization data were not collected. Analyzed outpatient services included family doctor, hospital, private nurse, physiotherapist, and home-help visits. Results showed that UFT plus oral calcium folinate may be associated with reductions in the use of inpatient services and work loss due to illness among patients with metastatic colorectal cancer.

UFT Plus Calcium Folinate vs 5-FU Plus Calcium Folinate in Colon Cancer

Roy Smith, MD, and D. Lawrence Wickerham, MDNational Surgical Adjuvant Breast and Bowel Project Operations Center, Allegheny University of Health Sciences, Pittsburgh, PennsylvaniaH. Samuel Wieand, PhD, and Linda Colangelo, MSNational Surgical Adjuvant Breast and Bowel Project, Biostatistical Center, Pittsburgh, PennsylvaniaEleftherios P. Mamounas, MD, MPHMt. Sinai Medical Center, Cleveland, Ohio

Adjuvant chemotherapy has been shown to alter the natural history of resected colon cancer. Two regimens (5-fluorouracil [5-FU] plus calcium folinate and 5-FU plus levamisole [Ergamisol]) have been found to prolong disease-free survival and overall survival in affected patients. Previous comparisons of these two regimens indicate that 5-FU plus calcium folinate may offer a small disease-free survival and overall survival advantage. The demonstration that UFT (uracil and tegafur) plus oral calcium folinate (Orzel) offers significant antitumor activity and an acceptable toxicity profile makes this a logical formulation for the adjuvant treatment of colon cancer. The National Surgical Adjuvant Breast and Bowel Project Protocol C-06 is a randomized comparison of the relative efficacies of 5-FU/calcium folinate vs UFT plus oral calcium folinate. Preliminary analysis of toxicity findings among 473 evaluable patients indicates that both regimens are well tolerated and have similar toxicity profiles. If, in the final survival analysis, UFT plus oral calcium folinate treatment yields the same or better disease-free survival and/or overall survival as the 5-FU/calcium folinate treatment and the toxicity profiles remain similar, it is likely that UFT plus oral calcium folinate will be accepted as a new standard for adjuvant treatment of colon cancer.

Oxaliplatin and UFT/Oral Calcium Folinate for Advanced Colorectal Carcinoma

Paulo M. Hoff, MD, and Richard Pazdur, MDDivision of Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

Oxaliplatin is a unique platinum compound with single-agent activity in both chemotherapy-naïve colorectal cancer patients and patients who progressed on 5-fluorouracil (5-FU). The combination of oxaliplatin and 5-FU has demonstrated preclinical synergy, and recent clinical trials have demonstrated enhanced activity for the combination in the clinical setting as well. UFT (uracil plus tegafur in a 4:1 molar ratio) plus oral calcium folinate (Orzel) is an oral fluoropyrimidine with several potential advantages over intravenous 5-FU and known activity in colorectal cancer. The current trial was designed to evaluate the role of these agents in combination in the treatment of patients with advanced colorectal cancer.

UFT Plus Calcium Folinate/Irinotecan in Colorectal Cancer

Chris Twelves, MD, FRCPDepartment of Medical Oncology, Glasgow, Scotland, UK

This phase I trial combining UFT plus oral calcium folinate (Orzel) with irinotecan (CPT-11) (Camptosar) for the treatment of patients with advanced or metastatic colorectal cancer will open shortly. Eligible patients will have locally advanced or metastatic colorectal cancer, and they may have received adjuvant chemotherapy (provided it has been completed more than 6 months prior to study entry), but will have not received any chemotherapy for advanced or metastatic disease. The primary objectives of this study will be to determine the side-effect profile, dose-limiting toxicities, and the maximum tolerated dose of this combination. A recommended starting dose for future trials will be defined. Response rates will also be observed as a secondary objective. The first cohort of six patients will receive irinotecan 200 mg/m² by intravenous infusion over 90 minutes on day 1 (the schedule that is in general use in Europe). On days 1 to 14, patients will receive UFT 250 mg/m²/d and calcium folinate 90 mg/d, both divided into three equal doses. This will be followed by a 1-week rest period with treatment for the next cycle resumed on day 22. In subsequent cohorts of six patients, UFT and irinotecan will in turn be escalated provided toxicity is acceptable. The calcium folinate dose will remain fixed at 90 mg/d throughout. The maximum tolerated dose is defined as that at which dose-limiting toxicities occur in more than one third of patients. The cohort of patients treated at the dose below the maximum tolerated dose will be expanded to a total of 20 patients to fully define the pattern of toxicities and activity of the combination.

Using Preoperative UFT to Predict Sensitivity to Fluoropyrimidines in Colorectal Cancer

Masashi Fujii, MDThird Department of Surgery, Nihon University School of Medicine, Tokyo, Japan

This study was designed to determine if histopathologic evaluation of patients with resectable colorectal cancer following preoperative chemotherapy with uracil and tegafur with a molar ratio of 4:1 (UFT) could predict chemosensitivity to postoperative fluoropyrimidines to prevent recurrence of disease. In this prospective randomized study involving 152 colorectal cancer patients, UFT 600 mg/day was administered for 10 days prior to surgery. Histopathology of the resected tumor was assessed, including the amount of necrosis or disappearance of tumor, and patients were thereafter stratified into two groups according to tumor response to preoperative therapy—grade ³ 2 (sensitive) vs those with grade £ 1B (not sensitive). The patients were then randomly assigned to postoperative adjuvant UFT (400 mg/day for 12 months) or no treatment. At the time of this evaluation, the mean total preoperative UFT dose per patient was 7.76 g ± 3.27 g. Thirteen patients were considered ineligible; therefore, 139 patients were included in the analysis. Stratification resulted in 22 (15.8%) cases in the sensitive group, of which 13 received adjuvant chemotherapy and nine were assigned to no treatment; 117 (84.2%) patients were considered nonsensitive, 60 of whom received adjuvant chemotherapy, and 57 of whom received no adjuvant therapy. Among nonsensitive patients, 3-year survival rates were 87.6% with adjuvant chemotherapy and 84.9% with no therapy, indicating no significant difference between groups. Among responders, however, there was a significant difference in 3-year survival rates: 100% for the adjuvant group and 62.5% for the no-treatment group (P = .0351). These findings suggest that histopathologic assessment following preoperative UFT chemotherapy provides information to predict fluoropyrimidine sensitivity. We believe grade 1B patients (19.8%) may respond to modulated fluorouracil. We also recommend the use of other drugs, such as irinotecan (CPT-11 [Camptosar]) and oxaliplatin, for patients with tumor responses of grades 0 and 1A.

UFT and Oral Calcium Folinate as First-Line Chemotherapy for Metastatic Gastric Cancer

Alain Ravaud, MD, PhDInstitut Bergonié, Bordeaux, FranceMarkus Borner, MDInselspital, Bern, SwitzerlandJan H. M. Schellens, MDNetherlands Cancer Institute,Amsterdam, The NetherlandsLionnel Geoffrois, MDCentre Alexis Vautrin, Nancy, FrancePatrick Schöffski, MDHannover Medical School, Hannover, GermanyJantien Wanders, MDNew Drug Development Office (NDDO), Amsterdam, The NetherlandsAxel R. Hanauske, MD, PhDProfessor of Oncology, U.Z. Gasthuisberg,Leuven, Belgium, Center for Hematology and Oncology,München, Germany

Locally advanced or metastatic adenocarcinoma of the stomach still carries a poor prognosis, with 5-year survival rates of < 15%. Palliative chemotherapeutic regimens for this disease are largely 5-FU–based. We have investigated the clinical activity of an oral combination of uracil and tegafur (UFT) with calcium folinate (Orzel), in patients with measurable metastatic disease. Thirty-six patients received a total of 94 courses of daily UFT 300 mg/m² plus calcium folinate 90 mg for 28 consecutive days followed by a 7-day rest. Planned treatment doses were maintained in 83% of all evaluable courses. Main toxicities included diarrhea (21 patients) and nausea and vomiting (20 patients). Other side effects were asthenia, malaise, stomatitis, and myelosuppression. At present, 26 patients are evaluable for response. Of these, one achieved a complete response and three achieved partial remissions. In addition, six patients reached stable disease, yielding an overall response rate of 27%. We conclude that the combination of UFT and calcium folinate is a feasible outpatient regimen that warrants further clinical evaluation.

Epirubicin, Cisplatin, Oral UFT, and Calcium Folinate in Advanced Gastric Carcinoma

Yeul Hong Kim, MD, Byung Soo Kim, MD, Jae Hong Seo, MD, Cheol Won Choi, MD, and Jjun Suk Kim, MDDepartment of Internal Medicine, Section of Hemato-OncologyJae Sun Kim, MD, Hoon Jai Chun, MD,and Jin Hai Hyun, MDDepartment of Internal Medicine, Section of Gastroenterology, College of Medicine, Korea University, Seoul, Korea

UFT (uracil and tegafur in a 4:1 molar ratio) plus calcium folinate treatment has favorable activity and tolerable toxicity in patients with advanced gastric carcinoma. High response rates have been reported in patients with advanced gastric carcinoma receiving a schedule of epirubicin, cisplatin (Platinol), and protracted infusion of 5-fluorouracil (5-FU). Replacing the inconvenient infusion pump and intravenous catheter needed for protracted infusion of 5-FU, we administered oral UFT plus calcium folinate (Orzel) to 37 patients (median age, 55 years; median World Health Organization [WHO] performance status of 1) with locally advanced or metastatic gastric carcinoma. Epirubicin 50 mg/m² and cisplatin 60 mg/m² were administered by intravenous injection on day 1; UFT 360 mg/m²/day po was administered in conjunction with oral calcium folinate 25 mg/m²/day in divided daily doses for 21 days, followed by a 7-day rest period. Courses were repeated every 4 weeks. Among 37 evaluable patients who received a median of four courses of treatment (range, 2 to 10), two achieved a complete response and 18 a partial response, for an overall response rate of 54% (95% confidence interval, 39% to 70%). Stable disease was reported in 12 patients (32.4%) and disease progression in another five (13.5%). The median duration of survival was 10 months (range, 2 to 15+). The main toxicities were nausea/vomiting, leukopenia, diarrhea, and oral mucositis. WHO grade 3 or 4 toxicity included leukopenia in 14 patients (37.8%), nausea/vomiting in 11 (29.7%), oral mucositis in five (13.5%), and diarrhea in four (10.8%). Epirubicin, cisplatin, and oral UFT plus calcium folinate, a convenient outpatient regimen, has significant activity and tolerable toxicities in patients with gastric carcinoma.

Paclitaxel, UFT, and Calcium Folinate in Metastatic Breast Cancer

Natalie R. Dickson, MD, Brenda P. Nicholson, MD, Kenneth Hande, MD, Charles Blanke, Md, and David Johnson, MD Departmentof Medicine, Vanderbilt University, Nashville, TennesseeAlan Cohen, MDDepartment of Medicine, St. Thomas Hospital, Nashville, Tennessee

This is a phase I dose-escalation study of uracil and tegafur (in a molar ratio of 4:1 [UFT]) administered in combination with calcium folinate and paclitaxel in metastatic breast cancer. This trial was initiated to 1) determine the maximum tolerated dose and dose-limiting toxicities of UFT plus calcium folinate (Orzel) administered three times per day for 21 days in combination with paclitaxel; and 2) define the appropriate dose for phase II testing. Thus far, 14 patients have been accrued to three dose levels. Two patients developed dose-limiting toxicities at dose level 3. One patient experienced grade 3 hypotension. A second patient experienced grade 3 vomiting, grade 4 diarrhea, and severe hand-foot syndrome. Two partial responses and one complete response have been observed. Early trends suggest that this regimen is active in metastatic breast cancer and is well tolerated. Completion of this study is anticipated in 1999.

Paclitaxel and UFT Plus Oral Calcium Folinate in Pretreated Metastatic Breast Cancer

Ute Klaassen, MD, David Borquez, MD, Stephanie Lang, MD, Carsten Oberhoff, MD, Andreas Harstrick, MD, and Siegfried Seeber, MDDepartment of Internal Medicine (Cancer Research), West German Cancer Center, University of Essen, GermanySteven Benner, MDBristol-Myers Squibb Company, Wallingford, Connecticut

This phase I study was designed to determine the maximum tolerated dose (MTD) and dose-limiting side effects of combination treatment with paclitaxel (Taxol) and UFT (uracil and tegafur in a 4:1 molar ratio) plus oral calcium folinate (Orzel) for advanced metastatic breast cancer. After premedication, patients received paclitaxel as a 3-hour IV infusion (175 mg/m²) on day 1; UFT was administered orally at 300 mg/day (dose level 1), 400 mg/day (dose level 2), 500 mg/day (dose level 3), or 600 mg/day (dose level 4) in combination with 90 mg/day of calcium folinate in three divided doses for 14 days. Twenty patients with pretreated metastatic breast cancer have entered the trial so far. The main toxicity was neutropenia, occurring in 68% of patients. World Health Organization grades 1 and 2 peripheral neuropathy, arthralgia, and myalgia were common but not dose-limiting. All patients had grade 3 alopecia due to paclitaxel. One of six patients treated at dose level 4 experienced a dose-limiting toxicity with neutropenic fever. But within four dose levels MTD was not reached, and the study will continue to accrue patients to dose level 5. Objective responses were observed at all dose levels. In conclusion, the combination of paclitaxel and UFT plus oral calcium folinate seems to be a convenient and effective regimen for patients with pretreated metastatic breast cancer. Phase I is ongoing in order to determine MTD and the recommended dose for phase II testing.

UFT/Oral Calcium Folinate Plus Weekly Paclitaxel for Metastatic Breast Cancer

H.-J. Lück, MD, U. Scholz, MD, and H. Kühnle, MDDepartment of Gynecologic Oncology, Frauenklinik der Medizinischen Hochschule Hannover, Hannover, GermanyJ. Dethling, MDBristol-Myers Squibb, Munich, Germany

Paclitaxel (Taxol) is one of the most active drugs in the treatment of ovarian and breast cancers. Combination therapy with paclitaxel and 5-fluorouracil (5-FU) exhibits high activity in anthracycline-pretreated breast cancer, yielding response rates of 54% to 69% in recent studies. Weekly dosing of paclitaxel produces notable activity, while maintaining relatively low toxicity in heavily pretreated metastatic breast cancer patients. Uracil and tegafur (UFT) plus oral calcium folinate constitute an orally administered compound known as Orzel. This agent provides activity comparable to that of intravenously administered 5-FU plus calcium folinate, with the additional attributes of ease of administration and a more favorable side-effect profile. We initiated a phase I dose-finding trial to determine the maximum tolerated dose and dose-limiting toxicities of the combination of weekly paclitaxel by 1-hour infusion plus UFT/oral calcium folinate administered to patients with anthracycline-resistant metastatic breast cancer.

Combination Therapy for Advanced Breast Cancer: Cyclophosphamide, Doxorubicin, UFT, and Tamoxifen

Mamoru Fukuda, MD, Susumu Yamaguchi, MD, Tomohiko Ohta, MD, Yoshiaki Nakayama, MD, Haruki Ogata, MD, Kaname Shimizu, MD, and Toru Nishikawa, MDThe First Department of Surgery, St. Marianna University School of Medicine, Kawasaki, JapanYukihiro Adachi, MDSt. Marianna University, Toyoko Hospital, JapanEisuke Fukuma, MDTeikyo University, Mizonokuchi Hospital, Japan

We evaluated combination therapy for advanced and recurrent breast cancer with cyclophosphamide (Cytoxan), doxorubicin (Adriamycin), uracil and tegafur (UFT), and tamoxifen (Nolvadex) (CAUT), designed as chemoendocrine therapy with a high antitumor effect and less severe adverse reactions. In this therapy, one 3-week cycle consisted of doxorubicin 30 mg/m² intravenously on day 1, cyclophosphamide 65 mg/m² orally (po) and UFT 300 mg/m² po on days 1 to 14, and tamoxifen at 20 mg/day po on days 1 to 21. Twenty patients were registered and 19 were eligible, including seven with advanced breast cancer and 12 with recurrent disease. Six patients had received previous treatment. The comprehensive evaluation for objective response revealed one patient with a complete response and 10 patients with partial responses, producing an overall response rate of 58% (95% confidence interval, 29% to 87%). Three patients experienced no change, and five patients had progressive disease. Adverse events ³ grade 3 were leukopenia in six patients, erythropenia in one patient, alopecia in four, and severe generalized malaise in one. One patient who developed grade 4 leukopenia and one of five patients who developed grade 3 leukopenia recovered after receiving granulocyte colony-stimulating factor. CAUT therapy produced high response rates and relatively mild adverse reactions and is considered useful for the treatment of advanced and recurrent breast cancer.

Epirubicin, Cyclophosphamide, and UFT Plus Oral Calcium Folinate in Advanced Breast Cancer

Ian E. Smith, MD, FRCP, FRCPESection of Medicine, Royal Marsden Hospital and Institute of Cancer Research, London, United Kingdom

Use of continuous-infusion 5-fluorouracil (5-FU) for the treatment of metastatic breast cancer has met with some success in recent years. In order to build on this experience, investigators at the Royal Marsden Hospital and Institute of Cancer Research have combined continuous-infusion 5-FU with other agents active in metastatic breast cancer and observed improved outcome. The current trial, described here, evaluates UFT (uracil plus tegafur in a 4:1 molar ratio) plus oral calcium folinate (Orzel), an orally delivered and tolerable prodrug of 5-FU, combined with epirubicin and cyclophosphamide, in the treatment of advanced breast cancer.

UFT Plus Oral Calcium Folinate/Vinorelbine for Advanced Breast Cancer

Pierre Fumoleau, MDDepartment of Medical OncologyRégine Déporte-Fety, PhDDepartment of Pharmacokinetics, Centre René Gauducheau, Nantes-St. Herblain, FrancePierre Kerbrat, MD, and Brigitte Laguerre, MDDepartment of Medical Oncology, Centre Eugène Marquis, Rennes, France

This phase I study was undertaken to define the maximum tolerated dose, dose-limiting toxicity, and recommended dosage of UFT (uracil and tegafur) plus oral calcium folinate (Orzel) and vinorelbine (Navelbine) in combination treatment of metastatic breast cancer in patients who have received one prior chemotherapy regimen. The pharmacokinetics of UFT and vinorelbine were also evaluated. Starting doses were UFT 300 mg/day, plus a fixed calcium folinate dose of 90 mg/day, both administered in three divided daily doses on days 1 through 21 and vinorelbine 15 mg/m² on days 1, 8, and 15. The regimen was repeated every 4 weeks. At least three patients were treated at each dose level before escalating to the next level. Prophylactic granulocyte colony-stimulating factor was not routinely given. The preliminary results are reported as we await further follow-up of this ongoing study.

UFT and Mitomycin Plus Tamoxifen for Stage II, ER-Positive Breast Cancer

Yoshinobu Hata, MD, PhDSapporo Social Insurance, General Hospital, Sapporo, JapanJunichi Uchino, MD, PhDKushiro Rosai Hospital, Kushiro, JapanKazuaki Asaishi, MD, PhDSapporo Kotoni Breast Clinic, Sapporo, JapanYoshihiko Kubo, MD, PhD, and Michio Mito, MD, PhDAsahikawa Medical College, Asahikawa, JapanTatsuzo Tanabe, MD, PhDNTT Sapporo Hospital, Sapporo, JapanMasami Ogita, MD, PhDNational Sapporo Hospital, Sapporo, JapanKoichi Hirata, MD, PhDSapporo Medical College, Sapporo, JapanHokkaido Acetbc Study Group

A trial was designed to examine the combination of UFT and mitomycin (Mutamycin) plus tamoxifen (Nolvadex) as postoperative adjuvant therapy in the treatment of patients with stage II, estrogen receptor (ER)-positive primary breast cancer. Mitomycin was administered intravenously at 13 mg/m² on the day of surgery. Patients judged to be ER-positive were randomly allocated to either group A, which received oral tamoxifen 20 mg/day 14 days after surgery for 2 years, or group B, receiving oral UFT 400 mg/day plus tamoxifen 20 mg/day. A total of 219 patients were enrolled in group A, of which 213 (97.3%) were determined to be eligible; 225 patients enrolled in group B and 223 (99.1%) were eligible. The 5-year survival rates were 93.0% for group A and 95.4% for group B, with no significant difference between groups. The 5-year relapse-free survival rates were 83.1% for group A and 90.7% for group B, a significant advantage (P = .020) for the UFT plus tamoxifen group. Combination therapy with mitomycin, tamoxifen, and UFT proved to be an effective postoperative chemoendocrine therapy for stage II, ER-positive breast cancer.

Uracil/Tegafur Plus Oral Calcium Folinate in Advanced Breast Cancer

Eduardo Richardet, MD, PhDCarrera de Postgrado en OncologiaCecilia Pedraza, MDUniversidad Catolica de Cordoba, Cordoba, ArgentinaElizabeth Mickiewicz, MD, Guillermo Lerzo, MD, Miguel Bonamasa, MD, Federico Coppola, MD, Alicia Elli, MD, Graciela Uranga, MD, Silvia Jovtis, MD, Mario Bruno, MD, Monica Ventriglia, MD, Maria Andrea Cuevas, MD, Ana Maria Alvarez, MD, and Luis Alberto Suarez, MDBuenos Aires, ArgentinaLuis Fein, MDSanta Fe, Argentina

Uracil and tegafur (in a molar ratio of 4:1 [UFT]) has proven activity against breast cancer and is delivered in an easy-to-administer oral formulation. Orzel, which combines UFT with the oral biomodulator, calcium folinate, may provide even greater antitumor efficacy against breast cancer. Here, we describe the preliminary results of this phase II trial investigating the feasibility of 250 mg/m²/day of UFT plus 45 mg/day of oral calcium folinate administered to highly pretreated patients with advanced breast cancer. The results indicate a highly tolerable regimen and an overall response rate of 27.8% in a group of poor-prognosis patients. These findings warrant continued investigation.

UFT Plus Cisplatin With Concurrent Radiotherapy for Locally Advanced Non–Small-Cell Lung Cancer

Yukito Ichinose, MDHead, Department of Chest SurgeryTokujiro Yano, MD, Hiroshi Asoh, MD, Hideki Yokoyama, MD, Riichiroh Maruyama, MD, Chie Ushijima, MD, Tadashi Uehara, MD, Takanori Kanematsu, MD, and Tomofumi Yohena, MDDepartment of Chest Surgery, National Kyushu Cancer Center, Fukuoka, JapanSusumu Wada, MDHead, Department of Radiotherapy, National Kyushu Cancer Center, Fukuoka, Japan

A phase II study of combined-modality treatment consisting of uracil and tegafur (in a molar ratio of 4:1 [UFT]) plus cisplatin (Platinol) and concurrent radiotherapy was conducted to evaluate the activity of this regimen in patients with locally advanced non–small-cell lung cancer. Eligible patients with cytologically or histologically confirmed, unresectable stage III non–small-cell lung cancer received UFT (400 mg/m² orally on days 1 through 52) and cisplatin (80 mg/m² intravenously on days 8, 29, and 50). Radiotherapy, with a total dose of 60.8 Gy, was delivered in 38 fractions on days 1 through 52. Among the 17 patients entered, 16 experienced partial responses (94%; 95% confidence interval, 83% to 100%). The median time to tumor progression was 30 weeks (range, 8 to 87 weeks), and the 1-year survival rate was 80%. Hematologic toxicity was moderate. Grade 3 leukopenia occurred in 10 patients (59%), but no grade 4 hematologic toxicity was observed. No grades 3 or 4 nonhematologic toxicities were reported. These observations suggest that oral UFT plus cisplatin with concurrent radiotherapy can be safely administered to patients with locally advanced non–small-cell lung cancer. The demonstrated antitumor activity is high, making this combined-modality treatment worthy of further investigation in a multi-institution trial.

Adjuvant Treatment of Early Stage Non–Small-Cell Lung Cancer

Hiromi Wada, MD, PhDDepartment of Thoracic Surgery, Kyoto University , Kyoto, Japan

Cure rates for non–small-cell lung cancer (NSCLC) remain low and the prognosis for patients with even stage IA disease is poor. Complete surgical resection is still the first-line treatment for NSCLC, but many investigators are studying the benefit of postoperative adjuvant chemotherapy as a means of destroying residual tumor and micrometastasis. However, given the high recurrence rate and the trauma of surgery, consideration of drug toxicity and the patient’s quality of life is important. Uracil and tegafur (UFT) is a tolerable and active drug in NSCLC that, as a prodrug and biochemical modulator, provides extended tumor exposure to 5-fluorouracil (5-FU). Early evidence from studies with UFT described here indicate that it may be a safe and effective alternative to cisplatin (Platinol)-based therapy for the postoperative adjuvant chemotherapy of early stage NSCLC. Further results are awaited.

UFT/Calcium Folinate Plus Weekly Paclitaxel for Solid Tumors

Carsten Bokemeyer, MD, Jörg Thomas Hartmann, MD, Christian Kollmannsberger, MD, Frank Mayer, MD, and Lothar Kanz, MD Eberhard-Karls-Universität Tübingen, Innere Medizin II, Tübingen, Germany

Since cancer is incurable in many patients, palliation of symptoms and quality-of-life issues are important aspects of therapy. Uracil and tegafur (UFT) plus calcium folinate are the components of the oral agent known as Orzel, which offers activity comparable to intravenously administered 5-fluorouracil (5-FU) combined with calcium folinate. Paclitaxel (Taxol), administered intravenously on a weekly schedule, offers high dose intensity and high response rates with limited hematologic toxicity. It is the aim of this phase I study to define the dose-limiting toxicity, possible antitumor activity, and appropriate phase II study dose for the combination of UFT plus calcium folinate administered orally for 4 weeks plus weekly doses of paclitaxel. The daily dose will be fixed at UFT 300 mg/m² plus calcium folinate 90 mg, both divided into three doses per day; paclitaxel will be escalated in each cohort of patients in 10-mg/m² steps, starting with 50 mg/m² weekly. This protocol will take the success of protracted 5-FU infusion—here achieved orally with UFT plus calcium folinate—in combination with paclitaxel one step further by using paclitaxel in a dose-dense, less toxic weekly schedule. It may be anticipated that an active outpatient therapy for a variety of solid tumors will result.

UFT in Bladder Cancer

Yoshinobu Kubota, MD, PhD, Sumio Noguchi, MD, PhD, and Masahiko Hosaka, MD, PhDDepartment of Urology, Yokohama City University, School of Medicine, Yokohama, Japan

UFT, a compound containing uracil and tegafur (a prodrug of 5-fluorouracil) in a 4:1 molar ratio, has been used in Japan for the treatment of and as adjuvant chemotherapy for bladder cancer. In phase II studies, 300 to 600 mg/day of UFT given orally for more than 4 weeks produced a 32% overall response rate, including a complete response rate of 19.0%. Toxicity was in general mild and reversible. Gastrointestinal toxicity affected 56% of patients receiving 600 mg/day and 24% of patients receiving 300 mg/day of UFT. A randomized, prospective trial was performed to determine whether long-term treatment with oral UFT (300 to 400 mg/day for 2 years) as adjuvant chemotherapy could prevent intravesical recurrence of superficial bladder cancer. Long-term UFT administration after transurethral resection, in fact, effectively prevented the recurrence of superficial bladder cancer, with acceptably low toxicity. These data suggest that UFT as a single agent is effective against bladder cancer, with mild toxicity when used properly.

Gemcitabine and UFT Plus Oral Calcium Folinate: Phase I Study

Philip Agop Philip, MD, PhD, Dina Ibrahim, MD, Mark Zalupski, MD, Patricia Arlauskas, and Anthony Shields, MD, PhDDivision of Hematology and Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, Michigan

Gemcitabine (Gemzar) is a nucleoside analog increasingly used in the treatment of a variety of solid tumors. DNA synthesis is inhibited by gemcitabine by masked chain termination and via inhibition of ribonucleotide reductase. Synergy may exist between gemcitabine and other antimetabolites, including 5-fluorouracil. The varying patterns of dose-limiting toxicities to gemcitabine and UFT (uracil and tegafur in a 4:1 molar ratio) plus oral calcium folinate (Orzel) permit their use in combination. The primary aim of this phase I study is to determine the maximum tolerated doses of gemcitabine and UFT plus oral calcium folinate in patients with a variety of solid tumors. Only eight patients have been recruited to date, with myelosuppression being the main toxicity observed.

Endocrine Plus Uracil/Tegafur Therapy for Prostate Cancer

Yoshinari Ono, MD, PhD, and Ohinichi Ohshima, MD, PhDDepartment of Urology, Nagoya University , School of Medicine, Nagoya, JapanYoshito Takahashi, MD, PhD, Manabu Kuriyama, MD, PhD, and Yukimichi Kawada, MD, PhDDepartment of Urology, Gifu University School of Medicine, Gifu, JapanHiroyuki Shimizu, Md, PhDDepartment of Public Health, Gifu University School of Medicine, Gifu, Japan

A prospective, randomized clinical trial was conducted to evaluate the efficacy of endocrine chemotherapy with uracil and tegafur (in a molar ratio of 4:1 [UFT]) in patients with prostate cancer. The study included two treatment arms: endocrine plus UFT vs endocrine-only therapy. Of the 136 patients with prostate cancer enrolled in this study from April 1990 to December 1992, 69 received endocrine plus UFT therapy and the remaining 67 received endocrine-only therapy. Among those receiving UFT therapy, eight patients had stage A2 and B prostate cancer, 11 had stage C disease, and 50 had stage D disease. In the endocrine-only group, 10 patients had stage A2 and B disease, seven had stage C disease, and 50 had stage D disease. Tumors were well differentiated in 20 patients, moderately differentiated in 38 patients, and poorly differentiated in 11 patients receiving UFT. The endocrine-only group included 29 patients with differentiated tumors, 26 with moderately differentiated tumors, and 12 with poorly differentiated carcinomas. After a mean follow-up period of 54.9 months for patients receiving endocrine plus UFT therapy and 47.8 months for patients receiving endocrine-only therapy, disease had not progressed in 53.0% of the UFT-treated patients and 43.8% of the endocrine-only–treated patients (P = .114). The 5-year cancer-specific survival rates were 67.4% for the UFT group and 49.5% for the endocrine-only group (P = .273). The 5-year survival rates were 47.4% for the UFT group and 35.4% for the endocrine-only group (P = .177). Adverse effects, such as bone marrow suppression, nausea, vomiting, and anorexia, occurred in 36 patients in the UFT group and 41 patients in the endocrine-only group. However, adverse effects were not specifically related to UFT use. It is concluded that endocrine chemotherapy plus UFT is a tolerable regimen that might be effective for patients with prostate cancer.

UFT Plus Calcium Folinate Plus Radiotherapy for Recurrent Rectal Cancer

Wolfgang Hoffmann, MD, and Martina Schiebe, MDDepartment of Radio-Oncology and Radiotherapy , Braunschweig Community Hospital, Academic Teaching Hospital, University of Hannover Medical School, Braunschweig, GermanyJuergen Dethling, MD, and Christophe Martin, MDBristol-Myers Squibb, Munich, Germany

Uracil and tegafur (in a molar ratio of 4:1 [UFT]) plus calcium folinate comprise the components of the oral agent, Orzel, which appears to have activity comparable to intravenously administered 5-fluorouracil. This article describes the design of an open-label, disease-oriented, phase I trial of UFT plus calcium folinate in combination with simultaneous pelvic radiation for recurrent rectal cancer. This trial is designed to determine the maximum tolerated dose and dose-limiting toxicity of this regimen.

UFT/Oral Calcium Folinate Plus Radiation in Pancreatic Cancer

Francisco Robert, MD, FACPDepartment of Medicine, University of Alabama at BirminghamDavid Raben, MDDepartment of Radiation Oncology, University of Colorado, Denver, ColoradoSharon Spencer, MDDepartmment of Radiation Oncology, University of Alabama at Birmingham Comprehensive Cancer Center, University of Alabama at Birmingham

A phase I, single-center, open-label, dose-escalation study (University of Alabama [UAB] 9614) has been undertaken to evaluate the feasibility and safety of uracil and tegafur (in a molar ratio of 4:1 [UFT]) plus oral calcium folinate (Orzel) plus radiotherapy in patients with pancreatic cancer. A total of 11 patients with a median age of 59 years have been treated for 35 days with 150 mg/m²/day of UFT and 90 mg/day of oral calcium folinate, divided into three daily doses. Radiotherapy began on day 1, to a total dose of 45 Gy at 1.8 Gy per day (for approximately 5 weeks). Dose escalation of UFT will be performed until the maximum tolerated dose is defined. Overall, therapy has been well tolerated and the maximum tolerated dose has not yet been reached.

Preoperative UFT and Calcium Folinate and Radiotherapy in Rectal Cancer

Paulo M. Hoff, MD, Yvonne Lassere,RN, and Richard Pazdur, MDDivision of MedicineNora Janjan, MD, and Christopher Crane, MDDivision of RadiotherapyJohn Skibber, MDDivision of Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

Protracted infusions of 5-fluorouracil (5-FU) combined with pelvic radiotherapy have been associated with improved survival and decreased local and distant metastases in the adjuvant therapy of rectal cancer. However, this method of 5-FU infusion requires the inconvenience and expense of central venous line placement and care, infusion pumps, and treatment of catheter-related complications. We previously demonstrated that a completely oral therapy with UFT (uracil plus tegafur in a 4:1 molar ratio) plus oral calcium folinate (Orzel) can achieve pharmacokinetic parameters similar to those associated with protracted 5-FU infusions. This trial examines the feasibility of using UFT plus oral calcium folinate both during preoperative pelvic radiation and postoperatively, and shows that patients can be treated safely and effectively with a completely oral chemotherapy program combining UFT plus oral calcium folinate with pelvic radiation therapy.

Adjuvant Postoperative Combined-Modality Therapy for Rectal Cancer

Bruce D. Minsky, MDDepartment of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York

A number of advances have been made in the use of adjuvant chemotherapy for resectable rectal cancer. Whereas pelvic radiation therapy has been shown to increase local control in patients with clinically resectable disease, systemic chemotherapy is needed in addition to further improve local control and overall survival. In this review, the experience treating patients with clinically resectable rectal cancer in the postoperative adjuvant setting will be examined. Data from ongoing and recently completed randomized trials as well as the design of innovative phase I/II programs will be discussed.

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