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The Oncologist, Vol. 7, No. 5, 444–450, October 2002
© 2002 AlphaMed Press

A Phase I Trial of Weekly Paclitaxel Plus Prolonged Oral Eniluracil/5-Fluorouracil in Patients with Refractory Malignancies

Suzanne F. Jones, F. Anthony Greco, John D. Hainsworth, Jeffrey W. Patton, John H. Barton, Noel T. Willcutt, Margaret N. Baker, Paul V. McGuirt, Jeremey Levin, Howard A. Burris, III

The Sarah Cannon Cancer Center and Tennessee Oncology, Nashville, Tennessee, USA

Correspondence: Howard A. Burris, III, M.D., The Sarah Cannon Cancer Center, 250 25th Avenue North, Suite 110, Nashville, Tennessee 37203, USA. Telephone: 615-342-1725; Fax: 615-342-1745; e-mail: hburris{at}tnonc.com


   ABSTRACT
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Purpose. This phase I study was conducted to determine the dose-limiting toxicity (DLT), maximum-tolerated doses, and recommended phase II doses of the combination of weekly intravenous paclitaxel and oral eniluracil/5-fluorouracil (5-FU).

Patients and Methods. Patients received paclitaxel i.v. over 1 hour weekly for four consecutive weeks of each cycle. Oral eniluracil/5-FU was administered orally twice daily for 28 consecutive days starting on day 1 of each cycle. Cycles were repeated every 35 days. Patients were accrued at six different dosing combinations. Weekly paclitaxel doses ranged from 60 mg/m2 to 80 mg/m2, and oral eniluracil/5-FU doses ranged from 8.0/0.8 mg/m2 to 11.5/1.15 mg/m2 twice daily.

Results. Thirty-seven patients received 126 cycles of therapy. Myelosuppression was minimal at all dose levels, with no grade 4 neutropenia or thrombocytopenia reported. DLT was reported in three out of six patients enrolled at the highest dose level and consisted of grade 3 diarrhea (two patients) and grade 3 mucositis (one patient). No DLTs were reported in patients enrolled at lower dose levels. One complete response and three partial responses were reported in patients with taxane-resistant metastatic breast cancer.

Conclusion. The combination of paclitaxel and eniluracil/5-FU was generally well tolerated. The recommended doses for further phase II testing are paclitaxel 80 mg/m2 i.v. weekly for 4 weeks plus eniluracil/ 5-FU 10.0/1.0 mg/m2 orally twice daily on days 1-28 with cycles repeated every 35 days.

Key Words. Paclitaxel • Fluorouracil • Pyrimidine • Clinical trials • Phase I


   INTRODUCTION
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
Fluorouracil (5-FU) and the taxane derivatives have demonstrated synergism preclinically in murine tumor models [1]. The combination of the fluoropyrimidines with the taxane derivatives also has been explored clinically. Weekly bolus dose administration of paclitaxel, leucovorin, and 5-FU produced an overall response rate of 47% in patients with previously untreated metastatic breast cancer [2]. Additional phase I/II studies using the combination of docetaxel and 5-day continuous infusion 5-FU have yielded response rates of 40%-55% in patients with metastatic breast cancer who have failed prior therapy including anthracyclines [3–5]. Capecitabine, an oral fluoropyrimidine that is converted to 5-FU following administration, also has been given in combination with paclitaxel in patients with previously treated metastatic breast cancer [6]. The regimen produced a 50% response rate among the initial 10 evaluable patients, with two responses occurring in patients who had experienced progressive disease following a prior transplant. More recently, the combination of oral capecitabine and intravenous docetaxel was approved by the U.S. Food and Drug Administration for the treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing chemotherapy [7]. In a randomized, multicenter trial comparing docetaxel monotherapy with docetaxel and capecitabine for the treatment of patients with metastatic breast cancer who had failed prior anthracycline therapy, the combination regimen resulted in a statistically significant (p < 0.05) improvement in response rate (32% versus 22%), time to disease progression (186 days versus 128 days), and overall survival (442 days versus 352 days).

Eniluracil (776C85, 5-ethynyluracil) is an effective inactivator of dihydropyrimidine dehydrogenase (DPD), the first enzyme in the 5-FU catabolism pathway [8, 9]. Concomitant administration of eniluracil markedly increased the bioavailability and the half-life of 5-FU while reducing the pharmacokinetic variability, thus allowing for oral drug administration [10]. In animal models, eniluracil increased the antitumor efficacy of 5-FU and increased the therapeutic index of 5-FU by up to sixfold [11, 12]. Eniluracil also decreased 5-FU catabolite formation, which may result in fewer toxicities attributed to catabolite accumulation, such as hand-foot syndrome, cerebellar ataxia, and mucositis. Prolonged oral administration of the combination of eniluracil/5-FU mimicked protracted continuous infusion of 5-FU, but appears to be better tolerated and avoids the use of infusion pumps.

This phase I trial was conducted to determine the maximum-tolerated doses of paclitaxel and eniluracil/5-FU when used in combination. Paclitaxel was administered as a 1-hour i.v. infusion weekly for four consecutive weeks, and eniluracil/5-FU was administered orally twice daily for 28 consecutive days. Cycles were repeated every 35 days. The toxicity and preliminary antitumor activity of the combination regimen administered on this schedule were also assessed.


   PATIENTS AND METHODS
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patient Selection
Patients aged >=18 years with a life expectancy of at least 3 months and an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 were enrolled. All patients were required to have a pathologic diagnosis of an advanced malignancy that was unresponsive to currently available therapy or for which there was no known effective treatment. Patients could have received no more than two prior chemotherapy regimens in the metastatic setting (one additional adjuvant treatment was allowed) and must have recovered from the toxicities of previous regimens prior to enrollment. At least 3 weeks must have elapsed since previous chemotherapy and 2 weeks since previous radiation therapy. Patients who had received previous treatment with paclitaxel or 5-FU were not excluded from the study. The following laboratory parameters were required for study eligibility: WBC >=3,000/µl; platelet count >=100,000/µl; total bilirubin <=1.5 mg/dl; serum creatinine <2.0 mg/dl, and estimated creatinine clearance >=50 ml/minute. Patients with a history of brain metastases were eligible, but only if the metastases had been treated and were inactive and asymptomatic at the time of enrollment. Patients with symptoms of malabsorption or who were unable to swallow the study medication were excluded, as well as any patients with active concurrent infections or serious underlying medical conditions. Female patients who were pregnant or lactating also were excluded from the study. The study was approved by the local institutional review board, and written informed consent was obtained from all patients prior to enrollment.

Treatment Plan
Treatment cycles were repeated every 35 days with weekly paclitaxel administered on days 1, 8, 15, and 22 and eniluracil/5-FU given orally twice daily on days 1-28 of each cycle. Sequential cohorts of five patients were treated at the escalating dose levels outlined in Table 1Go. Due to the similarity in dose intensity, patients were enrolled simultaneously in dose levels 4 and 5. Dose escalation continued until the maximum-tolerated dose, and dose-limiting toxicities (DLTs) were determined. The maximum-tolerated dose was defined as the level below the dose that produced DLT in two out of five patients. For the purposes of this study, acute DLT was defined as any of the following: A) absolute neutrophil count (ANC) nadir <500/µl for greater than 5 days or resulting in hospitalization for treatment of neutropenia and fever; B) platelet nadir <50,000/µl for greater than 4 days or documented bleeding episode associated with thrombocytopenia or requirement for platelet transfusion, or C) any grade 3 or 4 nonhematologic toxicity due to treatment, with the exception of alopecia, nausea, and vomiting. The National Cancer Institute Common Toxicity Criteria Version 2.0 was used to grade treatment-related toxicities.


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  		Table 1. Dose escalation and patient enrollment
 
Dosing and Administration
Paclitaxel (commercial supply) was administered weekly as a 1-hour i.v. infusion on days 1, 8, 15, and 22 with cycles repeated every 35 days. Actual height and weight were used to calculate body surface area (BSA) according to the DuBois formula at the beginning of each treatment cycle. The dose of paclitaxel was diluted in 0.9% normal saline to a concentration <=1.2 mg/ml and infused through 0.22-µm filters. Patients were premedicated with the following medications prior to paclitaxel administration: dexamethasone 10-20 mg i.v., cimetidine 300 mg or ranitidine 50 mg i.v., and diphenhydramine 25-50 mg i.v.

Eniluracil/5-FU was supplied by Glaxo Wellcome Inc., (Research Triangle Park, NC) as combination film-coated tablets in two dosing strengths: 10 mg eniluracil/1 mg 5-FU (white tablets) and 2.5 mg eniluracil/0.25 mg 5-FU (pink tablets). The dose of 5-FU was based on BSA calculated according to the DuBois formula using the patient’s actual body weight obtained at the beginning of each treatment cycle. The dose was rounded to the nearest 0.25 mg of 5-FU. The ratio of eniluracil:5-FU was maintained at 10:1 by the administration of the manufactured combination tablet. The dose was administered orally twice daily (approximately 12 hours apart) for 28 consecutive days followed by a 7-day rest period (35-day treatment cycles). Glaxo Wellcome provided blistercards for dispensing drug to patients. Each blistercard consisted of seven rows (days 1-7) and two columns (a.m. and p.m. doses) and were filled by the pharmacist or other responsible personnel prior to dispensing. Patient instruction labels were also provided. Each patient was dispensed up to four blistercards (one blistercard = 1 week) for each treatment cycle. Compliance was monitored by having patients return partially used or empty blistercards at their next clinic visit and by interviewing the patient. Because of DPD inhibition by eniluracil, patients were not allowed to receive any fluoropyrimidine-based therapy, leucovorin, flucytosine, or topical 5-FU solutions or creams during and up to 28 days following treatment with eniluracil/5-FU. Based on safety data obtained during the study, the posttreatment period was later extended to 8 weeks post-eniluracil/5-FU.

Dose Modification/Reduction Guidelines
Treatment cycles were scheduled to be repeated at 35-day intervals if toxicity allowed. The patient had to meet all of the following criteria in order to begin a new cycle of treatment: A) platelets >=75,000/µl; B) ANC >=1,500/µl; C) resolution of clinically significant nonhematologic toxicities (including diarrhea, mucositis, and hand-foot syndrome) to baseline levels, and D) estimated creatinine clearance >=40 ml/minute. If a patient did not meet these criteria 7 days after the last dose of study drug, treatment was delayed until all of the criteria were met. Patients who required a delay in dosing of more than 3 weeks (due to toxicity or decreased creatinine clearance) after the last dose of study drug were taken off treatment. If a patient experienced >=grade 2 diarrhea, mucositis, or hand-foot syndrome during oral drug dosing, they were instructed to stop taking the eniluracil/5-FU immediately. Upon resolution of the toxicity, treatment could be resumed. For patients who experienced grade 2 or 3 diarrhea, mucositis, hand-foot syndrome, or rash, the eniluracil/5-FU dose was decreased by one dose level. For grade 4 treatment-related nonhematologic toxicities, both the paclitaxel and the eniluracil/5-FU were decreased by one dose level. Patients who experienced febrile neutropenia or grade 3 or 4 thrombocytopenia required a decrease in subsequent paclitaxel dosing by one dose level. Paclitaxel was also decreased by one dose level in patients who experienced >=grade 2 neurotoxicity. Because eniluracil/5-FU is renally eliminated, the dose of the drug was decreased by one dose level in patients with a calculated creatinine clearance between 40 and 50 ml/minute. If the calculated creatinine clearance fell below 40 ml/minute, eniluracil/5-FU was held until the renal dysfunction resolved or the patient was discontinued from the study. The following are the dose levels for the individual drugs that were used for dose reductions: paclitaxel, 60, 70, and 80 mg/m2, and eniluracil/5-FU, 6.0/0.6, 8.0/0.8, 10.0/1.0, and 11.5/1.15 mg/m2.

Disease Assessment
Tumor response was assessed after every two treatment cycles using standard Southwest Oncology Group Criteria [13]. Tumor response was classified as complete when all detectable disease disappeared for at least 4 weeks, as partial when a decrease of >=50% in the sum of the products of perpendicular diameters of all lesions was determined by two consecutive observations at least 4 weeks apart, and as progressive disease when there was a >=25% increase in the size of any assessable lesion or when any new lesions appeared. Assessments not fulfilling any of the above criteria were considered stable disease. Patients with progressive disease were removed from study. Patients with an objective response or stable disease were allowed to continue to receive treatment with paclitaxel and eniluracil/5-FU for as long as the investigator and the patient felt that it was in the best interest of the patient to continue.


   RESULTS
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Thirty-seven patients received a total of 126 cycles of therapy (median three cycles/patient; range 1-10) at six different dose levels. Twenty-one patients received >=3 and nine patients received >=5 cycles of therapy. The demographic characteristics of the patients are listed in Table 2Go. The number of patients enrolled and DLTs experienced at each individual dose level are summarized in Table 1Go. No intrapatient dose escalations were permitted. DLT was reported in three of the six patients enrolled at the highest dose level, and consisted of grade 3 diarrhea (two patients) and grade 3 mucositis (one patient). Tables 3 and 4GoGo describe treatment-related toxicities (>=grade 2) that were encountered during the first cycle of treatment or during any cycle of treatment. Grade 3 treatment-related nonhematologic toxicities (with the exception of nausea and vomiting, which were not considered dose limiting) were not reported in patients enrolled in dose levels 1-5 during the first cycle of treatment. However, with subsequent treatment cycles, the incidence of grade 2 and 3 treatment-related nonhematologic toxicities, particularly diarrhea and rash, increased, resulting in eniluracil/5-FU doses being held (41% of patients) or in eniluracil/5-FU dose reductions (35% of patients). Any dose delays, reductions, or modifications instituted due to treatment-related toxicities are outlined in Table 5Go. Approximately one-third of the patients also had a dose of paclitaxel held secondary to treatment-related toxicity (primarily, neutropenia, diarrhea, and mucositis), but only one patient required a paclitaxel dose reduction.


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  		Table 2. Patient demographic data (n = 37)
 

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  		Table 3. Treatment-related toxicities (>=grade 2), worst grade, cycle 1 only
 

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  		Table 4. Treatment-related nonhematologic toxicities (>=grade 2), worst grade, any cycle
 

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  		Table 5. Dose delays, reductions, or modifications secondary to treatment-related toxicity
 
Hematologic Toxicity
Myelosuppression was minimal at all dose levels, with no grade 4 neutropenia or thrombocytopenia reported. Four patients experienced grade 3 thrombocytopenia (two patients at level 1, one patient at level 2, and one patient at level 5). Two of the four patients had undergone prior transplants for the treatment of breast cancer, one patient had a long history of significant alcohol consumption, and the final patient had community-acquired clostridium difficile, each of which were felt to be contributing factors for thrombocytopenia. Eighteen patients (49%) were already receiving or were started on erythropoietin therapy for the treatment of chemotherapy-related anemia. It is standard procedure in our practice to initiate erythropoietin therapy in any patient whose hemoglobin is <=10.5 g/dl in an attempt to minimize red blood cell transfusion requirements. Ten patients received packed red blood cell transfusions during treatment.

Nonhematologic Toxicity
The majority of nonhematologic toxicities reported are described in Table 4Go. The most common toxicity was diarrhea (65% overall; 30% grade 1, 14% grade 2, and 22% grade 3). Twenty-three patients (62%) reported treatment-related nausea/vomiting that was mild to moderate in the majority of patients and could be controlled with phenothiazine-type oral antiemetics. Mucositis occurred in 49% of patients overall, with 35% experiencing a severity of only grade 1. Mild-to-moderate paclitaxel-related neuropathy was reported in 41% of patients, and one patient developed grade 3 peripheral neuropathy resulting in treatment discontinuation. Thirty five percent of patients had grade 1/2 arthralgias/myalgias and 35% of patients had grade 1/2 anorexia. Nine patients (24%) developed a rash during treatment, which was graded as severe in four and warranted study discontinuation in one patient. Four additional patients developed treatment-related hand-foot syndrome consisting of redness and tenderness on the palms and feet (two patients with grade 1 and two patients with grade 2). No ulceration or desquamation of the palms or feet was reported, and the two patients experiencing grade 2 hand-foot syndrome were able to continue eniluracil/5-FU with a dose reduction. Interestingly, the two patients with grade 2 hand-foot syndrome were also the only patients to develop treatment-related nail changes as well. Three patients (8%) reported conjunctivitis or dry eyes, which is a side effect reported with i.v. 5-FU treatment. Seven patients (19%) also reported taste changes or alterations that they attributed to the chemotherapy regimen. All weekly paclitaxel infusions were administered over 1 hour per standard clinic procedures, and no hypersensitivity reactions were reported.

Antitumor Activity
Thirty-five of the 37 patients were evaluable for response. Two patients were removed from study prior to disease evaluation secondary to treatment-related toxicities (one diarrhea, one pneumatosis coli). One complete response was reported in a 41-year-old woman with metastatic breast cancer who had previously received two prior chemotherapy regimens (doxorubicin/methotrexate/5-FU followed by single-agent paclitaxel and paclitaxel/cyclophosphamide) and a peripheral stem cell transplant. This patient received a total of 10 cycles (dose level 6) of paclitaxel and eniluracil/5-FU and remained in complete remission with no further therapy for 19 months. Three additional patients with metastatic breast cancer experienced a partial response to treatment. One patient was a 38-year-old female with liver and skeletal metastases who was treated 3 years previously with a stem cell transplant followed by tamoxifen. She received eight cycles of therapy (dose level 1) and experienced a partial response in her liver metastases with stabilization of her bone disease. The patient was then observed for clinical progression, which occurred 16 months after her documented response. The second patient was a 46-year-old female who received both paclitaxel and docetaxel as well as 5-FU/leucovorin. The patient had a partial response documented 3 months after starting treatment and received a total of five cycles of treatment (dose level 4) before disease progression (3 month response duration). The final patient with a documented partial response was a 57-year-old woman who was previously treated with a stem cell transplant, paclitaxel/carboplatin, and numerous hormonal therapies. She experienced a 3 month partial response in her liver metastases and experienced disease progression manifested as malignant pleural effusions after five cycles of treatment (dose level 2).

Nineteen patients (51%) were considered to have stable disease as their best response to treatment, with a median duration of 5 months (range 3-11 months). Interestingly, the patient who experienced the longest duration of stable disease (11 months/eight cycles of treatment) was a young colon cancer patient who had previously received adjuvant 5-FU, single-agent irinotecan, and JM216 (an oral platinum analogue) in combination with tegafur and uracil/leucovorin (another oral fluoropyrimidine). Although classified as stable disease by disease assessment, there were four patients with unconfirmed responses. One patient with metastatic colon cancer, who was previously treated with adjuvant 5-FU/levamisole followed by 5-FU/leucovorin at relapse, received two cycles of treatment with complete disappearance of her 5 x 3.5 centimeter liver mass documented. Unfortunately, the patient fell and broke her hip and was unable to return to Nashville. Although repeat computerized tomography scans failed to demonstrate evidence of disease, the patient’s carcinogenic embryonic assay increased slightly, so her local physician opted to start i.v. 5-FU/leucovorin 2 months after the last doses of paclitaxel and eniluracil/5-FU. The last contact with the patient was 7 months after the initiation of i.v. 5-FU/leucovorin, and her scans continued to show no evidence of disease. A second patient with metastatic colon cancer previously treated with 5-FU/leucovorin and single-agent irinotecan also experienced a partial response in his liver metastases when scanned after two cycles of treatment. However, the patient experienced unacceptable dermatitis during cycle 3 of treatment and was removed from study due to toxicity. As a result, his response to treatment was never confirmed with follow-up scans. A third unconfirmed partial response was reported in a young man with esophageal cancer who was previously treated with cisplatin/5-FU and cisplatin/irinotecan. This patient experienced a 79% decrease in his disease after cycle 2, but had documented disease progression on scans performed after cycle 4. The final unconfirmed response was reported in a woman with previously treated metastatic uterine cancer. This patient received five cycles of therapy and had a 53% decrease in the size of her liver lesions on the last set of scans obtained prior to study removal. However, the patient, unfortunately, developed grade 3 peripheral neuropathy and was removed from the study due to treatment-related toxicities. Twelve patients (32%) had disease progression as their best response.


   DISCUSSION
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
This study demonstrated that the combination of paclitaxel and eniluracil/5-FU was generally well tolerated. The recommended doses for further phase II testing are paclitaxel, 80 mg/m2 i.v. weekly x 4 weeks, plus eniluracil/5-FU, 10.0/1.0 mg/m2 orally twice daily on days 1-28, with cycles repeated every 35 days. Interestingly, these doses are equivalent to the doses of each drug that would be administered when given as a single agent. The lack of myelosuppression and relatively mild toxicity profile associated with weekly paclitaxel administration allows the drug to easily be combined with another relatively nontoxic drug such as oral eniluracil/5-FU. The DLTs of the combination regimen were nonhematologic and consisted of diarrhea and mucositis, both of which were readily reversible with drug discontinuation, and hospitalization was never required for treatment. Patients were also able to continue to receive the combination regimen when appropriate dose reductions were instituted.

Paclitaxel and 5-FU both have a broad range of antitumor activity, which was demonstrated by the number of responses reported in a variety of tumor types. Despite the fact that many of the patients had previously been treated with 5-FU and/or a taxane derivative, activity was still observed, particularly in patients with previously treated breast and colon cancer. Further phase II testing of this combination regimen is certainly warranted in a variety of tumor types.


   ACKNOWLEDGMENT
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 
This research was supported by a grant from Glaxo Wellcome.

Presented in part at The American Society of Clinical Oncology Thirty-Sixth Annual Meeting, New Orleans, Louisiana, May 20-23, 2000 (Abstract #746).


   REFERENCES
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

  1. Bissery MC, Vrignaud P, Bayssas M et al. Taxotere synergistic combination with cyclophosphamide, etoposide, and 5-fluorouracil in mouse tumor models. Proc Am Assoc Cancer Res 1993;34:299a.
  2. Loesch DM, Robert NJ, Keller AM et al. Phase II multicenter trial of a weekly taxol, 5-fluorouracil, and leucovorin regimen in patients with metastatic breast cancer. Proc Am Soc Clin Oncol 1998;17:115a.
  3. Sano M, Adachi I, Watanabe T et al. A phase I/II study of docetaxel (TXT) in combination with continuous infusion of fluorouracil (5-FU) in patients with advanced or recurrent breast cancer. Proc Am Soc Clin Oncol 1997;16:189a.
  4. Lerebours F, Cottu PH, Hardy-Bessard AC et al. Combination of docetaxel (TXT) and continuous infusion 5-fluorouracil (5-FU) in patients with metastatic breast cancer (MBC). Proc Am Soc Clin Oncol 1998;17:154a.
  5. Lortholary A, Maillart P, Delva R et al. Phase I dose-finding study with the combination docetaxel (D) and continuous infusion (CI) 5-fluorouracil (5-FU) in metastatic breast cancer (MBC) patients after failure to anthracyclines (ANT). Proc Am Soc Clin Oncol 1997;16:180a.
  6. Khoury P, Villalona-Calero M, Blum J et al. Phase I study of capecitabine in combination with paclitaxel in patients with previously treated metastatic breast cancer. Proc Am Soc Clin Oncol 1998;17:206a.
  7. Xeloda® (capecitabine) Tablets Package Insert. Nutley, NJ: Roche Pharmaceuticals, September, 2001.
  8. Spector T, Porter DJT, Nelson DJ et al. 5-ethynyluracil (776C85), a modulator of the therapeutic activity of 5-fluorouracil. Drugs Future 1994;19:565–571.
  9. Porter DJT, Chestnut WG, Merrill BM et al. Mechanism-based inactivation of dihydropyrimidine dehydrogenase by 5-ethynyluracil. J Biol Chem 1992;267:5236–5242.[Abstract/Free Full Text]
  10. Schilsky RL, Hohneker J, Ratain MJ et al. Phase I clinical and pharmacologic study of eniluracil plus fluorouracil in patients with advanced cancer. J Clin Oncol 1998;16:1450–1457.[Abstract/Free Full Text]
  11. Baccanari DP, Davis ST, Knick VC et al. 5-Ethynyluracil (776C85): a potent modulator of the pharmacokinetics and antitumor efficacy of 5-fluorouracil. Proc Natl Acad Sci USA 1993;90:11064–11068.[Abstract/Free Full Text]
  12. Cao S, Rustum YM, Spector T. 5-Ethynyluracil (776C85): modulation of 5-fluorouracil efficacy and therapeutic index in rats bearing advanced colorectal carcinoma. Cancer Res 1994;54:1507–1510.[Abstract/Free Full Text]
  13. Green S, Weiss GR. Southwest Oncology Group standard response criteria, endpoint definitions and toxicity criteria. Invest New Drugs 1992;10:239–253.[CrossRef][Medline]
Received March 15, 2002; accepted for publication August 9, 2002.





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