|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
© 2000 American Society for Clinical Oncology Multicenter Phase II Study to Evaluate a 28-Day Regimen of Oral Fluorouracil Plus Eniluracil in the Treatment of Patients With Previously Untreated Metastatic Colorectal CancerFrom the University of Chicago Cancer Research Center, Chicago, IL; New York University Medical Center, New York, NY; Mountain States Tumor Institute, Boise, ID; St Elizabeth Health Center, Youngstown, OH; Hematology & Oncology Associates, PA, Greenville, SC; Response Oncology, Inc, Memphis, TN; Glaxo Wellcome Inc, Research Triangle Park, NC; and The Cancer Center of Boston, Boston, MA. Address reprint requests to Sridhar Mani, MD, Montefiore Medical Center, 111 East 210th St, Hoffheimer 107A, Bronx, NY 10467; email smani{at}montefiore.org
PURPOSE: To determine the efficacy of fluorouracil (5-FU) plus eniluracil when administered to patients with previously untreated metastatic colorectal cancer. PATIENTS AND METHODS: In this single-arm phase II study, patients with previously untreated metastatic colorectal cancer received oral eniluracil plus 5-FU (10:1 dose ratio), at 5-FU doses of 1.00 mg/m2 or 1.15 mg/m2 twice daily (every 12 hours) for 28 consecutive days repeated every 5 weeks (one cycle). Treatment continued until there was documented disease progression or unacceptable toxicity. RESULTS: Thirty and 25 patients were enrolled at a starting dose of 1.00 mg/m2 and 1.15 mg/m2, respectively. Fourteen (25%) of 55 patients (95% confidence interval, 15% to 39%) had a partial response, and 20 patients (36%) had stable disease. The median durations of the partial responses and stable disease were 23.9 weeks (range, 12.3 to 52.1+ weeks) and 24.1 weeks (range, 17.1 to 55.6+ weeks), respectively. The median durations of progression-free and overall survival were 22.6 weeks (range, 21.0 to 29.0 weeks) and 59 weeks (range, 4 to 84+ weeks), respectively. The response rate in the 1.15 mg/m2–dose group was similar to the 1.00 mg/m2–dose group (28% v 23%, respectively). Severe (grade 3/4) nonhematologic treatment-related toxicity included diarrhea (nine patients), nausea/vomiting (one patient each), mucositis (two patients), and anorexia (one patient). Severe hematologic toxicities were rare. At the 1.15 mg/m2–dose level, two patients exhibited grade 3 granulocytopenia, and two patients had grade 3 anemia. CONCLUSION: The response rate with oral 5-FU plus eniluracil is comparable with that observed with infusional 5-FU or bolus 5-FU and leucovorin. The toxicity profile of this oral regimen is acceptable for use in an outpatient home-based setting.
UNTIL RECENTLY, strategies to improve fluorouracil (5-FU)-based chemotherapy relied largely on increasing the intracellular conversion of 5-FU to its active phosphorylated moeities. As such, 5-FU/leucovorin is currently the standard against which all other treatments for colorectal cancer are compared.1,2 Prolonged 5-FU exposure yields equivalent, if not slightly superior, results to 5-FU/leucovorin both in terms of response rate and survival.3,4 However, the delivery of continuous intravenous 5-FU infusion is cumbersome, requires a central venous catheter and pump, and is expensive. To simulate infusional therapy, permit oral delivery of 5-FU with predictable absorption and bioavailability, and improve antitumor activity; strategies were adopted to inhibit dihydropyrimidine dehydrogenase (DPD), the catabolic enzyme of 5-FU.5,6 Variability in the expression of DPD in the gastrointestinal tract results in limited and erratic bioavailability of orally administered 5-FU.7-10 Plasma clearance of 5-FU varies to the same degree, partly because of variability in hepatic DPD expression.7-10 Additionally, recent data suggest that in certain tumors, DPD expression may be increased compared with its normal tissue counterpart, resulting in drug resistance to 5-FU–based therapy because of rapid intracellular degradation of the drug.11,12 Eniluracil (776C85), an orally administered effective inactivator of DPD, is a uracil analogue with an ethynyl substituent at the 5' position.13,14 In preclinical studies, doses of eniluracil sufficient to inactivate greater than 99% of endogenous DPD were nontoxic and did not exhibit antiproliferative activity.13-15 In preclinical tumor models, pretreatment with eniluracil increased the plasma half-life and anti-tumor efficacy of 5-FU.13,16,17 In humans, the half-life of 5-FU is prolonged because of decreased clearance without a change in volume of distribution.18 A 5-FU oral dose of 1 mg/m2 given bid with eniluracil results in plasma levels similar to 5-FU 300 mg/m2/d given by continuous infusion. Repeated dosing with the combination does not seem to alter the pharmacokinetics of 5-FU or eniluracil, and there is no evidence of cumulative drug effects.19,20 Phase I studies combining eniluracil and 5-FU show a toxicity profile similar to that seen with 5-FU alone, with the dose-limiting toxicity being either myelosuppression (5-day regimen) or diarrhea (28-day regimen).19-21 In the phase I study of the 28-day regimen, the maximum-tolerated dose was 1.8 mg/m2; three of six patients experienced grade 4 diarrhea. At the 1.35 mg/m2–dose level, six of 17 patients could not continue treatment for a full 28 days during the first course of treatment because of various toxicities, including dehydration, nausea, vomiting, anorexia, and diarrhea. In contrast, none of the 13 patients who received the 1.0-mg/m2 dose required dose reductions or delays in the first 28-day course because of toxicity. The 5-FU area under the curve (AUC)0-24 following the 1.0-mg/m2 dose (given with eniluracil 20 mg twice daily) was slightly higher than historic AUC0-24 values for a continuous infusion of 5-FU at 300 mg/m2/d. Based on these data, the recommended phase II 5-FU dose was 1.0 mg/m2 bid for 28 days.21 The eniluracil phase II dose of 10 mg/m2 bid was selected to ensure maximal DPD inactivation. This multi-institutional phase II trial (FUMA 2006) was designed to determine the efficacy of oral 5-FU plus eniluracil administered daily for 28 days repeated every 35 days. The primary objective of this trial was to determine the objective response rate of 5-FU/eniluracil in patients with previously untreated metastatic colorectal cancer. Secondary objectives included estimation of the duration of response, duration of progression-free survival, overall survival, and toxicities associated with chronic administration of this drug combination.
Patients Fifty-five patients with previously untreated metastatic colorectal cancer were enrolled onto this study by seven centers between November 1996 and October 1997. All patients gave informed consent according to federal and institutional guidelines before study registration. Eligibility for this study included histologically confirmed diagnosis of metastatic colorectal cancer, no prior systemic chemotherapy for metastatic disease (one prior 5-FU–based bolus adjuvant therapy regimen was allowed provided it was discontinued at least 12 months before study entry), Karnofsky performance status  70, age 18 years, and bidimensionally measurable disease as defined by the Southwest Oncology Group (SWOG). Histologic confirmation was mandatory for all solitary inoperable lesions. Radiation therapy must have been completed 2 weeks before study entry. Patients must have recovered from toxic effects of any prior therapy. Patients with unstable medical or psychiatric illness, known poor compliance behavior, malabsorption syndromes, including significant surgical resection of stomach or small bowel, or history of concurrent malignancy were excluded from study participation. Laboratory eligibility criteria included granulocyte count 2000/µL, hemoglobin 9 g/dL, platelet count 100,000/µL, estimated creatinine clearance 50 mL/min by the modified Cockcroft-Gault formula, total bilirubin  two times the upper limit of institutional normal, and serum transaminases three times the upper limit of institutional normal (or five times the upper limit of normal if hepatic metastases were present).
Methods Antitumor activity (ie, response rate) was the primary end point of this study and was evaluated according to the SWOG criteria.22 Responses were classified as complete, partial, stable disease, progressive disease, or unknown. Toxicity was evaluated weekly on treatment according to the modified SWOG criteria.22
Treatment Patients received one 10-mg tablet of eniluracil for every 1-mg 5-FU tablet given and one 2.5-mg tablet of eniluracil for every 0.25-mg 5-FU tablet. Doses of eniluracil were taken 12 hours apart at the same time as the dose of 5-FU. Eniluracil was provided by Glaxo Wellcome Inc as 2.5-mg and 10-mg off-white tablets. Eniluracil and 5-FU were administered with 180 mL of water after a 1 hour fast; there was also a 1 hour fast after dosing. Leucovorin, flucytosine, and certain antiviral drugs (eg, sorivudine) were prohibited during and after this treatment period. If the 5-FU dose was reduced for toxicity, eniluracil was also reduced such that the patients continued to receive eniluracil in a ratio of 10:1 (eniluracil:5-FU). If the 5-FU dose was stopped or delayed, the eniluracil dose was also stopped or delayed. The 5-FU dose modification was based on the maximum intensity of drug-related hematologic (granulocytopenia and thrombocytopenia) and nonhematologic (diarrhea, mucositis, hand-foot syndrome, or other clinically significant events) toxicity that occurred in the preceding course. Intrapatient dose reescalation was not allowed except for patients who completed one 5-week course at the 60% dosage level without experiencing any grade 2 toxicity. In these patients, doses could be escalated by one third (ie, the equivalent of 80% of the dosage given before the initial reduction to 60% of dosage level).
Treatment within a cycle was modified based on grade 2 or greater toxicity. For grade 2 or greater toxicity, doses were discontinued until resolution of toxicity. Dosing delays of more than 3 weeks because of toxicity resulted in discontinuation from study. For retreatment, patients had to have platelet counts
Statistical Methods
Patient Characteristics Fifty-five patients with previously untreated advanced colorectal cancer were entered onto this study. Their clinical characteristics are listed in Table 1. Six patients (11%) prematurely discontinued treatment after receiving only baseline disease assessments and showed no other documented evidence of disease progression. One patient receiving the 1.5-mg/m2 dose died after 27 days of dosing during cycle 1. The cause of death was recorded by the treating physician as being unrelated to study drug. Another patient treated at the 1.00 mg/m2–dose level received three doses in cycle 1 but failed to have baseline assessments recorded and was withdrawn for noncompliance. The third patient treated at 1.15 mg/m2 experienced diarrhea and leg weakness during cycle 1 of treatment that resolved, but the patient consequently withdrew consent before cycle 2. The fourth patient, also treated at 1.15 mg/m2, completed 6 days of dosing during cycle 1 and was taken off-study because of unresolved grade 2 neutropenia. The fifth patient was treated at 1.00 mg/m2 and withdrew consent after 21 days of cycle 1 dosing because of personal preferences. The sixth patient, treated at 1.15 mg/m2, only completed 16 days of cycle-1 dosing was taken off study because of severe treatment-related nausea, vomiting, and diarrhea. The majority of patients (69%) had good performance status (Karnofsky performance status, 90 to 100), and a minority of patients (16%) received adjuvant chemotherapy. Most patients had measurable liver metastases (88%), and only 16% of the patients had multiple ( three) metastatic sites.
Treatment and Dosing Data Two hundred eighty-one complete and partial cycles were delivered to 55 patients during the study. Of the 281 cycles of therapy delivered, 45 (16%) were partial cycles (median, 20 treatment days; range, 1 to 21 days). Dosing deviations were observed in 16 cycles (6%) because of patient noncompliance as determined by the pill count at each visit. All dosing noncompliance resulted in missed doses, and there were no cases of overdosing. The overall median number of cycles delivered was five (range, one to 12+ cycles). In 15 cycles of therapy (5%), there was a more than 7-day delay in reinitiating treatment because of toxicity. In the 30 patients receiving the 1.00-mg/m2 5-FU dose, 152 complete (86%) and partial (14%) cycles were delivered. In the 25 patients receiving the 1.15-mg/m2 dose, 129 complete (90%) and partial (10%) cycles were delivered. In the 1.00-mg/m2 and 1.15-mg/m2 dose groups, of the 152 cycles and 129 cycles delivered, respectively, 113 (74%) and 91 (71%) cycles were delivered at 100% of the starting dose, respectively. Overall, of the 281 cycles delivered, 97% of cycles were delivered at a dose 80% of the starting dose. In terms of dose reductions, in the 1.00 mg/m2–dose group, seven dose reductions were required because of toxicity, which represented 4.6% of cycles (seven of 152 cycles) administered. In the 1.15 mg/m2–dose group, nine dose reductions were required because of toxicity and 8.6% of cycles (11 of 129 cycles) were administered at a reduced dose.
Efficacy and Survival Overall, there were no complete responses, and 14 confirmed partial responses were observed. The overall response rate was 25% (95% CI, 15% to 39%). The response rate in the 1.00 mg/m2–dose treatment group was 23% (95% CI, 11% to 43%) compared with 28% (95% CI, 13% to 50%) in the 1.15 mg/m2–dose treatment group. The median number of cycles required to achieve an objective response was two (range, two to nine cycles). The median duration of response was 23.9 weeks (range, 12 to 52+ weeks). Twenty patients (36%; 95% CI, 23% to 50%) patients had stable disease, with a median stable disease duration of 24.1 weeks (range, 17.1 to 55.6 weeks). The estimated median duration of progression-free survival was 22.6 weeks (range, 1+ to 79+ weeks). This Kaplan-Meier survival estimate was based on 18% of patients censored at the time of analysis. In the 1.00 mg/m2–dose treatment group, 34.6% of patients progressed at or before the first assessment of tumor response (ie, two cycles of treatment), whereas, in the 1.15 mg/m2–dose treatment group, only 18.8% of patients progressed. The median overall survival was 59 weeks (range, 4 to 84 weeks), with 51.7% of patients alive at 12 months (Fig 1). This Kaplan-Meier survival estimate was based on 52.7% of patients censored at the time of analysis.
In the 1.00 mg/m2–dose treatment group, there were 11 patients (37%) with stable disease, and in the 1.15 mg/m2–dose level, nine patients (36%) had stable disease. Responses were noted in patients with large-volume disease, patients with symptomatic disease, elderly patients, and those with unresected primary cancer. One patient had a near complete response but was documented with a partial response because of residual perirectal edema (possible assessable disease); however, there was complete resolution of measurable pelvic and hepatic metastases.
Toxicity
Overall, hematologic toxicities were mild, with grade 3 neutropenia occurring in 4% of patients and 0.7% of the cycles. No patient had febrile neutropenia or required hospital admission for antibiotic treatment. Two patients receiving the 1.15-mg/m2 starting dose exhibited grade 3 granulocytopenia, one on cycle 3, day 6, lasting less than 7 days until granulocyte recovery 1500/µL, and the other on cycle 1, day 5, lasting more than 10 days until granulocyte recovery. Overall, thrombocytopenia was mild, and no grade 3 or 4 thrombocytopenia was observed. Grade 3 anemia was noted in two patients, one of whom required blood transfusion therapy. No grade 4 anemia was noted. Neuromotor and neurosensory toxicity were observed, although, in many cases, these toxicities were difficult to clearly ascribe to the study drugs. Partially reversible significant neuropathy manifest as grade 2 sensorimotor weakness in the lower extremities was observed in one patient with long-standing diabetes; reversible grade 2 ataxia related to study drug was observed in another patient. One patient, a 71-year-old male with a history of weakness and unsteady gait observed during cycle 1 of treatment, developed increased weakness, ataxia, and nystagmus 10 days after beginning cycle 2. Computed tomography scan of the brain revealed white matter disease consistent with small-vessel ischemia, which was confirmed with a magnetic resonance imaging scan. CSF did not reveal the presence of metastatic cancer. This patient had ongoing nystagmus despite discontinuation of study drugs. In the treating physicians’ opinion, the nystagmus was possibly related to treatment with 5-FU and eniluracil. Although corneal changes have been observed in dogs with this combination therapy, no corneal changes were observed in any patient in this study. Only one patient developed mild interstitial keratitis, which may have been drug-related and resolved with opthalmic corticosteroids. This patient continued 5-FU/eniluracil without recurrent symptoms. Two patients developed mild (grade 1) increased lacrimation without evidence for dacroadenitis or dacrocystitis. The increased lacrimation resolved once the patients stopped study medication.
This study provides efficacy and safety data for a protracted schedule of 5-FU and eniluracil administered on a 35-day cycle. The response rate and survival duration observed in this trial are comparable with those historically reported for intravenous 5-FU therapy.2 Responses were observed in symptomatic patients, elderly patients, patients with primary tumor in situ, and patients with large volume disease. Overall, treatment with eniluracil/5-FU was very well-tolerated. Grade 4 diarrhea was only seen in 5% of patients; grade 3 fatigue in 7% of patients; grade 3 anorexia in 4% of patients; and grade 3 granulocytopenia in 4% of patients. In contrast to infusional 5-FU, there was a very low incidence of hand-foot syndrome and mucositis; however, in comparison with bolus 5-FU regimens, hematologic toxicity was seen in the 1.15 mg/m2–dose cohort. The neurologic toxicity observed (ie, ataxia, nystagmus, and polyneuropathy) has also been described with continuous dosing of intravenous 5-FU and other fluoropyrimidines.24,25 The toxicity profile of this oral regimen makes it acceptable for use in an outpatient, home-based setting. Several other studies have been performed and have reached preliminary conclusions on the efficacy and safety of oral 5-FU/eniluracil combinations for patients with colorectal cancer. Phase II studies using both regimens (daily dosing for 5 days every 28 days or bid dosing for 28 days every 35 days) in patients with previously untreated advanced disease have now been completed. The North Central Cancer Treatment Group conducted a phase II study administering eniluracil 50 mg on days 1 through 7 and oral 5-FU 20 mg/m2/d on days 2 through 6 on a 28-day treatment cycle. The preliminary response rate was 18% in 44 treated patients, and the toxicities were predominantly hematologic.26 The Cancer and Leukemia Group B conducted a multicenter phase II trial administering eniluracil 50 mg on days 1 through 7, leucovorin 50 mg on days 2 through 6, and 5-FU 20 mg/m2 orally days 2 through 6 of a 28-day cycle. Sixty-four patients were enrolled, and 53 patients were assessable for response. Objective tumor responses were documented in 11 patients (one complete response, 10 partial responses) giving a response rate of 21%. By intent-to-treat analysis, the response rate was 17% (11 of 64 patients).27 These response rates are comparable with the 25.4% response rate by intent-to-treat analysis observed in this study. The most common severe toxicity on the Cancer and Leukemia Group B trial was granulocytopenia, which occurred at grade 4 in 46% of patients. Grade 4 diarrhea was reported in 21% of patients and severe (grade 3) fatigue and anorexia in 10% of patients.27 Recently, the Eastern Cooperative Oncology Group concluded a two-strata study evaluating a 28-day regimen of oral eniluracil/5-FU repeated every 35 days. One strata (n = 38) was composed of patients with a single prior treatment for metastatic colorectal cancer, and the other (n = 44) included patients with previously untreated metastatic disease. Response and toxicity data are pending. To put the results of this study in perspective with those reported for other oral fluoropyrimidines, it is important to note that the response rates are comparable with those seen with uracil/tegafur plus leucovorin (11%) and capecitabine (23.2%). The toxicity profiles seem to be similar, with capecitabine causing a higher frequency of hand-foot syndrome than the other two agents. The relative extent of efficacy and toxicity for each drug is unknown as there has been no direct comparison of these oral agents. Compliance remains a major issue with oral medications. The compliance rate with twice daily dosing of fluorouracil and eniluracil was high (94%) compared with more frequently dosed drugs, based on a single investigator’s experience (S.M.).28 However, such comparative data have not been published. The twice-daily dosing schedule of eniluracil/5-FU should provide an advantage in terms of compliance over uracil/tegafur/leucovorin, which is dosed three times per day. Further, the incidence of certain toxicities (eg, hand-foot syndrome) was uncommon in this study compared with that seen with capecitabine (53% to 56%), making oral 5-FU and eniluracil combination therapy attractive for long-term administration.29-31 In our study, patients were treated at two different dose levels, 1.00 and 1.15 mg/m2. The reason for the shift in dosing was the lack of toxicity observed at the lower dose level. At interim analysis of the toxicity data after 28 patients had enrolled, a decision was made to escalate the dose level by 15%, which was still below the maximum-tolerated dose of 1.8 mg/m2 in the original phase I study.21 At 1.15 mg/m2, dose-limiting side-effects were observed, implying that this was likely to be the recommended dose for this schedule in future studies. This 28-day schedule of 1.15 mg/m2 5-FU in combination with 11.5 mg/m2 eniluracil was chosen for comparison with a standard regimen of intravenous 5-FU plus leucovorin in two ongoing phase III studies of patients with previously untreated metastatic colorectal cancer. Accrual to these trials was completed in the spring of 1999, and preliminary results should be available in 2000.
Supported in part by a grant from Glaxo Wellcome Inc, Research Triangle Park, NC. We are grateful to Susan Cadle for assistance in preparing the manuscript. We also thank the nursing staff and medical oncology fellows at the participating institutions for the superb care provided to the patients in this study. We acknowledge the support of the other investigators without whom we would have been unable to complete this study.
Presented in part at the Thirty-Fourth Annual Meeting of the American Society for Clinical Oncology, Los Angeles, CA, May 16-19, 1998.
1. Mayer RJ: Chemotherapy for metastatic colorectal cancer. Cancer 70:1414-1424, 1992 (suppl 5)[Medline] 2. Piedbois P, Buyse M, Rustum Y, et al: Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer; evidence in terms of response rate. J Clin Oncol 10:896-903, 1992[Abstract] 3. Leichman CG, Fleming TR, Muggia FM, et al: Phase II study of fluorouracil and its modulation in advanced colorectal cancer: A Southwest Oncology Group study. J Clin Oncol 13:1303-1311, 1995[Abstract] 4. Rougier P, Buyse M, Ryan L, et al: Meta-analysis of all trials comparing intravenous bolus administration to continuous infusion of 5-fluorouracil in patients with advanced colorectal cancer. Proc Am Soc Clin Oncol 16:267A, 1997 (abstr 946) 5. Wei X, McLeod HL, McMurrough et al: Molecular basis of the human dihydropyrimidine dehydrogenase deficiency and 5-fluorouracil toxicity. J Clin Invest 98:610-615, 1996[Medline] 6. Naguib FN, el-Kouni MH, Cha S: Enzymes of uracil catabolism in normal and neoplastic human tissues. Cancer Res 45:5402-5412, 1985 7. Fleming RA, Milano GA, Gaspard MH, et al: Dihydropyrimidine dehydrogenase activity in cancer patients. Eur J Cancer 29A:740-744, 1993 8. Ho DH, Townsend L, Luna MA, et al: Distribution and inhibition of dihydrouracil dehydrogenase activities in human tissues using 5-fluorouracil as a substrate. Anticancer Res 6:781-784, 1986[Medline] 9. Christophidis N, Vajda FJE, Lucas I, et al: A pharmacokinetic comparison of various rates and routes of administration. Clin Pharmacokinetics 3:330-336, 1978[Medline] 10. Finch RE, Bending MR, Lant AF: Plasma levels of 5-fluorouracil after oral and intravenous administration in cancer patients. Br J Clin Pharmacol 7:613-617, 1979[Medline] 11. Beck A, Etienne MC, Cheradame S, et al: A role of dihydropyrimidine dehydrogenase and thymidylate synthase in tumor sensitivity to fluorouracil. Eur J Cancer 30A:1517-1522, 1994
12.
Etienne MC, Cheradame S, Fischel JL, et al: Response to fluorouracil therapy in cancer patients: The role of tumoral dihydropyrimidine dehydrogenase activity. J Clin Oncol 13:1663-1670, 1995 13. Spector T, Harrington JA, Porter DJT: 5-Ethnyluracil (776C85): Inactivation of dihydropyrimidine dehydrogenase in vivo. Biochem Pharmacol 46:2243-2248, 1993[Medline]
14.
Porter DJT, Chestnut WG, Merrill BM, et al: Mechanism-based inactivation of dihydropyrimidine dehydrogenase by 5-ethynyluracil. J Biol Chem 267:5236-5242, 1992 15. Spector T, Porter DJT, Nelson DJ, et al: 5-Ethynyluracil (776C85), a modulator of the therapeutic activity of 5-fluorouracil. Drugs Future 19:565-571, 1994
16.
Baccanari DP, Davis ST, Knick VC, et al: 5-Ethnyluracil (776C85): A potent modulator of the pharmacokinetics and antitumor efficacy of 5-fluorouracil. Proc Natl Acad Sci 90:11064-11068, 1993
17.
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 54:1507-1510, 1994 18. Baker SD, Peang Khor S, Adjei AA, et al: Pharmacokinetic, oral bioavailability, and safety study of fluorouracil in patients treated with 776C85, an inactivator of dihydropyrimidine dehydrogenase. J Clin Oncol 14:3085-3096, 1996[Abstract]
19.
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 16:1450-1457, 1998 20. Khor SP, Lucas S, Hsieh AY, et al: 776C85: Effect on renal elimination of 5-fluorouracil and uracil in cancer patients. Proc Am Assoc Cancer Res 37:371, 1996 (abstr)
21.
Baker SD, Diasio R, O’Reilly S, et al: Phase I and pharmacologic study of oral 5-fluorouracil on a chronic daily schedule in combination with the dihydropyrimidine dehydrogenase (DPD) inactivator eniluracil. J Clin Oncol 18:915-926, 2000 22. Green S, Weiss GR: Southwest Oncology Group standard response criteria, endpoint definitions and toxicity criteria. Invest New Drugs 10:239-253, 1992[Medline] 23. Gehan E: The determination of the number of patients required in a preliminary and a follow-up trial of a new chemotherapeutic agent. J Chronic Dis 13:346-353, 1961[Medline] 24. Levi F, Zidani R, Brienza S, et al: A multicenter evaluation of intensified, ambulatory, chronomodulated chemotherapy with oxaliplatin, 5-fluorouracil, and leucovorin as initial treatment of patients with metastatic colorectal carcinoma: International Organization for Cancer Chronotherapy. Cancer 85:2532-2540, 1999[Medline] 25. Stein ME, Drumea K, Yarnitsky D, et al: A rare event of 5-fluorouracil-associated peripheral neuropathy: A report of two patients. Am J Clin Oncol 21:248-249, 1998[Medline] 26. Goldberg RM, Kugler J, Sargent DJ, et al: A phase II trial of seven day regimen of oral 776C85 plus a five day regimen of oral 5-fluorouracil (5-FU) in untreated patients (pts) with metastatic colorectal cancer (M-CRC): A North Central Cancer Treatment Group study. Proc Am Soc Clin Oncol 17:282a, 1998 (abstr 1084) 27. Schilsky R, Mani S, Meropol N, et al: Clinical evaluation of eniluracil plus 5-fluorouracil in colorectal cancer. Chemother Strat Treat Colorectal Cancer 43-44, 1999 (abstr) 28. Mani S, Sciortino D, Samuels B, et al: Phase II trial of uracil/tegafur (UFT) plus leucovorin in patients with advanced biliary carcinoma. Invest New Drugs 17:97-101, 1999[Medline]
29.
Blum JL, Jones SE, Buzdar AU, et al: Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 17:485-493, 1999 30. Ignoffo RJ: Capecitabine: A new oral fluropyrimidine. Cancer Pract 6:302-304, 1998[Medline]
31.
Van Cutsem E, Findlay M, Osterwald B, et al: Capecitabine, an oral fluoropyrimidine carbanate with substantial activity in advanced colorectal cancer: Results of a randomized phase II study. J Clin Oncol 18:1337-1345, 2000 Submitted November 15, 1999; accepted March 27, 2000. This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
