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© 1999 American Society for Clinical Oncology Phase I and Pharmacokinetic Study of the Oral Fluoropyrimidine Capecitabine in Combination With Paclitaxel in Patients With Advanced Solid MalignanciesFrom the Institute for Drug Development, Cancer Therapy and Research Center, and The University of Texas Health Science Center at San Antonio, San Antonio; Brooke Army Medical Center, Fort Sam Houston, TX; and Hoffmann-LaRoche, Inc, Nutley, NJ. Address reprint requests to Miguel A. Villalona-Calero, MD, Division of Hematology Oncology, Ohio State University, B406 Starling-Louing Hall, Columbus, OH 43210; email villalona-1{at}medctr.osu.edu
PURPOSE: To evaluate the feasibility of administering the oral fluoropyrimidine capecitabine in combination with paclitaxel, to characterize the principal toxicities of the combination, to recommend doses for subsequent disease-directed studies, and to determine whether significant pharmacokinetic interactions occur between these agents when combined. PATIENTS AND METHODS: Sixty-six courses of capecitabine and paclitaxel were administered to 17 patients in a two-stage dose-escalation study. Paclitaxel was administered as a 3-hour intravenous (IV) infusion every 3 weeks, and capecitabine was administered continuously as two divided daily doses. During stage I, capecitabine was escalated to a target dose of 1,657 mg/m2/d, whereas the paclitaxel dose was fixed at 135 mg/m2. In stage II, paclitaxel was increased to a target dose of 175 mg/m2, and the capecitabine dose was the maximum established in stage I. Pharmacokinetics were characterized for each drug when given alone and concurrently. RESULTS: Myelosuppression, predominately neutropenia, was the principal dose-limiting toxicity (DLT). Othertoxicities included hand-foot syndrome, diarrhea, hyperbilirubinemia, skin rash, myalgia, and arthralgia. Two patients treated with capecitabine 1,657 mg/m2/d and paclitaxel 175 mg/m2 developed DLTs, whereas none of six patients treated with capecitabine 1,331 mg/m2/d and paclitaxel 175 mg/m2 developed DLTs during course 1. Pharmacokinetic studies indicated that capecitabine and paclitaxel did not affect the pharmacokinetic behavior of each other. No major antitumor responses were noted. CONCLUSION: Recommended combination doses of continuous capecitabine and paclitaxel are capecitabine 1,331 mg/m2/d and paclitaxel 175 mg/m2/d IV every 3 weeks. Favorable preclinical mechanistic interactions between capecitabine and paclitaxel, as well as an acceptable toxicity profile without clinically relevant pharmacokinetic interactions, support the performance of disease-directed evaluations of this combination.
THE ORAL FLUOROPYRIMIDINE capecitabine (Xeloda; Hoffmann-LaRoche, Inc, Nutley, NJ; N4-pentyloxycarbonyl-5'-deoxy-5-fluorocytidine) was rationally synthesized to be efficiently absorbed from the gastrointestinal tract as a prodrug and converted to fluorouracil (5-FU), preferentially in neoplastic tissues (Fig 1).1,2 After gastrointestinal absorption, capecitabine is metabolized to 5'-deoxy-5-fluorocytidine (5'-DFCR; Furtulon; Roche, Basel, Switzerland) by hepatic carboxyl esterase, and this intermediate is further metabolized to doxifluridine (5'-DFUR) by cytidine deaminase in both hepatic and extrahepatic tissues, including malignant tumors.3,4 5'-DFUR is subsequently metabolized to 5-FU by the enzyme thymidine phosphorylase (dThdPase), which is one of two types of pyrimidine nucleoside phosphorylases.5 dThdPase has recently been shown to be a potent tumor-associated angiogenesis factor with higher expression in tumor cells than normal cells, which may account for the intriguing results reported by some investigators that malignant cells preferentially convert 5'-DFUR to 5-FU.6,7
The immediate precursor to capecitabine, 5'-DFUR, underwent development as an oral fluoropyrimidine in the 1980s.3,4 In preclinical evaluations, the therapeutic index of 5'-DFUR was shown to be much more than that of 5-FU, and 5'-DFUR was shown to possess potent anticachectic and antimetastatic activity that was not noted with 5-FU.3,4,8,9 In clinical studies, high and predictable oral bioavailability was noted, and 5'-DFUR showed prominent antitumor activity in patients with breast, colorectal, and gastric cancers.10-12 However, diarrhea caused by the generation of 5-FU in gastrointestinal tissues that also highly express pyrimidine nucleoside phosphorylases limited the development of 5'-DFUR, although it is licensed in Japan.10 In contrast, the carbamate structure of capecitabine precludes its conversion to 5-FU in the intestines; therefore, capecitabine is much less likely to induce diarrhea than 5'-DFUR. Indeed, capecitabine administered daily for 3 weeks produced less gastrointestinal toxicity in animals and was more efficacious against the human colon cancer xenografts HCT116 and CXF280 across a broader dosing range than 5-FU administered either intravenously (IV) (three times weekly for 2 weeks) or orally (daily for 3 weeks), or 5'-DFUR given orally daily for 3 weeks.1,2 At equitoxic doses, treatment with capecitabine also resulted in substantially greater intratumoral exposure to 5-FU compared with 5-FU itself administered intraperitoneally.13 In early phase I and pharmacologic studies, capecitabine showed efficient and predictable gastrointestinal absorption, with 61% of the administered dose recovered in urine as drug-related material, and the agent was rapidly converted to 5'-DFCR and 5'-DFUR (time to peak plasma concentration [tmax], 30 minutes).14 In addition, 5-FU concentrations were 2.9-fold higher, on average, in malignant tissues compared with nonmalignant tissues.14 Diarrhea and hand-foot syndrome have been the principal toxicities of capecitabine, and severe myelosuppression has been uncommon on protracted dosing schedules.2,15,16 Recommended phase II dose schedules for capecitabine have included 1,331 mg/m2/d in two divided doses daily for 12 weeks and 2,510 mg/m2/d in two divided doses daily for 2 weeks every 3 weeks. Capecitabine on the latter schedule has recently received regulatory approval in the United States for treating patients with paclitaxel-refractory metastatic breast cancer.
Because a principal determinant of the therapeutic index of capecitabine-based treatment is the differential rate of conversion of 5'-DFUR to 5-FU in malignant and nonmalignant tissues, therapeutic strategies have focused on maximizing the ratio of dThdPase activity in malignant versus nonmalignant tissues. Transfection of the dThdPase gene into the DLD-1 human colon cancer cell line, which is dThdPase-deficient and highly resistant to 5'-DFUR, increases dThdPase activity by 1,068-fold and sensitivity to 5'-DFUR by 1,070-fold.17 In addition, treatment of malignant tumors with various cytokines, such as tumor necrosis factor-alpha, interleukin-1-alpha, and interferon-gamma (IFN- To date, these results with capecitabine provide both mechanistic and clinical rationale to evaluate the feasibility of administering it in combination with paclitaxel. In addition, the overlapping antitumor activities of both single-agent capecitabine and paclitaxel in several tumor types, particularly breast cancer, as well as the nonoverlapping principal toxicities of these agents, support a rationale for the evaluation of this combination regimen. The principal objectives of this phase I and pharmacokinetic study were as follows: (1) to determine the maximum-tolerated doses (MTDs) of capecitabine administered twice daily in combination with paclitaxel as a 3-hour IV infusion every 3 weeks to patients with advanced solid malignancies; (2) to describe and quantitate the toxicities of the capecitabine-paclitaxel regimen; (3) to characterize the individual pharmacokinetic behavior of both paclitaxel and capecitabine and determine whether significant pharmacokinetic interactions occur when the agents are administered in combination; and (4) to seek preliminary evidence of antitumor activity for this combination.
Eligibility Patients with histologically confirmed solid malignancies refractory to conventional therapy or for whom no effective therapy existed were candidates for this study. Eligibility criteria also included the following: age  18 years; Karnofsky performance status 70% (ambulatory and capable of self-care); a life expectancy 3 months; no major surgery, radiotherapy, or chemotherapy within 28 days (42 days for mitomycin or nitrosourea); no history of major disorders or surgery involving the stomach, small intestines, liver, or kidney that might affect the gastrointestinal absorption or clearance of capecitabine; adequate hematopoietic (WBC count 3,000/µL, absolute neutrophil count [ANC] 1,500/µL, platelet count 100,000/µL, and hemoglobin level 9.0 g/dL), hepatic (total bilirubin level < 1.5 times the upper normal limits; AST, ALT, and alkaline phosphatase < 2.5 times the upper normal limits), and renal (serum creatinine < 1.5 times the upper normal limits) functions; no clinically significant cardiac disease (New York Heart Association class III or IV); no history of seizures, CNS disorders, or psychiatric disease that might affect study compliance; no evidence of brain metastases; no history of hypersensitivity to paclitaxel or other drugs formulated in Cremophor EL (polyoxyethylated castor oil); no requirement for chronic corticosteroids except for inhalation therapy; and no prior documentation of hepatitis B surface antigen, hepatitis C antibodies, or human immunodeficiency virus type 1 antibodies, although such viral evaluations were not required for eligibility. All patients gave informed written consent before treatment.
Dosage and Dose Escalation
Drug Administration
Dosage Modifications
Pretreatment Assessment and Follow-Up Studies
Plasma Sampling and Assay
Pharmacokinetic Analysis
Descriptive statistics were used to summarize all pharmacokinetic parameters. Mean, SD, coefficient of variation, minimum, maximum, and median values were determined for all parameters. In addition, geometric mean and geometric coefficient of variation were determined for Cmax, AUC0-t, and AUC0-
General The number of new and total patients, courses, and rates of DLTs as a function of dose level are listed in Table 1. Seventeen patients received 66 assessable courses of paclitaxel and capecitabine. Two other patients were not assessable for toxicity because treatment was discontinued early during their first course as a result of rapidly progressive disease. Patient characteristics are listed in Table 2. Sixteen patients received prior chemotherapy and 10 subjects were previously treated with both chemotherapy and radiation therapy. During study stage I, the daily dose of capecitabine was increased from 1,004 to 1,657 mg/m2/d, and the dose of paclitaxel was fixed at 135 mg/m2. Because there were no dose-limiting events in patients treated with capecitabine doses as high as 1,657 mg/m2/d, which was the dose recommended for phase II studies of capecitabine as a single agent on a continuous treatment schedule,2 the study was amended, and further dose escalation of capecitabine was not pursued. Instead, the dose of paclitaxel was increased to 175 mg/m2, and because no DLTs were observed with capecitabine 1,657 mg/m2/d in study stage I, this dose was administered to the first cohort of patients in stage II. However, DLT, characterized by fever associated with neutropenia, occurred during course 1 in the first two patients treated at this dose level. Therefore, the daily dose of capecitabine was decreased to 1,331 mg/m2/d in combination with paclitaxel 175 mg/m2 in the next cohort of patients. None of the six new patients treated at this dose level developed DLTs during course 1, and only two of 24 total courses were associated with DLT, which consisted of grade 3 diarrhea that lasted longer than 2 days (course 2) and severe neutropenia associated with fever (course 3). No objective antitumor responses were observed.
Hematologic Toxicity
DLT, consisting of grades 3 to 4 neutropenia associated with fever, was initially noted in two patients treated with capecitabine 1,657 mg/m2/d and paclitaxel 175 mg/m2. Another individual developed grade 3 neutropenia associated with fever during his third course of capecitabine/paclitaxel at the next lower dose level (1,331 mg/m2/d and 175 mg/m2, respectively). Gram-negative bacteremia without sepsis was documented in two of these three patients. Complete recovery of the ANC to pretreatment levels occurred 5 days after the onset of neutropenia in all of these patients. In one of the patients who was initially treated with capecitabine 1,657 mg/m2/d and paclitaxel 175 mg/m2, grades 2 and 3 neutropenia were noted on two occasions soon after resumption of treatment with capecitabine 1,657 mg/m2/d.
Nonhematologic Toxicity
Elevations in serum bilirubin concentrations occurred in eight patients during 12 courses. The onset of bilirubin elevations occurred between days 8 and 22 (median, day 15). Concomitant elevations in serum transaminases and alkaline phosphatase were noted in one patient only. Fractionation of total bilirubin in two of the eight individuals showed that unconjugated bilirubin accounted for most of the elevation. The absolute elevations were generally modest (median peak serum bilirubin concentration, 1.4 mg/dL [range, 1.1 to 2.4 mg/dL]), and cumulative toxicity was not observed. In addition, treatment with capecitabine was never interrupted for hyperbilirubinemia, and hyperbilirubinemia resolved after a median of 8 days in all individuals. For these reasons, despite the fact that several of these elevations met the criteria for grade 3 toxicity using the National Cancer Institute Common Toxicity Criteria (1.5 to three times the upper normal limit), these adverse effects were not considered dose-limiting. One patient developed hand-foot syndrome. The patient, a 61-year-old man with metastatic colon cancer who was treated with capecitabine 1,657 mg/m2/d and paclitaxel 135 mg/m2, developed a symmetrical erythematous macular rash on both of his forearms and hands 15 days after beginning treatment. Because of the concomitant development of grade 3 neutropenia, treatment with capecitabine was delayed for 5 days and then begun again at the same dose after complete hematologic recovery and improvement of his rash. However, 7 days after treatment with his second dose of paclitaxel on day 22, he developed abdominal cramping (grade 2), nausea and vomiting (grade 2), diarrhea (grade 2), and neutropenia (grade 3). His hands were tender, edematous, and erythematous, and a rash involving his arms, shoulders, face, and trunk was also noted. These toxic manifestations resolved after capecitabine and paclitaxel were discontinued, and no further treatment was administered because of the development of progressive disease. Two additional patients treated with capecitabine 1,657 or 1,004 mg/m2/d and paclitaxel 135 mg/m2 developed erythematous pruritic eruptions on their hands, which was not typical of hand-foot syndrome, and therapy was not interrupted. Seven patients experienced myalgia and/or arthralgia. The onset of symptoms was typically 2 to 4 days after treatment with paclitaxel 135 and 175 mg/m2. Myalgia and arthralgia generally lasted 2 to 7 days and were managed successfully with either nonsteroidal anti-inflammatory medications or acetaminophen. Other mild to moderate drug-related toxicities, which seemed unrelated to dose level, included mucositis, nausea, vomiting, alopecia, conjunctivitis, facial flushing, lower extremity edema, paresthesia, and malaise. In addition, a 72-year-old man with rectal carcinoma and lung metastasis who was previously treated with radiation to his primary rectal lesion, as well as interstitial irradiation for a stage B prostate cancer, developed hemorrhagic cystitis 21 days after beginning his first course of capecitabine 1,331 mg/m2/d and paclitaxel 135 mg/m2. Cystoscopy showed a large, friable necrotic mass involving the left trigone of his bladder that was associated with extensive mucosal inflammation. Biopsy specimens of the mass and adjacent bladder showed cystitis, which was believed to be caused by a radiation recall phenomenon.
Pharmacokinetic Studies
At paclitaxel doses of 135 and 175 mg/m2, AUC0-
Scatterplots depicting AUC and Cmax values of capecitabine and capecitabine metabolites as a function of capecitabine dose are shown in Fig 3. Although the sample size was small, the relationship between capecitabine dose and AUC appeared linear in the capecitabine dosing range evaluated. Figure 4 shows plasma concentration-versus-time curves for capecitabine and capecitabine metabolites from a representative patient, and pharmacokinetic parameter values for prodrug and metabolites in patients treated with two daily doses of capecitabine 666.5 mg/m2 (1,331 mg/m2/d) on day 15 are listed in Table 6. Peak capecitabine plasma concentrations occurred at a median of 1.05 hours (range, 0.5 to 4.05 hours) after capecitabine administration, whereas maximum plasma concentrations of 5'-DFCR, 5'-DFUR, and 5-FU were noted at median of 2.02 hours (range, 0.50 to 4.05 hours) after treatment. Median tmax values for 5-FUH2 and FBAL were 3 hours (range, 1.03 to 4.05 hours) and 3.03 hours (range, 1.98 to 5.13 hours), respectively. Despite nearly identical tmax values for 5'-DFUR and 5-FU, AUC values for 5-FU were 26.5-fold lower, on average, than those for 5'-DFUR at the recommended dose of capecitabine (1,331 mg/m2/d) in this study.
The potential influence of capecitabine on paclitaxel pharmacokinetics was assessed. Paclitaxel AUC0-
The high and predictable oral bioavailability of capecitabine, as well as the preferential conversion of this prodrug to 5-FU in neoplastic tissues, as shown by several investigators,1,13,14 render capecitabine one of the most interesting fluoropyrimidines undergoing development. dThdPase, which is highly expressed in neoplastic tissue and may account for the preferential metabolism of 5'-DFUR to 5-FU in malignant neoplasms, has been shown to be upregulated in human colon cancer xenografts after treatment with paclitaxel, and synergy between paclitaxel and capecitabine has also been noted.19 On the basis of this preclinical rationale and the overlapping clinical antitumor spectra of these agents, this phase I pharmacologic study was performed to evaluate the feasibility of administering capecitabine and paclitaxel in combination and to study the pharmacologic profiles and potential for pharmacokinetic interactions between these agents. Myelosuppression, predominately neutropenia, was the principal DLT. However, clinically relevant single-agent doses of both paclitaxel and capecitabine were able to be administered in combination. Because the incidence of severe neutropenia associated with fever at the paclitaxel 175-mg/m2 and capecitabine 1,657-mg/m2/d dose level was unacceptably high, the dose level of paclitaxel 175 mg/m2 and capecitabine 1,331 mg/m2/d, consisting of paclitaxel 175 mg/m2 every 3 weeks and capecitabine in two divided daily doses of 666 mg/m2, was the MTD and recommended dose level for subsequent evaluations. Overall, both the qualitative and quantitative aspects of the hematologic effects at the paclitaxel 175-mg/m2 and capecitabine 1,331-mg/m2/d dose level were similar to those observed with paclitaxel 175 mg/m2 administered as a single agent over 3 hours.21,26 However, several observations, such as the recurrence of neutropenia when capecitabine was restarted after a treatment delay in a patient who had recovered from severe neutropenia, presumably caused by paclitaxel, indicates that capecitabine may also contribute to the neutropenia that occurs with the paclitaxel/capecitabine regimen. Qualitatively, the nonhematologic effects of the capecitabine/paclitaxel combination were similar to the toxicities of either capecitabine (diarrhea, rash, flushing, hand-foot syndrome, nausea, vomiting, and mucositis) or paclitaxel (myalgia, arthralgia, asthenia, peripheral neurotoxicity, malaise, and alopecia) administered as single agents.2,15,16,22 The development of hyperbilirubinemia in eight patients during 12 courses is of interest, but increases in serum bilirubin levels were also noted in early studies of capecitabine administered as a single agent, and, as in the present study, hyperbilirubinemia was not clinically significant.2,15,16 In contrast to the results of early studies, four of the eight individuals who developed hyperbilirubinemia in the present study did not have liver metastases, including two of the three patients with grade 3 toxicity, and only one subject had concomitant elevations of other liver function tests. In addition, the elevation was largely caused by unconjugated bilirubin. The relative early tmax values for all metabolites, particularly 5'-DFUR, and higher Cmax and AUC values for 5'-DFUR relative to both capecitabine and 5'-DFCR, indicate that capecitabine is rapidly and extensively metabolized to 5'-DFUR. Interestingly, systemic exposure to 5'-DFUR, as estimated from AUC values in plasma, was nearly 30-fold greater, on average, than that of 5-FU. However, because conversion of 5'-DFUR to 5-FU is largely an intracellular process that primarily occurs in peripheral tissues,5 the relative exposures of capecitabine and its metabolites based on AUC value estimates from plasma concentrations in this study may not accurately reflect the relative exposure of peripheral tissues and malignant tumors to capecitabine and capecitabine metabolites. Nevertheless, significant pharmacokinetic interactions between paclitaxel, capecitabine, and capecitabine metabolites were not evident. Although hepatic metabolism and/or biliary excretion play a principal role in the metabolism and clearance of both capecitabine and paclitaxel, significant pharmacokinetic interactions would not have been anticipated because the principal mechanisms of hepatic involvement in the metabolism and disposition of capecitabine and paclitaxel are different. Paclitaxel is primarily metabolized by hepatic cytochrome P450 isoform CYP2C to 6-alpha-hydroxypaclitaxel, with hepatic cytochrome P450 isoform CYP3A accounting for a minor degree of drug disposition,27 whereas capecitabine is not metabolized by hepatic cytochrome P450–dependent processes (Hirose et al, unpublished results). In fact, capecitabine neither inhibits nor induces hepatic cytochrome P450 mixed function oxidases. The fact that there were no major antitumor responses noted in the present study must be tempered by the knowledge that 15 of the 17 subjects were previously shown to be clearly refractory to 5-FU, with progressive tumor growth occurring during prior treatment with 5-FU–based regimens, and that at least 13 of the 17 patients had malignant neoplasms that are considered innately resistant to the taxanes. Still, the experimental evidence that paclitaxel upregulates dThdPase in malignant cells in vitro is intriguing and provides a rationale for further evaluations of combination regimens consisting of paclitaxel and capecitabine.19 In addition to this specific molecular interaction, perhaps the most impressive cytotoxic interactions between the taxanes and other cytotoxic agents have been between the taxanes and 5-FU, which further supports the development of this drug combination.28,29 Although the specific capecitabine/paclitaxel regimen that was evaluated in the present trial was selected, in part, to achieve protracted exposure to 5-FU and maximal convenience for patients, other capecitabine/paclitaxel treatment schedules may increase the likelihood that favorable pharmacologic and molecular drug interactions between these agents will occur. For example, administering paclitaxel on a more frequent schedule, such as on a weekly low-dose schedule, may result in more protracted periods of dThdPase upregulation, as well as coexposure of tumors to both capecitabine and paclitaxel. Alternatively, the administration of higher doses of capecitabine has been shown to be more feasible on less protracted capecitabine daily dosing (eg, 14-day) schedules compared with continuous daily treatment schedules.15 Also, the use of shorter, albeit more intensive, capecitabine regimens may hypothetically provide maximal concentrations of the 5-DFUR substrate to dThdPase during periods when the enzyme is maximally upregulated after treatment with paclitaxel. The overall results of this study indicate that the administration of clinically relevant single-agent doses of both capecitabine and paclitaxel is feasible in patients with solid malignancies, and that there are no relevant pharmacologic interactions between capecitabine and paclitaxel that might complicate the further development and broad usage of the regimen. On the basis of the toxicologic profile of the capecitabine/paclitaxel regimen shown in the present study, paclitaxel 175 mg/m2 as a 3-hour IV infusion every 3 weeks administered in combination with capecitabine 1,331 mg/m2/d in two divided doses is recommended for disease-directed evaluations. From a mechanistic standpoint, further evaluations of capecitabine/paclitaxel regimens that are rationally designed to optimize favorable subcellular interactions are warranted.
Supported in part by a grant from Hoffmann-LaRoche, Inc, and grant no. MO1 RR01346 from the National Institutes of Health to the Frederic C. Bartter Clinical Research Unit of The Audie Murphy Veterans Administration Hospital. This article is dedicated to the memory of Maura Kraynak.
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Alberto P: Phase II study of an oral combination of doxifluridine, prednimustine and idarubicin (FUPRIDA) for first line treatment of advanced breast cancer. Ann Oncol 4:423-425, 1993 13. Ishikawa T, Utoh M, Sawada N, et al: Xeloda (capecitabine): An orally available tumor-selective fluoropyrimidine carbamate. Proc Am Soc Clin Oncol 16:208a, 1997 (abstr 727) 14. Schuller J, Cassidy J, Reigner B, et al: Tumor selectivity of Xeloda in colorectal cancer patients. Proc Am Soc Clin Oncol 16:227a, 1997 (abstr 797)
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Mackean M, Planting A, Twelves C, et al: A phase I and pharmacologic study of intermittent twice-daily oral therapy with capecitabine in patients with advanced and/or metastatic cancer. J Clin Oncol 16:2977-2985, 1998 16. Taguchi T, Ishitani, K, Saitoh K, et al: A Japanese phase I study of continuous twice daily treatment with capecitabine in patients with advanced and/or metastatic solid tumors. Ann Oncol 7:87, 1996 (suppl 1) (abstr 299) 17. Eda H, Fujimoto K, Watanabe S, et al: Cytokines induce thymidine phosphorylase expression in tumor cells and make them more susceptible to 5'-deoxy-5-fluorouridine. Cancer Chemother Pharmacol 32:333-338, 1993[Medline] 18. Eda H, Fujimoto K, Watanabe S, et al: Cytokines induce uridine phosphorylase in mouse colon 26 carcinoma cells and make the cells more susceptible to 5'-deoxy-5-fluorouridine. Jpn J Cancer Res 84:341-347, 1993[Medline] 19. Sawada N, Ishikawa T, Fukase Y, et al: Induction of thymidine phosphorylase activity and enhancement of capecitabine efficacy by Taxol/Taxotere in human cancer xenografts. Clin Cancer Res 4:1013-1019, 1998[Abstract] 20. Bogdan C, Ding A: Taxol, a microtubule stabilizing antineoplastic agent, induces expression of tumor necrosis factor alpha and interleukin-1 in macrophages. J Leuk Biol 52:119-121, 1992[Abstract]
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
), increases intratumoral dThdPase activity and enhances tumor sensitivity to 5'-DFUR in vitro and in vivo.
grade 1 after a 1-week treatment delay, the patient was withdrawn from study unless clinical benefit was documented, in which case a treatment delay of up to 2 additional weeks was permitted. For patients who experienced DLTs during the previous course, the paclitaxel dose was reduced to the next lower dose level or by 25% if DLTs occurred at the 135-mg/m2 dose level. 
), and from time 0 to the last sampling time at which the concentration could be measured (AUC0-t). The following pharmacokinetic parameters were also determined: maximum plasma concentration (Cmax), tmax, and apparent half-life of elimination (t1/2). For paclitaxel, total clearance (CLs) was estimated by dividing the dose (in milligrams) by AUC0-
), 5-DFCR (
), 5-DFUR (•) and 5-FU (x) as a function of capecitabine dose.
