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Pharmacobiologically Based Scheduling of Capecitabine and Docetaxel Results in Antitumor Activity in Resistant Human Malignancies

From the Department of Medicine, Ohio State University College of Medicine and Public Health, and The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH.

Address reprint requests to Miguel A. Villalona-Calero, MD, The Arthur G. James Cancer Hospital, Ohio State University, B406 Starling-Loving Hall, 320 West 10th Ave, Columbus, OH 43210-1240; email: villalona-1{at}medctr.osu.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: Capecitabine and docetaxel have demonstrated preclinical antitumor synergy. This synergy is thought to occur from docetaxel-mediated upregulation of thymidine phosphorylase (dThdPase), an enzyme responsible for the relative tumor selectivity of capecitabine. On the basis of the time-dependency and transiency for this upregulation, we performed a phase I study of capecitabine in combination with weekly docetaxel. We hypothesized that weekly docetaxel would result in sustained dThdPase expression and that capecitabine administration at times of maximum dThdPase upregulation would increase the therapeutic index for this combination.

PATIENTS AND METHODS: Patients with advanced solid malignancies received docetaxel on days 1, 8, and 15, and capecitabine bid on days 5 to 18, every 4 weeks. Docetaxel was fixed at 36 mg/m²/wk, whereas capecitabine was escalated in successive patients cohorts.

RESULTS: Sixteen patients received 77 courses at capecitabine doses from 950 to 1,500 mg/m²/d. The most common toxicities were hand-foot syndrome, diarrhea, nausea/vomiting, and asthenia. Grades 3 to 4 hematologic toxicities were infrequent and no treatment-related hospitalizations occurred. Three of three patients treated at 1,500/36 mg/m² capecitabine/docetaxel developed grade 3 hand-foot syndrome or diarrhea during either their first or second course, whereas only two of 13 patients at 1,250/36 mg/m² doses developed significant toxicity. Antitumor responses (n = 7) occurred in patients with hepatocellular, non–small-cell lung, and chemotherapy-refractory breast, bladder, and colorectal carcinomas. Prolonged stabilizations occurred in patients with metastatic mesothelioma (n = 2), chemorefractory non–small-cell lung carcinoma, and bronchioloalveolar carcinoma.

CONCLUSION: Capecitabine in combination with weekly docetaxel is well tolerated. Recommended doses are capecitabine 1,250 mg/m²/d (625 mg/m² bid) with docetaxel 36 mg/m²/wk. The acceptable toxicity profile in this dose schedule, and the antitumor activity observed, warrant further evaluation of this regimen.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
THE ORAL FLUOROPYRIMIDINE capecitabine undergoes conversion to its active metabolite fluorouracil (5-FU) through a three-step enzymatic metabolic process.¹ The final step of this process, the conversion of 5'-deoxy-5-fluorouridine (5'-DFUR) to 5-FU, requires thymidine phosphorylase (dThdPase), a potent tumor-associated angiogenesis factor. Higher expression of dThdPase in tumor tissue provides for preferential conversion of capecitabine in neoplastic tissues.²

Given the prominent role of dThdPase in the therapeutic index of capecitabine-based treatment, it follows that maximizing dThdPase activity would result in an enhanced therapeutic index. Treatment of malignant tumors with various cytokines, such as tumor necrosis factor alpha, interleukin-1, and interferon gamma has been observed to produce increases in intratumoral dThdPase activity and to enhance tumor sensitivity to 5'-DFUR in vitro and in vivo.^3,4 In addition, paclitaxel (100 mg/kg), docetaxel (15 mg/kg), and mitomycin C (5 mg/kg) have also been shown to increase the levels of human dThdPase in human colon cancer xenograft studies by 8-fold, 6.1-fold, and 7.7-fold, respectively.⁴ These cytotoxic agents are thought to upregulate dThdPase through increases in tumor necrosis factor alpha levels.⁴ After single-dose administration of paclitaxel or docetaxel, dThdPase begins to increase at days 4 to 6, and peaks on days 6 to 8. Significantly, capecitabine in combination with either docetaxel or paclitaxel resulted in synergistic inhibition of tumor growth in breast and colorectal cancer xenograft models, whereas combination of 5-FU with the taxanes only produced additive effects.⁴

In humans, studies evaluating the combination of paclitaxel and capecitabine demonstrated no pharmacokinetic interactions and prominent antitumor activity, supporting the preclinical observations.^5-7 Similarly, evaluations of capecitabine in combination with docetaxel administered every 3 weeks did not show pharmacokinetic interactions between these agents.⁸ Furthermore, a recent clinical study randomized 511 women with locally advanced or metastatic breast cancer resistant to or recurrent after anthracycline-containing therapy, to receive docetaxel (every 3 weeks) in combination with capecitabine, or to receive docetaxel alone.⁹ Antitumor response rate (42% v 30%) and time to disease progression (6.1 v 4.2 months) favored the combination regimen. More importantly, median survival is significantly longer with the combination regimen (14.5 v 11.5 months, P = .0126). Toxicity, however, was considerable, including palmar-plantar dysesthesias (hand-foot syndrome [HFS]) in 65% of patients (grade 3 in 24%), diarrhea in 68% of patients (moderate to severe in 14%), and grade 4 neutropenia in 44% (febrile neutropenia in 16%) of patients receiving the combination. Sixty-two percent of patients receiving the combination required reduction in the doses of either one (15%) or both (47%) medications at least once during their period of treatment.

Weekly administration of paclitaxel or docetaxel has recently attracted interest, because of a more favorable toxicity profile with preservation of antitumor activity. Severe neutropenia is rare on this schedule, whereas neurologic toxicity (paclitaxel) or asthenia (docetaxel) are the primary toxicities limiting dose escalation.^10-12 For docetaxel, recommended weekly doses range from 36 to 43 mg/m².¹¹

In view of the transient and time-dependent character of docetaxel-mediated upregulation of dThdPase, along with the favorable toxicity profile of weekly docetaxel, we performed this phase I trial of the combination of weekly docetaxel and twice-daily capecitabine. We hypothesized that the combination of weekly docetaxel and twice-daily capecitabine, through a more sustained upregulation of dThdPase, would increase the therapeutic index for the combination. Furthermore, given that upregulation in preclinical studies was not observed until day 4 (maximal at days 6 to 10), we hypothesized that starting capecitabine on day 5 when dThdPase activity is induced would ensure more efficient conversion of the target substrate (5'-DFUR) to 5-FU.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Eligibility
Patients with histologically confirmed solid malignancies refractory to conventional therapy or for whom no effective therapy existed were eligible for this study. Eligibility criteria also included the following: (1) age 18 years; (2) Eastern Cooperative Oncology Group performance status of 0 to 2 (ambulatory and capable of self-care); (3) a life expectancy 3 months; (4) no major surgery, radiotherapy, or chemotherapy within 28 days of study entry; (5) no prior docetaxel or capecitabine treatment within the preceding 6 months; (6) no gastrointestinal disorder that might affect the absorption of capecitabine; (7) adequate hematopoietic WBC count 3,000/µL, absolute neutrophil count (ANC) of 1,500/µL, platelet count 100,000/µL, and hemoglobin level of 9.0 g/dL; (8) hepatic (total serum bilirubin level < 1.5 times institutional upper normal limits [UNL], AST and ALT < 3 times UNL) and renal (serum creatinine < 1.5 times UNL or calculated creatinine clearance 60 mL/min) functions; (8) no brain metastases, unless the lesions had been previously irradiated, and were stable and asymptomatic; (9) absence of organ allografts or serious uncontrolled infections; (10) no known human immunodeficiency virus type 1 infection; (11) no known existing coagulopathy or requirement of therapeutic doses of coumarin-based anticoagulants; and (12) no history of severe reaction to fluoropyrimidine therapy. Patients gave written informed consent according to federal and institutional guidelines before treatment.

Dosage and Dose Escalation
The starting doses were docetaxel 36 mg/m² administered as a 30-minute intravenous infusion on days 1, 8, and 15, and capecitabine 1,250 mg/m²/d in two equally divided oral doses of 625 mg/m² bid for 14 days starting on days 5 through 18. The starting dose of docetaxel was one of the two recommended doses of docetaxel for weekly administration,¹¹ whereas the capecitabine dose was selected to be half of the recommended single-agent dose (2,500 mg/m²/d). Treatment was repeated every 4 weeks. The dose of docetaxel was to remain fixed throughout the study, unless reduced because of toxicity, whereas the dose of capecitabine was to be increased by increments of 250 mg/m²/d in each successive cohort of new patients. A minimum of three new patients were to be treated at all tolerable dose levels. Intrasubject dose escalation was not permitted. Toxicities were graded according to the National Cancer Institute common toxicity criteria version 2.0.¹³ DLT was defined as one of the following: (1) an ANC less than 500/µL for more than 5 days, or associated with fever (temperature 38.5°C); (2) a platelet count less than 25,000/µL; (3) severe ( grade 3) nonhematologic toxicity (including diarrhea, nausea, and vomiting) that resulted in interruption of capecitabine for more than 3 days, or delay in the dose of weekly docetaxel for more than a week; and (4) clinical inability (because of toxicity) to start the next cycle of treatment within 2 weeks of the planned start date. The maximum-tolerated dose level was defined as the highest capecitabine dose level, which when combined with docetaxel 36 mg/m² as a 30-minute infusion on days 1, 8, and 15 every 4 weeks, resulted in dose-limiting toxicity (DLT) in less than two of six new patients, during both their first and second cycles of treatment.

Drug Administration
Capecitabine (Xeloda) was supplied by Hoffman-La Roche, Inc (Nutley, NJ). The total dose of capecitabine was calculated according to body-surface area and rounded off to the closest practical dose on the basis of a combination of 500- and 150-mg tablets. Capecitabine was to be taken every 12 ± 2 hours. Docetaxel (Taxotere; Aventis Pharmaceuticals, Bridgewater, NJ) was obtained from the hospital pharmacy in 15-mL clear glass vials and prepared according to the manufacturer’s directions in either 100 mL 0.9% sodium chloride solution or 5% dextrose and administered over 30 minutes using an infusion pump. Oral dexamethasone 8 mg was administered 12 hours before docetaxel, immediately before docetaxel, and 12 hours after docetaxel.

Dosage Modifications
A new course of treatment was to begin only when the granulocyte count was 1,500/mm³ and the platelet count was 100,000/mm³ and any other treatment-related toxicities were grade 1; otherwise, treatment was withheld for up to 1 week. If the toxicity had not resolved to grade 0 to 1 at the end of this period, the patient was withdrawn from study unless clinical benefit had been documented, in which case a treatment delay of up to 1 additional week to allow recovery was permitted.

Planned treatment with capecitabine within a cycle of therapy was withheld in the presence of grade 2 nonhematologic (except isolated hyperbilirubinemia or alopecia) or grade 3 hematologic toxicity. Treatment was resumed when hematologic or nonhematologic toxicity (except HFS) resolved to grade 0 to 2. In such cases, capecitabine was resumed at either the original dose level for grade 2 nonhematologic toxicity and grade 3 hematologic, or at the next lower dose level (25% reduction, if toxicity occurred at the first dose level) for grade 3 nonhematologic or grade 4 hematologic toxicity. For grade 2 to 3 HFS, capecitabine treatment was withheld until resolution to grade 1 and then restarted at the same dose (for grade 2 HFS) or at the preceding dose level (for grade 3 HFS). Capecitabine treatment was not interrupted for isolated hyperbilirubinemia.

Docetaxel treatment within a cycle was withheld for the presence of any grade 2 hyperbilirubinemia, or any other grade 3 toxicity during the scheduled day of docetaxel administration and the patient was re-evaluated weekly until resolution to grade 2. Missed doses of docetaxel were not to be made up. Treatment was restarted at the same dose for grade 3 toxicity, except hepatic, and reduced by 25% for grade 4 toxicity. Because of safety concerns, prompted by known alterations of docetaxel pharmacodynamics during elevations in hepatic functions tests,¹⁴ the docetaxel dose was reduced by 25% after recovery for grade 2 bilirubin elevations or for grade 3 elevations in alkaline phosphatase or AST (5.1 to 20 times UNL). Docetaxel was not withheld, but was reduced by 25% for concurrent grade 2 elevations of alkaline phosphatase (2.5 to 5 times ULN) and AST (1.6 to 5 times ULN) in the presence of normal bilirubin levels. For treatment during subsequent courses, docetaxel was reduced (25%) on the basis of the development of dose-limiting myelosuppression, or any grade 3 nonhematologic toxicity (except HFS and nausea/vomiting) during the previous course of treatment, whereas the capecitabine dose was not reduced for hematologic toxicity, but was reduced for grade 4 nausea/vomiting and any grade 3 nonhematologic toxicity, including HFS.

Pretreatment Assessment and Follow-Up Studies
Histories, physical examinations, and routine laboratory studies were performed before treatment and weekly. Routine laboratory studies included serum electrolytes, chemistries, complete blood cell counts with differential WBC counts, blood clotting times, and urinalysis. If patients developed toxicity manifested by grade 3 to 4 abnormalities in hematologic or biochemical laboratory parameters, the tests were repeated immediately and then daily until the toxicity resolved. Tumors were measured after every other course, and treatment was continued in the absence of progressive disease or intolerable toxicity. A complete response was defined as the disappearance of all disease on two measurements separated by a minimum of 4 weeks. A partial response required more than 50% reduction in the sum of the products of the bidimensional measurements of all measurable lesions documented by two measurements separated by at least 4 weeks, and progressive disease required an increase in 25% in the sum of the products of the bidimensional measurements of all measurable lesions or the appearance of new lesions.

	RESULTS

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General
The number of new and total patients, courses, and rates of DLTs are listed in Table 1. Sixteen assessable patients received 77 courses of docetaxel and capecitabine. Patient characteristics are listed in Table 2. Eleven patients had received prior chemotherapy, including eight who had received three or more chemotherapy regimens. The starting dose of capecitabine was 1,250 mg/m²/d in two divided doses of 625 mg/m². At this dose, only one of the first six patients developed DLT (grade 3 HFS during a second course) during either cycle 1 or 2; therefore, the dose of capecitabine was escalated to 1,500 mg/m²/d. At this higher dose, all three patients treated developed DLT during either the first (grade 3 diarrhea, one patient) or second course (HFS, two patients) of treatment. In order to better assess the true toxicity of the 1,250/36 mg/m² capecitabine/docetaxel dose, this dose level was expanded. Only one of seven additional patients treated at this dose developed DLT (grade 3 nausea and vomiting in the first cycle). Overall, only two of 12 patients receiving at least two courses (one patient received only one course) of docetaxel and capecitabine at the 1,250/36 mg/m² of capecitabine/docetaxel dose developed DLT. Therefore, this dose is recommended for efficacy trials of the combination on the schedule used in this study.

Hematologic Toxicity
Table 3 lists the number of courses associated with neutropenia, anemia, thrombocytopenia, and febrile neutropenia. Overall, moderate to severe hematologic toxicity was infrequent. Grade 3 neutropenia occurred in three patients (six courses) and grade 4 neutropenia in only one patient (one course). No febrile neutropenic episodes and no grade 3 or 4 anemia or thrombocytopenia occurred. The range of time to ANC nadir for patients experiencing grade 3 or 4 neutropenia was broad, occurring during days 8 to 29; only eight doses (3%) of docetaxel were missed because of neutropenia.

Nine patients (23 courses) developed diarrhea, which was typically of mild severity and duration. Five patients developed grade 2 diarrhea during 11 courses and one individual had one episode of grade 3 diarrhea. All episodes of diarrhea were successfully managed with brief courses of either loperamide or diphenoxylate hydrochloride. Other toxicities observed included grade 2 to 3 nausea/vomiting in three patients, pleural effusions in three patients, epiphora (excessive tearing) in six patients, and nail atrophy in seven patients. No moderate to severe elevations in bilirubin or other liver function tests were observed.

Antitumor Activity
Relevant details pertaining to the antitumor effects of the combination of docetaxel and capecitabine in all patients who participated in the study are listed in Table 4. Seven patients experienced discernible antitumor activity. These include six patients who met the definition of partial response as prospectively defined in this trial. One additional patient (a previously treated metastatic bladder cancer) had a 51% decrease in tumoral lesions after two courses of therapy, which was not maintained in a subsequent radiologic examination performed after four courses of therapy (unconfirmed response). The partial responses included partial remissions in two each of the following: previously treated metastatic breast cancer and colorectal cancer patients and individual patients with previously untreated metastatic non–small-cell lung cancer, and hepatocellular carcinoma. The latter, who had developed additional hepatic lesions and intra-abdominal extrahepatic metastatic disease after chemoembolization treatment, experienced a partial response lasting 9 months (time to tumor progression, 11 months). The median time to tumor progression among the six patients with confirmed responses was 8.8 months (range, 4.3 to 13 months). In addition, four patients experienced prolonged disease stabilization, which lasted an average of 8.5 months (range, 7.8 to 10 months). These include two patients with unresectable or metastatic mesothelioma, a chemotherapy-refractory non–small-cell lung cancer patient, and a previously untreated patient with multilobar bronchioloalveolar carcinoma.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

On the basis of this preclinical rationale, the overlapping and broad clinical antitumor spectra of capecitabine and docetaxel, and the hypothesis that weekly administration of docetaxel would enhance the therapeutic index of the combination, we performed this phase I study of capecitabine and weekly docetaxel. Capecitabine was administered daily for 14 days at the preclinically observed times of maximal upregulation of dThdPase (days 5 to 18), in order to further improve availability of the substrate for conversion into 5-FU. The results of this study showed that the combination is feasible, that myelosuppression is infrequent, and that the HFS syndrome is the primary toxicity limiting dose escalation. Recommended doses for the combination are docetaxel 36 mg/m² weekly x 3, every 4 weeks, and capecitabine 1,250 mg/m²/d (625 mg/m² bid) on days 5 to 18 of every course. The requirements of this study of tolerability during at least two cycles, and the absence of treatment-related hospitalizations throughout the study, considerably strengthen this recommendation.

Although the plan for dose modifications in this trial was designed for all hypothetical situations, the main relevance for clinical practice is the withholding of capecitabine in the presence of grade 2 to 3 HFS until this toxicity is grade 1 or less. No dose reduction appears necessary for grade 2 toxicity, whereas a 25% reduction after grade 3 toxicity may be warranted. Given the lack of evidence to suggest that capecitabine antitumor activity is compromised by dose reduction, and the excellent tolerability observed on this study, we recommend following this approach in the clinical setting. In addition, it is important to caution that eligibility for this trial was restricted to patients with none to mild elevations in bilirubin and hepatic transaminases (total serum bilirubin level < 1.5 UNL, AST and ALT < 3 times UNL). At this juncture, the toxicity profile and recommended phase II dose are applicable only to patients with characteristics similar to those of the patients evaluated in the present study. Additional evaluations are required to determine whether such recommendations can be generalized to patients with hepatic excretory dysfunction and/or more profound elevations in hepatic transaminases attributable to metastases.

Antitumor activity was observed in a variety of either previously untreated or chemotherapy-refractory solid malignancies, which include breast, colorectal, non–small-cell lung, hepatocellular, and urinary bladder carcinoma. It is interesting to note that although single-agent capecitabine did not produce major responses in pretreated colorectal cancer patients in a recent study¹⁵ and single-agent docetaxel has not shown significant antitumor activity in this malignancy,^16,17 the combination of capecitabine with docetaxel in this study resulted in major responses (partial response) in the two colorectal cancer patients who had been previously treated with either multiple chemotherapeutic or chemoembolization and biologic agents.

The concept of modulation of fluoropyrimidines to enhance their antitumor action is not new. Because of the complex enzymatic interactions and multiple molecular effects associated with cytotoxicity for the prototype fluoropyrimidine 5-FU, several attempts to modulate this agent have been made. These include increasing the concentrations of reduced folates to enhance 5-FU–mediated inactivation of thymidylate synthase; inhibition of natural uridine nucleotides that compete with incorporation of 5-FU metabolites into RNA and DNA; and, more recently, inhibition of enzymes associated with 5-FU catabolism.^18-24 Although results of early clinical trials appeared encouraging, more recent trials have failed to demonstrate antitumor advantages for these approaches.^25-27

In vitro studies have cautioned against combining antimitotic agents with G₁-S–arresting agents, because 5-FU was observed in these studies to interfere with the cell-killing activity of paclitaxel by preventing the tumor cells from entering the G₂-M phase of the cell cycle.^28,29 Fortunately, in vivo studies of 5-FU in combination with paclitaxel and docetaxel have shown at least additive antitumor activity, whereas capecitabine in combination has synergistic activity.⁴ The preferential expression of dThdPase in tumor tissue provides a mechanism for the enhanced therapeutic index of capecitabine compared with 5-FU. In fact, after capecitabine administration to colorectal cancer patients, the concentration of 5-FU in primary colorectal tumors was found to be on average 3.2 times higher than in adjacent healthy tissue.³⁰ Therefore, dThdPase portends an excellent target for the modulation of the antitumor action of capecitabine. Although induction of dThdPase after exposure to docetaxel has been documented in preclinical and clinical studies,^4,31 and enhanced clinical antitumor activity for the combination has been recently reported in breast cancer patients,⁹ it is not entirely clear whether the increased activity is related to dThdPase induction, or another not yet characterized mechanism.

The enhanced antitumor action of capecitabine in combination with docetaxel does not appear to be entirely dependent on the enhancement of dThdPase activity, as illustrated by a recent study in human cancer xenograft models evaluating different schedules for the combination of docetaxel and capecitabine.³² The combination was evaluated in the docetaxel-sensitive MX-1 and MAXF401 human mammary, A755 murine mammary, and the less-docetaxel-sensitive WiDr human colon xenograft. Synergy was demonstrated in all xenografts. However, in the breast tumor models, docetaxel administered on day 8 in combination with capecitabine daily for 14 days (days 1 to 14) every 3 weeks had higher antitumor activity than when administered on days 1 or 15. In contrast, in the colon cancer xenograft, docetaxel administered on day 1 demonstrated higher antitumor activity as compared with other days of administration.

The results obtained in the breast models are counterintuitive, because in vitro studies suggest that a substantial fraction of cells will be arrested in the G₁-S phase after 7 days of capecitabine treatment, thereby decreasing the fraction of cells entering the G₂-M phase, susceptible to docetaxel. In addition, if the enhanced antitumor effect would depend on dThdPase upregulation, the day-1 docetaxel/capecitabine combination would be expected to be more effective than the day-8 combination, because dThdPase upregulation reaches a peak at 6 days after docetaxel administration in human cancer xenograft studies.⁴ In fact, no significant dThdPase upregulation was seen in the MAXF401 and A755 models, and only slight upregulation (1.9-fold) in the MX-1 models was observed, whereas significant upregulation (4.8-fold) was observed on WiDr, the only model in which the day-1 combination was superior.³²

In our study, docetaxel was administered on days 1, 8, and 15, in combination with capecitabine from days 5 to 18. Docetaxel was administered at recommended doses for the weekly administration schedule (36 mg/m²), whereas capecitabine doses were substantially lower (625 mg/m² bid) than recommended when used as a single agent (1,250 mg/m² bid). In view of the above preclinical data and the antitumor activity observed in our clinical study, it could be speculated that for certain tumors or individuals, modulation of docetaxel by capecitabine may be more important than capecitabine modulation by docetaxel. Tumor-specific comparisons of the schedule evaluated in this study versus a schedule featuring maximum doses of capecitabine and suboptimal doses of docetaxel may help clarify this issue. Intratumoral evaluation of dThdPase and markers of apoptosis associated with docetaxel action would be essential components of such evaluation.

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Submitted November 5, 2001; accepted March 8, 2002.

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