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Journal of Clinical Oncology, Vol 23, No 6 (February 20), 2005: pp. 1070-1077
© 2005 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2005.03.082
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Prospective Evaluation of the Pharmacokinetics and Toxicity Profile of Docetaxel in the Elderly

Albert J. ten Tije, Jaap Verweij, Michael A. Carducci, Wilfried Graveland, Theresa Rogers, Tatjana Pronk, M.P. Verbruggen, Fitzroy Dawkins, Sharyn D. Baker

From the Erasmus University Medical Center, Rotterdam, the Netherlands; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; and Howard University Cancer Center, Washington, DC

Address reprint requests to Sharyn D. Baker, PharmD, PhD, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Bunting-Blaustein Cancer Research Building, 1650 Orleans St, Room 1M87, Baltimore, MD 21231-1000; e-mail: sdbaker{at}jhmi.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
PURPOSE: To prospectively study the pharmacokinetics and toxicity profile of docetaxel in elderly patients with cancer.

PATIENTS AND METHODS: Docetaxel was administered at a dose 75 mg/m2 once every 3 weeks to 25 elderly cancer patients aged ≥ 65 years and 26 cancer patients aged younger than 65 years. Pharmacokinetic studies and toxicity assessments were performed during the first cycle of therapy.

RESULTS: Of 51 patients treated, 20 aged ≥ 65 years (median, 71 years; range, 65 to 80 years) and 20 aged younger than 65 years (median, 53 years; range, 26 to 64 years) were assessable for pharmacokinetic studies, and 39 were assessable for toxicity. Patient characteristics were similar (P ≥ .15) between the two cohorts. Mean docetaxel clearance was not altered in the elderly versus younger patients: 30.1 L/h (standard deviation [SD] 18.3 L/h) v 30.0 L/h (SD, 14.8 L/h; P = .98). The percentage of patients with grade 4 and febrile neutropenia was higher in the elderly (63% and 16%, respectively) versus younger (30% and 0%, respectively) cohort, although this observation did not reach a level of statistical significance (P = .056). From logistic regression analysis, the odds ratio for a patient aged 65 years was 1.98 for developing grade 4 neutropenia compared with a patient aged 50 years (P = .091).

CONCLUSION: Docetaxel plasma pharmacokinetics are unaltered in elderly patients. Patients aged ≥ 65 years appear to be more sensitive to docetaxel-induced neutropenia.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
Docetaxel is a semisynthetic taxane derived from an extract of the needles of the European yew tree (Taxus baccata), and acts by disrupting the microtubule network.1 The drug has significant antitumor activity against numerous tumors and is approved for treatment of locally advanced or metastatic breast, non–small-cell lung cancers, and androgen-independent prostate cancer. In patients with advanced breast cancer receiving docetaxel 100 mg/m2 as a 1-hour infusion every 3 weeks (3-week regimen), grade 4 and febrile neutropenia occur in 84% and 11.8% of patients, respectively (see http://www.taxotere.com/); in patients with non–small-cell lung cancer receiving 75 mg/m2, grade 3 to 4 and febrile neutropenia occur in 65% and 6.3% of patients, respectively. Other adverse effects include alopecia, asthenia, dermatologic reactions, fluid retention, hypersensitivity reactions, and stomatitis. Drug exposure-toxicity relationships have been studied extensively for docetaxel monotherapy administered in the 3-week regimen and indicate that the area under the curve (AUC) of total plasma concentrations during the first cycle of treatment is related to incidence of grade 4 neutropenia and febrile neutropenia.2

As the population in Western countries ages and life expectancy increases,3 there is an increasing number of cancer patients 65 years of age or older that might benefit from chemotherapeutic treatment. There is often hesitation to treat elderly patients with chemotherapy, in part because the older patient is more susceptible to therapy-related toxicity.4-6 However, studies have demonstrated that elderly patients with good performance status and lacking comorbidities are not at increased risk for treatment-related toxicities.4,7 Studies also indicate that undertreatment is associated with inferior outcome in older patients.8-10 Little is known about the clinical pharmacokinetics and pharmacodynamics of anticancer agents, including docetaxel, and their relation to drug tolerance and outcome in the elderly.4-6 Docetaxel administered in weekly schedules at lower doses has been found to be both efficacious and generally well tolerated in elderly patients,11-13 and a study evaluating the population pharmacokinetics of weekly docetaxel showed no effect of age on drug clearance.14 There is general reluctance to administer docetaxel in the 3-week regimen to elderly patients because of the prevalence of neutropenia with docetaxel therapy,15 although this has not been adequately evaluated in a clinical trial.

The objective of this study was to characterize prospectively the pharmacokinetic and toxicity profile of docetaxel during one cycle of treatment when administered at a dose of 75 mg/m2 once every 3 weeks to a cohort of patients aged younger than 65 years and ≥ 65 years.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
Study Design
Two groups of patients were studied on the basis of age. The control group consisted of patients aged 18 to 64 years, and the elderly group consisted of patients aged ≥ 65 years. The elderly group (group 2) was one treatment arm of a larger ongoing clinical trial designed to address prospectively several objectives investigating the effects of race or ethnicity, elderly age, and varying degrees of liver impairment on docetaxel pharmacokinetics.16 Group 1A consists of 45 black and group 1C consists of 45 white (European and European American) patients aged younger than 65 years and with normal liver function as defined in Patient Eligibility. Group 3A consists of 20 patients with liver dysfunction, defined as total bilirubin less than 1.5 x the institutional upper limit of normal (ULN) and elevations in AST and/or ALT ≥ 1.5 x ULN concurrent with alkaline phosphatase ≥ 2.5 x ULN. Group 3B consists of 10 patients with liver impairment defined as total bilirubin ≥ 1.5 x ULN with any elevations in liver AST and/or ALT or alkaline phosphatase. Groups 2, 3A, and 3B are not stratified for race or ethnicity. The control group (aged < 65 years) consisted of consecutive patients enrolled onto group 1A or 1C until 20 patients younger than 65 years were assessable for pharmacokinetic studies. Likewise, patients aged ≥ 65 years were consecutively enrolled onto group 2 until 20 patients were assessable for pharmacokinetic studies.

Patient Eligibility
Patients were eligible when they had histologically or cytologically confirmed solid tumor malignancies for which docetaxel was a viable treatment option. Other criteria for patient enrollment were age ≥ 18 years; performance score less than 3 according to the Eastern Cooperative Oncology Group criteria; adequate bone marrow function as defined by pretherapy values of hemoglobin ≥ 8.0 g/dL, absolute neutrophil count (ANC) ≥ 1,500/µL, and platelet count ≥ 100,000/µL; creatinine ≤ 2.0 x ULN; total bilirubin less than 1.5 x ULN; if alkaline phosphatase was less than 2.5 x ULN, any elevations in AST and/or ALT; or if AST and/or ALT were less than 1.5 x ULN, any elevation in alkaline phosphatase (patients with ALT and/or AST ≥ 1.5 x ULN with concomitant alkaline phosphate ≥ 2.5 x ULN were not eligible for treatment); peripheral neuropathy ≤ grade 1 and no symptomatic brain metastasis; no previous treatment with docetaxel; and no concomitant use of phenytoin, carbamazepine, barbiturates, rifampicin, phenobarbital, St. John's wort, or ketoconazole. All concomitant drugs and the use of herbal medicines were recorded. The clinical protocols were approved by the local institutional review boards (Baltimore, MD; Rotterdam, the Netherlands; and Washington, DC), and all patients provided written informed consent before enrollment. Before treatment, a complete registration form was received by the coordinating center (Baltimore, MD), and a study number was assigned. Patients who did not have complete pharmacokinetic studies during cycle 1 were replaced.

Drug Treatment
The clinical docetaxel preparation (Taxotere; Aventis Pharmaceuticals, Bridgewater, NJ) containing 20 or 80 mg of the drug formulated in 0.5 and 2.0 mL of polysorbate 80, respectively, was diluted with a solution of 13% ethanol in water to a 10 mg docetaxel/mL concentration. This solution was diluted further in a 250-mL infusion bag or bottle of either 0.9% sodium chloride solution or 5% dextrose solution to produce a final concentration of 0.30 to 0.74 mg/mL. Individual drug doses were normalized to body-surface area and administered intravenously during 1 hour at a dose of 75 mg/m2 every 3 weeks in both treatment groups. Dexamethasone, 8 mg orally every 12 hours for five doses (3 days), was administered starting 24 hours before drug treatment. Patients did not routinely receive antiemetic prophylaxis. After one cycle of therapy, treatment continued at the discretion of the treating physician until tumor progression, development of unacceptable toxicity, or patient withdrawal.

Patient Evaluation
The extent of prior treatment was assessed using two conditions. The first condition was the number of prior treatment regimens. For the second condition, patients were considered heavily pretreated if they received ≥ two cycles of mitomycin, ≥ four cycles of carboplatin, ≥ six cycles with cisplatin or an alkylating cytostatic drug, as previously described.17 Pretreatment evaluations included assessment of performance score, height, weight, toxicity assessment, a CBC with differential, and the following serum chemistries: creatinine, alkaline phosphatase, AST, ALT, total bilirubin, alpha1-acid glycoprotein, and albumin.

Toxicity assessment and a CBC with differential were performed weekly for a total of 3 weeks (one cycle). Toxicity assessments were performed according the National Cancer Institute Common Toxicity Criteria version 2.0. Management of toxicity was at the discretion of the treating physician per institutional guidelines.

Pharmacokinetic Sampling and Assay
Blood samples were collected for docetaxel pharmacokinetic studies during the first cycle of treatment at the following time points: pretreatment; 30 minutes during the infusion; 59 minutes (immediately before the end of the infusion); and postinfusion at 10 and 30 minutes, 1, 3, 7, 24, and 48 hours, and on day 8. Samples were collected in a 10-mL heparinized tube and placed on ice until additional processing within 30 minutes of collection. Plasma was isolated by centrifugation at 4°C, at 1,000 x g for 10 minutes and frozen at or below –20°C until the time of analysis.

Docetaxel was quantitated in plasma over the range of 0.50 to 100 nmol/L using a validated liquid chromatographic method with tandem mass-spectrometric detection, as previously described.18 The bias and precision of quality control samples, which included docetaxel concentrations of 2.0, 20.0, and 80.0 nmol/L, and an 80-nM quality control that was diluted 100-fold before processing, were less than 15%. At the assay lower limit of quantitation of 0.50 nmol/L (approximately 400 pg/mL), bias and precision were less than 20%.

Individual docetaxel pharmacokinetic parameters were estimated using model-dependent methods as implemented in Adapt II release 4 (Biomedical Simulations Resource, Los Angeles, CA).19 Concentration-time data were fit with a three-compartment model using weighted least squares as the estimation procedure, and inverse variance of the output error (linear) as the weighting option. Calculated secondary pharmacokinetic parameters included half-life during the terminal phase of the disposition curve (t1/2,{lambda}z) and systemic clearance (CL). The AUC was calculated as dose divided by CL. Maximum plasma concentration (Cmax) values were the observed values.

Statistical Analysis
Group sample sizes of 20 in both age groups (< 65 and ≥ 65 years) were calculated using a two-sample comparison of means analysis. Considering a mean CL of 30 L/h, a change in CL by 15 L/h (50%) with a standard deviation (SD) of 16 L/h (coefficient of variation, 53%) could be detected with a power of 84% and a significance level ({alpha}) of .05. Sample size calculations were performed using STATA version 8.2 (STATA Corp, College Station, TX).

Docetaxel pharmacokinetic parameters were summarized as the mean, SD, and range. Interpatient variation in drug CL and exposure was described as fold difference, determined from the ratio of the observed maximum and minimum values within the stated group. For continuous variables, nonparametric tests were used to compare mean values between the two age groups. When three or more groups were compared, a trend test was used.20 Categoric variables were compared using two-tailed Fisher's exact test for 2 x 2 tables. When the percentage of patients with grade 4 neutropenia in each age group was compared, CIs were determined. Linear regression analysis was used to determine the CL association between age (continuous variable) and docetaxel. Logistic regression was used to determine the association between age (continuous variable) and worst grade of neutropenia (grades 0 to 3 v 4).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
Between August 2002 and September 2003, 51 patients (26 were aged < 65 and 25 were ≥ 65 years) were enrolled onto this study. Of these patients, 40 (20 in each age group) were assessable for pharmacokinetic studies. Patients were not assessable for pharmacokinetic studies for the following reasons: severe hypersensitivity reaction with discontinuation of drug treatment (one patient); inability to perform pharmacokinetic studies because of poor venous access (two patients); plasma samples became thawed during shipment for analytic analysis (seven patients); and erroneous administration of a lower docetaxel dose of 50 mg/m2 (one patient). Patient characteristics for the 40 assessable patients are listed in Table 1. Body-surface area, liver function, performance status, and prior treatment were similar between the two cohorts (P ≥ .15), although pretreatment serum alpha1-acid glycoprotein concentrations were 20% lower in the elderly (mean, 126 [≥ 65 years] v 159 mg/dL [< 65 years]; P = .04).


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  		Table 1. Patient Demographics and Characteristics

 
Plasma Pharmacokinetics
Docetaxel pharmacokinetic parameters were similar in the elderly and younger patient cohorts (P ≥ .15; Table 2). Mean docetaxel CL was 30.1 L/h (SD, 18.3 L/h) in patients aged ≥ 65 years and 30.0 L/h (SD, 14.8 L/h) in patients younger than 65 years (P = .98). No correlation was observed between age and docetaxel CL (R2 = 0.0032; P = .9126; Fig 1A); likewise, age was not correlated with AUC (R2 = 0.0008; P = .8618). Interpatient variability in CL was larger in the elderly (9.6-fold) versus the younger patients (5.0-fold; Fig 1B). One patient aged 70 years had the highest CL of 91.6 L/h. This patient was not taking concurrent medications known to induce cytochrome P450 3A (CYP3A), and the use of herbal preparations with CYP3A-inducing properties was not disclosed by the patient after questioning. Removal of this outlier clearance value (> 3 SDs) from the elderly group resulted in a mean CL of 27 L/h (range, 9.5 to 48.3 L/h) and interpatient variation (5.1-fold) similar to that of the younger patients. It is possible that the patient with an outlier CL value was in the elderly group by chance, and hence, there appears to be no age-related interpatient variation in docetaxel CL.


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  		Table 2. Docetaxel Pharmacokinetic Parameters

 


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  		Fig 1. Docetaxel clearance as a function of age as a continuous variable (A) and age group (B). (——), mean values.

 
Toxicity
Twenty patients aged younger than 65 years and 19 patients aged ≥ 65 years, respectively, were assessable for hematologic toxicity. The incidence of grade 3 and 4 neutropenia and febrile neutropenia, the ANC nadir, and percentage decrements in ANC are summarized in Table 3. The ANC nadir occurred on day 8 in 85% and 80% of patients in the younger and elderly groups, respectively, and no patient had grade 4 neutropenia for more than 7 days without the administration of growth factors. Grade 4 neutropenia occurred more frequently in the elderly compared with younger patients (63% [95% CI, 38% to 84%] v 30% [95% CI, 12% to 54%]), but the difference was not statistically significant (P = .056). The association of age and grade of neutropenia was also assessed using logistic regression analysis, for which the relationship was positive. The odds ratio for a patient aged 65 years is 1.98 for developing grade 4 neutropenia compared with a patient of 50 years (P = .091). Although the sample size was not calculated to detect statistical differences in docetaxel-mediated neutropenia between the two groups, the possibility of a clinically relevant difference cannot be excluded fully. Three elderly patients developed febrile neutropenia. One patient had metastatic pancreatic cancer with a performance status of 2, and her disease progressed rapidly 3 weeks after docetaxel treatment at cycle 1. One patient had metastatic prostate cancer and had received prior treatment with bicalutamide, and one patient had adenocarcinoma of unknown primary without any prior chemotherapy. All three patients were treated with broad-spectrum antibiotic therapy without administration of growth factors, and ANC values returned to pretreatment values on day 15.


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  		Table 3. Hematologic Toxicity

 
The association between docetaxel AUC and neutropenia was assessed (Fig 2). Patients with grade 4 neutropenia did not have significantly higher AUC values (mean, 6.39 µg/mL · h) than patients with grade 0 to 3 neutropenia (mean AUC, 5.6 µg/mL · h; P = .2309; Fig 2A). However, of 10 patients with AUC values in the upper quartile, six were elderly and three of these patients (50%) experienced febrile neutropenia versus none of the four patients (0%) aged younger than 65 years. Percentage decrements in ANC were greater in those patients with AUC values in the upper quartile (mean decrement, 93%) compared with those with AUC values in the interquartile range (mean, 77%) or lower quartile (mean, 85%; P = .0390 for trend; Fig 2B).



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  		Fig 2. Worst grade of neutropenia (A) and percentage decrease in absolute neutrophil count (ANC; B) as a function of docetaxel area under the time-concentration curve (AUC). ({diamond}) Patients aged younger than 65 years; ({square}) patients aged ≥ 65 years; solid symbols are patients who developed febrile neutropenia; ( · · · ) the 25% quantile; (– – – –) the 75% quantile.

 
Nineteen patients in both age groups were assessable for nonhematologic toxicity. Nonhematologic toxicities that were monitored are listed in Table 4. The most frequent toxicities occurring in more than 20% of patients were grade 1 or 2 alopecia, asthenia, nausea, oral mucositis, cutaneous toxicity, and neuropathy. The frequency of nonhematologic toxicities appeared similar between the two age groups, although the small number of patients and low incidence precluded statistical evaluation.


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  		Table 4. Maximum Grade of Nonhematologic Toxicity

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
Authors' Disclosures of...
 REFERENCES
 
Despite the widespread clinical use of docetaxel, only few data are available on the effect of aging on the pharmacokinetic and pharmacodynamic behavior of this drug. Recent investigations have emphasized the disappointingly low participation of elderly patients in cancer treatment trials and the barriers associated with patient accrual.3 Several of the factors identified include the lack of information on age-related changes in organ function and on the pharmacokinetics and pharmacodynamics of anticancer agents. Indeed, although some studies have examined the efficacy and feasibility of chemotherapy in elderly patients, including several studies with weekly docetaxel in breast and non–small-cell lung cancers,11-13 little is known about the pharmacokinetic behavior of the anticancer agents under evaluation. A few exceptions include studies that evaluated the pharmacokinetics of anthracyclines, cisplatin, ifosfamide, methotrexate, and paclitaxel in elderly patients, although most of these studies provide data for a limited number of patients (< 10 patients aged older than 65 years) and did not include a comparative cohort of younger patients.4,21 In an attempt to fill this gap of knowledge, we prospectively evaluated the pharmacokinetics and toxicity profile of docetaxel administered at a dose of 75 mg/m2 once every 3 weeks in elderly cancer patients in comparison with younger patients. Overall, the results indicate that there is no statistically significant change in the pharmacokinetics of docetaxel between the two studied age groups. A clinically relevant 50% decrease in docetaxel CL, which has been associated with a 3.0 increase in the odds of developing febrile neutropenia,2 was not observed in elderly patients compared with the younger patients, which was based on a sample size calculation with 84% power to detect a 50% change in CL between the two cohorts. It is important to consider that a 27% decrease in docetaxel CL has been associated with a 1.5 increase in the odds of developing febrile neutropenia,2 and thus the sample size studied in the present study was not adequate to detect what is considered the smallest clinically significant change in docetaxel CL. With regard to the incidence of myelosuppression between the two groups, although not statistically significant, a clinically relevant increase in grade 4 neutropenia was observed in the elderly cohort versus the younger cohort.

The influence of age on the expression and activity of drug-metabolizing enzymes remains controversial, with reports describing either a decline in activity or no change in activity in elderly patients.22-24 In the current study, docetaxel CL and the associated interpatient variability (approximately five-fold) were found to be similar in both treatment groups. Prior in vitro studies have suggested an age-related decline in CYP3A activity, the enzyme that is responsible for docetaxel metabolism.25 However, our results showing no change in docetaxel CL in younger and older patients are consistent with in vivo studies applying the erythromycin breath test as a phenotyping probe of CYP3A-mediated drug clearance, for which no decrease in CYP3A activity was observed as a function of age.22,24

The current pharmacokinetic findings with docetaxel are in contrast with recent data obtained for the related drug, paclitaxel, for which drug CL was found to be inversely correlated with patient age. In addition, exposure to the pharmacologically active fraction of unbound paclitaxel was approximately 25% increased in the elderly compared with younger patients.21 The mechanisms underlying the discrepant findings observed with paclitaxel and docetaxel are not clear, but may involve age-dependent differences in elimination pathways involved with each agent as well as a differential influence of pharmacokinetic interference by their respective formulation vehicles (eg, polysorbate 80 v Cremophor EL [BASF, Ludwigshafen, Germany]). Regardless, these discrepant findings further emphasize the importance of conducting appropriately designed prospective clinical trials to recognize potential alterations in the pharmacokinetic profile of anticancer drugs with advancing age.

After administration of docetaxel monotherapy at a dose of 75 mg/m2 once every 3 weeks, the incidence of grade 4 neutropenia was higher in patients aged ≥ 65 years (63%) compared with those younger than 65 years (30%). The increased incidence of neutropenia in the elderly should be interpreted with caution, given that the present trial was not designed to detect statistical differences in variability in docetaxel-mediated neutropenia between the tested groups with sufficient power. However, the higher incidence of docetaxel-induced neutropenia is consistent with other studies showing increased bone marrow sensitivity to cytotoxic chemotherapy in the elderly, which has been attributed to declining bone marrow reserve at older age.4-6 Febrile neutropenia was also more frequent in the elderly group (16%) versus the younger group (0%), although the sample size was too small to evaluate the reliability of this observation. It is noteworthy that of 10 patients with docetaxel AUC values in the upper quartile, three of six elderly patients and none of four younger patients experienced febrile neutropenia. This suggests that given the same docetaxel exposure, elderly patients may be more sensitive to neutropenia than nonelderly patients with regard to fever.

The present results showing no difference in docetaxel pharmacokinetics but greater sensitivity to neutropenia in the elderly are consistent with a recent study conducted in Japan evaluating weekly docetaxel 20 or 35 mg/m2 administered in combination with cisplatin to elderly (≥ 75 years) and nonelderly (< 75 years) patients, respectively, with non–small-cell lung cancer.26 Both docetaxel and cisplatin pharmacokinetic parameters were similar between the elderly and nonelderly groups. However, exposure (AUC) to docetaxel, but not cisplatin, was positively correlated with neutropenia. To determine if the relationship between docetaxel AUC and neutropenia (percent change in neutrophil counts) was different between the two age groups, a pharmacodynamic model, which was developed in the nonelderly patients, was used to predict neutropenia in the elderly. Elderly patients experienced greater neutropenia than that predicted by the pharmacodynamic model, indicating the elderly were more sensitive to docetaxel exposure.

The incidence of nonhematologic toxicities was also similar between both age groups. It is important to note, however, that docetaxel-mediated nonhematologic toxicity was not assessed over multiple cycles of treatment as has been done with weekly docetaxel schedules,11-13 in which the development of nonhematologic toxicities often occur at later cycles. Additional investigation is clearly required to shed light on this aspect as well as on efficacy of the 3-week treatment schedule in elderly cancer patients.

This study evaluated the pharmacokinetic and toxicity profile of docetaxel 75 mg/m2, which is the recommended dose for non–small-cell lung and prostate cancers. However, at standard doses of 100 mg/m2, docetaxel is one of the most active single agents in breast cancer,27-29 and extrapolation of the present results to elderly patients with breast cancer receiving higher doses of docetaxel should be done with caution. Even so, interpatient variation in docetaxel clearance and exposure in both the older and younger groups was five-fold (500%), which most likely contributed to interpatient variation in toxicity. This extent of interpatient variation in exposure could obscure dose-toxicity and dose-activity relationships between docetaxel 75 and 100 mg/m2, which represent only a 25% difference in dose. In light of this extent of interpatient variation in docetaxel pharmacokinetics and drug effects, evaluation of alternative dosing strategies should continue to be focused on individual characteristics.

In conclusion, this study indicates that docetaxel pharmacokinetics are not altered in the elderly and that age appears to be an unimportant factor in drug dosing when considering the potential for age-related changes in drug clearance. However, the incidences of grade 4 and febrile neutropenia were greater in the elderly cohort, indicating that patients aged ≥ 65 years are more sensitive to docetaxel-induced neutropenia. In view of the wide degree of interindividual variability in drug clearance and hematologic toxicity in both age groups, additional evaluations of alternative dosing strategies for individual patients to decrease this variability and improve therapy are still urgently needed.


   Authors' Disclosures of Potential Conflicts of Interest
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
REFERENCES
 
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Honoraria: Michael Carducci, Aventis; Sharyn Baker, Aventis. Research funding: Sharyn Baker, Aventis. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section of Information for Contributors found in the front of every issue.


   Acknowledgment
 
We thank Alex Sparreboom, PhD, for helpful discussions and critical review of the manuscript.


   NOTES
 
Supported by Aventis Pharmaceuticals (Bridgewater, NJ) GIA 19075.

Presented at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004.

Authors' disclosures of potential conflicts of interest are found at the end of this article.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
1. Clarke SJ, Rivory LP: Clinical pharmacokinetics of docetaxel. Clin Pharmacokinet 36:99-114, 1999[CrossRef][Medline]

2. Bruno R, Hille D, Riva A, et al: Population pharmacokinetics/pharmacodynamics of docetaxel in phase II studies in patients with cancer. J Clin Oncol 16:187-196, 1998[Abstract/Free Full Text]

3. Yee KW, Pater JL, Pho L, et al: Enrollment of older patients in cancer treatment trials in Canada: Why is age a barrier? J Clin Oncol 21:1618-1623, 2003[Abstract/Free Full Text]

4. Baker SD, Grochow LB: Pharmacology of cancer chemotherapy in the older person. Clin Geriatr Med 13:169-183, 1997[Medline]

5. Lichtman SM, Skirvin JA: Pharmacology of antineoplastic agents in older cancer patients. Oncology (Huntingt) 14:1743-1755, 2000

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7. Siu LL, Shepherd FA, Murray N, et al: Influence of age on the treatment of limited-stage small-cell lung cancer. J Clin Oncol 14:821-828, 1996[Abstract/Free Full Text]

8. Popescu RA, Norman A, Ross PJ, et al: Adjuvant or palliative chemotherapy for colorectal cancer in patients 70 years or older. J Clin Oncol 17:2412-2418, 1999[Abstract/Free Full Text]

9. Sargent DJ, Goldberg RM, Jacobson SD, et al: A pooled analysis of adjuvant chemotherapy for resected colon cancer in elderly patients. N Engl J Med 345:1091-1097, 2001[Abstract/Free Full Text]

10. Bouchardy C, Rapiti E, Fioretta G, et al: Undertreatment strongly decreases prognosis of breast cancer in elderly women. J Clin Oncol 21:3580-3587, 2003[Abstract/Free Full Text]

11. Hainsworth JD, Burris HA III, Litchy S, et al: Weekly docetaxel in the treatment of elderly patients with advanced nonsmall cell lung carcinoma: A Minnie Pearl Cancer Res Network Phase II Trial. Cancer 89:328-333, 2000[CrossRef][Medline]

12. Hainsworth JD, Burris HA III, Yardley DA, et al: Weekly docetaxel in the treatment of elderly patients with advanced breast cancer: A Minnie Pearl Cancer Research Network phase II trial. J Clin Oncol 19:3500-3505, 2001[Abstract/Free Full Text]

13. Hainsworth JD, Erland JB, Barton JH, et al: Combination treatment with weekly docetaxel and gemcitabine for advanced non-small-cell lung cancer in elderly patients and patients with poor performance status: Results of a Minnie Pearl Cancer Research Network phase II trial. Clin Lung Cancer 5:33-38, 2003[Medline]

14. Slaviero KA, Clarke SJ, McLachlan AJ, et al: Population pharmacokinetics of weekly docetaxel in patients with advanced cancer. Br J Clin Pharmacol 57:44-53, 2004[CrossRef][Medline]

15. Wildiers H, Paridaens R: Taxanes in elderly breast cancer patients. Cancer Treat Rev 30:333-342, 2004[CrossRef][Medline]

16. Baker SD, ten Tije AJ, Carducci MA, et al: Evaluation of CYP3A activity as a predictive covariate for docetaxel clearance. Proc Am Soc Clin Oncol 23:128, 2004 (abstr 2006)

17. de Bono JS, Stephenson J Jr, Baker SD, et al: Troxacitabine, an L-stereoisomeric nucleoside analog, on a five-times-daily schedule: A phase I and pharmacokinetic study in patients with advanced solid malignancies. J Clin Oncol 20:96-109, 2002[Abstract/Free Full Text]

18. Baker SD, Zhao M, He P, et al: Simultaneous analysis of docetaxel and the formulation vehicle polysorbate 80 in human plasma by liquid chromatography/tandem mass spectrometry. Anal Biochem 324:276-284, 2004[CrossRef][Medline]

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20. Cuzick J: A Wilcoxon-type test for trend. Stat Med 14:445-446, 1985

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Submitted March 11, 2004; accepted November 23, 2004.


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