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Clinical Cancer Research Vol. 12, 6100-6105, October 15, 2006
© 2006 American Association for Cancer Research

Cancer Therapy: Clinical

Pharmacokinetics and Toxicity of Weekly Docetaxel in Older Patients

Arti Hurria1, Mark T. Fleming1, Sharyn D. Baker2, Wm. Kevin Kelly1, Katie Cutchall2, Katherine Panageas1, James Caravelli1, Henry Yeung1, Mark G. Kris1, Jorge Gomez1, Vincent A. Miller1, Gabriella D'Andrea1, Howard I. Scher1, Larry Norton1 and Clifford Hudis1

Authors' Affiliations: 1 Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York City, New York and 2 Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland

Requests for reprints: Arti Hurria, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. Phone: 212-639-3263; Fax: 212-717-3821; E-mail: hurriaa{at}mskcc.org.


   Abstract
Top
 Abstract
Patients and Methods
 Results
 Discussion
 References
 
Purpose: To evaluate the pharmacokinetics of weekly docetaxel in a cohort of older patients with metastatic cancer and to explore the relationship of pharmacokinetic variables, Erythromycin Breath Test results, age, geriatric assessment variables, and toxicity to therapy.

Experimental Design: Twenty patients ages ≥65 years with metastatic breast, prostate, or lung cancer entered an Institutional Review Board–approved protocol to evaluate the pharmacokinetics of weekly docetaxel administered at 35 mg/m2 i.v. for 3 weeks followed by a 1-week break. The Erythromycin Breath Test and geriatric assessment were done before the first dose. Blood samples were collected for pharmacokinetic analysis with the first dose of docetaxel.

Results: Of the 20 patients who entered the study, 19 were evaluable. There were no age-related differences in the pharmacokinetics of weekly docetaxel. Fifty-eight percent (11 of 19) experienced grade ≥3 toxicity: 16% (3 of 19) grade ≥3 hematologic toxicity, and 53% (10 of 19) grade ≥3 nonhematologic toxicity. There was an association between the Erythromycin Breath Test results and docetaxel pharmacokinetic variables; however, there was no association between Erythromycin Breath Test results or docetaxel pharmacokinetics with frequency of grade ≥3 toxicity.

Conclusions: Despite no statistically significant age-related differences in weekly docetaxel pharmacokinetics, over half of these older patients experienced a grade ≥3 toxicity at the 35 mg/m2 starting dose. We advocate a starting dose of 26 mg/m2 on this weekly schedule and dose escalating if no toxicity.

Although older individuals constitute the majority of patients with cancer, patients over the age of 65 years have been underrepresented in clinical trials (1–3). As a result, the recommended dose and schedule of chemotherapy is often based on clinical trials done in younger patients. Despite known changes in the distribution, metabolism, and excretion of drugs with aging (4, 5), there are limited data on the pharmacokinetics and pharmacodynamics of commonly used chemotherapies in older patients and few guidelines regarding the optimal starting doses. In addition, even fewer studies have included a comprehensive geriatric assessment, which might provide an understanding of the "functional" versus "chronological" age of older patients included on clinical trials. In this article, we investigate the relation of age, pharmacokinetics of docetaxel, geriatric assessment variables, and toxicity in a cohort of older patients with metastatic cancer.

Docetaxel, a widely used chemotherapy agent with broad antitumor activity, acts as a spindle poison by promoting tubulin assembly into microtubules and inhibiting depolymerization (6). It is administered on a weekly or every-3-week schedule. The pharmacokinetic profile of every-3-week docetaxel in older patients has been recently reported. Although there was no significant difference in the pharmacokinetics between patients ages ≥65 years compared with those ages <65 years, there was an increased incidence of neutropenia in older patients (7). In a phase I study of docetaxel in combination with cisplatin (25 mg/m2 every 4 weeks), a lower dose of weekly docetaxel was recommended for patients over the age of 75 years (docetaxel 20 mg/m2 days 1, 8, and 15 every 4 weeks) compared with those younger than age 75 years (docetaxel 35 mg/m2 days 1, 8, and 15 every 4 weeks; ref. 8). Previous reports have suggested that docetaxel, administered on a weekly schedule, has been generally well tolerated and efficacious in older patients; however, the majority of these patients had minimal prior treatment and the toxicity profile was not correlated to a pharmacokinetic analysis (9–11).

Docetaxel is primarily metabolized by the liver. The main enzyme responsible for docetaxel metabolism is the hepatic enzyme cytochrome 3A4 (CYP3A4), a member of the cytochrome p450 family. Although hepatic mass and blood flow decrease with age (4, 5, 12), the effect of this decline on hepatic enzyme activity remains controversial (13–16). Thus, the goal of this study was to describe the pharmacokinetics of weekly docetaxel in the older patient and to correlate the pharmacokinetic profile and toxicity to CYP3A4 activity as measured by the Erythromycin Breath Test (17). Previous studies have shown no difference in docetaxel pharmacokinetics with age. Therefore, we chose to focus on an older cohort of patients, a group in which age-related decline in hepatic function and physiologic reserve might influence the pharmacokinetic profile and toxicity.


   Patients and Methods
Top
 Abstract
 Patients and Methods
Results
 Discussion
 References
 
Study design. Twenty patients ages ≥65 years with metastatic breast, prostate, or lung cancer were enrolled in this study to evaluate the pharmacokinetics of weekly docetaxel in older patients. This study was approved by the Memorial Sloan-Kettering Cancer Center Institutional Review Board. All study participants provided written informed consent before enrollment. The Erythromycin Breath Test and a geriatric assessment were performed before the first dose of docetaxel (Table 1 ). Docetaxel 35 mg/m2 was administered i.v. as a 30-minute infusion weekly for 3 weeks followed by a 1-week break. Blood samples were collected for pharmacokinetic analysis with the first dose of docetaxel. Patients continued on study until disease progression or unacceptable toxicity.


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  		Table 1. Geriatric assessment scores before chemotherapy

 
Eligibility criteria. Patients were eligible if they were ages ≥65 years with metastatic breast, lung, or prostate cancer. Other criteria for patient enrollment were Karnofsky performance status (KPS) ≥70%; adequate bone marrow function as defined by pre-therapy values of hemoglobin ≥8.0 g/dL, absolute neutrophil count ≥1,500/µL, and platelet count ≥100,000/µL; adequate liver function with total bilirubin within normal limits and transaminases (aspartate aminotransferase and/or alanine aminotransferase) up to 2.5x institutional upper limit of normal if alkaline phosphatase was less than or equal to the upper limit of normal, or alkaline phosphatase could be up to 4x upper limit of normal if transaminases were less than or equal to upper limit of normal; and peripheral neuropathy less than or equal to grade 1. Patients were not eligible if they had a history of severe hypersensitivity reaction to docetaxel or other drugs formulated with polysorbate 80, or if they had an allergy to macrolide antibiotics; had untreated central nervous system metastases or symptomatic central nervous system metastases requiring escalating doses of corticosteroids; had a history of untreated or unstable cardiac arrhythmias, congestive heart failure, or myocardial infarction in the past 6 months; or were on medications or herbal remedies that induce or inhibit CYP3A4. Patients were advised to avoid grapefruit juice and ethanol while on study because of potential inhibition/modulation of CYP3A4.

Patient evaluation. Pretreatment evaluation included medical history and physical examination, laboratory assessment (complete blood count with differential, comprehensive biochemical screening profile, lactate dehydrogenase), and electrocardiogram. Additional laboratory assessments for patients with prostate cancer included a prostate-specific antigen, and for patients with breast cancer, a carcinoembryonic antigen and CA15-3. Initial extent of disease staging workup for patients with breast or prostate cancer included a bone scan and computed tomography scan of the chest, abdomen, and pelvis. Patients with lung cancer underwent a computed tomography scan of the chest.

The Erythromycin Breath Test was done before initiation of docetaxel. This test involved administration of a 3 µCi dose of radioactive erythromycin (14C N-methyl) i.v. A breath sample was collected into a device 20 minutes later and sent to Metabolic Solutions, Inc. (Nashua, NH), for analysis of the amount of expired 14CO2 resulting from the oxidation of 14C N-methyl-erythromycin. The data were reported as the flux of 14CO2, expressed as a percentage of dose exhaled per minute [C20min (% dose/min)], assuming a CO2 output of 5 mmol/min/m2 body surface area.

A geriatric assessment was done before start of treatment consisting of validated scales of functional status (activities of daily living, instrumental activities of daily living, and KPS), comorbidity (via the age-adjusted Charlson scale), and psychological state (Geriatric Depression Scale) (Table 1).

A CBC was done before each docetaxel treatment. A history and physical exam, KPS, and toxicity assessment were done before the first and third docetaxel infusions of each cycle. A comprehensive metabolic panel and tumor markers (patients with breast cancer: carcinoembryonic antigen, CA15-3; patients with prostate cancer: prostate-specific antigen) were done before the initiation of each cycle. Restaging computed tomography and bone scans were done every three cycles.

Patients were removed from study if they became ineligible, developed progressive disease, had unacceptable toxicity, experienced prolonged treatment delays (≥3 weeks), or if the patient or investigator considered it in the patient's best interest to discontinue the study.

Drug treatment. Docetaxel was administered i.v. as a 30-minute infusion at a dose of 35 mg/m2. A treatment cycle consisted of weekly docetaxel for 3 weeks followed by a 1-week break. For cycle 1, week 1, 8 mg dexamethasone was administered orally the night before, the morning of, and the evening after docetaxel administration. For subsequent doses of docetaxel, dexamethasone was either given orally as specified above or 10 mg i.v. pretreatment at the discretion of the treating physician.

Pharmacokinetic sampling and assay. Blood samples were collected for docetaxel pharmacokinetic studies during the first cycle of treatment at the following time points: Pretreatment; 15 minutes (mid infusion); 29 minutes (immediately before end of infusion); and after infusion: 10 minutes, 30 minutes, 1 hour, 3 hours, 7.5 hours, 24 hours, 48 hours, and day 8 (pretreatment week 2). Total docetaxel concentrations in plasma were measured using a validated method based on high-performance liquid chromatography with tandem mass spectrometric detection as previously described (18). Unbound docetaxel concentrations in plasma were measured using a validated method based on equilibrium dialysis as previously described (19). Pharmacokinetic variables were calculated using noncompartmental analysis implemented in the computer software program WinNonlin version 5.0 (Pharsight Corporation, Mountain View, CA).

Statistical analysis. Twenty patients were accrued to the study. Patient characteristics and prior treatment data were stratified by age (65-74 and ≥75 years). Geriatric assessment was summarized using median score and range. Docetaxel pharmacokinetic variables were summarized as mean, SD, median, and range. Pharmacokinetic variables, Erythromycin Breath Test results, and baseline laboratory data were correlated with toxicity using univariate logistic regression. Geriatric assessment variables were correlated with pharmacokinetic variables by ordinary regression.


   Results
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 Abstract
 Patients and Methods
 Results
Discussion
 References
 
Between March 2003 and March 2005, 20 patients over the age of 65 years (median age 75 years; range 66-84 years) with metastatic breast, lung, or prostate cancer were enrolled in this study. Baseline characteristics are shown in Table 2 .


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  		Table 2. Patient demographics and characteristics

 
Of the 20 patients enrolled in the protocol, 19 patients were assessable for pharmacokinetic analysis. One patient was excluded from pharmacokinetic analysis because the data seemed erroneous: The value for Cmax was 38.2 µg/mL, which was >15 SDs from the mean value of 4.85 µg/mL. Of the 19 patients assessable for pharmacokinetic analysis, 13 (68%) had received prior cytotoxic treatment (median 1; range 0-3), 9 (47%) patients had received four or more prior hormonal or cytotoxic treatments, and 16 (84%) were on concurrent medications (median 3; range 0-10).

A baseline geriatric assessment was obtained on all patients. Measures of functional status showed high median scores—Katz Activities of Daily Living 18 (range 16-18), Lawton Instrumental Activities of Daily Living 20 (range 14-21), and KPS 80% (range 70-100%). Table 1 summarizes the prechemotherapy geriatric assessment scores.

Plasma pharmacokinetics. Docetaxel pharmacokinetic variables of the 19 assessable patients are summarized in Table 3 . Mean (SD) value for total clearance (CL) was 18.3 L/h (7.85); mean area under the curve (AUC) was 4.12 µg/mL·h (2.13); mean Cmax was 4.85 µg/mL (2.10). Despite wide variations in docetaxel pharmacokinetics, significant associations were not observed between increased age and increased total docetaxel AUC (P = 0.24), decreased clearance (P = 0.24), or increased Cmax (P = 0.12). In addition, there was no significant association between increased age and unbound docetaxel pharmacokinetic variables. Representative plasma concentration-time profiles for total and unbound docetaxel are presented in Fig. 1 . Geriatric assessment variables were correlated with pharmacokinetic variables by ordinary regression. A lower score on the Lawton Instrumental Activities of Daily Living scale (indicating increased need for assistance in completing instrumental activities of daily living) correlated with a longer terminal half-life of bound docetaxel (P = 0.02). A higher score on the Geriatric Depression Scale correlated with a higher volume of distribution (P = 0.01) at steady-state and longer terminal half-life (P = 0.01) of bound docetaxel.


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  		Table 3. Docetaxel pharmacokinetic variables

 

Figure 1
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  		Fig. 1. Representative plasma concentration-time profiles for total ({circ}) and unbound ({square}) docetaxel.

 
The Erythromycin Breath Test. The mean Erythromycin Breath Test score was 3.01% dose/h (range 1.68-4.98; SD 0.78). By univariate analysis, no statistically significant association was observed between age and CYP3A4 activity as measured by the Erythromycin Breath Test (P = 0.35); however, there was an association between the Erythromycin Breath Test score and the total pharmacokinetic variables [AUC (P = 0.02) and clearance (P = 0.09)] and unbound pharmacokinetic variables [AUC (P = 0.01) and clearance (P = 0.04)]. Scatterplots of associations between the Erythromycin Breath Test variable C20 (%dose/min), and total and unbound docetaxel clearance and AUC are shown in Fig. 2 .


Figure 2
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  		Fig. 2. Scatterplots of associations between CYP3A4 activity, by assessment of the Erythromycin Breath Test variable C20 (%dose/min), and total (A and B) and unbound (C and D) docetaxel clearance and AUC.

 
Toxicity. Toxicity following docetaxel is summarized in Table 4 . Of the 11 of 19 (58%) patients who experienced grade ≥3 toxicity, 3 of 19 (16%) had grade ≥3 hematologic toxicity and 10 of 19 (53%) had grade ≥3 nonhematologic toxicity. Diarrhea and fatigue were the most common nonhematologic toxicities, and leukopenia was the most common hematologic toxicity (Table 5 ). One patient experienced a grade 5 toxicity consisting of infection without neutropenia, which occurred after her first dose of docetaxel. This 74-year-old patient had a KPS of 90%, was independent in her activities of daily living and instrumental activities of daily living. She had received no prior chemotherapy in the past. Her only distinguishing clinical feature was a longstanding history of anorexia (her baseline weight was 35 kg). Pharmacokinetic analysis revealed that this patient had an extremely high docetaxel AUC (total AUC = 11.2 µg/mL · h) and low clearance (total CL = 4.1 L/h), the highest and lowest, respectively, on the study.


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  		Table 4. Grade ≥3 toxicity attributable to docetaxel

 

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  		Table 5. Treatment-related adverse events (n = 19)

 
Overall, however, there was no association by univariate analysis between grade ≥3 toxicity and pharmacokinetic variables, baseline geriatric assessment scores, or baseline laboratory data other than for baseline alanine aminotransferase value in which there was a trend toward significance (P = 0.06). There was no association between increased age and all grade ≥3 (P = 0.48), nonhematologic (P = 0.97), or hematologic (P = 0.29) toxicities.


   Discussion
Top
 Abstract
 Patients and Methods
 Results
 Discussion
References
 
In this study, we report on the pharmacokinetics of weekly docetaxel in an older population with metastatic cancer that incorporated geriatric assessment and assessment of CYP3A4 activity. In this cohort, we found no age-related differences in docetaxel pharmacokinetics. These results are consistent with other studies (7, 20, 21). Ten Tije et al. (7) evaluated the pharmacokinetics of docetaxel at a dose of 75 mg/m2 given once every 3 weeks and found no difference between patients older or younger than age 65 years; however, older patients experienced a higher rate of grade 4 and febrile neutropenia. Minami et al. (20) evaluated docetaxel pharmacokinetics at a dose of 35 mg/m2 for patients ages <65 years and 20 mg/m2 for patients ages ≥65 years, in combination with cisplatin at a dose of 25 mg/m2 given every 4 weeks. They found no age-related differences in the pharmacokinetics of either drug; however, older patients experienced greater neutropenia. The authors chose a lower dose of docetaxel for older patients based on data from a phase I study of patients above and below the age of 75 years. Slaviero et al. (21) evaluated the pharmacokinetics of weekly docetaxel at a dose of 40 mg/m2 and found no age-related differences.

The results of these studies are inconsistent with the results of the pharmacokinetic study done by Bruno et al. (22), who showed that docetaxel clearance was related to age in a cohort of 640 patients; however, even in that study, the effect of age was modest (estimated at a 7% decrease of mean clearance for a 71-year-old patient).

Despite studies showing no difference or modest differences in docetaxel pharmacokinetics with age, older patients are at increased risk of toxicity. The pharmacodynamics of the drug differ in younger and older patients, likely because of a decreased physiologic reserve in older compared with younger patients. For example, older patients are more susceptible to myelosuppression and myelosuppressive-associated complications, likely because of decreased bone marrow reserve (23–26).

An advantage of a weekly schedule of docetaxel compared with an every-3-week schedule is the decreased risk of hematologic toxicity; however, even on the weekly schedule in our cohort, over half of patients developed a grade 3 or higher, primarily nonhematologic, toxicity, necessitating dose reduction. Diarrhea and fatigue were the most common nonhematologic toxicities. A possible explanation for the comparatively increased toxicity in our study population is that our patients were more heavily pretreated than patients described in previously reported studies where the range of prior cytotoxic therapy was 0% to 51% (9, 10). In our study, 65% of patients had received prior cytotoxic therapy, and our patients were of an older median age than patients in other studies (27).

These data raise questions regarding the optimal starting dose of weekly docetaxel in patients ages ≥65 years, especially in those patients who have received prior therapy. Based on the high incidence of grade 3 and higher toxicity, we advocate starting at 26 mg/m2 and escalating the dose if the patient tolerates therapy. Minami et al. (20) used an even lower starting dose of docetaxel (20 mg/m2) when administered in combination with cisplatin, based on their phase I data in patients ages >75 years. The typical geriatric adage of "start low and go slow," referring to beginning medications at a low dose and escalating if no toxicity ensues, might be applicable to the dosing of chemotherapy as well. Further studies are needed to determine whether efficacy is compromised by this "start-low" approach. In this study, we attempted to determine whether the Erythromycin Breath Test, as a surrogate measure of CYP3A4 activity, could predict toxicity and therefore be used to individualize dosing in the future. Our results show that although there was an association between the Erythromycin Breath Test results and docetaxel pharmacokinetic variables, there was no association between either of these results and risk of grade ≥3 toxicity to weekly docetaxel in this cohort. Further studies in a larger cohort of patients are needed to explore these relationships.

Incorporation of a geriatric assessment is being increasingly viewed as an important aspect of clinical trial design in geriatric oncology. Guidelines, including those from the National Comprehensive Cancer Network and International Society of Geriatric Oncology, advocate the use of comprehensive geriatric assessment as a tool to stratify baseline characteristics and to predict tolerance to chemotherapy (28). No type of geriatric assessment was included in the previously reported papers of docetaxel pharmacokinetics and toxicity in older patients. We can only speculate that this information might provide insight regarding the differential incidence of toxicity among the patients in this trial and those included in other clinical trials. We incorporated standard measures of geriatric assessment in our study and found that the study participants had high mean scores, likely reflecting the healthier older patient who is included in trials. Different geriatric assessment measures that evaluate a broader range of physical functioning will be needed to evaluate older individuals included in clinical trials.

Limitations to our study include the modest sample size and the fact that patients were accrued from a single tertiary care cancer center. The results of the geriatric assessment might be more informative in a group of patients with a broader range of physical functioning. The range of tumor types represented also limits our power to assess the clinical response within each tumor type; therefore, based on the small subsets, we did not report treatment efficacy. We focused our study on patients age 65 and older, thinking that if age-related differences in pharmacokinetics existed, they would be most pronounced in this age group. We did not compare these results to a younger cohort of patients.

On the other hand, our study has important strengths. We showed the feasibility of performing a pharmacokinetic study in older patients. In addition, we showed the feasibility of incorporating a geriatric assessment in the baseline evaluation of older adults on clinical trials. Through this study, we identified barriers to accrual in pharmacokinetic studies of older patients. Our biggest accrual barrier was lack of patient transportation to and from the hospital for the extensive pharmacokinetic sampling required. Our study accrual increased dramatically after amending the study to provide housing for patients during the pharmacokinetic portion of the study. These costs should be considered as part of the trial design of future pharmacokinetic studies in the elderly patient.

Ideally, within the metastatic setting, the goal of care should be to balance efforts to prolong life with efforts to maintain quality of life. This is particularly true in the older population, where decreased physiologic reserve and comorbidity can lead to increased toxicity from cancer treatment. Further studies of chemotherapy efficacy, toxicity, and optimal dosing are needed. A comprehensive geriatric assessment is an essential component of clinical trial design in the older patient.


   Acknowledgments
 
We thank Carol A. Pearce, MFA, Department of Medicine, for her assistance in the preparation of the manuscript.


   Footnotes
 
Grant support: Dr. Hurria's Merck/American Federation for Aging Research Junior Investigator Award for Geriatric Clinical Pharmacology, K23 AG026749-01 (Paul Beeson Career Development Award in Aging Research), American Society of Clinical Oncology-Association of Specialty Professors-Junior Development Award in Geriatric Oncology, and Sanofi-Aventis Pharmaceuticals.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 1/27/06; revised 4/12/06; accepted 6/12/06.


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 Abstract
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 References
 

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