This randomized, controlled, multicenter, open-label, phase III study compared docetaxel versus paclitaxel in patients with advanced breast cancer that had progressed after an anthracycline-containing chemotherapy regimen.

Patients (n = 449) were randomly assigned to receive either docetaxel 100 mg/m2 (n = 225) or paclitaxel 175 mg/m2 (n = 224) on day 1, every 21 days until tumor progression, unacceptable toxicity, or withdrawal of consent.

In the intent-to-treat population, both the median overall survival (OS, 15.4 v 12.7 months; hazard ratio [HR], 1.41; 95% CI, 1.15 to 1.73; P = .03) and the median time to progression (TTP, 5.7 months v 3.6 months; HR, 1.64; 95% CI, 1.33 to 2.02; P < .0001) for docetaxel were significantly longer than for paclitaxel, and the overall response rate (ORR, 32% v 25%; P = .10) was higher for docetaxel. These results were confirmed by multivariate analyses. The incidence of treatment-related hematologic and nonhematologic toxicities was greater for docetaxel than for paclitaxel; however, quality-of-life scores were not statistically different between treatment groups over time.

Docetaxel was superior to paclitaxel in terms of OS and TTP. ORR was higher for docetaxel. Hematologic and nonhematologic toxicities occurred more frequently in the docetaxel group. The global quality-of-life scores were similar for both agents over time.

Both paclitaxel and docetaxel were approved for use in patients with metastatic breast cancer (MBC).1 Clinical and laboratory evidence suggested that they had different effects. Paclitaxel, isolated from the bark of the Pacific yew tree (Taxus brevifolia), was discovered in a National Cancer Institute (NCI) program created to screen natural compounds. Docetaxel, synthesized from extracts of the needles of the European yew tree (Taxus baccata), was selected for development after an extensive search for taxane derivatives with features that might improve on the potential of paclitaxel. Both drugs have similar chemical structures, bind to tubulin, promote stabilization of microtubules, and cause G2M cell cycle arrest. Although the patterns of tumor cell line and xenograft sensitivity are similar for the two agents, they are not identical.2-4 Compared with paclitaxel, docetaxel demonstrated greater affinity for the tubulin-binding site,5 a different microtubule polymerization pattern,5-7 longer intracellular retention time and higher intracellular concentration in target cells,8 greater thymidine phosphorylase upregulation,9 more potent antitumor activity in in vitro and in vivo models,2-4 and more potent induction of bcl-2 phosphorylation and apoptosis.10 In early clinical studies, docetaxel demonstrated linear pharmacokinetics11 and less schedule dependence12 than paclitaxel. The dose-limiting toxicity for both drugs is neutropenia, but differences in nonhematologic toxicities are evident. Hypersensitivity reactions and neurotoxicity are described more commonly with paclitaxel, whereas fluid retention and fatigue are seen with docetaxel administration.13,14

Until this time, only indirect clinical comparisons of the two taxanes have been performed and they have been imprecise because of differences in patient populations. Therefore, a head-to-head comparison was necessary to compare more accurately the safety and efficacy of the two taxanes. This randomized phase III trial was designed to compare docetaxel and paclitaxel at approved doses and schedules.

Patient Population

Women 18 years or older with adenocarcinoma of the breast and disease progression after one prior chemotherapy regimen for locally advanced or MBC, or with locally advanced or MBC that progressed during or within 12 months of completing an adjuvant or neoadjuvant chemotherapy regimen, were eligible for the study. Prior therapy with an anthracycline was required, unless medically contraindicated. Prior chemotherapy had to be completed at least 3 weeks before random assignment; exceptions were oral cyclophosphamide (2 weeks) and nitrosoureas or mitomycin (6 weeks). Prior hormonal therapy in the adjuvant and/or metastatic setting was allowed. Additional requirements included bidimensional, measurable disease; Karnofsky performance score (KPS) ≥ 60; neutrophils ≥ 2,000/μL and platelets ≥ 100,000/μL; a total bilirubin less than the upper limit of normal (ULN); AST and ALT level less than 3× the ULN if the alkaline phosphatase level was less than 5× the ULN, or AST and ALT less than 1.5× the ULN if alkaline phosphatase level was less than 2.5× the ULN; and creatinine ≤ 2 mg/dL. Written informed consent was required. Patients with NCI Common Toxicity Criteria (CTC) grade 2 or greater peripheral neuropathy or a history of hypersensitivity reaction to products containing polysorbate 80 or polyoxyethylated castor oil (Cremophor EL) were excluded. Prohibited prior treatments included taxanes, bone marrow transplantation or stem-cell support, recent radiotherapy to bone marrow, surgery within the prior 2 weeks, and an investigational drug within 4 weeks of study registration. Bisphosphonate therapy was permitted. The study was conducted after approval by the institutional review board or ethics committee of each participating center.

Study Design

This randomized, controlled, multicenter, open-label, phase III study was designed to compare the antitumor activity and toxicity of docetaxel 100 mg/m2 1-hour intravenous (IV) infusion every 21 days versus paclitaxel 175 mg/m2 3-hour IV infusion every 21 days. Registration and randomization were centralized. The randomization schedule used a block design that was balanced by study site. For docetaxel patients, premedication consisted of dexamethasone 8 mg by mouth twice daily beginning on the day before the infusion and continuing for a total of 5 days. For paclitaxel patients, premedication included dexamethasone 20 mg by mouth administered 12 and 6 hours before the paclitaxel infusion, diphenhydramine 50 mg IV, and either ranitidine 50 mg IV or cimetidine 300 mg IV administered 30 to 60 minutes before the infusion. Treatment continued until tumor progression, unacceptable toxicity, or withdrawal of consent.

Dose reductions (docetaxel 75 mg/m2 then 55 mg/m2; paclitaxel 130 mg/m2 then 100 mg/m2) were implemented after recovery from grade 3/4 toxicities. Patients experiencing grade 2 neuropathy were treated without delay, but at a reduced dose. Treatment delays due to toxicities were limited to 2 weeks; if patients did not recover, they were taken off study. Secondary prophylaxis with granulocyte colony-stimulating factor (G-CSF) was permitted after a febrile grade 4 leukopenia or neutropenia ≥ 7 days duration or when associated with fever. Recurrences of these events despite G-CSF use required dose reduction with subsequent cycles.

Assessments

Radiologic tests, medical history, and physical examination were performed within 22 days before random assignment to treatment. KPS assessments, ECG, clinical laboratory testing, clinical tumor measurements, and neurologic examinations were performed within 8 days before random assignment to treatment.

Tumor measurements were scheduled at the end of each cycle for clinically assessable disease and after every two cycles for lesions assessed radiographically. The minimum dimensions for measurable lesions were computed tomography and magnetic resonance imaging scans, 20 mm in at least one dimension; x-ray and skin lesion, 10 mm × 10 mm; and superficial lymph node, 20 mm × 20 mm. Tumor response was classified in accordance with World Health Organization (WHO) criteria: complete response, disappearance of all clinical and radiologic evidence of tumor; and partial response, at least a 50% reduction in the sum of the products of the longest perpendicular diameters of all target lesions and no evidence of disease progression. Responses were confirmed by repeat complete tumor assessments performed at least 4 weeks after the initial observation of a response. Disease progression was defined as ≥ 25% increase in the size of any single measurable lesion or in the sum of the sizes of all measurable lesions compared with measurements at the time of best response, a significant increase (ie, ≥ 100%) in the size of a previously identified but nonmeasurable lesion, or the appearance of a new lesion. Clinical responses were assessed initially by the investigators and subsequently reviewed for consistency during a review of the clinical data. When discrepancies occurred in response assessments, a subgroup of investigators conducted a blinded review of the available clinical data, and these assessments were used for the final analyses.

During the first two cycles, blood counts were performed weekly; thereafter, they were performed before each cycle and as clinically indicated. Toxicities were assessed at the end of each cycle using the NCI-CTC (version 1). Toxicities that could not be graded using the NCI-CTC (eg, asthenia) were graded as mild, moderate, severe, or life threatening. Febrile neutropenia was prospectively defined as grade 4 neutropenia concomitant with fever ≥ 38.1°C requiring hospitalization or IV antibiotic administration in the absence of documented infection. On completion of study treatment, patients were observed every 3 months.

Statistical Methodology and Analysis

The primary end points were the objective response rate and toxicity. Secondary end points included duration of response, time to progression (TTP), overall survival (OS), and quality of life (QOL). The primary and secondary efficacy end points were analyzed for both the intent-to-treat (ITT) and the assessable populations.

The prestudy hypothesis assumed response rates of 42% and 28% for the two treatment arms. Using a two-sided test with a type I error rate of 5% and 80% power, 200 patients were needed in each arm. To obtain the necessary number of assessable patients, random assignment of a total of 490 patients was planned. The analysis was performed by Aventis Pharmaceuticals Inc. The statistical analysis plan and the results were reviewed and approved by the study investigators.

The ITT population included all randomly assigned patients, including those who did not receive treatment, with analyses performed based on the treatment assigned. Eligible patients included all patients with no major inclusion or exclusion criteria deviations. Patients assessable for response included those who met major eligibility criteria; received at least two cycles of treatment, unless progression occurred before the second cycle, in which case the patients were considered to have progressive disease; had at least one complete tumor assessment after the second cycle; and had no major protocol violations. All patients who received at least one dose of study drug were assessable for safety assessment; safety analyses were performed based on the actual treatment administered.

Response rate was defined as the sum of the percentage of patients who achieved a complete response or partial response in each treatment group. Duration of response was defined as the time from the first documentation of response to the date of disease progression or the date of death as a result of any cause if death occurred within 6 months after the last dose of study drug. TTP was defined as the time interval between the date of random assignment and the date of disease progression or the date of death as a result of any cause if death occurred within 6 months after the last dose of study drug. For response duration and TTP analyses, patients were censored at the time of last clinical contact if they were lost to follow-up, died later than 6 months after the last dose of study drug, or did not experience disease progression or die before the cutoff date for the analyses, which was April 22, 2003. Patients were also censored on the date that they received any subsequent anticancer therapy before documented tumor progression. OS was calculated from the date of random assignment to the date of death or to the date of last contact (censored observation).

Overall response rates were compared between the treatment groups using the χ2 test. Other categoric data were compared using the Cochran-Mantel-Haenszel test or Fisher's exact test. Stepwise logistic regression was implemented to determine the influence of selected prognostic factors, stratified by prior chemotherapy for advanced disease.15

The Kaplan-Meier method was used to estimate the distribution of time to events (ie, TTP, duration of response, and OS), and the log-rank test, adjusted for prior chemotherapy for advanced disease, was used to compare the distributions between the two treatment groups. A Cox proportional hazards model16 was used to assess the importance of prospectively defined, potential prognostic factors. All laboratory values were normalized using NCI standard values. Adverse experiences of particular interest, which were specifically queried, included febrile neutropenia, peripheral edema, and neurotoxicity. The incidence of adverse events between treatment groups was compared using a two-tailed Cochran-Mantel-Haenszel test.

Global QOL was assessed using the Functional Assessment of Cancer Therapy measurement system for breast cancer, FACT-B.17 Higher scores reflect a poorer QOL. Questionnaires were to be completed before the first infusion, at the end of cycle 4, and at the end of study treatment. Assessable questionnaires contained responses to at least 80% of the questions. A nonparametric Wilcoxon rank sum test was done to analyze global QOL scores based on the average change from baseline to cycle 4 or the end of study. For those patients who came off study before cycle 4, the end of study assessment was used as the comparator.

Patients

Between October 1994 and October 2001, a total of 449 patients at 53 institutions (48 in the United States and five in Canada) were randomly assigned. There were no statistically significant differences between the two groups in baseline patient and tumor characteristics (Table 1). The median age was 56 years for docetaxel patients and 54 years for paclitaxel patients. Both groups had a median of two sites of disease, more than 90% of patients had metastatic disease, and most patients were postmenopausal. More patients had estrogen receptor–positive tumors in the docetaxel arm (51% v 42%), but this difference was not statistically significant.

Two hundred twenty-five patients were randomly assigned to the docetaxel arm and 224 patients were randomly assigned to the paclitaxel arm. Of these, 211 patients in the docetaxel arm and 214 patients in the paclitaxel arm were eligible and 189 docetaxel patients and 205 patients paclitaxel patients were considered assessable for efficacy. Major reasons for ineligibility and nonassessability are summarized in Table 2. One additional ineligible patient assigned to the docetaxel arm did not receive treatment, resulting in 222 patients who were assessable for safety in each treatment arm. The median duration of follow-up was 5.1 years.

Exposure to Study Medication

The median number of treatment cycles administered was higher in the docetaxel group (six cycles; maximum, 32 cycles) than in the paclitaxel group (four cycles; maximum, 35 cycles). The median relative dose-intensity was 1 (range, 0.62 to 1.00) for docetaxel and 1 (range, 0.72 to 1.00) for paclitaxel. The mean dose administered per cycle was 95 mg/m2 for docetaxel and 173 mg/m2 for paclitaxel.

The primary reason for discontinuation from the study was disease progression in both groups. A smaller percentage of docetaxel patients (47%) discontinued because of progressive disease than did paclitaxel patients (75%; P = .001). Adverse experiences resulted in discontinuation for 26% of docetaxel patients and 8% of paclitaxel patients (P = .001). In the docetaxel group, the adverse events that most frequently resulted in discontinuation were neurosensory toxicity (8%), neuromotor toxicity (5%), peripheral edema (5%), infection (3%), and asthenia (3%), whereas in the paclitaxel group, they were neurosensory toxicity (4%), neuromotor toxicity (1%), and asthenia (1%). Fifteen percent of docetaxel patients and 7% of paclitaxel patients withdrew consent or refused additional treatment.

Efficacy

In the ITT population, the overall response rate was higher for docetaxel than for paclitaxel (32% v 25%, respectively; P = .10; Table 3). The median response durations were 7.5 and 4.6 months in the docetaxel and paclitaxel groups, respectively (P = .01). Eighteen percent of docetaxel patients and 30% of paclitaxel patients had progressive disease as the best response. The median TTP was significantly longer in the docetaxel group than in the paclitaxel group (5.7 v 3.6 months; hazard ratio [HR], 1.64; 95% CI, 1.33 to 2.02; P < .0001; Fig 1). The median OS was significantly longer in the docetaxel group than in the paclitaxel group (15.4 v 12.7 months; HR, 1.41; 95% CI, 1.15 to 1.73; P = .03; Fig 2). Annual survival rates for docetaxel and paclitaxel, respectively, were 60% v 51% for 1 year (P = .096) and 33% v 22% for 2 years (P = .009).

In the assessable population, the overall response rate was higher for the docetaxel group than the paclitaxel group (37% v 26%, respectively; P = .02), as was the median response duration (7.5 v 4.6 months, respectively; P = .01). The median TTP was 5.5 months in the docetaxel group and 3.6 months in the paclitaxel group (P < .0001). As with the ITT population, in the assessable population, the median OS was longer in the docetaxel group than in the paclitaxel group (16.1 v 12.7 months; P = .02).

Chemotherapy after study discontinuation was administered to 64% of patients randomly assigned to docetaxel and 70% of patients randomly assigned to paclitaxel. Among the patients randomly assigned to docetaxel, 20% were later treated with paclitaxel, whereas 19% of patients randomly assigned to paclitaxel received docetaxel as salvage therapy. Thirteen percent of docetaxel patients and 17% of paclitaxel patients were re-treated with the taxane to which they had been randomly assigned in the study.

On the basis of multivariate analysis, significant prognostic indicators emerged for prolonged survival, TTP, and response for the ITT population. Predictors for OS included treatment with docetaxel (HR, 1.41; 95% CI, 1.15 to 1.73); KPS ≥ 80 (P = .005), less than 12 months from initial diagnosis to initial infusion (P = .003), and fewer involved organs (P = .01).

Toxicity

There were four treatment-related deaths (three as a result of infection and one as a result of a GI bleed in a nonthrombocytopenic patient) in the docetaxel group and none in the paclitaxel group (P = .123, Fisher's exact test). One death as a result of infection occurred in a patient with a baseline KPS less than 60. Three patients died less than 30 days after docetaxel infusions (two patients in cycle 1 and the other in cycle 7); the fourth death occurred more than 30 days after the cycle 2 infusion. Toxicities were more frequent with docetaxel (Tables 4 and 5); grade 3/4 asthenia and stomatitis were the only nonhematologic toxicities present in more than 10% of patients. G-CSF or granulocyte macrophage colony-stimulating factor was administered in 7% of docetaxel cycles (n = 116 patients) and 1% of paclitaxel cycles (n = 25 patients); all such treatments were administered in patients who had experienced complicated grade 3/4 neutropenia in a prior cycle.

Although more neurotoxicity was seen overall with docetaxel; at four cycles, the incidence of grade 3/4 neurosensory toxicity was 2% in both groups. Among patients experiencing grade 2 or greater neurotoxicity, the mean cumulative dose to onset of an event was 371 mg/m2 for docetaxel and 715 mg/m2 for paclitaxel.

QOL

At baseline, the mean (± standard deviation) global FACT-B scores for docetaxel and paclitaxel patients were similar (45.6 ± 18.7 v 46.8 ± 20.5, respectively; P = .60). This was also the case at cycle 4 (48.9 ± 17.8 v 50. 5 ± 19.7, respectively; P = .75) and the end of the study (54.9 ± 23.0 v 53.7 ± 22.5, respectively; P = .94). Similarly, there were no significant differences in the mean change from baseline to cycle 4 or from baseline to the end of study for global FACT-B scores (P ≥ .68; Fig 3).

This is the first clinical trial to compare directly the taxanes, docetaxel and paclitaxel, as monotherapy for patients with advanced breast cancer. Using US Food and Drug Administration–approved doses and schedules for each agent, this phase III study has demonstrated that docetaxel is superior to paclitaxel in TTP (5.7 v 3.6 months; P < .0001), response duration (7.5 v 4.6 months; P = .01), and OS (15.4 v 12.7 months; P = .03). The overall response rate was also greater with docetaxel (32% v 25%; P = .10). The survival advantage for docetaxel was observed despite the increased incidence of toxicities leading to dose reductions and treatment withdrawal, and the slightly greater use of salvage treatment in patients randomly assigned to paclitaxel. The results of this study are consistent with those reported for previous phase III studies of single-agent docetaxel18-23 and paclitaxel.24-27,28-33

The doses used in this study reflect clinical experience from dose-finding studies that have been reported before and since the initiation of this study.31-33 In studies of patients with MBC, no other dose of paclitaxel administered every 3 weeks has led to significantly greater clinical benefit than that seen with 175 mg/m2/3 h.32 Results from another phase III trial confirmed that docetaxel 100 mg/m2 is associated with a higher response rate and favorable TTP and OS compared with lower doses.34

Randomized trials of chemotherapy for the treatment of women with MBC rarely demonstrate significant differences in OS.18,20,22,24-26,28 Superior survival was demonstrated for docetaxel compared with mitomycin/vinblastine19; docetaxel/capecitabine compared with docetaxel alone23; chemotherapy with trastuzumab compared with chemotherapy alone27; trastuzumab/docetaxel compared with docetaxel alone21; doxorubicin/docetaxel and doxorubicin/paclitaxel compared with fluorouracil, doxorubicin, and cyclophosphamide35,36; vinorelbine compared with melphalan37; fluorouracil, doxorubicin, and cyclophosphamide compared with cyclophosphamide, mitoxantrone, and fluorouracil38; oral versus IV cyclophosphamide, methotrexate, and fluorouracil39; and gemcitabine with paclitaxel versus paclitaxel monotherapy.40 Some of these studies were in the first-line setting, whereas the present study was of second-line therapy, which, given the availability of multiple lines of potential salvage therapy and the more progressive nature of the disease, might make it more difficult to demonstrate a survival advantage.

The results from this trial are encouraging for the use of docetaxel in the adjuvant setting. A definitive assessment will be available with the results from the Eastern Cooperative Oncology Group 1199 study, which compares weekly and every third week schedules of paclitaxel and docetaxel after doxorubicin/cyclophosphamide in patients with node-positive, early-stage breast cancer.

The incidence of grade 3/4 hematologic toxicities in patients receiving docetaxel in this study was similar to that reported in the literature.11,18-23,34 Prophylactic use of G-CSF has been shown to reduce the incidence of neutropenia and febrile neutropenia associated with the use of docetaxel.41-43 The incidence of grade 3/4 nonhematologic toxicities experienced by docetaxel patients was comparable to that reported in other studies.14,28-20,22,23 Exceptions include pain, asthenia, and neurotoxicity, which had a slightly higher incidence in this study. For paclitaxel patients in this study, the incidence of grade 3/4 hematologic and nonhematologic toxicities was comparable to that reported in the literature with the exception of infection, neutropenia, and neurotoxicity, which were less frequent in this study, and pain, which occurred more frequently.13,31 Despite a higher incidence of adverse events, many of which resulted in treatment discontinuation, patients in the docetaxel arm received more cycles of therapy. This reflects the higher incidence of discontinuations due to disease progression that was seen for paclitaxel patients. The higher incidence of adverse events in the docetaxel arm did not influence quality of life as measured by the FACT-B; there were no significant differences between treatments over time.

In conclusion, docetaxel (100 mg/m2 every 3 weeks) demonstrated superior efficacy compared with paclitaxel (175 mg/m2 every 3 weeks), providing significant clinical benefit in terms of survival and time to disease progression, with a numerically higher response rate and manageable toxicities.

The following institutions participated in the study: Froedtert Memorial Lutheran Hospital (Milwaukee, WI), Ohio State University Hospital (Columbus, OH), Scripps Memorial Hospital (San Diego, CA), Oklahoma Memorial Hospital (Oklahoma City, OK), Cancer Care Associates, PC (Royal Oak, MI), Baptist Regional Cancer Center (Knoxville, TN), Baptist Regional Cancer Institute (Jacksonville, FL), Roger Williams Medical Center (Providence, RI), Cancer and Hematology Centers of Western Michigan (Grand Rapids, MI), Marin Oncology Associates (Greenbrae, CA), New England Medical Center (Boston, MA), Medical Oncology/Hematology Program (Louisville, KY), Sharp Health Care (San Diego, CA), Interlakes Oncology (Rochester, NY), St John's Mercy Hospital (St Louis, MO), Eastern Connecticut Hematology/Oncology Association (Norwich, CT), Maine Center for Cancer Medicine (Scarborough, ME), University of Kansas Medical Center (Kansas City, KS), Pennsylvania Oncology/Hematology Associates (Philadelphia, PA), Hospital of The University of Pennsylvania (Philadelphia, PA), Cooper Cancer Institute (Voorhees, NJ), Sidney Kimmel Cancer Center (San Diego, CA), Montclair Regional Cancer Center (Birmingham, AL), University of Arkansas Cancer and Research Network (Little Rock, AR), University of South Carolina (Charleston, SC), University of Colorado Health Sciences Center (Denver, CO), Georgia Cancer Care Specialists (Decatur, GA), Cross Cancer Institute (Edmonton, Alberta, Canada), Hematology & Oncology Associates, LLC (Greenville, SC), Mayo Clinic Jacksonville (Jacksonville, FL), City of Hope Medical Center (Duarte, CA), Hospital Docteur Georges-L. Dumont (Moncton, New Brunswick, Canada), Toronto-Sunnybrook Regional Cancer Centre (Toronto, Ontario, Canada), Department d'Oncologie Hospital du Saint-Sacrement (Quebec, Canada), University of Colorado Health Sciences Center (Denver, CO), Nova Scotia Cancer Care and Research (Halifax, Nova Scotia, Canada), Providence Portland Medical Center, (Portland, OR), Southfield Oncology Institute (Southfield, MI), Response Oncology, Inc (Memphis, TN), Roger Williams Medical Center (Providence, RI), Scripps Memorial Hospitals San Diego Regional Cancer Center (San Diego, CA), Scott and White Clinic Medical Oncology (Temple, TX), Centre d'Oncologie Hospital Notre Dame (Montreal, Quebec, Canada), The Milton S. Hershey Medical Center (Hershey, PA), Texas Oncology, PA (Dallas, TX), Hematology & Oncology Consultants Inc. (Worthington, OH), Rush-Presbyterian St Luke's Medical Center (Chicago, IL), Wayne State University (Detroit, MI), University of Cincinnati (Cincinnati, OH), University of Michigan (Ann Arbor, MI), University of California Davis (Sacramento, CA), The Cleveland Clinic Foundation (Cleveland, OH), University of Texas Health Science Center (San Antonio, TX), Albany Medical College (Albany, NY), Sylvester Comprehensive Cancer Center (Miami, FL), Cedars Sinai Comprehensive Cancer Center (Los Angeles, CA), George Washington University (Washington, DC).

Although all authors have completed the disclosure declaration, 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. For a detailed description of the disclosure 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 in Information for Contributors.

AuthorsEmploymentLeadershipConsultantStockHonorariaResearch FundsTestimonyOther
S.E. JonesAventis (A)Aventis (B)
J. ErbanAventis (A)
B. OvermoyerAventis (A)Aventis (A)
G.T. BuddAventis (A); Novartis (A);
 Amgen (A)Sanofi-Aventis (B);
 Novartis (A);
 Amgen (A)
L. HutchinsAventis (A);
 AstraZeneca (A);
 Genentech (A);
 Pfizer (A)
E. LowerAventis (B)
L. LaufmanAventis (A)Aventis (A)
S. Sundaram
W.J. UrbaAventis Pasteur (A)
K.I. PritchardPharmacia (A);
 AstraZeneca (A);
 Pfizer (A)Pharmacia (A);
 AstraZeneca (A);
 Pfizer (A)
R. Mennel
D. RichardsGenentech (A)Pfizer (A)Sanofi (A)
S. OlsenSanofi-AventisSanofi-Aventis (A)
M.L. MeyersAventis PharmaceuticalsSanofi-Aventis
P.M. RavdinAventis (A)Aventis (B)

Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) ≥ $100,000 (N/R) Not Required

Table

Table 1. Baseline Characteristics of Randomly Assigned Patients

Table 1. Baseline Characteristics of Randomly Assigned Patients

CharacteristicDocetaxel (n = 225)
Paclitaxel (n = 224)
No. of Patients%No. of Patients%
Age, years
    Median5654
    Range22-9328-82
Karnofsky performance score
    Median9090
    Range40-10060-100
Menopausal status
    Premenopausal2712.03013.4
    Postmenopausal19888.019486.6
Extent of disease at random assignment
    Local/regional135.8188.0
    Metastatic21294.220692.0
Time from start of prior therapy to relapse, months
    Median20.320
    Range0-1520.92-144
Number of disease sites at random assignment
    Median22
    Range1-51-6
ER positive11551.19442.0
PR positive8236.47935.3
ER positive or PR positive12656.011250.0
ER negative/unknown and PR negative/unknown9944.011250.0
Prior treatment
    Any chemotherapy for MBC13158.211852.7
        Anthracycline22198.222098.2
            Neo/adjuvant10747.610948.7
            Adv/metastatic10446.210145.1
            Both94.0104.5
            Unknown10.400.0
    Hormonal therapy13459.611752.2
    Surgery19586.720290.2
    Radiotherapy13359.113058.0

Abbreviations: ER, estrogen receptor; PR, progesterone receptor; Neo, neoadjuvant; Adv, advanced.

Table

Table 2. Major Reasons for Ineligibility and Nonassessability Among Randomly Assigned Patients

Table 2. Major Reasons for Ineligibility and Nonassessability Among Randomly Assigned Patients

ReasonDocetaxel
Paclitaxel
No. of PatientsNo. of Patients
Randomly assigned patients225224
Reasons for ineligibility
    Lack of bidimensional disease54
    Laboratory values did not meet inclusion         criteria13
    Baseline laboratory values missing40
    Karnofsky performance score < 6020
     > One prior chemotherapy regimen for         advanced disease12
     < 3 weeks since last chemotherapy01
     > 12 months since adjuvant therapy10
Eligible patients211214
Reasons for nonassessability
    Received < two cycles of drug without         early progressive disease154
        Death30
        Treatment-related toxicity72
        Consent withdrawn51
        Noncompliance01
    Incomplete tumor assessments31
    Administration of incorrect study drug11
    > 6-week interval between cycle 1 and         cycle 211
    Study drug not administered22
Assessable patients189205
Table

Table 3. Response to Treatment (intention to treat population)

Table 3. Response to Treatment (intention to treat population)

ResponseDocetaxel (n = 225)
Paclitaxel (n = 224)
No. of Patients%No. of Patients%
CR52.2125.4
PR6729.84419.6
Overall response rate (CR + PR)7232.0*5625.0
95% CI25.9% to 38.1%19.3% to 30.7%
Stable disease8638.28939.7
Disease progression4017.86830.4
Nonassessable2712.0114.9
Duration of response, months7.54.6
95% CI5.8 to 9.13.9 to 6.0

Abbreviations: CR, complete response; PR, partial response.

*P = .10.

†Nonassessable because of incomplete tumor assessment.

P = .01.

Table

Table 4. Hematologic Adverse Events

Table 4. Hematologic Adverse Events

ToxicityDocetaxel (n = 222)
Paclitaxel (n = 222)
P
No. of Patients%No. of Patients%
Neutropenia
    Overall21395.918583.3< .0001<
    Grade 3/420793.312154.5< .0001
Febrile neutropenia3314.941.8< .001
Anemia
    Overall17177.013661.3< .0001
    Grade 3/42310.4167.3.24
Thrombocytopenia
    Overall11652.37031.5.0006
    Grade 3/4104.662.8.31
Table

Table 5. Nonhematologic Adverse Events Possibly or Probably Related to Treatment*

Table 5. Nonhematologic Adverse Events Possibly or Probably Related to Treatment*

Adverse EventTreatment Group
P
Docetaxel (n = 222)
Paclitaxel (n = 222)
Overall
Grade 3/4
Overall
Grade 3/4
No.%No.%No.%No.%
Any adverse event21998.612355.420994.15123.0< .001
Pain5223.4146.3602773.2.778
Asthenia16574.34620.712255.0115.0< .001
Peripheral edema10245.9156.82913.110.5< .001
Neurosensory14364.4167.213159.094.1.08
Nausea10949.1125.47132.062.7< .001
Stomatitis11451.42410.83616.200.0< .001
Diarrhea8538.3125.43716.710.5< .001
Infection7433.3229.9229.941.8< .001
Neuromotor6127.5115.02812.652.3.001
Myalgia5223.462.77433.373.2< .001
Skin disorders8337.4104.53214.400.0< .001
Vomiting6227.973.23515.800.0.0002

*Incidence of 3% or greater in either treatment group.

†For grade 3/4 toxicities.

© 2005 by American Society of Clinical Oncology

Supported by Aventis Pharmaceuticals, Bridgewater, NJ.

Presented at the European Cancer Conference (ECCO12), Copenhagen, Denmark, September 21-25, 2003, and the 26th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 3-6, 2003.

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

We thank Marianne Cascino for her clinical support and Meghan Shannon, PharmD, for the preparation and editorial review of this manuscript. We also thank Robert Earhart and Howard Fingert for their contributions at the initiation of this project.

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ARTICLE CITATION

DOI: 10.1200/JCO.2005.02.027 Journal of Clinical Oncology 23, no. 24 (August 20, 2005) 5542-5551.

Published online September 21, 2016.

PMID: 16110015

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