Originally published as JCO Early Release 10.1200/JCO.2005.05.0294 on October 10 2006

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Phase III Trial Comparing Three Doses of Docetaxel for Second-Line Treatment of Advanced Breast Cancer

Vernon Harvey, Henning Mouridsen, Vladimir Semiglazov, Erik Jakobsen, Edouard Voznyi, Bridget A. Robinson, Vanina Groult, Michael Murawsky, Soeren Cold

From the Department of Oncology, Auckland Hospital, Auckland; Department of Oncology, Christchurch Hospital, Christchurch, New Zealand; Department of Oncology, Rigshospitalet, Copenhagen; Department of Oncology, Vejle Sygehus, Vejle; Department of Oncology, Odense Universitetssygehus, Odense, Denmark; Department of Oncology, Petrov Research Institute of Oncology, St Petersburg; Department of Oncology, Research Institute of Diagnostics and Surgery, Moscow, Russian Federation; and Sanofi-Aventis, Antony, France; Sanofi-Aventis, Antony, France

Address reprint requests to Vernon Harvey, MD, Department of Oncology, Auckland Hospital, Private Bag 92-024, Auckland, New Zealand; e-mail: vernonh{at}adhb.govt.nz

	ABSTRACT

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Purpose To evaluate whether a relationship exists between docetaxel dose and clinical response in the treatment of patients with advanced breast cancer.

Patients and Methods Patients whose cancer had progressed after one prior chemotherapy regimen for advanced breast cancer or had recurred during or within 6 months of adjuvant chemotherapy were randomly assigned to docetaxel 60, 75, or 100 mg/m² intravenously every 3 weeks.

Results Five hundred twenty-seven patients were randomly assigned (intent to treat [ITT]), and 524 were assessable for toxicity. In the population assessable for efficacy (n = 407), logistic regression analysis showed that increasing docetaxel dose was significantly associated with higher response rate (P = .007) and improved time to progression (TTP; P = .014). In the ITT analysis, a significant dose-response relationship was observed for tumor response (P = .026) but not for TTP (P = .067). The incidences of most hematologic and nonhematologic toxicities were related to increasing dose, with grade 3 to 4 neutropenia occurring in 76.4%, 83.7%, and 93.4% and febrile neutropenia occurring in 4.7%, 7.4%, and 14.1% of patients administered the 60, 75, and 100 mg/m² doses, respectively. One death was considered treatment related.

Conclusion A relationship between increasing dose of docetaxel and increased tumor response was observed across the dose range of 60 to 100 mg/m² every 3 weeks. Toxicities were related to increasing dose. Depending on the therapy goal, any of the doses studied may be appropriate for second-line treatment of advanced breast cancer.

	INTRODUCTION

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Docetaxel is one of the most active chemotherapies in breast cancer. Phase II studies of second-line single-agent docetaxel 100 mg/m² every 3 weeks showed overall objective tumor response rates exceeding 50%.^1,2 Phase III trials showed higher response rates with second-line single-agent docetaxel compared with doxorubicin (47.8% v 33.3%, respectively; P = .008),³ mitomycin plus vinblastine (30.0% v 11.6%, respectively; P < .0001),⁴ or methotrexate plus fluorouracil (42% v 21%, respectively; P < .001)⁵ but not compared with fluorouracil plus vinorelbine (43.0% v 38.9%, respectively; P = .69)⁶ and paclitaxel (32.0% v 25.0%, respectively; P = .1).⁷ Time to tumor progression (TTP) was better with docetaxel than with mitomycin plus vinblastine (19 v 11 weeks, respectively; P = .001),⁴ methotrexate plus fluorouracil (6.3 v 3 months, respectively; P < .001),⁵ and paclitaxel (5.7 v 3.6 months, respectively; P < .0001),⁷ and docetaxel improved overall survival compared with mitomycin plus vinblastine (11.4 v 8.7 months, respectively; P < .01)⁴ and paclitaxel (15.4 v 12.7 months, respectively; P = .03).⁷ Toxicity of docetaxel was generally predictable and manageable.

Docetaxel is active over a range of dosages, with toxicities dependent on the dose. Studies have shown substantial antitumor activity, with potential tolerability advantages, in patients with previously treated metastatic breast cancer who received 60 mg/m^{2 8-10} or 75 mg/m² every 3 weeks.^11,12 One study showed an overall response rate of 33% in 129 patients treated with second-line docetaxel 75 mg/m² every 3 weeks,¹¹ and overall response rates of 40% to 56% were reported in three Japanese studies, with 183 patients receiving 60 mg/m².^8-10

Phase II and III trials suggest a dose relationship exists for both antitumor activity and toxicity. In addition, the linear pharmacokinetics of docetaxel suggest a predictable relationship between the dose administered and tumor exposure.¹³ The aim of the present study was to assess whether a dose-response relationship exists in efficacy and to compare the overall response rates with three doses of docetaxel (60, 75, and 100 mg/m² every 3 weeks) in patients with advanced breast cancer who experienced treatment failure with prior chemotherapy.

	PATIENTS AND METHODS

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This open-label, randomized, phase III trial involving 70 centers in 14 countries was conducted in accordance with the Declaration of Helsinki and local regulations and was approved by independent ethics committees and review boards. Eligible patients were female, aged 18 years, and had cytologically or histologically confirmed unresectable locally advanced or metastatic breast cancer. Other eligibility criteria included the following: at least one bidimensionally measurable lesion, failure of a single prior chemotherapy regimen for advanced disease, or relapse during or within 6 months of adjuvant chemotherapy; Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2; absolute neutrophil count 2,000/µL; platelets 100,000/µL; total bilirubin institution upper limit of the normal (ULN); ALT and AST 2.5x ULN; alkaline phosphatase 5x ULN; negative pregnancy test (if appropriate); and written informed consent.

Exclusion criteria included history of other malignancy (except nonmelanoma skin cancer and cervical carcinoma in situ); brain metastases; National Cancer Institute Common Toxicity Criteria (NCI-CTC) peripheral neuropathy grade 2; and other serious illness or medical conditions. Chemotherapy, immunotherapy, or biologic systemic anticancer therapy within 21 days of study entry (42 days for mitomycin and nitrosoureas); prior taxanes; radiation therapy within 28 days (3 months for bone marrow exposure 20%); hormonal therapy within 4 weeks; and concomitant bisphosphonates were not permitted.

Treatment
The trial was originally designed with two arms (100 and 75 mg/m²); the 60 mg/m² arm was introduced in a protocol amendment (October 1996). Docetaxel was administered as a 1-hour intravenous infusion every 3 weeks for at least six cycles until disease progression, unacceptable toxicity, or discontinuation at the request of the patient or investigator. Dexamethasone 8 mg premedication was administered orally every 12 hours, starting 24 hours before docetaxel infusions, for 2.5 days (five doses).

An absolute neutrophil count 1,500/µL and platelet count 100,000/µL were required on the day of treatment. Granulocyte colony-stimulating factor (G-CSF) was administered to patients who, in a previous cycle, developed grade 4 neutropenia lasting more than 7 days or that was associated with fever (at least three readings 38°C within 24 hours or one reading 38.5°C) requiring parenteral antibiotics or with documented infection. For grade 4 neutropenia (as described earlier) despite secondary G-CSF prophylaxis, docetaxel was withheld until recovery (up to 3 weeks), and subsequent doses were reduced.

Up to two dose reductions per patient were allowed for the 100 mg/m² arm (to 75 then to 60 mg/m²) and 75 mg/m² arm (to 60 then to 45 mg/m²), and one dose reduction was allowed in the 60 mg/m² arm (to 45 mg/m²). Patients were withdrawn for grade 3 to 4 peripheral neuropathy or grade 4 hypersensitivity.

Evaluations
Pretreatment evaluations included complete medical history, physical examination, tumor evaluation, hematology and biochemistry, and an ECG. Assessments of clinically measurable (two dimensions) and assessable (one dimension only) tumors were made after each cycle. Radiologic tumor assessments were performed every three cycles to confirm response and every 3 months during follow-up until progression. Responses were classified according to WHO criteria.¹⁴ Adverse events (monitored at each cycle, at treatment completion, and 1 month after last treatment) were graded according to NCI-CTC version 2.0.¹⁵ Adverse events not included in NCI-CTC were graded mild, moderate, severe, or life threatening. Hematology was assessed either weekly or every 2 days in cases of febrile or grade 4 neutropenia.

Pharmacokinetic studies were optional. Blood samples were collected during the first cycle before, just before the end of, and 1 to 5 hours after completion of the docetaxel infusion. Samples were analyzed by high-performance liquid chromatography. Docetaxel clearance was estimated using the NONMEM program (version V, 2.0; GloboMax, San Francisco, CA), and the area under the plasma drug concentration versus time curve (AUC) for docetaxel was calculated as dose divided by clearance.

Data Analysis
The primary objectives were to assess the relationship between docetaxel dose and overall tumor response (complete and partial responses) and to compare the response rates between the three docetaxel doses. Secondary efficacy end points included TTP (from random assignment until first documented tumor progression or death), duration of response (from first response until disease progression), and overall survival (from random assignment to death from any cause). For TTP and duration of response, patients without disease progression were censored at the date of last tumor assessment or beginning of new systemic antitumor therapy, whichever came first.

Statistical analyses for tumor response, TTP, and duration of response were performed on the assessable and intent-to-treat (ITT) populations. Assessable patients had no major protocol violations and received two treatment cycles (or one cycle if progression was best response) and had one follow-up assessment 4 weeks after the initial evaluation. For overall survival, only the ITT analysis was protocol planned. Safety was analyzed for all patients who received at least one docetaxel infusion.

The study was designed to detect an odds ratio for tumor response of 1.019 per mg/m² of docetaxel using a 5% two-sided test (equivalent to a 62% improvement in the odds of a response for docetaxel 100 v 75 mg/m², and a 33% improvement for docetaxel 75 v 60 mg/m²). A 30% to 40%⁴ tumor response rate for docetaxel 100 mg/m² was expected, and assuming 10% nonassessable patients, a sample size of 150 patients per group (450 total patients) would ensure a power of 80% to 86%.

Dose-response relationships were assessed by logistic regression models for tumor response and by Cox's proportional hazards models for time-to-event variables. Overall response rates were compared using ² tests. Time-to-event variables were summarized using the Kaplan-Meier method, and treatment groups were compared using the log-rank test. The Cochran-Mantel-Haenszel test for overall proportions was used to compare toxicities. All statistical tests were two sided and at the 5% significance level; no corrections for multiplicity were made.

	RESULTS

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Patient Characteristics
From September 1995 to April 2001, 527 patients underwent random assignment (the 60 mg/m² group had fewer patients because it was added later). A total of 407 patients were assessable for efficacy (122, 146, and 139 patients in the 60, 75, and 100 mg/m² groups, respectively), 81 patients were ineligible, and 39 patients were nonassessable. Main reasons for ineligibility were failure to meet criteria for having unresectable locally advanced/metastatic disease with failure of only one previous chemotherapy regimen for advanced disease (n = 29) and no baseline bidimensionally measurable lesion (n = 10). Three patients with an ECOG PS of more than 2 were ineligible. Main reasons for nonassessability for efficacy were lack of tumor assessment after baseline (n = 15) and on-study bisphosphonate use (n = 11). Groups were well balanced with respect to age and ECOG PS (Table 1).

There was a statistically significant dose-response relationship for TTP in the assessable population (P = .014) and a difference in TTP among treatment groups (P = .037; Fig 1A). The TTP in the assessable population was better with docetaxel 100 mg/m² compared with both 75 mg/m² (median TPP, 18.6 v 13.9 weeks, respectively; P = .033) and 60 mg/m² (median TTP, 18.6 v 13.7 weeks, respectively; P = .023), but TTP was similar for the two lower doses (Table 3). A secondary ITT analysis of TTP showed only borderline evidence of a dose-response relationship (P = .067) and no significant difference in TTP among the treatment groups (P = .16; Fig 1B), and only the pair-wise comparison between the 60 and 100 mg/m² groups approached statistical significance (P = .060).

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. (A) Time to progression in the assessable population. (B) Time to progression in the intent-to-treat population.

View larger version (14K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Overall survival in the intent-to-treat population.

The incidence of febrile neutropenia increased with dose (Table 4), and approximately 50% of cases occurred at first cycle. The proportion of patients requiring at least one course of prophylactic G-CSF increased with dose (8.7%, 17.9%, and 30.3% of patients receiving 60, 75, and 100 mg/m², respectively), as did the use of prophylactic antibiotics.

The most common nonhematologic adverse effects are listed in Table 5. There was a statistically significant relationship between treatment group and overall frequency of treatment-related adverse events for alopecia (P = .003), hypersensitivity (P = .045), asthenia (P = .005), fever in the absence of infection (P < .001), infection (P = .005), neuromotor toxicity (P = .004), neurosensory toxicity (P < .001), pain (P = .005), pulmonary toxicity (P = .033), nail disorders (P < .001), peripheral edema (P < .001), skin toxicity (P = .002), and stomatitis (P = .001). In the 60, 75, and 100 mg/m² groups, one or more treatment-related adverse events were reported in 87.2%, 93.7%, and 95.1% of patients, respectively, and one or more grade 3 to 4 treatment-related adverse events were reported in 18.8%, 27.9%, and 44.3% of patients, respectively. Treatment discontinuations caused by adverse events occurred in 5.3%, 6.9%, and 16.5% of patients in the 60, 75, and 100 mg/m² groups, respectively.

Pharmacokinetics
Pharmacokinetic analyses were conducted at cycle 1 in 69 patients. Docetaxel clearance was similar among groups (Table 6). The relationship between dosage and AUC was linear across the dose range studied. Figure 3 shows a regression analysis of the AUC versus the initial dose in responders and nonresponders. There was no statistically significant relationship between objective response rate and docetaxel exposure (AUC). There was no statistically significant relationship between docetaxel dose and tumor response in the 60 assessable patients.

View larger version (8K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Area under the plasma drug concentration versus time curve (AUC) against initial dose in responders and nonresponders (intent-to-treat population).

	DISCUSSION

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Phase II studies of docetaxel 75 and 100 mg/m² administered every 3 weeks in metastatic breast cancer patients have shown overall response rates of up to 68% for first-line chemotherapy¹⁶ and up to 58% for second-line chemotherapy, with rates of 29% to 50% in anthracycline-resistant patients.¹⁶ Antitumor activity has been demonstrated at docetaxel doses as low as 60 mg/m² every 3 weeks.^8-10

The overall tumor response observed with 100 mg/m² is comparable with response rates of 30% to 43% in previous phase III studies in patients with metastatic breast cancer who experienced treatment failure with anthracycline treatment.^4-7,17 The response rates observed for the 60 and 75 mg/m² doses of docetaxel in our trial (22.1% and 23.3%, respectively) were lower than those reported in previous phase II studies (33% to 40%^8-12). However, most of these studies were small and not directly comparable with the present trial. No other phase III study has investigated these doses of docetaxel as monotherapy.

Median TTP showed greater benefit for docetaxel 100 mg/m² than for 75 mg/m² and 60 mg/m² in the assessable population (18.6 v 13.9 and 13.7 weeks, respectively). However, the results in the ITT population were less clear for TTP, particularly in the comparison of 75 mg/m² (15.0 weeks) and 100 mg/m² (16.6 weeks). Overall survival in the ITT population was similar across groups (up to 12.3 months). Analysis of survival in assessable patients suggested a dose-response relationship, although this analysis was retrospective and unplanned and may be subject to bias. The similar efficacy of the 60 and 75 mg/m² doses suggests that the difference in the doses was too small to detect differences in activity.

We observed no statistically significant relationship between objective response rate and docetaxel exposure (AUC) probably because of the small number of patients evaluated. Because approximately 75% of patients received additional antitumor treatment after completing the trial, the contribution of subsequent therapy to survival cannot be excluded.

In general, the incidence and severity of adverse events increased with docetaxel dose. Hematologic toxicity predominated as expected and as reported previously. The 93.4% incidence of grade 3 to 4 neutropenia with docetaxel 100 mg/m² agrees with other phase III trials in metastatic breast cancer,^4-6 although the 76.4% incidence with docetaxel 60 mg/m² was somewhat lower than in phase II studies (85.9% to 94.1%).^8-10 Interestingly, despite the increased incidence of adverse events, dose intensity was more than 97% in all groups, perhaps assisted by the greater use of G-CSF in the higher dose groups (8.7%, 17.9%, and 30.3% of patients in the 60, 75, and 100 mg/m² groups, respectively). The incidences and severities of most other adverse events, including fluid retention, were associated with increasing docetaxel dose. Although frequencies of febrile neutropenia and grade 3 to 4 infection were dose related, the only treatment-related death was in the lowest dose group and was not associated with hematologic toxicity. Treatment discontinuations were more than twice as frequent with the highest dose than with the other doses. Adverse events generally associated with cumulative dose, such as nail changes, neuropathy, and fluid retention, were more common at higher doses.

Enrollment exceeded the target of 450 patients, and the size of the assessable population was close to this target. Hence, any potential loss of statistical power as a result of nonassessable patients (23%) is likely to be minimal. Importantly, the results for the ITT and assessable populations concur in terms of data interpretation.

In conclusion, a dose-response relationship is apparent across the dose range of 60 to 100 mg/m² every 3 weeks for docetaxel. The highest dose (100 mg/m²) achieved the greatest activity in terms of response rate and TTP in assessable patients; the higher incidence and severity of adverse events in this group did not compromise drug delivery. Overall, all three doses of docetaxel were active, with manageable toxicity. Depending on the goals of therapy and the individual characteristics of the patient, each of the doses evaluated in this trial may be appropriate, with lower doses having potential utility in patients who are frail or have specific tolerability concerns.

	Authors' Disclosures of Potential Conflicts of Interest

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Although all authors completed the disclosure declaration, the following authors or their immediate family members 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.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Vanina Groult Sanofi-Aventis Michael Murawsky Sanofi-Aventis Sanofi-Aventis

	Author Contributions

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Provision of study materials or patients: Vernon Harvey, Henning Mouridsen, Vladimir Semiglazov, Erik Jakobsen, Bridget A. Robinson, Soeren Cold Collection and assembly of data: Vernon Harvey, Henning Mouridsen, Vladimir Semiglazov, Bridget A. Robinson, Vanina Groult, Soeren Cold Data analysis and interpretation: Vernon Harvey, Henning Mouridsen, Vanina Groult, Michael Murawsky Manuscript writing: Vernon Harvey, Bridget A. Robinson Final approval of manuscript: Vernon Harvey, Henning Mouridsen, Erik Jakobsen, Edouard Voznyi, Bridget A. Robinson, Soeren Cold

 

	ACKNOWLEDGMENTS

 
We thank the women who participated in this study and the investigators who recruited patients. We thank May Alakl, MD, and Steve Olsen, MD, PhD, for their contribution to this project.

	NOTES

 
published online ahead of print at www.jco.org on October 10, 2006.

Supported by Sanofi-Aventis, Paris, France.

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

	REFERENCES

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5. Sjöström J, Blomqvist C, Mouridsen H, et al: Docetaxel compared with sequential methotrexate and 5-fluorouracil in patients with advanced breast cancer after anthracycline failure: A randomised phase III study with crossover on progression by the Scandinavian Breast Group. Eur J Cancer 35:1194-1201, 1999[CrossRef][Medline]

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Submitted December 4, 2005; accepted September 1, 2006.

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