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The Oncologist, Vol. 9, Suppl 2, 24–32, June 2, 2004
© 2004 AlphaMed Press

Docetaxel and Paclitaxel in the Treatment of Breast Cancer: A Review of Clinical Experience

John Crown, Michael O’Leary, Wei-Seong Ooi

St. Vincent’s University Hospital, Dublin, Ireland

Correspondence: John Crown, M.D., Medical Oncology Research Unit, St. Vincent’s University Hospital, Elm Park, Dublin 4, Ireland. Telephone: 353-1-2094839; Fax: 353-1-2837719; e-mail: john.crown{at}icorg.ie


   LEARNING OBJECTIVES
Top
 Learning Objectives
Abstract
 Introduction
 Taxanes in Metastatic Breast...
 Taxanes in Early-Stage Breast...
 Summary
 References
 
After completing this course, the reader will be able to:

  1. Describe randomized trial data from studies evaluating taxanes in anthracycline-naïve or anthracycline-pretreated metastatic breast cancer patients.
  2. Discuss recent findings of randomized trials evaluating docetaxel as neoadjuvant therapy.
  3. Compare and contrast efficacy end point data from three adjuvant taxane trials with mature results.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 Taxanes in Metastatic Breast...
 Taxanes in Early-Stage Breast...
 Summary
 References
 
In the 10 years since their initial licensing in Europe, the taxanes, paclitaxel and docetaxel, have emerged as fundamental drugs in the treatment of breast cancer. Clinically meaningful benefits were first shown in the metastatic setting, and large-scale exploration of their roles in the adjuvant therapy of early-stage disease is ongoing. Benefits have been seen in the neoadjuvant setting as well, mainly with docetaxel. This paper reviews the current roles of the taxanes in the treatment of metastatic and early-stage breast cancer. Also addressed are outstanding issues involving optimal dosing and sequencing, as well as a discussion of the relative merits of each agent in this setting. Clinicians should choose a taxane-based regimen for their patients with breast cancer based on consideration of the pharmacokinetics, clinical activity, and dosing schedule that best meets the patients’ needs. At the current time, the pharmacokinetic profile, consistent positive clinical results, and convenience of an intermittent, short-infusion schedule have made docetaxel the preferred taxane for many clinicians treating patients with breast cancer.

Key Words. Taxanes • Docetaxel • Paclitaxel • Breast cancer • Metastatic breast cancer • Adjuvant treatment • Neoadjuvant treatment


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Taxanes in Metastatic Breast...
 Taxanes in Early-Stage Breast...
 Summary
 References
 
The taxanes have emerged as critically important drugs in the treatment of patients with breast cancer. The relatively accelerated clinical development of these agents can be attributed to the rapid collection of an unprecedented amount of data from numerous large, high-quality prospective random assignment trials, trials that involved literally tens of thousands of patients.

As a result of these investigations, the taxanes were generally recognized as evidence-based components of therapy for metastatic breast cancer (MBC) within a few short years of their initial phase II evaluations. In addition, the data in support of their use in the adjuvant and neoadjuvant settings continue to strengthen. In this paper, we review the current status of taxane therapy of breast cancer, with a particular emphasis on data from random assignment trials.


   TAXANES IN METASTATIC BREAST CANCER
Top
 Learning Objectives
 Abstract
 Introduction
 Taxanes in Metastatic Breast...
Taxanes in Early-Stage Breast...
 Summary
 References
 
Evaluation as Single Agents
The activity of the taxanes in breast cancer was initially demonstrated in single-arm studies in women with metastatic disease [1–3]. Subsequent single-agent random assignment trials took place in two clinical settings, that is, in patients with and without prior anthracycline exposure.

Anthracycline-Naïve Patients
Three studies in anthracycline-naïve MBC patients have been performed. In the Aventis-sponsored TAX 303 trial, patients with prior alkylating agent exposure were randomly assigned to receive either docetaxel, 100 mg/m2, or doxorubicin, 75 mg/m2, every 3 weeks. Docetaxel produced a superior response rate (48% versus 33%; p = 0.008) and time to treatment failure. In addition, docetaxel was less myelotoxic, with statistically significantly lower rates of thrombocytopenia, anemia, transfusions of blood and platelets, and neutropenic sepsis [4].

Paclitaxel has been compared with doxorubicin in two trials. In a European Organization for Research and Treatment of Cancer study, paclitaxel (200 mg/m2 administered in a 3-hour infusion) was inferior to doxorubicin [5]. In an Eastern Cooperative Oncology Group (ECOG) trial, 24-hour paclitaxel and doxorubicin (60 mg/m2) produced equivalent results [6]. Paclitaxel has also been shown to be equivalent to CMFP (cyclophosphamide, methotrexate, fluorouracil, prednisone) chemotherapy as front-line treatment for patients with MBC [7]. Response rates (29% versus 35%; p = 0.37) and progression-free survival times (5.3 versus 6.4 months; p = 0.25) were similar in both arms. In the univariate analysis of the study, there was no difference in the overall survival (OS) time (estimated median OS: 17.3 months in the paclitaxel arm versus 13.9 months in the CMFP arm; p = 0.068), but in a multivariate analysis, the difference was significant (p = 0.025).

Anthracycline Pretreated Patients
Docetaxel has been extensively studied in MBC patients with prior anthracycline treatment. Single-agent docetaxel was superior to two combination regimens (mitomycin/vinblastine and methotrexate/5-fluorouracil [5-FU]) and equivalent to a third very intensive regimen (continuous infusion fluorouracil with vinorelbine) (Table 1Go) [8–10].


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  		Table 1. Randomized trials of single-agent docetaxel in MBC patients with prior anthracycline exposure
 
Single-agent paclitaxel has also been studied in patients with prior anthracycline exposure in a randomized trial [11]. When compared with the salvage regimen cisplatin/etoposide, paclitaxel was found to be inferior with respect to response rate and time to progression in this population.

These data suggest that docetaxel might be the more active taxane in MBC. A degree of support for this hypothesis was recently provided by the results of the first direct randomized comparison between paclitaxel and docetaxel. In that study, reported by Ravdin and colleagues [12], docetaxel, 100 mg/m2, was compared with paclitaxel, 175 mg/m2, given every 3 weeks in a group of 449 women with advanced breast cancer and prior anthracycline treatment. While the difference in overall response rate (ORR) did not reach statistical significance, the time to progression (TTP) and OS time were significantly superior for docetaxel (Table 2Go). The incidence of febrile neutropenia (15% versus 2%) was significantly higher in the docetaxel arm. While the incidences of other nonhematologic toxicities (vomiting, diarrhea, stomatitis, asthenia, neuromotor toxicity, and peripheral edema) were significantly higher in the docetaxel arm, this may be partly artifactual, reflecting the fact that docetaxel patients developed progressive disease later and, as a result, had more cycles of taxane treatment.


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  		Table 2. Results of a phase III trial of docetaxel versus paclitaxel in MBC patients (intent-to-treat population) [12]
 
Combination Regimens in MBC
Docetaxel and paclitaxel have also been studied in combination with anthracyclines (Table 3Go) [6, 13–19]. In all four studies that compared docetaxel/anthracycline with older anthracycline regimens, the docetaxel/anthracycline arm produced a superior response. In three of the four studies, there was also an advantage for the docetaxel combination in time to progression, and in two of the four studies, a benefit in overall survival was observed for the docetaxel combination.


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  		Table 3. Randomized trials of anthracycline/taxane combinations versus polychemotherapy for MBC patients
 
The data for anthracycline/paclitaxel combinations are less consistent, and advantages over traditional anthracycline-containing regimens were seen in only one of those four trials. In addition, the combination of paclitaxel and an anthracycline is potentially cardiotoxic, presumably due to a pharmacokinetic interaction that results in increased levels of doxorubicinol, a cardiotoxic metabolite of doxorubicin [20, 21]. Two approaches have been used to minimize this interaction: administering paclitaxel at a standard rate of infusion several hours to 1 day prior to doxorubicin and prolonging the paclitaxel infusion to 24 hours and administering the dose after completion of doxorubicin. There is no such interaction between conventional doses of docetaxel and anthracyclines, and the risk of cardiotoxicity is not increased with this combination.

The combination of docetaxel plus capecitabine was superior to single-agent docetaxel in patients with anthracycline-pretreated MBC [22]. Patients were randomized to treatment with either capecitabine, 1,250 mg/m2 twice a day on days 1–14, plus docetaxel, 75 mg/m2 on day 1 (n = 255), or docetaxel, 100 mg/m2, alone (n = 256) in this phase III trial. Cycles were repeated every 3 weeks. The overall survival time (median OS: 14.5 versus 11.5 months, respectively; p = 0.0126), TTP (median TTP: 6.1 versus 4.2 months; p = 0.0001), and ORR (42% versus 30%; p = 0.0006) all favored the combination. The toxicities associated with each regimen were manageable; there were more grade 3 events with the combination regimen and more grade 4 events with docetaxel alone. There was limited crossover.

Taxane/Trastuzumab Combinations
In a pivotal registration trial, which was partly based on laboratory observations that showed a beneficial interaction between paclitaxel and anti-HER-2 antibodies, the combination of trastuzumab and paclitaxel was compared with the taxane as a single agent in patients with HER2-overexpressing MBC [23]. The combination produced superior response and progression-free and overall survival rates.

Other taxane-based combinations are also under investigation. For example, based on in vitro synergistic activity [24], a combination of docetaxel, a platinum salt, and trastuzumab is under investigation in patients with HER2-positive breast cancer. The Breast Cancer International Research Group (BCIRG) recently completed two phase II trials that evaluated the combination; BCIRG 101 used cisplatin in the regimen (TCisH), while BCIRG 102 used carboplatin (TCarboH) [25]. Sixty-two patients participated in each study. Each regimen was generally well tolerated, and more than 80% of the patients in each study completed six or more cycles of treatment. The ORR to TCisH was 79%, and the ORR to TCarboH was 64% in patients found to be HER2 positive by fluorescence in situ hybridization (FISH). Median TTPs were 9.9 months overall and 12.7 months for patients with HER2-positive disease who received TCisH. Median TTPs were 12 months overall and 17 months for HER2-positive patients treated with TCarboH. These results formed the basis for BCIRG trials 006 and 007. The BCIRG 007 trial is comparing TCH (doctaxel, carboplatin, trastuzumab) with TH (docetaxel/trastuzumab) as first-line chemotherapy in women with FISH-confirmed, HER2-positive advanced breast cancer. The BCIRG 006 trial is a three-arm study comparing: A) TCH; B) doxorubicin/cyclophosphamide followed by docetaxel (AC->T); and C) doxorubicin/cyclophosphamide followed by docetaxel and trastuzumab (AC->TH) as adjuvant treatment for women with HER2-positive, node-positive or high-risk node-negative operable breast cancer. Both trials are currently enrolling patients, with accrual expected to be complete in 2004.

The combination of paclitaxel, carboplatin, and trastuzumab (TPC) produced a superior response rate and TTP, relative to paclitaxel/trastuzumab (TP), in patients with HER2-positive advanced breast cancer [26]. TTP was 11.2 months (versus 6.9 months; p = 0.007), and the response rate was 52% (versus 36%; p = 0.04) with this approach, providing support for the University of California-Los Angeles work that suggested that platinums might produce a major benefit in this setting.


   TAXANES IN EARLY-STAGE BREAST CANCER
Top
 Learning Objectives
 Abstract
 Introduction
 Taxanes in Metastatic Breast...
 Taxanes in Early-Stage Breast...
Summary
 References
 
Taxane-Based Neoadjuvant Therapy
Docetaxel is under active investigation in the neoadjuvant setting. The results of three randomized trials demonstrate that the sequential use of neoadjuvant docetaxel produces superior clinical and pathological responses in locally advanced breast cancer (Table 4Go) [27–29].


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  		Table 4. Randomized trials of sequential docetaxel as neoadjuvant therapy
 
Trial B-27 from the National Surgical Adjuvant Breast and Bowel Project (NSABP) demonstrated that the addition of four cycles of sequential, preoperative docetaxel to preoperative AC chemotherapy produced a significantly superior outcome relative to four cycles of AC alone [27]. In that study, 2,411 women with operable primary breast cancer were enrolled to one of three treatment groups: four cycles of neoadjuvant AC followed by surgery; four cycles of neoadjuvant AC followed by four cycles of docetaxel followed by surgery; or four cycles of neoadjuvant AC followed by surgery followed by four cycles of docetaxel. Women receiving the sequential AC/docetaxel neoadjuvant regimen had significantly greater clinical, overall, and pathologic complete response (pCR) rates than those receiving AC alone. Further follow-up is needed to determine if the superior pCR rate and superior rate of negative axillary lymph nodes will result in better long-term survival.

Some have criticized the design of the NSABP B-27 trial because the preoperative regimens were of different durations (four versus eight cycles) and suggested that the favorable results in the AC/docetaxel arm may be due to the delivery of additional cycles of chemotherapy rather than a distinct taxane benefit. However, the results of a study conducted at the University of Aberdeen, in which eight cycles of neoadjuvant CVAP (cyclophosphamide/vincristine/doxorubicin/prednisolone) chemotherapy were compared with four cycles of CVAP followed by four cycles of docetaxel (eight cycles total) prior to surgery, suggest that the addition of the taxane is indeed beneficial [28]. In that trial, 162 patients with large or locally advanced breast cancer were randomized to the study regimens, and 145 patients completed eight cycles of neoadjuvant therapy. The ORR and pCR rate were higher for the patients who received docetaxel than for those who received eight cycles of CVAP. The results were statistically significant in the primary analysis and in the intent-to-treat population. Furthermore, two patients who received eight cycles of CVAP developed progressive disease after initially responding to the first four cycles of CVAP, which suggests the development of acquired resistance to the regimen. This observation was not seen in the docetaxel group, and this finding supports the use of non-cross-resistant chemotherapy combinations such as anthracyclines plus taxanes.

The NSABP B-27 data are corroborated by the results of the GEPARDUO trial conducted by the German Adjuvant Breast Cancer Group, which compared four cycles of dose-dense AT (doxorubicin/docetaxel) given concomitantly with a sequential regimen of four cycles of doxorubicin/cyclophosphamide followed by four cycles of docetaxel (AC-T) as neoadjuvant therapy in 913 patients with operable breast carcinoma [29]. In the primary analysis, AC-T was associated with a superior pCR rate and ORR, as well as a greater rate of breast-conserving surgery and higher incidence of pathologically negative axillary lymph nodes.

Conversely, interim results of a phase III trial conducted by the Anglo-Celtic Cooperative Oncology Group showed that there was no benefit to using a concomitant docetaxel/doxorubicin regimen every 3 weeks, relative to AC, in the neoadjuvant setting [30]. A total of 363 women with locally advanced breast cancer were randomized in that trial. At the time of analysis, there was a trend toward a higher ORR with AT (72% versus 62%; p = 0.07), but there were no differences in rates of pCR, axillary lymph node involvement, relapse-free survival, or overall survival. Follow-up continues, although these early results suggest the importance of scheduling with respect to outcomes.

Taxane-Based Adjuvant Therapy
The clinical activity of the taxanes in the MBC setting mandated their evaluation as postoperative adjuvant therapy for patients with early-stage disease. To date, mature data are available from three trials in which taxane-containing regimens were compared with nontaxane-containing regimens.

In the Cancer and Leukemia Group B (CALGB) 9344 trial, patients with node-positive breast cancer were randomly assigned to receive either four cycles of AC alone, or that treatment followed by four cycles of paclitaxel (in a subrandomization, variation in doxorubicin dosage had no impact) [31–34]. The results at each analysis are presented in Table 5Go. The addition of paclitaxel produced superior disease-free and overall survival rates. The adequacy of the control arm in this (and the next) study have been the subject of discussion.


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  		Table 5. Interim analyses of the CALGB 9344 trial of AC versus AC->paclitaxel in early breast cancer
 
In the NSABP B-28 trial, 3,060 patients with node-positive operable breast cancer were randomized to receive either AC for four cycles or AC for four cycles followed by paclitaxel (at a dose of 225 mg/m2) every 3 weeks for 4 cycles [35]. With a median follow-up of 64 months, the results of the definitive analysis, presented in 2003, showed a significantly higher disease-free survival rate with sequential paclitaxel than with AC alone (76% versus 72%; p = 0.008). There was no difference in overall survival between treatment groups (85% both groups).

The BCIRG has reported interim results from the first large-scale, international trial that evaluated docetaxel in place of fluorouracil in the FAC (fluorouracil/doxorubicin/ cyclophosphamide) regimen for the adjuvant treatment of early breast cancer [36, 37]. In the BCIRG 001 trial, 1,491 patients were randomized to receive treatment with either TAC (docetaxel/doxorubicin/cyclophosphamide at doses of 75/50/500 mg/m2, respectively) or FAC (fluorouracil/doxorubicin/cyclophosphamide at doses of 500/50/500 mg/m2, respectively) every 3 weeks for six cycles. The median follow-up was 33 months at the time of the first planned interim analysis and 55 months at the second planned analysis. Both treatments were generally well tolerated, with high rates of treatment compliance and completion. In both analyses, the TAC regimen was found to be superior to FAC in terms of the primary end point, disease-free survival (DFS) (Table 6Go). TAC produced a 28%-32% reduction in the risk of recurrence in the two analyses. At the time of the interim analyses, too few events had occurred to demonstrate a significant difference in the subgroup of patients with four or more positive nodes; however, the study is powered to detect a difference in this group in the final analysis. The higher DFS rate in the TAC group translated into a survival benefit; the trend toward longer survival with TAC at 33 months reached statistical significance at the 55-month median follow-up.


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  		Table 6. Interim results of the BCIRG 001 trial of TAC versus FAC in early-stage breast cancer [36, 37]
 
The principal toxicity associated with both the TAC and FAC treatments was myelosuppression. Febrile neutropenia was significantly more common in patients treated with TAC than in those treated with FAC (24% versus 2.4%, respectively; p <= 0.05), although the incidence of grade 3/4 infections was low in both groups (3.1% and 1.5%, respectively). There were no deaths due to sepsis. Nonetheless, the prophylactic use of growth factors may be warranted with TAC to ameliorate febrile neutropenia and its consequences.

Optimal Taxane Schedules
In most random assignment trials, paclitaxel and docetaxel have been given every 3 weeks; however, nonclassic schedules may favorably affect the therapeutic ratio. In phase II trials, weekly lower dose taxanes were associated with a lower incidence of febrile neutropenia [38–42]. Efficacy appeared to be maintained while toxicity was lower, which may allow certain older or frail patients or those with low baseline blood counts to be treated [43]. For example, rates of grade 3/4 neutropenia ranged from 4%-14% in the docetaxel trials and from 15%-24% in the paclitaxel trials. Rates of febrile neutropenia were less than 2% in all five studies. Weekly docetaxel was generally well tolerated in a group of elderly or frail patients who were studied in a nonrandomized trial [40]. One randomized trial compared weekly docetaxel (40 mg/m2 weekly x 6 weeks followed by 2 weeks of rest) with docetaxel at a dose of 100 mg/m2 given every 3 weeks in MBC patients [44]. Among 83 enrolled patients, the response rates and TTP were similar (ORR: 44% versus 38%, respectively; TTP: 3.7 versus 4.4 months, respectively), and there was a trend toward lower incidences of grade 3/4 neutropenia and febrile neutropenia in the weekly docetaxel group.

Weekly administration of paclitaxel showed promising activity in a randomized trial comparing weekly with every-3-week paclitaxel monotherapy followed by four cycles of FAC as neoadjuvant therapy in 258 women with operable breast cancer [45]. Weekly paclitaxel produced a higher pCR rate than the conventional schedule (28.8% versus 13.6%; p < 0.01). While the results to date are encouraging, data from additional large randomized controlled trials are needed.

Another dosing strategy under active investigation is dose-dense therapy, in which the chemotherapy schedule is compressed. According to the Gompertzian model proposed by Norton, dose-dense therapy would improve clinical outcomes by preventing significant tumor regrowth between cycles [46]. The first clinical trial to demonstrate survival benefits associated with dose-dense therapy, CALGB 9741, evaluated a taxane-based adjuvant chemotherapy regimen in patients with early breast cancer [47]. A total of 2,005 patients with operable breast cancer were randomized to one of four treatment groups in this 2 x 2 factorial design study. The study sought to evaluate sequential ATC (doxorubicin followed by paclitaxel followed by cyclophosphamide) chemotherapy versus concurrent AC followed by paclitaxel (T), as well as standard every-3-week dosing and biweekly (dose-dense) dosing. There were no differences in DFS or OS for the concurrent or sequential schedules. However, DFS and OS were significantly better with dose-dense therapy; the relative risk of recurrence was 26% lower and the relative risk of death was 31% lower. Additionally, there was a lower incidence of severe neutropenia in the dose-dense arm, in which prophylactic G-CSF was used per protocol with each cycle. At the current time, administering AC followed by paclitaxel every 2 weeks, instead of every 3 weeks, is a reasonable treatment strategy.

Which Is the Preferred Taxane?
Based on indirect comparisons as well as the results of the recent randomized trial conducted in patients with MBC, docetaxel appears to be the more active taxane. In addition to its longer half-life, docetaxel also has a more rapid cellular uptake and longer intracellular retention than paclitaxel [48]. Because of its pharmacokinetics, the efficacy of paclitaxel is schedule dependent. In general, trends of superior response rates have been associated with higher doses and prolonged infusions times, but no regimen of paclitaxel has been shown to be statistically superior to any other in MBC. Docetaxel is highly active when given as a short, intermittent infusion. The theoretical evidence supporting docetaxel has been borne out by the results of the randomized trial previously discussed (Table 2Go) [12]. The results of the ECOG 1199 trial, a randomized trial comparing AC followed by paclitaxel with AC followed by docetaxel in the adjuvant setting, are eagerly awaited.


   SUMMARY
Top
 Learning Objectives
 Abstract
 Introduction
 Taxanes in Metastatic Breast...
 Taxanes in Early-Stage Breast...
 Summary
References
 
Taxane-containing regimens improve outcomes for patients with breast cancer in the metastatic, adjuvant, and neoadjuvant settings. Docetaxel is the only drug to have shown superiority over single-agent anthracycline therapy as well as combination regimens in the metastatic setting. Furthermore, recent data from a head-to-head comparison demonstrate that docetaxel is superior to paclitaxel for patients with MBC previously treated with anthracyclines. In the adjuvant setting, both docetaxel and paclitaxel improve outcomes when incorporated into current anthracycline-based polychemotherapy regimens. With paclitaxel, scheduling appears to be important, and a sequential regimen administered over a total of 24 weeks may be optimal. Docetaxel has been administered in place of fluorouracil, changing the FAC regimen to TAC, in the adjuvant setting, and six cycles of TAC have been shown to be superior with respect to disease-free and overall survival rates. Similarly, the addition of docetaxel in the neoadjuvant setting has resulted in better outcomes for patients with locally advanced disease.

Research continues regarding the optimal taxane administration schedule. Weekly administration appears promising in phase II clinical trials, particularly for older or frail patients, and the results of randomized trials will further define those patients most likely to benefit from this approach. Dose-dense paclitaxel-based therapy, in which chemotherapy cycles are administered every 2 weeks, has produced impressive results in the adjuvant setting. It remains to be determined if this approach is superior to conventional docetaxel-based therapy in this setting or if a dose-dense docetaxel-based regimen will be similarly effective. At the current time, clinicians should choose a taxane-based regimen for their patients with breast cancer based on consideration of the pharmacokinetics, clinical activity, and dosing schedule that best meets the patient’s needs. To that end, the pharmacokinetic profile, consistent positive clinical results, and convenience of the intermittent, short-infusion schedule favor the use of docetaxel for many patients with breast cancer at this time.


   ACKNOWLEDGMENT
Top
 Learning Objectives
 Abstract
 Introduction
 Taxanes in Metastatic Breast...
 Taxanes in Early-Stage Breast...
 Summary
 References
 
J.C. receives speaking honoraria and research support from Aventis, Bristol Myers Squibb, Roche, Genentech, and Amgen.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Taxanes in Metastatic Breast...
 Taxanes in Early-Stage Breast...
 Summary
 References
 

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Received March 11, 2004; accepted for publication March 22, 2004.




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