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Abstract

Breast cancer is the most frequent cancer of women in developed countries. Systemic adjuvant chemotherapy has dramatically improved the outcome of patients treated for early stage invasive breast cancer. Among novel chemotherapeutic agents, the taxanes have emerged as the most powerful compounds since anthracycline regimens. Two taxanes are available (paclitaxel and docetaxel) and they share some characteristics, while having a number of significant differences, both in terms of preclinical and pharmacokinetic profiles and, most importantly, clinical consequences. In clinical practice, the taxanes are now standard therapy in metastatic breast cancer. Their role as monochemotherapy or in combination with anthracyclines in advanced breast cancer has suggested their potential therapeutic impact in the treatment of patients with early breast cancer. Available results in the adjuvant and neoadjuvant setting demonstrate that taxanes, used in combination with other chemotherapeutic agents or trastuzumab, or in sequential therapy, possess the capability to induce significant improvements, in particular in terms of survival, confirming the positive impact of taxanes on the natural history of breast cancer.

Keywords

adjuvant anthracyclines breast cancer docetaxel neoadjuvant paclitaxel taxanes

More than a million new breast cancer cases are diagnosed worldwide every year, while the breast cancer death rate is approximately 350,000/year [1]. There is evidence, despite the formidable recent increase in incidence, that the 1990s have witnessed the first decrease in breast cancer mortality rates [1]. This downturn is probably related to a variety of factors, including the implementation of screening programs, as well as the impact of various adjuvant therapies [2].

Over the past four decades, the clinical introduction of new adjuvant chemotherapies has progressed through several periods. The first period was characterized by preanthracycline polychemotherapy (e.g., cyclophosphamide, methotrexate and 5-fluorouracil [CMF] and cyclophosphamide, methotrexate, 5-fluorouracil and prednisone [CMFV]), with results reporting improvement in disease-free survival (DFS) combined with a modest but definitive improvement in overall survival (OS), in particular for premenopausal patients (1970s). The second period followed the introduction of anthracyclines and led, in the 1980s, to the development of multiple anthracycline-based combination chemotherapies. In both node-negative and -positive patients, as confirmed by an update of the meta-analysis performed by the Early Breast Cancer Trialists' Collaborative Group, anthracycline-based adjuvant chemotherapy significantly improved DFS and OS in young and, to a lesser extent, older patients [3].

Among the novel chemotherapeutic drugs introduced in the 1990s, the taxanes have emerged as the most powerful compounds and the available results suggest that they will be remembered in the future as the breast cancer chemotherapy of the 1990s. The impact of the taxanes on the natural history of early breast cancer appears at least similar, if not superior, to the impact of anthracyclines. This article will update our present knowledge on the taxanes and discuss their current role in the management of patients with early breast cancer.

Taxane development in metastatic disease: the rationale for early breast cancer trials

Initially extracted from the bark of the Pacific yew, Taxus brevifolia, paclitaxel (Taxol®) was isolated and characterized in 1971 by Wani and colleagues [4]. Subsequent research showed that paclitaxel had activity against several human malignancies, including breast cancer [5]. With the idea of providing a renewable source of taxane, docetaxel, a semisynthetic analog of paclitaxel, was synthetized several years ago (1986) using a precursor extracted from the needles of the European yew, Taxus baccata [6]. Differing from paclitaxel by only two minor structural modifications, docetaxel was shown to have favorable preclinical in vitro and in vivo characteristics that prompted its clinical development [7] (Table 1).

Table 1.

Preclinical and early clinical development differences between docetaxel and paclitaxel.

Property	Docetaxel	Paclitaxel
β-tubulin affinity	1.9	1
Cell-cycle specificity	S/G2/M	G2/M
Uptake vs efflux	1 vs 1/3	1 vs 1
Plasma clearance	Linear	Non-linear
Drug interactions	No cardiotoxic effects Effects not sequence dependent	Enhanced cardiac toxicity, specifically with anthracyclines Effects are sequence dependent
Hypersensitivity	None	Attributed to Cremophor
Fluid retention	Partially preventable with prophylactic treatment	None
Phase I results	Two possible regimens 3-weekly 1 h infusion 100 mg/m² Weekly 1 h infusion 35–40 mg/m²	Different schedule and doses possible 3-weekly 3 h infusion 175–225 mg/m² 3-weekly 24 h infusion 135–250 mg/m² Weekly 1 h infusion 80–100 mg/m²

The two taxanes had a different clinical-development profile in breast cancer. This was related to several factors, including the determination of the optimal dose and schedule for each taxane and their individual pharmacologic interactions with anthracyclines. Taking into account these differences is key to understanding the development of taxanes and interpreting the results of Phase III trials performed in patients with early breast cancer [8].

For paclitaxel, the first important issue was the fact that no particular schedule and dose emerged as the optimal method of using this agent for further development in Phase II and III studies. Although still debated by some authors, the question of the optimal schedule and dose for paclitaxel has largely been answered [9 –19]. In fact, schedule and dose seem to play a combined role in the definition of the efficacy:toxicity ratio. Paclitaxel was initially shown to be very active when given at high doses (250 mg/m²) over long schedules (24 h): response rates were, in this context, consistently in the 50% range. However, this was obtained with a high toxicity (e.g., neutropenia and fatigue) and poor practicality. Although lower doses (175–200 mg/m²) given over short infusions (3 h) were more feasible, with easy outpatient administration, they consistently showed lower efficacy (response rates in the 25–30% range) in large-scale, randomized trials. More recently, weekly infusions have displayed some significant advantages both in terms of efficacy and safety profile, and some authors consider weekly paclitaxel at a dose of 80–90 mg/m² as the optimal schedule and dose for paclitaxel administration [17 –19]. This hypothesis has been tested by the Eastern Cooperative Oncology Group (ECOG) in their 1199 adjuvant trial comparing, after four courses of doxorubicin and cyclophosphamide (AC), docetaxel with paclitaxel either weekly or 3-weekly. The results of this study are eagerly awaited. Nevertheless, the majority of large-scale adjuvant trials with paclitaxel have used moderate doses and 3-weekly short infusion schedules.

The second issue that impaired the development of paclitaxel in the treatment of early breast cancer emerged from the reported pharmacologic interaction between the drug and anthracyclines, with an increased risk of cardiac toxicity when paclitaxel was delivered by short infusions in combination with doxorubicin [20,21]. Despite several Phase III trials in advanced disease demonstrating encouraging efficacy data for the combination of paclitaxel and doxorubicin [22 –25], the risk of potential cardiac toxicity has limited the adjuvant strategies using this combination therapy. In addition, mostly for practical reasons, it was decided not to pursue the development of adjuvant programs based on the combination of paclitaxel given over 24 h plus doxorubicin. This accounted for the fact that the majority of the anthracycline–paclitaxel trials were sequentially designed and, furthermore, in North America, the adjuvant sequential strategies based upon the AC regime followed by paclitaxel. Only one study, the European Cooperative Trial in Operable breast cancer (ECTO), has opted for a paclitaxel–doxorubicin combination regimen in the adjuvant setting [26].

For docetaxel, the situation was more straightforward and there has been no particular controversy surrounding the recommended schedule and dose. This was clearly established as a 100 mg/m², 1-h infusion every 3 weeks, and subsequently used for docetaxel monochemotherapy Phase III trials in advanced disease [27 –30]. As for paclitaxel, recent data have been presented on the use of weekly docetaxel and have confirmed the same trend, with a threshold of toxicity at approximately 40 mg/m²/week [32].

Several trials using anthracycline–docetaxel-based combinations did not report any pharmacokinetic difficulties in combining these two agents, accounting for the lack of added cardiotoxicity with these combinations above that expected from anthracycline therapy [33 –39]. The development of docetaxel–doxorubicin-based combinations was swift, with reports of high efficacy. In terms of safety, neutropenia and febrile neutropenia were the most common toxicities; however, neutropenia was generally brief in duration and infections infrequent. Nonhematologic toxicities were mild overall and docetaxel-specific toxicities (e.g., fluid retention and nail changes) are no longer a significant clinical problem. In addition, there was no evidence of added cardiac toxicity, with an incidence in congestive heart failure between 0 and 4%. Overall, these trials consistently showed improved response rates and time to progression (TTP) with docetaxel–anthracyline combinations, but thus far no definitive evidence of a survival advantage has emerged.

These results led to further development of docetaxel in the adjuvant setting, using both sequential and polychemotherapy strategies.

Taxanes in the adjuvant setting

As previously described, two different strategies were pursued in assessing the potential role of taxanes in adjuvant setting (Tables 2, 3 & 4).

Table 2.

Results from adjuvant taxane trials.

Study	Design	N0 Patients and characteristics	DFS benefit	OS benefit	Subgroup analysis	Ref.
Paclitaxel
CALGB-9344	4 AC (60 vs 75 vs 90 mg/m²) + 4 P vs nothing	n = 3170 N⁺ 47% 1–3 N⁺ 42% 4–9 N⁺ 12% + 10 N⁺ 69 months FU	17% relative decrease (p = 0.0023)	18% relative decrease (p = 0.0064)	Benefit only for hormone receptor-negative patients	[40]
NSABP B-28	4 AC 60 + 4 P vs nothing	n = 3060 N⁺ 70% 1–3 N⁺ 26% 4–9 N⁺ 4% + 10 N⁺ 64 months FU	17% relative decrease (p = 0.008)	NS	NS	[41]
CALGB-9741	4 A + 4 C+ 4 P vs 4 AC + 4 T + dose-dense randomization	n = 2005 N⁺ 60% 1–3 N⁺ 29% 4–9 N⁺ 11% + 10 N⁺ 36 months FU	26% relative decrease (p = 0.01) In favor of 2- vs 3-weekly schedules	31% relative decrease (p = 0.013) In favor of 2- vs 3-weekly schedules	No difference between sequential and combination	[43]
ECTO	4 AP + 4 CMF (neoadjuvant or adjuvant) vs 4 A + 4 CMF	n = 1355 N⁺ and N⁻	34% relative decrease (p = 0.01)	NS	No difference between neoadjuvant and adjuvant arms	[26]
Docetaxel
BCIRG 001	6 FAC 50 vs 6 TAC	n = 1491 N⁺ 62% 1–3 N⁺ 38% + 4 N⁺ 55 months FU	38% relative decrease (p = 0.001)	30% relative decrease (p = 0.008)	Benefit independent of HER2 and hormone receptor status	[51,52]
PACS 001	6 FEC 100 vs 3 FEC100 + 3 T 100	n = 1491 N⁺ 62% 1–3 N⁺ 38% + 4 N⁺ 60 months FU	17% relative decrease (p = 0.041)	23% relative decrease (p = 0.05)	Benefit statistically significant for pN1 and women more than 50 years	[53]
ECOG 2197	4 AC vs 4 AT	n = 2889 35% N⁺ 53 months FU	NS	NS	No benefit	[54]

A: Doxorubicin; AC: Doxorubicin and cyclophosphamide; AT: Doxorubicin and docetaxel; BCIRG: Breast Cancer International Research Group; C: Cyclophosphamide; CALGB: Cancer and Leukemia Group B; CMF: Cyclophosphamide, methotrexate and 5-fluorouracil; DFS: Disease-free survival; ECTO: European Cooperative Trial in Operable breast cancer; FAC: Fluorouracil, adriamycin and cyclophosphamide; FEC: 5-fluorouracil, epirubicin and cyclophosphamide; F: Fluorouracil; HER: Human epidermal growth factor receptor; N0: No clinically palpable axillary nodes; N⁺: Node-positive; N⁻: Node negative; NS: Not significant; NSABP: National Surgical Adjuvant Breast and bowel project; OS: Overall survival; P: Paclitaxel; PACS: Programme Adjuvant Cancer du Sein; pN1: Node positive confirmed pathologically; T: Docetaxel; TAC: Docetaxel, doxorubicin and cyclophosphamide; FU: Follow-up.

Table 3.

Completed nonreported or ongoing studies designed to evaluate docetaxel in adjuvant therapy.

Design	Study
First-generation trials
A × 4 → CMF × 3	BIG
A × 3 → T × 3 → CMF × 3
AT × 4 → CMF × 3
AC × 4 → CMF × 3
E (days 1 and 8) × 6	ICCG
E (days 1 and 8) × 3 → T × 3
E × 4 → CMF × 4	Italian Adjuvant Group
E × 4 → T × 4 → CMF × 4
E75 + T75×6FEC 100	PACS 04
Second-generation trials
AC × 4 → T 3-weekly × 4	North American Intergroup E1199
AC × 4 → P 3-weekly × 4
AC × 4 → T 3-weekly × 12
AC × 4 → T 3-weekly × 12
AC × 4 → T × 4	BCIRG 005
TAC × 6
AC × 4 → T × 4	NSABP B-30
AT × 4
TAC × 4
AC × 4 biweekly → P weekly × 12 + G	NSABP B-38
AC weekly × 15 + C oral daily × 15 weeks → P weekly
x 12
TAC × 6

A: Doxorubicin; AC: Doxorubicin and cyclophosphamide; BCIRG: Breast Cancer International Research Group; BIG: Breast InterGroup; C: Cyclophosphamide; CMF: Cyclophosphamide, methotrexate and 5-fluorouracil; E: Epirubicin; EEC: 5-fluorouracil, epirubicin and cyclophosphamide; G: Gemcitabine; ICCG: International Collaborative Cancer Group; NSABP: National Surgical Adjuvant Breast and bowel Project; P: Paclitaxel; T: Docetaxel; TAC: Docetaxel, doxorubicin and cyclophosphamide.

Table 4.

Completed nonreported or ongoing studies designed to evaluate paclitaxel in adjuvant therapy.

Cooperative group	Regimens
First-generation trials
Italian Cooperative Group (Gono-MIG)	CEF × 6
	EP × 4
Second-generation trials
North American IntergroupE1199	AC × 4 → T 3-weekly × 4AC × 4 → P 3-weekly × 4AC × 4 → T weekly × 12AC × 4 → P weekly × 12
NSABP B-38	AC × 4 biweekly → P weekly × 12A weekly × 15 + C oral daily × 15 weeks → P weekly × 12TAC × 6
SWOG 0221	AC × 6 biweekly → P biweekly × 12A weekly × 15 + C oral daily × 15 weeks →P biweekly × 12AC × 6 biweekly →P weekly × 12A weekly × 15 + C oral daily × 15 weeks → P weeklyx 12

A: Doxorubicin; AC: Doxorubicin and cyclophosphamide; C: Cyclophosphamide; CEF: Cyclophosphamide, epirubicin and 5-fluorouracil; EP: Epirubicin and paclitaxel; NSABP: National Surgical Adjuvant Breast and Bowel Project; P: Paclitaxel; SWOG: South West Oncology Group; T: Docetaxel; TAC: Docetaxel, doxorubicin and cyclophosphamide.

The first strategy followed the concept of sequential chemotherapy, for which both paclitaxel and docetaxel were investigated. In contrast, the second strategy focused on combination chemotherapy and was mostly developed with docetaxel.

Two generations of trials were implemented with each taxane. The first-generation studies investigated the impact of a taxane-based treatment versus a nontaxane therapy. The goal was to assess the differential efficacy and toxicity profiles when using a taxane in the adjuvant setting (Cancer and Leukemia Group B [CALGB]-9344, National Surgical Breast and bowel Project [NSABP] B-28, MD Anderson, ECTO, Breast Cancer International Research Group [BCIRG] 001, Programme Adjuvant Cancer du Sein [PACS] 01, ECOG 2197). The second-generation trials used taxanes in all arms and aimed at optimizing the adjuvant taxane strategy, ranging from dose-dense or pharmacokinetic approaches for paclitaxel (CALGB 9741, US Oncology Network trial) to comparing docetaxel in sequence versus combination (BCIRG 005, NSABP B-30) or comparing paclitaxel with docetaxel in sequence and weekly to 3-weekly infusion of the taxanes (the ECOG 1199 trial).

Adjuvant trials with paclitaxel

Several large-scale studies with paclitaxel have been published or presented. All except one (the ECTO trial) used the sequential strategy (usually AC followed by paclitaxel). Three are first-generation trials (CALGB 9344, NSABP B-28 and ECTO), while two are second-generation studies (CALGB 9741 and US Oncology Network).

The results of two conceptually identical first-generation trials have been reported by the CALGB-9344 [40] and the NSABP B-28 [41]. Both were based upon the use of four cycles of the standard AC regimen, followed by the addition of four courses of single-agent paclitaxel given over 3 h or no paclitaxel (175 mg/m² in the CALGB trial and 225 mg/m² in the NSABP trial). After more than 5 years of follow-up, results from the CALGB-9344 revealed a significant improvement in outcomes for patients treated with paclitaxel [40]. Adding paclitaxel to four courses of AC resulted in a 17% decrease in the hazard of recurrence (hazard ratio [HR]: 0.83; p = 0.023) and an 18% decrease in the hazard of death (HR: 0.82; p = 0.0064). This translated into an absolute improvement in DFS and OS at 5 years of 5 and 3%, respectively. A retrospective analysis suggested that patients with negative hormone receptors or who were not exposed to tamoxifen were the only ones benefiting from the addition of paclitaxel.

Results of the NSABP B-28 trial demonstrated, with a median follow-up of 64.8 months, a significant improvement in DFS in favor of the paclitaxel-containing arm (HR: 0.83; p = 0.008), but no difference in OS [41]. In addition, when performing an analysis of DFS and time to treatment failure (TTF) according to the hormone receptor status, no significant difference was seen between hormone receptor-positive and -negative subgroups. Overall, these data suggested the existence of a potential benefit when adding paclitaxel to AC, and thus confirmed, to a lesser extent, the results of the CALGB-9344 trial. However, the modest results of the NSABP study should be interpreted carefully, taking into account two reasons that may have partially impaired the ability to observe a difference between the two treatment arms. The first reason relates to the NSABP study population, which appears to have been of particularly good prognosis, with a large number of tumors having a low chemosensitivity (majority of postmenopausal patients, hormone receptor-positive tumors and a low number of patients with more than three positive nodes in the axilla). The second, and probably the most important, reason relates to the use of tamoxifen in 84% of the patient population and the fact that tamoxifen was given concomitantly with the chemotherapy as opposed to the CALGB trial (sequential tamoxifen, started at completion of chemotherapy). This factor may be critical for the interpretation of the NSABP trial in light of the results of the Intergroup trial 0100, which clearly showed that concomitant chemotherapy and tamoxifen is significantly detrimental compared with the sequential use of both therapies (p = 0.045) [42]. It has been estimated that the concomitant use of both therapies could decrease the relative efficacy of the chemotherapy by up to 50%. In this context, the NSABP results should be interpreted as potentially lacking power to show a large benefit when AC is followed by paclitaxel already given suboptimally (low doses, short infusion). Nevertheless, these results strengthened the evidence that paclitaxel improves the outcome of patients with node-positive breast cancer and thus support the positive results of the self-standing CALGB-9344 trial.

However, several general observations should be considered when interpreting the results of these two trials. The first observation relates to the potential underuse of anthracyclines, as there is currently a strong suggestion that four cycles of AC may represent an underexposure to anthracyclines. The second observation relates to the taxane itself: paclitaxel given as a short infusion (3 h), at a dose of 175 or 225 mg/m² every 3 weeks, clearly appears suboptimal. Consequently, a fundamental question remains unanswered in these trials: what is the role of suboptimal paclitaxel in: first, palliating the underuse of anthracyclines (four AC) and; second, adding a specific taxane effect? This suboptimal use of paclitaxel may be one of the reasons why the benefit of adding the taxane to AC was mainly seen in the most chemosensitive population in the CALGB trial.

The first published second-generation adjuvant sequential study with paclitaxel was the CALGB-9741 [43]. This two by two factorial program compared:

A monochemotherapy sequence (doxorubicin followed by paclitaxel [175 mg/m² over 3 h], followed by cyclophosphamide [APC]) with the classical AC followed by paclitaxel (175 mg/m² over 3 h).

These chemotherapy regimens given every 2 weeks (so called dose-dense) with the conventional 3-weekly schedule.

With 36-months median follow-up, the biweekly arm was shown to be superior to the conventional 3-weekly schedule in terms of DFS (relative risk [RR]: 0.74; p = 0.010) and OS (RR: 0.69; p = 0.013). However, there was no clinically or statistically significant difference in DFS or OS between sequential monochemotherapy ATC and AC followed by paclitaxel. Although these results appear to support the concept of dose density, caution must be exercised in their interpretation. We have learned from previous Phase III trials that there was no evidence in favor of increasing the dose intensity of anthracyclines and cyclophosphamide beyond the optimal conventional doses of 60 mg/m² (20 mg/m²/week) for doxorubicin and 600 mg/m² (200 mg/m²/week) for cyclophosphamide [40,44,45]. As a consequence, the observed difference between the 2- and 3-weekly schedules in the CALGB-9741 trial may not be related to either doxorubicin or cyclophosphamide, but most probably to the paclitaxel schedule and dose. In this study, paclitaxel was delivered over 3 h at either 175 mg/m² every 3 weeks (approximately 58 mg/m²/week) or 175 mg/m² every 2 weeks (approximately 87 mg/m²/week). From previous randomized trials, there is evidence that paclitaxel delivered on a weekly basis at doses ranging from 80 mg/m²/week to approximately 112 mg/m²/week is more efficient than 3-weekly infusions [19,46], capitalizing on the pharmacokinetics of the drug as well as on the possible metronomic dosing effect with enhancement of the anti-angiogenic and cytotoxic effects [47]. Overall, the authors believe that the superiority of the biweekly schedule (very similar to the weekly schedule in terms of dose delivered per week) appears to be more a consequence of the optimization of a suboptimal use of paclitaxel (175 mg/m² over 3 h every 3 weeks), rather than a pure proof of the dose-dense concept.

Two smaller adjuvant trials from the MD Anderson Cancer Center and the US Oncology group exploring have been published or presented.

The MD Anderson first-generation, Phase III trial was published with a median follow-up of 60 months [48]. A total of 524 patients were randomized to receive either eight courses of 5-fluorouracil, doxorubicin and cyclophosphamide (FAC) 50 or four courses of paclitaxel 250 mg/m² (24 h continuous infusion) followed by four courses of FAC 50. Results showed no statistically significant difference between the two treatment groups in terms of DFS and OS. There was only a trend in favor of the paclitaxel–FAC 50 arm in the estrogen receptor (ER)-negative patient population, without reaching significance. Overall, this study was underpowered and did not demonstrate any impact of paclitaxel in the adjuvant setting.

Based on the efficacy of doxorubicin and paclitaxel, the US Oncology Network undertook a second-generation adjuvant Phase III trial comparing four cycles of AC followed by four cycles of paclitaxel (175 mg/m²) given every 3 weeks, with four cycles of doxorubicin (50 mg/m²) plus paclitaxel (AP) (200 mg/m²) administered every 3 weeks, followed by paclitaxel 80 mg/m²/week for 12 weeks. The results, with a median follow-up of 3 years, were presented at the 2004 San Antonio Meeting (TX, USA). A total of 1830 patients were enrolled. The 3-year DFS was 88% with AP followed by weekly paclitaxel compared with 85% with AC followed by 3-weekly paclitaxel (HR: 0.74; p = 0,05), and 3-year OS was 95 and 92%, respectively (HR: 0.65; p = 0.005) [49]. Clearly, longer follow-up is needed before any definitive conclusion can be reached.

Recently, data from the only Phase III trial exploring the paclitaxel–doxorubicin combination were presented at the 2005 American Society of Clinical Oncology (ASCO) meeting. In this three-arm trial, patients with node-positive and high-risk node-negative tumors were randomized to four cycles of doxorubicin (60 mg/m²) with paclitaxel (200 mg/m²), followed by four cycles of intraveous CMF or four cycles of doxorubicin (75 mg/m²), followed by four cycles of intravenous CMF, either in the adjuvant or neoadjuvant setting. After a median follow-up of 43 months, freedom from progression (FFP) was significantly better for women receiving adjuvant AP followed by CMF than doxorubicin followed by CMF (HR: 0.65; range 0.48–0.90, p = 0.01). In a multivariate analysis, paclitaxel-containing treatment was significantly associated with longer FFP (HR: 0.66; p = 0.012), together with clinical tumor diameter size of less than 4 cm, positive progesterone receptor (PR) and negative nodal status. There was no difference in OS between the three arms. Symptomatic cardiac toxicity was low, with a common toxicity criteria grade 3 rate of 0.7% for women receiving doxorubicin followed by CMF, and 0.4% for those receiving AP followed by CMF [26].

Adjuvant trials with docetaxel

Presently, data are only available from three first-generation trials with docetaxel. Two are combination trials with anthracyclines (docetaxel, doxorubicin and cyclophosphamide [TAC], doxorubicin and docetaxel [AT]) [58 –60] and one is exploring the sequential strategy (5-fluorouracil, epirubicin and cyclophosphamide [FEC] followed by docetaxel) [61] (Table 2).

The first trial is the registration trial of docetaxel in the adjuvant setting, performed by the BCIRG (trial 001). This study compared TAC (75/50/500 mg/m² every 3 weeks) with FAC (500/50/500 mg/m² every 3 weeks) in 1491 patients with node-positive breast cancer [51,52]. With 55 months of median follow-up, the TAC regimen was shown to be superior to FAC in terms of DFS (RR: 0.72; p = 0.001; absolute difference at 5 years: 7%; 75 vs 68%). This difference in DFS translated into a significant improvement in OS in favor of TAC (RR: 0.70; p = 0.008; absolute difference at 5 years: 6%; 87 vs 81%). In addition, TAC provided added clinical benefit regardless of the tumor hormone receptor status or human epidermal growth factor receptor type 2 (HER2)-expression level. The efficacy seen in the hormone receptor-positive subgroup could be partially explained by the fact that more premenopausal patients were reported to become amenorrheic following TAC compared with FAC (51.4 vs 32.8%; p < 0.05 at 33 months median follow-up and 61.7 vs 52% at 55 months, respectively). In addition, the magnitude of the differential effect between TAC and FAC appeared to be inversely correlated with the number of positive axillary nodes: the lower the number of nodes, the greater the benefit of TAC over FAC, with a HR of 0.61 for 1–3 positive nodes (p = 0.0009) (stratification prospectively defined), but no significant difference, despite a trend, for patients with four or more positive nodes. When retrospectively stratifying the four or more positive nodes group into two subgroups, 4–9 positive nodes and ten or more positive nodes, there was no observed benefit for TAC over FAC in the ten or more positive node subgroup, while some advantage in favor of TAC was observed in the four to nine positive nodes subgroup. In terms of the toxicity profile, as expected from metastatic trials, myelosuppression was the main toxicity, with a high incidence of grade 4 neutropenia and febrile neutropenia (25%), in contrast with a low incidence of documented infections and the absence of any toxic death. It should be noted that this study did not incorporate any upfront prophylactic use of cytokines (granulocyte colony-stimulating factor [G-CSF]). These results should be put into perspective with the results of a prospective, controlled trial investigating the prophylactic use of G-CSF with TAC for patients with advanced breast cancer, in whom the incidence of febrile neutropenia was 6.7%, the documented infection rate was only 1% and no septic deaths were recorded [52]. Overall, these results confirmed the feasibility of AT or TAC without systematic use of prophylactic cytokine support; however, G-CSF dramatically reduces the risk of granulocytopenia, febrile neutropenia and related infectious complications to a level close to what is expected with anthracycline-containing polychemotherapies.

The second first-generation trial of combination therapy is the ECOG 2197 Phase III trial, the results of which were recently presented at the 2005 ASCO meeting. In this study, involving 2889 patients with node-positive or high-risk node-negative tumors, the two treatment arms consisted of either four courses of AT (60 mg/m² and 60 mg/m²) or AC (60 mg/m² and 600 mg/m²) given on a 3-weekly basis. With a median follow-up of 53 months, there was no difference observed in terms of DFS or OS, although there were fewer events in the AT arm [54].

One of the main criticisms of this trial relates to the design itself, as four courses of AC and four courses of AT most likely represent a potential underexposure to anthracyclines and docetaxel. As a consequence, more exposure to both drugs may have unveiled a differential effect between the two treatment arms. This fact, combined with a patient population of good prognosis (mostly node-negative), may account for the lack of significant difference between the two treatment arms. However, further follow-up is clearly needed in this trial.

The third first-generation trial with docetaxel was a sequential trial (PACS01). This is a French Cooperative Group study comparing six courses of FEC 100 (5-fluorouracil 500 mg/m², epirubicin 100 mg/m² and cyclophosphamide 500 mg/m² every 3 weeks) with a sequence of three courses of FEC 100 followed by three courses of docetaxel (100 mg/m² every 3 weeks) [53]. The study enrolled 1999 pre- and postmenopausal women with node-positive breast cancer. After 60 months median follow-up, the results showed an increase in DFS of 5% for patients treated with the docetaxel-containing sequence (78.3 vs 73.2%; p = 0.014). This translated into a 4% increase in OS (90.7 vs 86.7%; p = 0.017). There were no unexpected safety concerns. Patients receiving docetaxel following FEC 100 experienced a 2.8% higher rate of febrile neutropenia (11.2 vs 8.4%) as well as more nail disorders compared with FEC 100 alone. Patients treated in the FEC 100 arm experienced higher rates of neutropenia, anemia and nausea/vomiting, and more asymptomatic cardiac toxicity (decreased left ventricular ejection fraction [LVEF]) at the end of their chemotherapy treatment.

In general, the patient population of this trial was not well balanced between the two treatment arms in terms of tumor hormone receptor status (there were significantly more hormone receptor-positive patients in the docetaxel arm). In theory, this fact should have acted against a differential of efficacy between the two arms (patients with positive hormone receptors may be less chemosensitive). However, this observation may confirm the efficacy of docetaxel in a hormone receptor-positive population, as seen prospectively in the BCIRG 001 trial. Additionally and surprisingly, a subgroup analysis comparing the impact of both treatments in patients younger or older than 50 years of age suggested a significant benefit for the docetaxel-containing arm only for patients aged over 50 years. As in the BCIRG study, the magnitude of the differential effect appears to be inversely related to the number of positive axillary nodes: the lower the number of nodes, the higher the benefit of FEC 100 followed by docetaxel compared with FEC 100 alone.

Overall, these two trials confirm the impact of docetaxel either in combination or in sequence, on the outcome of patients with node-positive breast cancer treated in the adjuvant setting. In terms of safety, the feasibility of AT or TAC without systematic use of prophylactic cytokine support is shown in the BCIRG 001 trial; however, G-CSF dramatically reduces the risk of granulocytopenia, febrile neutropenia and related infectious complications. As a consequence, the use of G-CSF, if available, with taxane–anthracycline combinations is reasonable and advisable when treating patients in the adjuvant setting. The PACS01 results confirm the efficacy, feasibility and low toxicity rate of a sequential approach with docetaxel.

The second-generation trials (e.g., BCIRG 005 and NSABP B-30) will give prospective answers to questions related to the choice of strategy between combination and sequential doxorubicin–docetaxel approaches, as well as weekly versus 3-weekly scheduling and docetaxel versus paclitaxel (ECOG 1199). A large number of adjuvant trials with taxanes have been performed in the adjuvant setting. Some of them are further described in Tables 3 & 4. The results of these studies are eagerly awaited.

Taxanes in the neoadjuvant setting

Neoadjuvant chemotherapy was historically used for the treatment of inoperable breast cancer. Several trials have demonstrated the impact of this approach on OS, especially for inflammatory breast cancers [55]. Trials comparing neoadjuvant with adjuvant therapy using anthracycline-based chemotherapies have shown no advantage for either in terms of DFS and OS. The only advantage in favor of neoadjuvant strategies was the increase in conservative surgery rates for large tumors (more than 5 cm in diameter) [56]. Furthermore, a retrospective analysis of the NSABP B-18 trial results suggested that patients achieving a pathologic complete response (pCR) after neoadjuvant chemotherapy may have a statistically significant improvement in DFS and OS [56].

Since these results were published and confirmed by several other retrospective analyses from neoadjuvant trials, the pCR rate became one of the end points for neoadjuvant trials prospectively evaluating the role of taxanes in this setting.

Taxane monotherapy

For paclitaxel, there is only one small, first-generation, randomized trial of 174 patients with stage II–IIIA disease (38% clinically and/or radiologically node-positive), comparing four cycles of either 3-weekly paclitaxel 250 mg/m² or 3-weekly FAC at standard doses. After local therapy, all patients received an additional four cycles of FAC. There was a trend toward a higher pCR rate with FAC (16%) versus paclitaxel (8%), and a higher proportion of patients receiving neoadjuvant FAC had less residual disease in the breast and axilla compared with the paclitaxel arm. The 2-year DFS rates were not statistically different between the two arms (94% paclitaxel, 89% FAC) [57].

Only abstracted data from the MD Anderson Cancer Center is available on the comparison between weekly and 3-weekly paclitaxel followed by FAC in neoadjuvant setting [18]. Available data on pCR rates in 236 patients showed a statistically significant increase with the weekly regimen (28%) versus the 3-weekly 24 h schedule (14%).

For docetaxel, only single-agent Phase II studies have so far been published in the neoadjuvant setting using either a 3-weekly regimen [58,59] or weekly docetaxel [60].

In a French study, 80 patients with stage II and III breast cancer received six cycles of neoadjuvant docetaxel, 100 mg/m² 3-weekly, and achieved a 36% pCR rate (Sataloff's classification) [59]. The Spanish Breast Cancer Research Group (GEICAM) recently published a Phase II trial evaluating weekly neoadjuvant docetaxel in 56 patients. Docetaxel 40 mg/m² was administered weekly over 6 consecutive weeks, followed by 2 weeks rest. A 16-week treatment (two cycles) was performed before surgery. The pCR rate, with no evidence of tumor in the breast and lymph nodes, was confirmed to be 16%.

Taxane–anthracycline regimens

Both sequential and combination chemotherapy strategies have been evaluated in the neoadjuvant setting. The high response rates of combination regimens in metastatic disease and the promising results of sequential therapy in the adjuvant setting represented the rationale for using anthracyclines and taxanes with the goal of improving the pCR rate and, potentially, the outcome for early stage breast cancer patients.

Two studies are available with paclitaxel. The first is a recently published Phase II, randomized trial. A total of 200 patients with stage II and III disease were randomly assigned in a 2:1 ratio to receive preoperative chemotherapy with either AP (doxorubicin 60 mg/m² plus paclitaxel 200 mg/m²) or AC (doxorubicin 60 mg/m² plus cyclophosphamide 600 mg/m²) every 3 weeks for four courses, followed by surgery. A pCR was reported by individual study center pathologists in 16 and 10% of patients in the AP and AC arms, respectively. However, this rate fell to 8 and 6%, respectively, when assessed by an independent centralized pathologist process. At a median follow-up of 31 months, DFS was longer for patients who reached a pCR versus those without pCR, but there was no statistically significant difference between the two treatment arms [61]. Data from the Milan group were recently presented on 892 early breast cancer patients. In this three-arm trial, patients were randomized to two adjuvant arms consisting of either four cycles of doxorubicin followed by four cycles of intravenous CMF, or four cycles of AP followed by four of CMF, while this latter regimen was tested in the third arm as neoadjuvant therapy. The combination of four cycles of a neoadjuvant AP regimen followed by four cycles of intravenous CMF demonstrated a 23% pCR with no impact on DFS or OS compared with the same adjuvant regimen or the adjuvant regimen without paclitaxel [26]. However, caution should be exercised in the interpretation of these data, in particular considering the small sample size of this three-arm early stage breast cancer trial.

Several trials have evaluated the role of docetaxel in the neoadjuvant setting. Small, randomized trials have compared docetaxel–anthracycline-based combinations with anthracycline polychemotherapies. First, a study comparing AC to AT (doxorubicin 50 mg/m² and docetaxel 75 mg/m²) in 362 patients reported comparable pCR rates between both arms (24 and 21%, respectively) [62]. Similar results were found in a trial of 90 patients treated with an epirubicin and docetaxel (ET) regimen (epirubicin 100 mg/m² and docetaxel 75 mg/m²), bearing a 24% pCR rate, which was comparable to the rate seen in the control FEC 100 arm [63].

The NSABP B-27 neoadjuvant trial was designed to evaluate the sequence of AC followed by docetaxel versus AC alone, and to prospectively confirm the predictive value of the pCR. This three-arm, randomized study investigated the effect of adding four courses of sequential docetaxel (100 mg/m²), either preoperatively or postoperatively to four courses of neoadjuvant AC [64]. Results from 2411 patients, with a median follow-up of 69 months, were presented at the 2004 San Antonio Breast Cancer meeting. Despite the fact that the sequential neoadjuvant treatment arm, with four courses of AC followed by four courses of docetaxel, had a doubled pCR rate (26.1 vs 12.8%) compared with four courses of AC, there was no statistically significant difference in OS for patients stratified by treatment arm. However, overall, study patients who reached a pCR had a statistically significant increase in OS. As discussed with the NSABP B-28 trial, the lack of added benefit with the sequence in the B-27 trial may also be partly explained by the fact that tamoxifen was given concurrently with chemotherapy and, thus, could have reduced the efficacy of the chemotherapy and, consequently, downgraded the scientific hypothesis of this trial. In addition, another limitation of the study is related to the patient population, with a majority of patients presenting with small tumors (55% ≤4cm), a context in which the differential impact of neoadjuvant treatments could be more difficult to demonstrate.

Data regarding the use of a sequential docetaxel–anthracycline-based regimen versus an anthracycline polychemotherapy regimen were reported from a Scottish study, known as the Aberdeen study [65]. This small, randomized trial, including 162 patients, was a two-step designed study. All patients first received four cycles of a 3-weekly cyclophosphamide, vincristine, doxorubicin and prednisone (CVAP) regimen. Response was clinically and radiologically evaluated. The originality of this study lies in the fact that patients who were responding to CVAP were subsequently randomized between four cycles of the same regimen or four cycles of 3-weekly 100 mg/m² docetaxel. This resulted in a comparison of eight cycles of anthracycline-containing regimen with the sequence of the same followed by docetaxel in patients selected as being chemosensitive, using the neoadjuvant setting for predictive selection of appropriate subpopulations. In the case of no response after the first evaluation, patients received four cycles of the docetaxel regimen (classical strategy used in resistant patients). The mean tumor size was 7 cm and patients with T2-4, N0-N2 were included.

In responding patients, the pCR rate was significantly higher for those who received the sequential CVAP therapy followed by docetaxel versus eight cycles of CVAP (34 vs 16%, respectively). In patients who failed to respond to the initial CVAP, four cycles of docetaxel resulted in only a 2% pCR. While the study was not designed for evaluating OS, the sequential addition of four cycles of docetaxel significantly improved the OS compared with eight cycles of anthracycline polychemotherapy in patients known to be sensitive to chemotherapy [65].

Finally, recently published data from the German Breast Group study (GEPARDUO) concluded that the sequential AC regimen followed by docetaxel is more effective at inducing pCR than dose-dense AT as preoperative treatment for patients with operable breast cancer [66].

This Phase III study investigated 913 women with untreated operable breast cancer, randomly assigned to receive either AT (doxorubicin 50 mg/m² plus docetaxel 75 mg/m²) every 14 days for four cycles with filgrastim support, or AC (doxorubicin 60 mg/m² plus cyclophosphamide 600 mg/m²) every 21 days followed by docetaxel 100 mg/m² every 21 days for four cycles each (total of eight cycles). The pCR was significantly greater with AC followed by T (14.3%) than with AT alone (7.0%). However, these results should be interpreted in light of the fact that four cycles of AT is certainly an underexposure to taxane-based polychemotherapy.

Overall, there is no definitive evidence so far that the taxanes used in the neoadjuvant setting add any significant benefit over their use in the adjuvant setting. The ability to potentially identify chemosensitive patients and focus on them with the introduction of additional noncross-resistant chemotherapies, as seen in the Aberdeen trial, is an important observation, which should be further explored.

Taxanes & trastuzumab in the adjuvant setting

Given the significant antitumor activity of trastuzumab in the treatment of advanced HER2-overexpressing breast cancer, trastuzumab and taxanes were evaluated in the adjuvant setting [67]. At present, the most commonly used cytotoxic regimens for adjuvant therapy include an anthracyline, either in sequence with a taxane (e.g., AC followed by paclitaxel or docetaxel) or in combination with or without a taxane. However, the cardiac toxicity reported with the use of concurrent anthracyclines–trastuzumab in advanced breast cancer led to the development of alternate strategies for the integration of taxanes and trastuzumab in the adjuvant setting [67].

To circumvent the problem of combining anthracyclines with trastuzumab in adjuvant programs, two approaches have been taken. The first strategy consisted of using trastuzumab (alone or in combination with a taxane) sequentially after anthracycline-containing chemotherapy. In the NSABP B-31 trial, node-positive, HER2-positive patients were randomized to either four cycles of AC followed by paclitaxel, or four cycles of AC followed by four cycles of paclitaxel (every 3 weeks) plus trastuzumab for 1 year. The US Intergroup trial randomized node-positive, HER2-positive patients to one of three arms: AC for four cycles followed by 12 weekly cycles of paclitaxel; AC followed by concurrent trastuzumab–paclitaxel and further trastuzumab for a total of 1 year; or AC followed by paclitaxel and sequential trastuzumab for 1 year. A third study, the HERceptin Adjuvant (HERA) trial, used a sequential design, randomizing patients to either observation or two 3-weekly trastuzumab arms (1 vs 2 years) following the completion of primary therapy, including various chemotherapy regimens, some of them with a taxane.

The second strategy for trastuzumab in the adjuvant setting introduced a nonanthracycline-containing regimen (BCIRG 006). This three-arm trial enrolled patients with node-positive or high-risk, node-negative disease with fluorescent in situ hybridization (FISH)-positive tumors only. Patients were randomized to either AC (four cycles) followed by docetaxel (four cycles); or AC followed by concurrent docetaxel and weekly trastuzumab, followed by 3-weekly trastuzumab for a total of 1 year; or the docetaxel–carboplatin (TCH) regimen for six cycles, with concurrent weekly trastuzumab, followed by 3-weekly trastuzumab for a total of 1 year.

All four trials using trastuzumab in the adjuvant setting mandated intense cardiac monitoring to ensure that excess cardiac dysfunction did not occur in patients receiving the antibody.

The first results of the NSABP, US Intergroup and HERA trials were presented at the 2005 ASCO meeting in a special session (‘Advances in Monoclonal Antibodies for Breast Cancer’ on Monday, May 16th, 2005).

The combined analysis of the NSABP B-31 study and the US Intergroup study reported data on 3351 patients with a median follow-up of 2 years. With 4-years projected results, there was a 52% relative reduction in the odds of being free of disease in favor of the trastuzumab-containing arms (HR: 0.48; 2p < 3.10⁻¹²), translating into a 19% absolute benefit in terms of DFS (primary study end point). In addition, there was a 53% relative reduction in the odds of distant recurrence for the trastuzumab-containing arms (HR: 0.47; 2p < 8.10⁻¹⁰), with an absolute benefit of 26%. OS was also improved by an absolute benefit of 4% (33% relative reduction; HR: 0.67; 2p < 0.015). Further information was provided from the Intergroup trial, suggesting that the concurrent use of trastuzumab and paclitaxel was superior to the sequential use of both agents in terms of DFS (36 vs 13% relative improvement of DFS, respectively; p = 0.0114).

Preliminary data from the HERA trial were reported at same meeting on 3387 patients, with median follow-up of 1 year. All patients received an adjuvant chemotherapy prior to the institution of trastuzumab therapy. The chemotherapy consisted of an anthracycline-containing regimen in 96% of cases, including a taxane–anthracycline program in 26% of patients. The 2-year projected results showed an absolute DFS benefit of 8.4% in favor of the trastuzumab arms (46% relative reduction; HR: 0.54; p < 0.0001). No improvement in OS has been noted so far in this trial.

The cumulative incidence of cardiac events in the NSABP B-31 and US Intergroup trials was 3.3–4.3% at 4 years in the concurrent trastuzumab–paclitaxel arms versus 0–0.7% in the control arms (AC followed by paclitaxel). Cardiac events were observed in 0.5–2.2% of cases in the sequential trastuzumab arms (HERA and the Intergroup trials, respectively). Moreover, in the HERA study, the incidence of decreased LVEF was 7.1% in the trastuzumab arms compared with 2.2% in the control arm.

Results from the BCIRG 006 trial will be presented at the upcoming San Antonio Breast Cancer Meeting.

The major therapeutic impact of trastuzumab on breast cancer with HER2-overexpression or -amplification already appears to be clear. Further results will help to define the optimal use of trastuzumab and taxanes.

Conclusions

The 1990s have witnessed the introduction of exciting new agents for the treatment of breast cancer. Among the new chemotherapeutic drugs, the taxanes have emerged as the most powerful compounds and the results available to date confirm that they will be remembered in the future as the breast cancer chemotherapy of the 1990s.

The two members of the taxane family (paclitaxel and docetaxel) share some characteristics, but are also significantly different in terms of preclinical characteristics and, most importantly, clinical profile. One difference is related to their different efficacy:toxicity ratio in relation to dose and schedule: high and comparable efficacy can be obtained with both agents (paclitaxel given weekly or docetaxel 100 mg/m² over 1 h); however, practicality and toxicity must be properly considered. Alternatively, lower doses and short schedules of paclitaxel (175 mg/m² over 3 h) are well tolerated and practical, but with compromised efficacy.

The second clinical difference is related to the integrability of taxanes in anthracycline–taxane-containing regimens, secondary to different pharmacokinetic interactions between each taxane and the anthracyclines. The difficulties of integrating paclitaxel in polychemotherapies have led to sequential adjuvant strategies. In contrast, docetaxel showed no pharmacokinetic interaction with the anthracyclines, allowing for the development of both sequential and combination adjuvant strategies.

The taxanes have entered our clinical practice and should be considered standard therapy in metastatic breast cancer, either in mono- or polychemotherapy.

The results of the adjuvant trials shed new light on the clinical role of taxanes. It is now becoming clear that paclitaxel and docetaxel are inducing substantial benefits in terms of DFS and OS. Paclitaxel in sequence (e.g., AC followed by paclitaxel) and docetaxel both in combination (e.g., TAC) and sequence (e.g., FEC followed by docetaxel) are producing superior results to anthracycline-containing regimens for patients with node-positive breast cancer. Neoadjuvant strategies with taxanes do not appear to add a significant benefit compared with adjuvant strategies so far, except for a potential capability to select chemosensitive patients, for whom the sequence with a taxane may be promising.

The integration of taxanes with trastuzumab is already showing promising results in the adjuvant management of patients with HER2-positive breast cancer. However, the optimal use of these therapies still needs to be defined.

In conclusion, all the available results confirm the ability of the taxanes to impact on the natural history of breast cancer. Today, taxanes should be considered in clinical practice as part of the therapeutic armamentarium for the treatment of patients with node-positive breast cancer. Nevertheless, further results from second-generation, large-scale, randomized, adjuvant trials will help to define the most effective adjuvant strategies with the taxanes (i.e., combination or sequence, weekly schedules). They will also confirm the extent to which paclitaxel and docetaxel will improve the management and outcome of patients with breast cancer.

Future perspective

Ongoing clinical trials will confirm the already established role of taxanes and define the role of combinations and/or sequences with anthracycline-containing regimens or other new chemotherapeutic agents in the adjuvant and neoadjuvant settings. Dose-dense strategies, mostly with paclitaxel, are being pursued and will establish if there is more than a mere pharmacokinetic optimization of the taxane. Results so far available indicate the ability of taxanes to change the natural history of breast cancer, in particular for patients with early breast cancer. Further results will confirm the best therapeutic strategies with taxanes in order to optimize the already-shown benefit and define more precisely the maximum possible extent of the outcome improvement. In addition, several trials will add to our understanding of the best strategies to integrate taxanes and trastuzumab, with or without the use of anthracyclines.

More research will continue in an effort to characterize potential clinical advantages. The challenge will be double.

On one hand, the integration of taxanes in novel strategies with biologic modifiers will accelerate. It has already started with taxanes and trastuzumab in patients with HER2 abnormalities, and their potential role in advanced and, most importantly, early breast cancer management. It is also likely that docetaxel will be evaluated with other new approaches, such as tyrosine kinase inhibitors and antiangiogenesis compounds.

On the other hand, the identification of predictive factors is critical and more efforts should be deployed in this regard. Clear identification of such factors as responsiveness and resistance to taxanes should allow for better selection of patients and thus expose all patients to this therapy who absolutely need it, while sparing those who would not derive any benefit from it.

Executive summary

Breast cancer is the most frequent cancer in women in developed countries.

Systemic adjuvant chemotherapy has dramatically improved the outcome of patients treated for early stage invasive breast cancer.

Among novel chemotherapeutic agents, the taxanes have emerged as the most powerful compounds since anthracycline regimens.

Two taxanes are available (paclitaxel and docetaxel) and they share some characteristics, while having some significant differences, both in terms of preclinical and pharmacokinetic profiles and, most importantly, clinical consequences.

In clinical practice, the taxanes are now standard therapy in metastatic breast cancer.

Available results in adjuvant and neoadjuvant setting show that taxanes, used in combination with other chemotherapeutic agents (e.g., docetaxel, doxorubicin and cyclophosphamide [TAC]) or trastuzumab, or in sequential therapy (doxorubicin and cyclophosphamide [AC] followed by paclitaxel, or 5-fluorouracil, epirubicin and cyclophosphamide [FEC] followed by docetaxel), possess the capability to induce significant improvements, in particular in terms of survival.

These data confirm the positive impact of taxanes on the natural history of breast cancer.

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Taxane Therapy for Early Stage Breast Cancer

Abstract

Keywords

Taxane development in metastatic disease: the rationale for early breast cancer trials

Taxanes in the adjuvant setting

Adjuvant trials with paclitaxel

Adjuvant trials with docetaxel

Taxanes in the neoadjuvant setting

Taxane monotherapy

Taxane–anthracycline regimens

Taxanes & trastuzumab in the adjuvant setting

Conclusions

Future perspective

References