Taxanes in the adjuvant treatment of breast cancer: why not yet?

The taxanes paclitaxel and docetaxel represent the most active chemotherapeutic agents developed for the treatment of advanced breast cancer in the last decade, and they are now being incorporated into adjuvant chemotherapy trials for lymph node-positive breast cancer with the hope of improving on the results achieved with CMF (cyclophosphamide, methotrexate, 5-fluorouracil) or anthracycline-based regimens. So far, three randomized paclitaxel-based adjuvant clinical trials enrolling 3170 women (Cancer and Leukemia Group B [CALGB] 9344), 3060 women (National Surgical Adjuvant Project for Breast and Bowel Cancers [NSABP]-B28), and 524 women (M. D. Anderson), respectively, have been reported with respective median follow-up times of 52, 34, and 43 months. This article critically reviews these three studies and gives an overview of the many other randomized clinical trials, due to accrue more than 17 000 women, which are investigating the potential of taxanes in adjuvant breast cancer therapy. Given that the early promise of taxanes suggested by CALGB 9344 is not yet confirmed by the two other trials, only level 2 evidence has been reached to date in regard to a positive contribution of these agents to breast cancer outcome in the adjuvant setting. It is argued that level 1 evidence is highly desirable before adopting taxane-based regimens in standard practice. It is anticipated that a meta-analysis will be needed to comprehensively define the value of taxanes in early breast cancer, and a new model of international collaboration is proposed to find a balance between the need to offer new, more effective therapies to patients as soon as possible and the danger of drawing wrong, premature conclusions regarding the magnitude of benefit of a new regimen.     

Drug treatments for adjuvant chemotherapy in breast cancer: recent trials and future directions

Adjuvant chemotherapy with anthracycline-based regimens has been proven to decrease the risk of relapse and cancer-related mortality in women with early-stage breast cancer. The taxanes, paclitaxel and docetaxel, have been incorporated into several adjuvant chemotherapy regimens in recent studies. Some of these trials have matured and demonstrated a definitive benefit with the use of taxanes. The available studies reveal that the addition of a taxane after an anthracycline or the substitution of a taxane into a three-drug regimen, such as docetaxel, doxorubicin and cyclophosphamide, clearly demonstrate a benefit for taxanes in the adjuvant treatment of breast cancer. The toxicities of the taxanes are generally acceptable. Targeted therapy, such as with trastuzumab, has demonstrated a large benefit that previously has never been seen in adjuvant chemotherapy trials, and thus, should now be part of the standard in the treatment of HER-2/neu positive breast cancer. Newer agents are on the horizon.     

Optimum anthracycline-based chemotherapy for early breast cancer

Adjuvant chemotherapy improves the overall survival of women treated after surgery for early breast cancer. Several trials have suggested that anthracycline-containing regimens are more effective than those that do not contain anthracyclines. A modest overall benefit has also been confirmed by the Early Breast Cancer Trialists' Collaborative Group overview. Newer agents, such as the taxanes, are now being tested in the adjuvant setting in randomised trials. The control group of such studies should receive the optimum standard treatment. There are several anthracycline-based regimens in common use, varying in terms of the type of anthracycline used, the dose, and drug scheduling. We review the available evidence and consider whether the optimum anthracycline-containing chemotherapy schedule has now been identified.     

Adjuvant use of taxanes for patients with breast cancer: we see the tip of the iceberg

Advances in screening techniques for breast cancer have led to the diagnosis of more patients at earlier disease stages at which time the possibility of a cure is more likely. Adjuvant chemotherapy with anthracycline-based regimens has proven to reduce the risk of relapse and cancer-related death in women with early-stage breast cancer. Recent studies have aimed at integrating the taxanes, paclitaxel and docetaxel, into the adjuvant setting, but to date, we are still in the earliest stages of the study of patients with operable breast cancer. Adjuvant trials now require thousands of patients and many years to reach maturity. Many of the trials began in the late 1990s and are not yet mature. For node-positive patients, the available evidence supports the use of taxanes as adjuvant treatment since they are safe and appear to provide benefit. Going forward, docetaxel holds significant promise in the adjuvant setting, and further trials as well as further follow-up of existing trials are eagerly awaited to help us determine whether docetaxel is best given sequentially to, or concurrently with, doxorubicin or epirubicin.     

Evidence-based use of taxanes in the adjuvant setting of breast cancer. A review of randomized phase III trials

Six major randomized clinical trials evaluating the role of taxanes in the adjuvant setting of breast cancer have demonstrated significant improvements in terms of efficacy in favour of the taxane treatment arm. In all cases, different anthracycline-based regimens were used as the control arm. Nevertheless, many clinicians are still not sufficiently convinced to incorporate the routine use of taxanes in the adjuvant treatment of breast cancer. There are two main objections, first the possible lack of effectiveness of chemotherapy in hormone-receptor positive tumors and second, some of the anthracycline-based control arms used in these trials were not the optimal ones. In this review, we have searched and analyzed all randomized studies that evaluated the role of taxanes in the adjuvant setting of breast cancer patients and have reported results in terms of efficacy or tolerance. The suitability of the control arm, the prospective definition of patient's subgroups and the statistical methodology were taking into account. The objective of this review was to analyze if, at this point in time, there is sufficient evidence to support the routine use of taxanes in the adjuvant setting of breast cancer, and if it is valid for all subgroups including hormone-receptor and Her2/neu positive breast cancer patients. Other objectives of this review were to define the optimal regimen for administration of taxanes, how the tolerability of taxanes may be improved and also, to investigate any potential differences in efficacy or tolerability between docetaxel and paclitaxel.     

Gemcitabine and platinum combinations in patients with breast cancer previously treated with anthracyclines and/or taxanes

As anthracycline-based regimens have become a standard treatment and are frequently used in the adjuvant therapy of breast cancer, the number of anthracycline-resistant cancers has begun to increase. Taxanes have also become more commonly used in the first-line metastatic and adjuvant setting, producing a need for new treatment options that are not cross-resistant with anthracyclines or taxanes and that have a relative non-overlapping toxicity profile with these agents. The combination of gemcitabine/cisplatin has been shown to have synergistic cytotoxic activity in vitro in breast cancer cell lines. In addition, several phase II trials have suggested that this combination is feasible and active in patients who have received prior anthracycline and/or taxane therapy.     

Adjuvant taxanes in the treatment of breast cancer: no longer at the tip of the iceberg

Breast cancer is one of the leading causes of cancer-related mortality, and a cure is desperately needed. Adjuvant chemotherapy with anthracycline-based regimens has been proven to decrease the risk of relapse and cancer-related mortality in women with early-stage breast cancer. The taxanes (paclitaxel and docetaxel) have been incorporated into several adjuvant chemotherapy regimens in recent studies. Some of these trials are now mature and have demonstrated a definitive benefit with the use of taxanes. Thus, taxanes should be incorporated into the adjuvant treatment of breast cancer. To date, the available data do not allow one to select a single best taxane, schedule, or overall regimen.     

The choice of adjuvant combination therapies with taxanes: rationale and issues addressed in ongoing studies

The taxanes are emerging as the most powerful compounds in breast cancer. Both compounds, paclitaxel and docetaxel, have been evaluated in the metastatic setting before proceeding with adjuvant trials. Docetaxel was shown in phase III trials to be superior, in particular, in terms of time to progression and survival, to salvage polychemotherapies after failure of prior chemotherapy including anthracyclines. Also, after failure of alkylating agents, a benefit in favor of docetaxel was reported when compared to doxorubicin, whereas paclitaxel was reported to be either as efficacious or inferior to doxorubicin, while being comparable to cyclophosphamide/methotrexate/5-fluorouracil. The role of taxanes in combination with anthracyclines in first-line therapy of advanced breast cancer is still unclear although emerging. One phase III trial showed the significant superiority of doxorubicin/docetaxel (AT) versus doxorubicin/cyclophosphamide (AC) in terms of response and time to progression. Several phase II studies with paclitaxel (over 3 hours) and anthracyclines in the metastatic setting showed high efficacy, but they also showed cardiac toxicity related to a pharmacokinetic interaction between the 2 agents. This fact led to the implementation of metastatic strategies (several phase III trials) aimed at avoiding the pharmacokinetic interaction or specifically limiting the cardiac toxicity that resulted in contradictory results. Consequently, adjuvant strategies with paclitaxel focused mostly on the sequential approach (AC followed by paclitaxel). In contrast, adjuvant strategies with docetaxel/anthracycline-based programs were implemented following both sequential and combination approaches. Results of all of these trials in the adjuvant setting are eagerly awaited in order to establish the role of taxanes in adjuvant breast cancer.     

The role of taxanes in the adjuvant treatment of early stage breast cancer

Adjuvant chemotherapy plays a significant incremental role in improving survival in patients with early stage breast cancer. Survival benefits gained in the adjuvant setting with anthracycline-based polychemotherapy regimens are now level- 1 evidence based, and in an attempt to further these gains, many randomized trials are examining new treatment options. Other important goals include defining the magnitude of benefit with current and investigational regimens in prospectively defined risk groups. The taxanes, docetaxel and paclitaxel, are under investigation in the adjuvant setting in a large series of randomized clinical trials that will enroll not less than 56,000 women, among whom 22,000 women will contribute to paclitaxel-related questions and 34,000 to docetaxel-related questions. The main focus of this review will be the first-generation trials (N = 31,000), which include at least one non-taxane arm. For the most part, trials with paclitaxel have evaluated the agent in sequence with anthracycline-based therapy, while trials with docetaxel are evaluating it as an alternative to one of the standard drugs in a combination regimen as well as in sequence with anthracycline-based regimens. To date, results from four randomized trials with adjuvant paclitaxel and two with docetaxel have been presented. All reports but one are based on interim analyses. Only one of the paclitaxel trials so far demonstrated a statistically significant improvement in disease-free and overall survival relative to the comparator, while a second trial demonstrated superiority of dose-dense chemotherapy over conventional dosing. Interim results with docetaxel suggest that substituting docetaxel for fluorouracil in combination with doxorubicin and cyclophosphamide results in improved disease-free survival, with a trend toward improved overall survival. Completion of ongoing trials and maturation of the current data will further define the role of taxanes in the adjuvant treatment of early stage breast cancer.     

Three Years' Follow-up from the ATAC Trial is Sufficient to Change Clinical Practice: A Debate

The taxanes and anthracyclines have emerged as the most active agents for treating women with advanced breast cancer. As such, investigation of the two drug classes in combination regimens has been eagerly pursued. The rationale for combining docetaxel with an anthracycline includes high clinical activity of each individual agent, lack of complete clinical cross resistance, and non-overlapping toxicity profiles. Phase II trials of the docetaxel combinations with either doxorubicin or epirubicin showed high activity, with acceptable tolerability in patients with metastatic breast cancer. Consequently, three randomized trials have compared docetaxel–anthracycline-based regimens with standard anthracycline-based polychemotherapies as first-line therapy for women with advanced breast cancer. Improved outcome was reported in favor of the docetaxel–anthracycline combinations, with manageable hematologic toxicity and favorable non-hematologic safety profiles. Therefore, docetaxel–anthracycline combinations represent a validated option in first-line treatment for women with advanced breast cancer, and are further evaluated as adjuvant treatment for early stage breast cancer, with already promising prospects and the potential to change the natural history of breast cancer.     

Introduction

Since their introduction in the 1960s, anthracyclines such as doxorubicin have attained a central place in the management of a number of solid tumours and haematological malignancies. Anthracycline-based regimens constitute a standard of care in patients with metastatic breast cancer; anthracycline monotherapy compares favourably with taxanes alone, while combinations of anthracyclines and taxanes have been shown to be superior to anthracycline-based regimens in terms of response rates and progression-free survival. Similarly, in patients with early breast cancer, adjuvant therapy with anthracycline-based regimens significantly reduces breast cancer mortality, compared with cyclophosphamide-methotrexate-fluorouracil regimens. However, a major limitation to the use of anthracyclines is cumulative cardiotoxicity, which can result in irreversible congestive heart failure. A number of strategies to reduce cardiotoxicity have been investigated, including modification of the dosing regimen, use of cardioprotective agents, and the development of liposomal doxorubicin formulations. The central place of anthracyclines in breast cancer management is likely to continue: the challenge now is to identify those patients most likely to respond to, and benefit from, anthracyclinebased therapy.     

Systematic review of taxane-containing versus non-taxane-containing regimens for adjuvant and neoadjuvant treatment of early breast cancer

The use of taxanes in early breast cancer is increasing. However, there are few mature studies of taxanes in this setting, and their role is uncertain. Our systematic review of randomised trials of adjuvant or neoadjuvant systemic therapy identified ten reported trials comparing a taxane-containing group with a non-taxane-containing control group in women with early breast cancer. Four of five neoadjuvant trials showed higher rates of complete response with taxanes, although differences were not significant. All five adjuvant trials showed improvements in disease-free survival with taxanes, and these improvements were significant in three trials and independent of oestrogen-receptor status. Two trials showed a significant improvement in overall survival. These results support the use of adjuvant taxanes in women with early breast cancer and involved lymph nodes. Longer follow-up of these trials and results from continuing trials are needed to clarify the best use of taxanes in early breast cancer.     

Docetaxel-anthracycline combinations in metastatic breast cancer

The taxanes and anthracyclines have emerged as the most active agents for treating women with advanced breast cancer. As such, investigation of the two drug classes in combination regimens has been eagerly pursued. The rationale for combining docetaxel with an anthracycline includes high clinical activity of each individual agent, lack of complete clinical cross resistance, and non-overlapping toxicity profiles. Phase II trials of the docetaxel combinations with either doxorubicin or epirubicin showed high activity, with acceptable tolerability in patients with metastatic breast cancer. Consequently, three randomized trials have compared docetaxel-anthracycline-based regimens with standard anthracycline-based polychemotherapies as first-line therapy for women with advanced breast cancer. Improved outcome was reported in favor of the docetaxel-anthracycline combinations, with manageable hematologic toxicity and favorable non-hematologic safety profiles. Therefore, docetaxel-anthracycline combinations represent a validated option in first-line treatment for women with advanced breast cancer, and are further evaluated as adjuvant treatment for early stage breast cancer, with already promising prospects and the potential to change the natural history of breast cancer.     

Taxane/anthracycline combinations: setting a new standard in breast cancer?

Among the novel chemotherapeutic drugs introduced in the 1990s, the taxanes have emerged as the most powerful compounds in breast cancer. Both compounds, paclitaxel and docetaxel, have been evaluated in metastatic settings before adjuvant trials proceeded. Docetaxel was shown in several phase III trials to be superior, particularly in terms of survival, for salvaging polychemotherapies after failure of prior chemotherapy, including that with anthracyclines. A benefit of docetaxel was also reported when compared with doxorubicin after failure of alkylating agents. In phase III trials paclitaxel was reported to be as efficacious over 24 hours as doxorubicin 60 mg/m(2), while paclitaxel was significantly inferior to doxorubicin 75 mg/m(2) over 3 hours and was close to CMF in another trial. The role of taxanes in combination with anthracyclines in first-line therapy of advanced breast cancer is emerging. Following several phase II studies, a phase III trial showed the significant superiority of docetaxel/doxorubicin (AT) versus doxorubicin/cyclophosphamide (AC) in terms of response and time to progression. In several phase II studies with paclitaxel (3 hours), anthracyclines in the metastatic setting showed high efficacy but produced cardiac toxicity related to a pharmacokinetic interaction between the two agents. This finding led to the implementation of metastatic strategies (phase III trials) aimed at avoiding the pharmacokinetic interaction, while the adjuvant strategies with paclitaxel focused primarily on the sequential approach (AC followed by paclitaxel). In contrast, adjuvant strategies with docetaxel/anthracycline-based programs were implemented following both sequential and combination approaches.     

Breast cancer: achievements in adjuvant systemic therapies in the pre-genomic era

In recent decades, the use of adjuvant systemic therapies for early breast cancer has increased extensively and has most likely contributed to the decline in breast cancer mortality observed in the U.S. and in some European countries. The last few years have witnessed accelerated progress in the treatment of early breast cancer, with the introduction of taxanes and aromatase inhibitors and, most impressively, trastuzumab to the adjuvant portfolio. When compared with anthracycline-based regimens, the addition of taxanes to treatments for patients with node-positive breast cancer has shown benefits in disease-free survival and, in some trials, in overall survival; however, these drugs are not yet universally accepted as standard treatment. Significant improvements in endocrine therapy in both pre- and postmenopausal patients with endocrine-responsive disease have been made. In the postmenopausal setting, aromatase inhibitors have shown superiority over tamoxifen in a direct comparison upfront or when given in sequence after 2-5 years of tamoxifen, but the optimal modality of administration remains unclear. For premenopausal women, ovarian function suppression with luteinizing hormone-releasing hormone analogues combined with tamoxifen has generated similar results to cyclophosphamide, methotrexate, 5-fluorouracil (CMF)-based regimens. Recently, trastuzumab has had a dramatic impact on the evolution of human epidermal growth factor receptor 2 (HER-2)-positive early breast cancer treated with standard adjuvant modalities; specifically, relapses, including distant relapses, have been halved. In this review, we summarize these main achievements, discuss the currently available adjuvant treatment options for breast cancer patients, and emphasize the need for more efficient translational research to improve individual treatment tailoring.     

A review of vinorelbine in the treatment of breast cancer

As combinations and sequences of anthracyclines and taxanes increasingly become standard adjuvant treatment for early breast cancer, a major need for new treatment options for metastatic breast cancer will arise. Vinorelbine is highly active in the treatment of metastatic breast cancer, both as a single agent and in combination regimens. Furthermore, it is well tolerated, with a low incidence of subjective toxicities. It is anticipated, therefore, that vinorelbine will become increasingly utilized for treating metastatic breast cancer due to its favorable safety profile, good tolerability, and promising results in combination with other chemotherapy agents. Combinations with trastuzumab and newer molecular targeting agents are being explored. Doublets or triplets of vinorelbine with drugs other than anthracyclines and taxanes could be considered in the next generation of adjuvant and neoadjuvant trials, where it is anticipated that anthracycline/taxane combinations are likely to replace anthracycline/cyclophosphamide combinations as the mainstay of adjuvant treatment.     

Docetaxel for treatment of solid tumours: a systematic review of clinical data

Docetaxel is a semisynthetic taxane, a class of anticancer agents that bind to beta tubulin, thereby stabilising microtubules and inducing cell-cycle arrest and apoptosis. Docetaxel was first approved for the treatment of anthracycline-refractory metastatic breast cancer in the mid-1990s. Since then, several randomised trials have reported improved time-to-progression, overall survival, or both in metastatic breast cancer treated with single-agent docetaxel or docetaxel-based combination regimens. Data from two adjuvant trials have shown a survival benefit with the addition of docetaxel to standard anthracycline-based regimens in patients with high-risk early breast cancer. In four randomised studies, docetaxel improved survival in locally advanced or metastatic non-small-cell lung cancer. Moreover, two trials have shown that docetaxel combined with estramustine or corticosteroids improves survival in metastatic androgen-independent prostate cancer. Here, we review major randomised phase III trials with docetaxel in the treatment of solid malignant disease.     

Taxanes in breast cancer: An update

Over the past decade the taxanes have proved to be fundamental in the treatment of breast cancer. Initially found to have efficacy in metastatic breast cancer, the taxanes are now vital components in the treatment of early-stage disease, in which their addition to adjuvant treatment of early breast cancer has been shown to improve overall survival. In addition, the taxanes have demonstrated a role in first-line therapy for metastatic disease, with some of the highest efficacy of any class of chemotherapy. Targeted therapies in combination with the taxanes have further improved survival for both early and metastatic disease. New formulations of taxanes may both improve antitumor activity and reduce toxicity.     

Current perspectives for treatment of Breast Cancer

Conclusions  The last 2–3 years have brought significant changes to both the adjuvant and palliative treatment of breast cancer. The addition of paclitaxel to the adjuvant setting has brought the largest increase in benefit from adjuvant therapy since the initial CMF trials in the 1970s. Changes in the schedule of administration of the taxanes in the palliative setting have substantially diminished the toxicity without an apparent compromise in the efficacy of these important agents. The combination of chemotherapy and Herceptin in the first line treatment of metastatic breast cancer has resulted in enhancement of survival of women with advanced disease. In only a few short years, the future for women diagnosed with breast cancer has come to look substantially brighter.     

Advances in the use of taxanes in the adjuvant therapy of breast cancer

Among the novel chemotherapeutic drugs introduced in the 1990s, the taxanes have emerged as the most powerful compounds in breast cancer. Paclitaxel and docetaxel have been evaluated in the metastatic setting before proceeding with adjuvant trials. The adjuvant strategies of development of both taxanes have been different, mostly as a result of pharmacokinetic differences and dose-schedule issues. As a consequence, paclitaxel was studied nearly exclusively in sequential programs such as AC (doxorubicin/cyclophosphamide) followed by paclitaxel or doxorubicin, followed by paclitaxel, followed by cyclophosphamide. In contrast, docetaxel has been investigated in sequence (AC followed by docetaxel) and in combination chemotherapy (doxorubicin/docetaxel and docetaxel/doxorubicin/cyclophosphamide). Available results of large-scale phase III trials confirm that the taxanes have the potential to change the natural history of early-stage breast cancer. It is becoming clear that sequential chemotherapy and polychemotherapy approaches with taxanes are to be considered in the treatment of patients with node-positive breast cancer. Further results are eagerly awaited to fully understand the role of taxanes and to optimize their impact on early-stage breast cancer. It is our opinion that the real pending issue is no longer whether taxanes will make a difference in the adjuvant setting (the answer is most likely yes), but the definition of their optimal strategic use for maximum patient benefit.