Adjuvant therapy approaches to breast cancer: Should taxanes be incorporated?

The triplet of docetaxel, doxorubicin, and cyclophosphamide (TAC) has emerged as an alternative chemotherapy regimen for adjuvant management of node-positive breast cancer. Based on recently reported 3-year data from the Breast Cancer International Research Group (BCIRG) 001, disease-free survival was significantly higher in patients who underwent adjuvant chemotherapy with TAC rather than the established regimen of 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC). TAC reduced the risk of disease recurrence in estrogen receptor-positive and -negative patients. Whereas overall survival was not significantly different between the two groups, TAC led to a significant reduction in mortality in the subset of patients with one to three involved axillary lymph nodes. Overall, these interim BCIRG 001 results, coupled with those from Cancer and Leukemia Group B-9344 and National Surgical Adjuvant Breast and Bowel Project (NSABP) B-28 (phase III trials of sequential adjuvant chemotherapy with doxorubicin and cyclophosphamide followed by paclitaxel), suggest that taxanes are a valuable component of adjuvant chemotherapy for patients with node-positive breast cancer, including those with estrogen receptor positivity and/or extensive lymph node involvement. Accumulating data in the neoadjuvant setting lend further support to the view that the taxanes confer clinically meaningful benefits in the management of early-stage breast cancer. Such ongoing studies as NSABP B-30 will be instrumental in establishing the relative merits of sequential versus concurrent taxane-anthracycline adjuvant regimens for patients with node-positive breast cancer.     

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.     

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.     

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.     

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.     

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.     

The Double-Edged Sword: Controversies in Anthracycline-Based Chemotherapy for Breast Cancer

Purpose of Review

This review article seeks to summarize the existent literature regarding the use of anthracyclines (specifically doxorubicin) in the treatment of early-stage breast cancers, reviewing the clinically significant side effects of said therapy, and discussing new tools to risk stratify patients.

Recent Findings

The 2010 Early Breast Cancer Trialists’ Cooperative Group meta-analysis again found anthracycline-containing regimens to improve outcomes, while the ABC Trials have shown the superiority of regimens including doxorubicin versus regimens with docetaxel and cyclophosphamide alone in early-stage breast cancer. New risk stratification tools—such as Oncotype DX®—are helping oncologists decide which patients may be able to avoid chemotherapy.

Summary

Sequential doxorubicin/cyclophosphamide therapy, followed by treatment with docetaxel, improves outcomes in nearly all early-stage breast cancer, with the notable exception of Her2+ disease. Newer risk stratification tools allow better risk/reward calculations in which patients may be able to avoid anthracycline-based chemotherapy and its significant side effects.

     

Docetaxel

? Docetaxel, a potent taxoid analog that primarily exerts its antineoplastic activity via tubulin stabilization and cell cycle arrest, is well established as a chemotherapeutic agent in the treatment of breast cancer. Docetaxel-containing neoadjuvant regimens have been investigated in terms of pathologic complete response (pCR) in four fully published phase III trials in women with early-stage or locally advanced breast cancer, and in terms of disease-free and overall survival in the largest trial, the National Surgical Adjuvant Breast and Bowel Project Protocol (NSABP) B-27. ? In the NSABP B-27, neoadjuvant docetaxel 100 mg/m²every 3 weeks sequential to doxorubicin plus cyclophosphamide every 3 weeks achieved a pCR of 26% in women with operable breast cancer versus 14% with neoadjuvant doxorubicin/cyclophosphamide. Nevertheless, between-group differences in disease-free and overall survival rates were not evident after a median 77.9 months’ follow-up. ? Neoadjuvant docetaxel 100 mg/m²every 3 weeks sequential to cyclophosphamide/doxorubicin/vincristine/prednisone (CVAP) [Aberdeen trial] or doxorubicin/cyclophosphamide (GEPARDUO study) every 3 weeks doubled the pCR rate compared with CVAP every 3 weeks or concomitant doxorubicin plus docetaxel 75 mg/ m²every 2 weeks in women with early-stage or locally advanced breast cancer. ? Similar pCR rates were seen with neoadjuvant doxorubicin plus docetaxel 75 mg/m²or doxorubicin/cyclophosphamide every 3 weeks in women with large or locally advanced breast cancer in the Anglo-Celtic Cooperative Oncology Group study. ? Severe hematologic toxicity, including febrile neutropenia and/or neutropenic sepsis, was generally more frequent with docetaxel-containing regimens than with doxorubicin/cyclophosphamide in phase III trials. Most other adverse events associated with docetaxel were mild to moderate in severity.      

Multicentric, randomized phase III trial of two different adjuvant chemotherapy regimens plus three versus twelve months of trastuzumab in patients with HER2- positive breast cancer (Short-HER Trial; NCT00629278)

Trastuzumab, a monoclonal antibody against the HER2 receptor, is currently approved as a part of adjuvant therapy for patients with HER2-overexpressing breast tumors. The Short-HER study is a phase III randomized, multicentric Italian trial aimed at testing the optimal duration of adjuvant trastuzumab. In this trial, 2500 patients with HER2-positive breast cancer will be randomized to receive the following: (arm A, long) 4 courses of anthracycline- based chemotherapy (doxorubicin/cyclophosphamide or epidoxorubicin/cyclophosphamide) followed by 4 courses of docetaxel or paclitaxel in combination with trastuzumab, followed by 14 additional courses of trastuzumab administered every 3 weeks (for a total of 18 3-weekly doses of trastuzumab); or (arm B, short) 3 courses of 3-weekly docetaxel in combination with weekly trastuzumab (for a total of 9 weekly doses of trastuzumab) followed by 3 courses of 5-fluorouracil/epirubicin/cyclophosphamide. The primary objective is disease-free survival.     

Overview of epirubicin-based adjuvant therapy in breast cancer

Clinical trial data indicate that epirubicin-based adjuvant treatment of breast cancer is associated with marked improvement in relapse-free and overall survival compared with traditional cyclophosphamide/methotrexate/5-fluorouracil. The outcomes are comparable to those achieved with sequential use of doxorubicin/cyclophosphamide and paclitaxel. Dose intensification of epirubicin is feasible, with tolerable side effects and no increased risk of cardiotoxicity beyond that expected. Clinical trial data coupled with pharmacokinetic evidence provide a strong foundation and rationale for current and future investigation of epirubicin in combination with the taxanes in the adjuvant setting. An ongoing German study is evaluating epirubicin/cyclophosphamide in combination with trastuzumab as first-line therapy of metastatic breast cancer in patients whose tumors overexpress HER2/neu protein. These results, particularly the tolerability of this regimen, will form the basis for future adjuvant and neoadjuvant studies of epirubicin/trastuzumab-based regimens.     

Rationale and design of a phase III trial of adjuvant sequential epirubicin/ cyclophosphamide and taxane versus concurrent epirubicin/taxane in operable node-positive breast cancer

The sequential use of a doxorubicin combination followed by paclitaxel has been reported to improve disease-free and overall survival in patients with node-positive breast cancer beyond that obtained with doxorubicin/cyclophosphamide combinations. Epirubicin is associated with less cardiotoxicity than doxorubicin and can be used at cumulative dose levels or intensities that cannot be safely achieved with doxorubicin. Epirubicin/taxane combinations have exhibited significant activity when used in the treatment of metastatic breast cancer. Based on these safety and efficacy data, a phase III adjuvant trial will compare the efficacy of a concurrent epirubicin/taxane regimen with sequential epirubicin/cyclophosphamide followed by taxane treatment in patients with operable node-positive breast cancer.     

A phase II feasibility trial of dose-dense docetaxel followed by doxorubicin/cyclophosphamide as adjuvant or neoadjuvant treatment for women with node-positive or high-risk node-negative breast cancer

PURPOSE: Dose-dense adjuvant chemotherapy with doxorubicin/cyclophosphamide (AC) followed by paclitaxel has improved results compared with standard dosing at 3-week intervals. Because docetaxel might be more active than paclitaxel in the treatment of metastatic breast cancer, we explored the feasibility of substituting docetaxel for paclitaxel in dose-dense adjuvant therapy. PATIENTS AND METHODS: Seventy-six patients with node-positive breast cancer received treatment with 4 cycles of docetaxel followed by 4 cycles of AC administered with pegfilgrastim at 2-week intervals. When treatment proved difficult for the first 33 patients, 2 additional cohorts were treated: first, with a reduction of pegfilgrastim and dexamethasone prophylaxis doses (cohort 2) and then with a reduction of docetaxel from 100 mg/m2 to 75 mg/m2 (cohort 3). RESULTS: Treatment with dose-dense docetaxel at 100 mg/m2 resulted in unacceptable toxicity (24% of patients required hospitalization) and compromised subsequent dosing of AC as a result of neutropenia on the day of scheduled treatment. Only 21 patients (40%) who received docetaxel 100 mg/m2 were able to receive all 8 doses at full dose and on schedule. Reduction of docetaxel to 75 mg/m2 allowed 74% of patients to receive all 8 doses as scheduled. Delivery of AC as scheduled occurred in 82% of patients who received docetaxel 75 mg/m2 versus 40% when docetaxel 100 mg/m2 was administered. CONCLUSION: Full-dose docetaxel is difficult to administer as part of this dose-dense treatment regimen. Docetaxel 75 mg/m2 can be administered with improved subsequent delivery of 4 courses of dose-dense AC. Until comparative clinical studies are available, docetaxel should not be substituted for paclitaxel in dose-dense adjuvant chemotherapy for patients with high-risk breast cancer.     

Dose-dense therapy in the treatment of early-stage breast cancer: an overview of the data

Breast cancer represents a significant public health burden with > 200,000 new cases diagnosed in the United States each year. Although a significant proportion of these new diagnoses represent early-stage disease, many of these women will eventually experience a distant relapse and ultimately die of complications of metastatic breast cancer. Consequently, innovations in adjuvant treatment strategies are critical as we strive to further optimize outcomes. One such innovation, the dose-dense approach, is intended to specifically optimize the administration of standard chemotherapy regimens. Specifically, models of tumor growth and response, based on the Norton-Simon hypothesis, were translated into regimens which aim to increase tumor cell kill by decreasing the time intervals between treatments. This strategy, fully evaluated with doxorubicin/cyclophosphamide and paclitaxel in Cancer and Leukemia Group B 9741, demonstrated significant benefits compared with conventionally scheduled adjuvant chemotherapy. Dose density has since been applied to a number of other chemotherapy regimens and evaluated in clinical trials. An overview of the pivotal dose-dense trials will be reviewed herein.     

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.     

Pegylated liposomal doxorubicin in the treatment of breast cancer

Anthracyclines, particularly conventional doxorubicin, play an important role in the treatment of breast cancer, both in the adjuvant and metastatic settings. However, the benefits of conventional doxorubicin in terms of antitumor activity are limited by its therapeutic index. Liposomal formulations were developed to increase the therapeutic index of conventional doxorubicin. Pegylated liposomal doxorubicin, the most widely studied liposomal doxorubicin formulation in breast cancer, has been evaluated in > 20 clinical trials. Pegylated liposomal doxorubicin provides tumor-targeted efficacy without many of the toxicities associated with conventional doxorubicin, including myelosuppression, alopecia, nausea and vomiting, and most importantly, cardiac toxicity. As a single agent, pegylated liposomal doxorubicin has demonstrated similar efficacy to that of conventional doxorubicin in patients with metastatic breast cancer. It has also demonstrated efficacy in combination with other agents or modalities, including cyclophosphamide, paclitaxel, docetaxel, gemcitabine, vinorelbine, and hyperthermia. Response rates in patients with metastatic breast cancer receiving pegylated liposomal doxorubicin either alone or in combination regimens range from 27% to 83%, with median survival estimated at 7-20 months. Small studies also suggest a role for pegylated liposomal doxorubicin in the treatment of locally advanced breast cancer. Preliminary results suggest that pegylated liposomal doxorubicin may be safely administered in combination with docetaxel and trastuzumab in patients with HER2-positive disease. Owing to its comparable efficacy and favorable safety profile, pegylated liposomal doxorubicin may be a useful alternative to conventional doxorubicin, as well as other agents commonly used in the treatment of breast cancer.     

Rationale and use of epirubicin-based therapy in the adjuvant setting

The taxanes paclitaxel and docetaxel have an important role in the treatment of breast cancer, and numerous randomized trials have evaluated their efficacy for this indication. A systematic, evidence-based review was performed, which included all randomized, controlled trials evaluating taxanes for the treatment of early- or advanced-stage breast cancer that were identified in CANCERLIT and MEDLINE searches. The primary objectives of this review were to determine the dose and schedule for each taxane that was associated with the most favorable therapeutic index, and to determine whether (and under what circumstances) the taxanes improved survival. The search revealed 18 randomized phase II (n=1) or phase III (n=17) trials. For metastatic breast cancer, the dose and schedule associated with the most favorable therapeutic index for paclitaxel was 175 mg/m2 given as a 3-hour infusion every 3 weeks, and docetaxel was 60-100 mg/m2 given as a 1-hour infusion every 3 weeks. Survival was improved under the following circumstances: (1) when 4 cycles of paclitaxel (175 mg/m2 every 3 weeks) was given following 4 cycles of conventional doxorubicin- cyclophosphamide for axillary node-positive operable breast cancer, (2) when trastuzumab was added to paclitaxel as first-line therapy for metastatic breast cancer that overexpressed HER2/neu, and (3) when docetaxel was given as second-line therapy for anthracycline-resistant disease. Although a survival benefit was found for taxanes as a component of first-line therapy in two of six trials, the interpretation of both positive trials was confounded by a lack of crossover to taxane therapy in those who were initially randomized to receive standard therapy. The taxanes improve survival in patients with early-stage breast cancer and selected patients with metastatic breast cancer. Further research is necessary in order to identify the efficacy of docetaxel relative to paclitaxel, the optimal dose of docetaxel, the role of weekly taxane therapy, the role of trastuzumab plus taxanes in early-stage disease, and whether taxanes are more effective when given concomitantly or sequentially in patients with early-stage disease     

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.     

Future treatment options with capecitabine in solid tumours

The oral fluoropyrimidine, capecitabine is attracting great interest in the context of tumour-selective therapy and rationally designed combination regimens. Agents such as taxanes upregulate thymidine phosphorylase (TP), and there is therefore a clear rationale for their combination with capecitabine. Preclinical studies of capecitabine/taxane combination therapy demonstrated synergistic antitumour activity and phase I studies showed encouraging efficacy. Therefore, a randomised, phase III trial (docetaxel versus docetaxel/capecitabine) has been initiated in anthracycline-refractory metastatic breast cancer patients. Recruitment is complete. In colorectal cancer, capecitabine/oxaliplatin combination therapy is promising and a phase I, dose-finding trial has been conducted in patients with refractory metastatic solid tumours. A similar trial has evaluated capecitabine/irinotecan combination treatment. Capecitabine is also being investigated as adjuvant therapy for colorectal and breast cancers. The primary objective of the ongoing X-ACT trial in almost 2000 Dukes' C colon cancer patients is to demonstrate at least equivalent disease-free survival between capecitabine and the Mayo Clinic regimen. In addition, the CALGB is planning a randomised, phase III trial of capecitabine versus doxorubicin/cyclophosphamide or cyclophosphamide/methotrexate/5-fluorouracil (CMF) as adjuvant treatment in high-risk, node-negative breast cancer patients aged >65 years.     

Optimizing adjuvant chemotherapy in early-stage breast cancer

Mortality in breast cancer has declined in the past decade, owing to advances in diagnosis, surgery, radiotherapy, and systemic treatments. Adjuvant chemotherapy has had a major effect on increasing survival in women with locoregional breast cancer. Like all treatments, adjuvant chemotherapy is a work in progress, and it has evolved from single oral agents to complex multidrug regimens. The choice of regimens is not without controversy, however, and several have been shown to be more effective than others, especially in patients who are at high risk for recurrence. The taxanes paclitaxel and docetaxel (Taxotere) have been shown to be effective in the adjuvant setting, and they have also been shown to improve the outcomes in node-positive disease. Both disease-free and overall survival are greater with doxorubicin, paclitaxel, and cyclophosphamide given in a dose-dense, every-2-week schedule with growth factor support than with the same agents given in an every-3-week schedule. Disease-free and overall survival in patients with node-positive disease are greater with docetaxel, doxorubicin (Adriamycin), and cyclophosphamide (TAC) than with fluorouracil, doxorubicin, and cyclophosphamide (FAC). Febrile neutropenia is common with the TAC regimen, but it can be minimized with growth factor support. Based on these findings, dose-dense therapy and TAC are the current adjuvant treatments of choice in patients with node-positive disease; other, less-intense regimens may be appropriate in patients with lower-risk disease. Ongoing trials are investigating the efficacy of commonly used regimens, new chemotherapeutic and biologic agents, and novel doses and schedules of currently available agents.     

Adjuvant therapy of breast cancer

The treatment of early-stage breast cancer includes the use of chemotherapeutic and hormonal agents. Both chemotherapy and hormonal therapy have been shown by large, randomized trials to offer a survival advantage. The most commonly used chemotherapeutic agents used in the United States are doxorubicin and cyclophosphamide (AC). However, 3 studies have suggested that there may be an advantage in the use of taxanes in the adjuvant treatment of breast cancer. Furthermore the use of dose dense chemotherapy, incorporating AC and paclitaxel, has shown very promising results. It is well established that tamoxifen, a selective estrogen receptor modulator (SERM), improves overall survival (OS) in women with hormone receptor (HR) positive breast cancer. However, the results from large multicenter, randomized trials, suggest the potential superiority of aromatase inhibitors, compared to tamoxifen or an advantage of sequencing tamoxifen followed by an aromatase inhibitor (AI). The role of ovarian suppression is still being investigated in patients who have received prior chemotherapy. Newer agents, such as the monoclonal antibody against the HER2/neu receptor, trastuzumab, are now being studied as adjuvant therapy in early-stage breast cancer. In the next few years, with the completion of several large randomized trials, we will be able to answer several questions, including the optimal way of incorporating AIs into adjuvant therapy, the long-term sequella of using trastuzumab in the adjuvant treatment of breast cancer and the role of ovarian suppression combined with an aromatse inhibitor in premenopausal women with breast cancer.