Adjuvant Chemotherapy for Early-Stage Breast Cancer

Hematol Oncol Clin N Am 21 (2007) 207–222

HEMATOLOGY/ONCOLOGY CLINICS OF NORTH AMERICA

Adjuvant Chemotherapy for Early-Stage Breast Cancer Heather L. McArthur, MD*, Clifford A. Hudis, MD Breast Cancer Medicine Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA

B

reast cancer is the most commonly diagnosed cancer and the second leading cause of cancer-related mortality among North American women [1]. In recent years, the incidence of early-stage breast cancer has been increasing, largely as a result of improvements in public education, screening programs, and technology [1a,1b]. Despite early diagnosis and increasingly efficacious treatment paradigms, however, a significant proportion of women who have early-stage disease experience relapse at distant sites and ultimately die of recurrence-related complications. The significant rate of distant treatment failures indicates that some women have clinically undetectable micrometastatic disease at the time of diagnosis, and therefore locoregional therapy is insufficient for cure. To address these subclinical metastases, systemic therapy has become an integral component of the adjuvant treatment strategy. Adjuvant systemic therapy may be composed of chemotherapy, hormonal maneuvers, immunotherapy, or experimental agents. This article focuses on the role of adjuvant chemotherapy in the management of early-stage breast cancer. RISK STRATIFICATION Recommendations regarding adjuvant chemotherapy are generally made by estimating an individual’s risk for recurrence and the expected benefit of therapy. The treatment strategy is further individualized by considering the acceptability of anticipated toxicity, the desire for the expected benefit, and other patientspecific characteristics, including age, comorbidities, and patient preference. Historically, prognostic estimates were largely derived from information on tumor size, extent of lymph node involvement, and histologic grade or degree of differentiation. More recently, however, prognostic profiling has become increasingly sophisticated as our understanding of biologic and molecular markers continues to expand. These advances have augmented rather than

*Corresponding author. c/o Sherdina Erwin, Breast Cancer Medicine Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. E-mail address: [email protected] (H.L. McArthur). 0889-8588/07/$ – see front matter doi:10.1016/j.hoc.2007.03.008

ª 2007 Elsevier Inc. All rights reserved. hemonc.theclinics.com

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supplanted the prognostic significance of the readily available histologic stage and grade information, resulting in new paradigms for risk stratification. Tumor Size, Nodal Involvement and Histologic Grade (or Degree of Differentiation) Increasing tumor size and nodal involvement are well-established adverse prognostic factors for patients who have early-stage breast cancer [1]. The enduring relevance of tumor size as an important prognostic factor was recently demonstrated in a retrospective analysis of women who had early stage, node-negative, lymphovascular-negative breast cancer [2]. As predicted, increasing tumor size proved a powerful adverse prognosticator within this cohort. Predicted outcomes were further refined when stratified by histologic grade within each size category. The prognostic impact of tumor grade was particularly pronounced among women who had tumors less than or equal to 2.0 cm. The extent of nodal involvement has traditionally conferred the most compelling prognostic information. The advent of sentinel node sampling, a technique that involves the injection of radioactive colloid or blue dye into the breast to identify the lymph nodes that first receive drainage from the tumor, has presented new challenges in risk stratification. Isolated tumor cells or micrometastases that were undetectable by traditional haematoxylin and eosin techniques are now detectable in sentinel nodes evaluated by immunohistochemistry (IHC). The prognostic significance of IHC-detected isolated tumor cells and micrometastases in histologically negative lymph nodes has not yet been fully elucidated [2a–2e]. Hormone Receptor Status Hormone receptor status is a well-established prognostic and predictive factor. The role of estrogen receptor (ER) status as a prognostic factor was confirmed in a meta-analysis of seven cooperative group adjuvant therapy trials [1c]. For women who had ER-negative tumors, there was a peak annual hazard of recurrence of 18.5% at approximately 1 to 2 years after surgery that declined rapidly thereafter to a rate of 1.4% in years 8 through 12. Most breast cancers, however, are ER-positive. The early annual hazard of recurrence for women who have ER-positive breast cancer was more modest than that of the ER-negative cohort with a peak at 11.0% in years 2 to 3. Despite the smaller risk for early recurrence among the ER-positive population, a significant risk of approximately 5% persisted through to year 12. The role of ER status as a predictive factor was recently evaluated in a retrospective subset analysis of three cooperative group adjuvant chemotherapy trials [3]. Among women who had node-positive breast cancer, the absolute benefit of chemotherapy was more pronounced for the ER-negative cohort compared with the ER-positive cohort, with corresponding absolute 5-year overall survival improvements of 16.7% and 4.0%, respectively. HER2 Status The HER2 receptor is a member of the epidermal growth factor receptor (EGFR) family and is overexpressed in approximately 20% to 25% of human

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breast cancers. HER2 overexpression has historically conferred a worse prognosis compared with non-overexpressing cohorts. Given the significant disease free survival (DFS) and overall survival (OS) benefits observed in three recently reported trials of adjuvant trastuzumab (Herceptin), the prognostic significance of HER2 status has become less relevant [4,5]. HER2 status remains an important predictive factor, however, for responses not only to trastuzumab but also to other chemotherapeutic agents. For example, coamplification of the HER2 receptor and topoisomerase IIa, a DNA replication and recombination enzyme, has provided a theoretic foundation for the observed clinical responses to topoisomerase inhibitors, such as anthracyclines, among women who have HER2-positive breast cancer [6,6a]. The results of coamplification studies have not been consistent, however [6a,7,8]. Furthermore, recent evidence suggests that not only topoisomerase amplification but also deletion are predictive of clinical responsiveness to anthracyclines in selected cohorts [9]. There is also a growing body of evidence suggesting synergy or additive effects when trastuzumab is administered in combination with other cytotoxic therapies, such as taxanes and vinorelbine, among HER2-positive patients [10,11]. HER2 status is also an important predictor of response to hormone therapy. For example, HER2-positive breast cancers are relatively resistant to tamoxifen therapy, presumably as a result of cross-talk between intracellular signaling pathways [12]. Hormone therapy with aromatase inhibitors, however, which have a unique mechanism of action compared with tamoxifen, has not demonstrated similar resistance patterns [13]. Combination therapy with trastuzumab and the aromatase inhibitors therefore remains an active area of investigation. One recently reported study of anastrazole and trastuzumab versus anastrazole alone in chemotherapy-naı¨ve postmenopausal women who had metastatic breast cancer demonstrated a modest improvement in progression-free survival with the combination [14]. Whether this approach will translate into an adjuvant treatment strategy is not yet known. Risk Calculation Tools Given the increasing complexity of prognostic profiling, multiple tools have been developed to increase the accuracy of recurrence risk estimations. The most notable of these is the Adjuvant! (www.adjuvantonline.com) web-based prognostic tool that was recently validated in British Columbia [15]. The Adjuvant! tool estimates 10-year relapse and mortality rates for various adjuvant systemic treatment strategies compared with no adjuvant systemic therapy among patients who have breast cancer. Gene Expression Profiling Decisions regarding adjuvant systemic therapy are often challenging for patients who have small, node-negative, ER-positive, early-stage breast cancer who are at a low risk for recurrence. As outlined in a recent meta-analysis [16], hormonal maneuvers remain the therapeutic cornerstone for this cohort and any additional benefit with cytotoxic chemotherapy is often difficult to

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quantify. To facilitate risk profiling among women who have tamoxifentreated, node-negative, early-stage breast cancer, investigators generated a multigene assay (Oncotype DX), which quantifies recurrence risk for individual patients [17]. The 21-gene expression profile categorizes a woman’s risk for recurrence as low, intermediate, or high, with associated 10-year distant recurrence rates of 6.8%, 14.3%, and 30.5%, respectively. This assay may be a useful tool in the risk–benefit calculus, ensuring that truly low-risk women are not overtreated and exposed to the deleterious effects of treatment and that women at a higher risk for recurrence may be considered for a more aggressive therapeutic strategy. The ideal management strategy for women at intermediate risk for recurrence is uncertain, however. To further refine the risk–benefit calculus in this cohort, the TAILORRx trial is currently randomizing women at intermediate risk to hormone therapy alone or in combination with chemotherapy. In addition, the US Food and Drug Administration has also recently approved the MammaPrint gene expression profile, which evaluates a panel of 70 genes from fresh-frozen tissue samples and stratifies women into ‘‘high’’ and ‘‘low risk’’ categories [17a]. Timing of Adjuvant Chemotherapy The importance of timely initiation of systemic therapy was recently reconfirmed in a retrospective analysis of 2594 patients who had early-stage breast cancer [18]. The investigators were able to demonstrate that delays in initiating chemotherapy were associated with significant increases in relapse risk and adverse survival outcomes, particularly if the delay from definitive surgery exceeded 12 weeks. Conversely, prospective randomized trials of preoperative versus postoperative systemic chemotherapy have failed to demonstrate consistent survival benefits for earlier systemic treatment [19–22]. Rationale for adjuvant chemotherapy Systemic chemotherapy has been an integral component of the adjuvant treatment strategy for women who have early-stage breast cancer since investigators began reporting significant DFS improvements with single-agent chemotherapy after radical mastectomy in the 1970s. The role of systemic therapy has since been an active area of investigation with investigators endeavoring to optimize the adjuvant regimen by refining formulations, schedules, and doses. An early modification of the adjuvant strategy was the administration of polychemotherapy, whereby a minimum of two agents are administered in combination. This strategy was first evaluated by Bonadonna and colleagues [23,24], who randomized women who had node-positive breast cancer to 12 monthly cycles of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) chemotherapy or no further therapy after radical mastectomy. After almost 20 years of follow-up, significant improvements in relapse-free survival (RFS, relative risk 0.65) and overall survival (relative risk 0.76) were observed. The polychemotherapy strategy has since undergone extensive modifications. In 2005, the fourth collaborative meta-analysis of the Early Breast Cancer Trialists’ Collaborative Group [16] (EBCTCG), or Oxford overview, was reported. In this

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study, data from more than 145,000 women who participated in 194 trials that began before 1995 were evaluated. Predominantly older regimens, which predated the taxanes, trastuzumab, and aromatase inhibitors, were evaluated. The investigators confirmed that adjuvant polychemotherapy improves RFS and OS among women who have early-stage breast cancer compared with singleagent strategies. Among women younger than 50 years, for example, the risks of recurrence and death were decreased by 12.3% and 10.0%, respectively, at 15 years with the administration of polychemotherapy. Although this younger cohort derived the greatest benefit with polychemotherapy, a reduction in the risk for recurrence and death of 4.1% and 3.0%, respectively, was also observed at 15 years among women aged 50 to 69 years. The observed benefits were most pronounced among women who had ER-poor tumors. Although adjuvant polychemotherapy is superior to single-agent strategies, the magnitude of the therapeutic benefit varies across different cohorts. The EBCTCG also demonstrated that outcomes varied with specific polychemotherapy formulations. Specifically, 6 months of treatment with an anthracycline-containing regimen proved more efficacious than 6 months of treatment with a non-anthracycline regimen, CMF. The most commonly investigated anthracycline regimens were combinations of 5-fluorouracil and cyclophosphamide with either doxorubicin or epirubicin (FAC or FEC, respectively). Anthracycline-containing regimens were associated with a decrease in the annual breast cancer death rate by 38% for women less than 50 years of age and by 20% for women 50 to 69 years of age largely irrespective of tamoxifen use, ER status, nodal status, or other tumor characteristics. Although anthracycline-containing polychemotherapy regimens conferred a significant survival advantage, the effect seemed to diminish with advancing age. It should be noted, however, that the benefit of systemic chemotherapy for women 70 years of age or older is largely unknown because this is a typically underrepresented population in clinical trials. Since the introduction of anthracyclines, there have been numerous further modifications to the adjuvant strategy, including the incorporation of taxanes, the addition of targeted therapy with agents such as trastuzumab (Herceptin), and the adoption of dose-escalation and dose-dense strategies. Because many of these regimens have not been directly compared in clinical trials, superiority determination has proved challenging, resulting in significant regional variations in clinical practice. An overview of the most prevalent clinical strategies is outlined below. Systemic chemotherapy in lymph node-negative, estrogen receptor–negative, early-stage breast cancer There is a modest risk for recurrence for women who have node-negative breast cancer that may be reduced with adjuvant systemic therapy. A series of clinical trials by the National Surgical Adjuvant Breast and Bowel Project (NSABP) have evaluated the role of postoperative chemotherapy in women who have ER-negative, node-negative breast cancer (Table 1). The NSABP

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Table 1 National Surgical Adjuvant Breast and Bowel Project trials of adjuvant chemotherapy among women who have node-negative, estrogen receptor–negative, early-stage breast cancer Trial

N

Control arm

Experimental arm

Follow-up (y)

Surgery alone

MF

16

13

NSABP B13

760

NSABP B19

1095

MF

CMF

NSABP B23

2008

CMF 6  tamoxifen

AC 4  tamoxifen

8

RFS

OS

63% versus 77% (P<.001) 73% versus 83% (P<.001) 85% versus 85% (P ¼ .97)

65% versus 74% (P ¼ .03) 74% versus 82% (P ¼ .01) 85% versus 86% (P ¼ .51)

Abbreviations: AC, doxorubicin and cyclophosphamide; CMF, cyclophosphamide, methotrexate, and 5-fluorouracil; MF, methotrexate and 5-fluorouracil; OS, overall survival; RFS, relapse-free survival.

B13 study confirmed that despite curative intent surgery, a significant risk for recurrence and death persisted among this ‘‘low-risk’’ population, which could be reduced with adjuvant chemotherapy [20]. In NSABP B23, CMF administered every 4 weeks proved as efficacious as doxorubicin and cyclophosphamide (AC) administered every 3 weeks for four cycles. The duration and total anthracycline dose administered in this study was less than the 6 months of anthracycline-based therapy represented by most trials included in the Oxford overview. Given the benefits observed with adjuvant systemic therapy in the node-negative ER-negative cohort, chemotherapy is typically considered for younger women or patients who have high-risk tumor characteristics. Because of the long-term toxicity associated with anthracyclines, CMF is a reasonable option for patients who have lower-risk tumors. Given the validity of arguments for and against anthracycline-containing regimens, however, significant regional variations in clinical practice are observed. Furthermore, with the recently reported benefits of adjuvant trastuzumab, this monoclonal antibody is often incorporated into the adjuvant strategy for patients who have HER2-positive node-positive and high-risk, node-negative tumors, frequently in combination with an anthracycline and a taxane (see later discussion) [4,5,11]. Systemic chemotherapy in lymph node-negative, estrogen receptor–positive, early-stage breast cancer Because of the opportunity for hormonal maneuvers, the scope of therapeutic options for women who have node-negative, ER-positive breast cancer is broader than that of their ER-negative counterparts. The NSABP B14 investigators first demonstrated the role of tamoxifen in the management of

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ER-positive, node-negative breast cancer when they randomized approximately 3000 women to receive either adjuvant tamoxifen or placebo [25]. The study was updated in 2004 after 15 years of follow-up, with a recurrence-free survival (78% versus 65%) and overall survival (71% versus 65%) benefit with the addition of tamoxifen [26]. The 35% treatment failure rate and 35% overall mortality rate in patients assigned to the placebo arm confirmed a significant relapse risk despite low-risk disease. In the subsequent NSABP B20 study, more than 2000 ER-positive, node-negative women were randomized to adjuvant tamoxifen alone, CMF, and tamoxifen or MF and tamoxifen [27]. The study was updated after 12 years of follow-up with recurrence-free survival (89% versus 79%) and OS (87% versus 83%) benefits with the addition of CMF to tamoxifen [26]. In subgroup analyses, however, the greatest benefit for the addition of chemotherapy was observed among premenopausal women, women less than 50 years of age, and women who had low tumoral ER positivity. Conversely, women aged 50 years or greater, postmenopausal women, and women who had strong ER positivity derived little benefit from the addition of CMF to tamoxifen. Investigators from the International Breast Cancer Study Group reported similar results [28]. Specifically, three cycles of CMF followed by tamoxifen conferred no DFS or OS benefit over tamoxifen alone among postmenopausal women who had ER-positive, node-negative breast cancer. Although the short duration of this regimen may be less effective than 6 months of therapy, these findings are further supported by the recent Oxford overview wherein 5 years of tamoxifen decreased the annual breast cancer death rate among women who had ER-positive disease by 31%, largely irrespective of the use of chemotherapy [16]. Systemic chemotherapy in lymph node-positive, HER2-negative, early-stage breast cancer Anthracyclines. As previously outlined, the Oxford overview concluded that an optimal adjuvant strategy incorporates polychemotherapy with an anthracycline-containing regimen. Standard adjuvant anthracycline-containing regimens include AC; cyclophosphamide, doxorubicin, and 5-fluorouracil (CAF); 5flourouracil, doxorubicin, and cyclophosphamide (FAC); 5-flourouracil, epirubicin, and cyclophosphamide (FEC or CEF); docetaxel, doxorubicin, and cyclophosphamide (TAC); and AC followed by paclitaxel (AC-T) or docetaxel (AC-D). Because many of these regimens have not been directly compared in randomized control trials the superiority of any given regimen has not been established. Furthermore, it is uncertain whether there are specific subgroups that might benefit from one regimen over another. Given the small but statistically significant benefit observed with anthracycline-containing regimens, but an increase in associated toxicity, these regimens may be reserved for higher-risk node-positive patients in some communities, whereas CMF may be offered to patients who have lower-risk node-negative disease. In the NSABP B15 study, four cycles of AC were compared with six cycles of CMF or four cycles of AC followed, after about 6 months, by CMF [29]. No significant

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DFS, distant disease-free survival (DDFS), or OS differences were observed between the study arms, although the lack of benefit may be attributable to the difference in the number of cycles administered. Studies of other anthracycline-containing regimens, however, have demonstrated superiority over CMF. In a National Cancer Institute of Canada (NCIC) trial of six cycles of CEF versus six cycles of CMF among premenopausal women, CEF was associated with improved RFS and OS, particularly among women who had more than three involved lymph nodes [30]. Similar benefits for CEF versus CMF were seen in a Danish trial of premenopausal node-positive and node-negative women [31]. Taxanes. Several studies have recently demonstrated the superiority of taxanecontaining regimens with paclitaxel or docetaxel in the adjuvant setting. The CALGB 9344 study, for instance, randomized women who had node-positive breast cancer to four cycles of AC or four cycles of AC followed by four cycles of paclitaxel (AC-T) with dose-escalated doxorubicin [32]. The addition of paclitaxel was associated with significant 5-year DFS (70% versus 65%) and OS (80% versus 77%) benefits. There was no benefit observed with dose escalation of doxorubicin beyond 60 mg/m2/dose. The NSABP B28 study, which evaluated four cycles of AC versus AC-T with a slightly higher paclitaxel dose, also demonstrated a 5-year DFS (76% versus 72%) benefit but no OS benefit [33]. Compared with the CALGB trial, patients in the NSABP trial were older and had lower-risk disease with fewer involved lymph nodes. Furthermore, hormone receptor–positive women received tamoxifen concurrently rather than sequentially with their chemotherapy in the NSABP study, which may have blunted the expected benefits. The efficacy of adjuvant docetaxel has also been evaluated in several clinical trials. The BCIRG 001 study, which randomized women who had node-positive disease to either six cycles of TAC (where T ¼ docetaxel) or six cycles of FAC, was the first study to demonstrate a benefit with the addition of docetaxel to the adjuvant strategy [34]. TAC was associated with 5-year DFS (75% versus 68%) and OS (87% versus 81%) benefits, regardless of ER status. The benefits proved most pronounced for women who had HER2-positive disease. The docetaxelcontaining regimen, however, was associated with significant toxicity, including neutropenia, febrile neutropenia, asthenia, hypersensitivity, and stomatitis. Adjuvant docetaxel was also evaluated in a French study of six cycles of FEC or three cycles of FEC followed by three cycles of docetaxel (FEC-D) among node-positive women [35]. The addition of docetaxel was associated with 5-year DFS (78% versus 73%) and OS (91% versus 87%) benefits. Furthermore, in contrast to the findings of the Oxford overview, the benefits were most pronounced among women aged 50 years or older. There was no benefit with the addition of docetaxel among women receiving adjuvant tamoxifen. It is difficult to account for the benefits of docetaxel among older patients and those women who had limited nodal involvement. It is also difficult to account for the absence of benefit among the tamoxifen-treated cohort. It is anticipated that the

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role of adjuvant docetaxel among these subgroups will be further defined with the reporting of studies currently underway by the NSABP and BCIRG investigators. Although the taxanes seem to confer survival benefits among specific subgroups, data regarding the superior taxane and taxane schedule are conflicting. Evidence from the metastatic breast cancer literature suggests superiority of docetaxel over paclitaxel using the approved doses and schedules for each agent [36] and superiority of a weekly paclitaxel regimen over an every 3 weeks regimen [37]. The recently reported ECOG 1199 trial was designed to evaluate the selection and scheduling of paclitaxel versus docetaxel [38]. Almost 5000 women were randomized after standard-dose AC to either weekly or every 3 weeks paclitaxel or docetaxel. Although there was a trend in favor of improved DFS with weekly paclitaxel, particularly in patients who had ER-negative disease, there was no significant DFS or OS benefit with either taxane or with either schedule. Toxicities were more frequent and severe with docetaxel. Dose escalation and dose density Dose escalation. In the last decade several strategies, including dose escalation and dose density, have been used in attempts to optimize the efficacy of adjuvant chemotherapy. Dose-escalation strategies compare the efficacy of varying doses of specific therapeutic agents and have been extensively investigated, with variable success. The NSABP B22 and B25 studies demonstrated that dose escalation of cyclophosphamide beyond standard doses of 600 mg/m2/ dose did not improve patient outcomes, and in one study was associated with a significantly increased risk for myeloproliferative disorders [39,40]. The CALGB 9344 study demonstrated that dose escalation of doxorubicin did not improve survival over standard-dose regimens (typically 60 mg/m2/ dose) [32]. Furthermore, a threshold doxorubicin dose was established by the CALGB 8541 investigators who demonstrated inferior outcomes with doses less than 40 to 60 mg/m2/dose when combined with standard doses of cyclophosphamide [41]. Several studies have also investigated the role of epirubicin dose escalation. Three trials, including a Belgian study, the NCIC MA.5 study, and the French Adjuvant Study Group (FASG) 05 study demonstrated improved survival with escalated epirubicin doses as high as 100 mg/m2/dose [30,42–45]. A small study of high-risk premenopausal patients did not support these findings, however [46]. The survival benefits reported from a few small, relatively uncontrolled clinical trials with myeloablative doses of chemotherapy followed by peripheral stem cell transplantation were not reproduced in several subsequent randomized control trials [47–49]. Perhaps because of cost and toxicity, along with the lack of early benefit, this strategy has since been abandoned in the treatment of early-stage breast cancer outside of the clinical trial setting. Dose density. An alternative approach to optimizing cell kill is the dose-dense strategy. This strategy was developed from the Norton-Simon model, which

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predicts that the most efficient way to treat a heterogeneous population of cancer cells is to eradicate the numerically dominant, more rapidly proliferating cell populations first, followed by eradication of more indolent, resistant cells [50]. The magnitude of the chemotherapy impact depends on several variables, including the extent of cell kill with each dose, the duration of therapy, and the rate of tumor growth during and between treatments. Regrowth of treatmentresistant tumor cells is believed to be a principal cause of treatment failure. By decreasing the interval between treatments, the dose-dense strategy aims to optimize the fixed cell kill with each cycle, thereby improving the overall impact of therapy. One of the first studies to exploit the dose-dense strategy compared sequential and alternating doxorubicin and CMF regimens among women who had nodepositive disease [51]. The sequential strategy is considered dose dense compared with the alternating strategy because the doxorubicin and CMF regimens were delivered over shorter periods of only 9 and 21 weeks, respectively. Ultimately, the sequential strategy proved clinically superior to the alternating strategy. Dose-dense therapy not only optimizes tumor cell kill but also affects other rapidly proliferating cells, including bone marrow progenitor cells, leaving the host at risk for granulocytopenia and serious infections. With the development of hematopoietic growth factors, which may be administered concurrently with chemotherapy, dose-dense therapies may now be administered relatively safely. After promising results were obtained in pilot studies, this approach was first tested in the CALGB 9741 study. In this large phase III study, women who had node-positive breast cancer were randomized to standard doses of sequential doxorubicin, paclitaxel, and cyclophosphamide or concurrent AC followed by paclitaxel in a 2  2 factorial design [52]. Each regimen was administered at either standard intervals every 3 weeks or at dose-dense intervals every 2 weeks with G-CSF support. All patients received the same number of drug cycles and the same cumulative dose of each drug. All four treatment schedules proved feasible and safe. In fact, the incidence of grade 4 neutropenia and treatment delays attributable to hematologic toxicity was significantly reduced with the dose-dense strategy. After a median follow-up period of 3 years, the dose-dense strategy proved more efficacious with significant DFS (RR 0.74) and OS (RR 0.69) benefits that endured at a further update after a median follow-up period of 6.5 years [53]. These benefits proved particularly pronounced among the subgroup of women who had ER-negative tumors. Toxicity Hematologic toxicity. The toxicity profile of a selected regimen is a critical consideration in the adjuvant calculus. Hematologic toxicity, and most notably neutropenia, is a common manifestation of all adjuvant regimens, with the exception of dose-dense regimens that incorporate prophylactic granulocytecolony stimulating factor (G-CSF). Febrile neutropenia is a particularly worrisome sequela of cytotoxic therapy with significant associated morbidity and mortality. Among the non–dose-dense trials, febrile neutropenia rates have

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been lowest with AC, AC-T, CMF, and FAC regimens (0%–3%), slightly higher with CEF (9%), and even higher with TAC (24%) [33,34,43]. The rate of febrile neutropenia requiring hospitalization was 6% in the standard arm and 2% in the G-CSF–supported dose-dense arm of the CALGB 9741 study [52]. The American Society of Clinical Oncology practice guidelines on white blood cell growth factors were recently updated to recommend the use of colony stimulating factors (CSFs) with regimens in which the risk for febrile neutropenia is greater than or equal to 20% (ie, TAC) or for use with dose-dense regimens [54]. Secondary leukemia. Secondary leukemia is a rare but serious and well-documented late toxicity associated with alkylating agents and topoisomerase inhibitors, such anthracyclines. Furthermore, dose-escalated epirubicin regimens, such as CEF, have an increased associated risk (1.7%) compared with standard dose anthracycline regimens, such as AC (1.3%) or CMF regimens (0.4%) [55]. The incidence of acute leukemia or myelodysplastic syndrome (MDS) in the reported trials of combined anthracycline-taxane regimens is 0.27% with TAC [34] and 0.39% to 0.51% with AC-T [32,33]. The incidence of acute myelogenous leukemia or MDS in the dose-dense arm of the CALGB 9741 study was 0.4% at 6.5 years versus 1% in the every 3weeks arm but these were not statistically significant [53]. Non-hematologic toxicity Cardiotoxicity. With advances in the therapeutic strategy of early-stage breast cancer, breast cancer–specific mortality rates are declining as more women become long-term survivors. Clinicians are thus faced with the challenge of minimizing long-term treatment-related toxicity while maintaining or improving on the survival benefits observed with adjuvant treatment. Cardiotoxicity has proved a particularly worrisome dose-related phenomenon among anthracycline-treated women. Anthracyclines may evoke irreversible myocyte damage resulting in cardiomyopathy, particularly at cumulative doxorubicin doses exceeding 550 mg/m2 [56]. At standard cumulative doses of doxorubicin of 240 to 300 mg/m2, the incidence of doxorubicin-mediated cardiotoxicity is typically less than 1% [57] but may increase with the administration of chest wall radiation, trastuzumab, or paclitaxel [58–62]. Chemotherapy-induced amenorrhea. The administration of systemic chemotherapy may result in premature termination of ovarian function among premenopausal women. The incidence of chemotherapy-induced amenorrhea (CIA) depends primarily on the patient’s age, the specific regimen administered, the duration of therapy, the time since administration of chemotherapy, and the use of tamoxifen [63]. The median time to onset of amenorrhea is shorter and less likely to be reversible for older women [64]. In a study of women younger than 35 years, the incidence of chemotherapy-induced CIA was 31.3% with CMF versus 42.5% with an anthracycline-containing regimen [65]. Menses was restored in 80.0% of CMF-treated patients and 85.3% of

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anthracycline-treated patients. In another study of women aged 20 to 45 years, 48% versus 16% of women treated with CMF versus AC, respectively, were still menstruating one month after completing chemotherapy. A slow 9-month recovery phase was observed with AC such that menses was restored in approximately 50% of women at 12 months, whereas a slow decline to 18% was observed after 36 months among the CMF-treated cohort [63]. In the NCIC MA.5 trial of CMF versus CEF in premenopausal women, the rate of was higher in the CEF group at 6 months (relative risk 1.2) but equivalent at 12 months [66]. Among premenopausal women the addition of a taxane to an anthracycline-containing regimen does not seem to increase the CIA incidence from approximately 17% [67,68]. There is an increasing body of literature to suggest that the induction of premature menopause may confer outcome advantages for premenopausal women who have breast cancer. In fact, it is postulated that one of the reasons for the magnitude of benefit observed with systemic chemotherapy in the Oxford overview may reflect the success of early ovarian failure induction among premenopausal women. SUMMARY Systemic chemotherapy is an integral component of the adjuvant treatment strategy for women who have early-stage breast cancer and accounts for significant improvements in breast cancer–specific mortality [1a,1b]. Decisions regarding adjuvant therapy are increasingly complex with the advent of new therapeutic strategies, a growing body of literature on the molecular biology and natural history of breast cancer, and advances in therapeutic techniques and early detection. Ultimately, the risk–benefit calculus will continue to evolve in response to these advances and one hopes that clinicians will soon be able to tailor treatment recommendations to the biology of an individual cancer and the needs of the affected individual. References [1] American Cancer Society. Available at: http://www.cancer.org. [1a] Berry DA, Cronin KA, Plevritis SK, et al. Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med 2005;353(17):1784–92. [1b] Elkin EB, Hurria A, Mitra N, et al. Adjuvant chemotherapy and survival in older women with hormone receptor-negative breast cancer: assessing outcome in a population-based, observational cohort. J Clin Oncol 2006;24(18):2757–64. [1c] Saphner T, Tormey DC, Gray R. Annual hazard rates of recurrence for breast cancer after primary therapy. J Clin Oncol 1996;14(10):2738–46. [2] Chia SK, Speers CH, Bryce CJ, et al. Ten-year outcomes in a population-based cohort of node-negative, lymphatic, and vascular invasion-negative early breast cancers without adjuvant systemic therapies. J Clin Oncol 2004;22(9):1630–7. [2a] Susnik B, Frkovic-Grazio S, Bracko M. Occult micrometastases in axillary lymph nodes predict subsequent distant metastases in stage I breast cancer: a case-control study with 15-year follow-up. Ann Surg Oncol 2004;11:568–72. [2b] Cummings MC, Walsh MD, Hohn BG, et al. Occult axillary lymph node metastases in breast cancer do matter: results of 10-year survival analysis. Am J Surg Pathol 2002;26: 1286–95.

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