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First Published Online December 17, 2008
The Oncologist, Vol. 13, No. 12, 1224-1234, December 2008; doi:10.1634/theoncologist.2008-0112
© 2008 AlphaMed Press

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Breast Cancer

Multidisciplinary Strategy for Managing Cardiovascular Risks When Treating Patients with Early Breast Cancer

Daniel J. Lenihana, Francisco J. Estevab

aDepartment of Cardiology and bDepartment of Breast Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA

Key Words. Adjuvant therapy • Aromatase inhibitors • Adverse events • Trastuzumab • Chemotherapy

Correspondence: Francisco J. Esteva, M.D., Ph.D., Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard., Unit 1354, Houston, Texas 77030, USA. Telephone: 713-792-2817; Fax: 713-563-0739; e-mail: fjesteva{at}mdanderson.org

Received May 7, 2008; accepted for publication November 11, 2008; first published online in THE ONCOLOGIST Express on December 17, 2008.

Disclosure: Employment/leadership position: None; Intellectual property rights/inventor/patent holder: None; Consultant/advisory role: None; Honoraria: Francisco J. Esteva, Genentech; Research funding/contracted research: Francisco J. Esteva, GlaxoSmithKline; Ownership interest: None; Expert testimony: None; Other: None.


   ABSTRACT
Top
 Abstract
Introduction
 Treatment of ER+ EBC
 Overview of the Cardiovascular...
 Recommendations and Suggested...
 Conclusions
 Author Contributions
 References
 
Adjuvant systemic therapies for the treatment of early-stage breast cancer (EBC) effectively treat the tumor and significantly decrease the risk for recurrence. However, some of these treatments are associated with an increased risk of cardiovascular adverse events. Cardiovascular complications related to cancer therapy may be a prominent concern in postmenopausal women with existing cardiovascular disease or in those who are at high risk for developing cardiovascular disease. The increased risk for cardiac toxicity in women receiving radiation, anthracyclines, and/or trastuzumab for the adjuvant treatment of EBC is well established. The risk of thromboembolic disease is higher in patients with estrogen receptor–positive EBC receiving tamoxifen in the adjuvant setting, whether it is given before or instead of an aromatase inhibitor. In addition, while available data suggest no substantial differences in the risk for ischemic cardiovascular events between aromatase inhibitors and tamoxifen, investigation is still ongoing. Based on this information, it is important for health care providers to understand the cardiovascular risks of treatment and how to monitor at-risk patients, particularly when multiple agents are used in combination or in succession. Improving cardiovascular outcomes in patients with EBC requires cardiovascular risk assessment, management, and long-term follow-up care. Because of the multimodal treatment of EBC patients, their care requires a multidisciplinary approach to reduce not only the risk for breast cancer recurrence but also the risk for treatment-related cardiac toxicities.


   INTRODUCTION
Top
 Abstract
 Introduction
Treatment of ER+ EBC
 Overview of the Cardiovascular...
 Recommendations and Suggested...
 Conclusions
 Author Contributions
 References
 
The treatment of early-stage breast cancer (EBC) includes local treatment with surgery and/or radiation therapy, and systemic treatment of potential residual breast cancer with cytotoxic chemotherapy, hormonal therapy, biologic therapy, or combinations of these therapies [1]. Selection of the exact treatment regimen varies between patients and is based on prognostic factors (e.g., lymph node status, tumor size) as well as predictive factors including estrogen receptor (ER) and human epidermal growth factor receptor (HER)-2 status [1]. In women with ER+ disease who receive hormonal therapy, the treatment of EBC lasts at least 5 years to mitigate the risk for recurrence [1]. Because a large percentage of these women become long-term breast cancer survivors, it is important to weigh the benefits of long-term therapy with the risks for serious adverse events. Although these EBC therapies have well-established clinical benefits, several are associated with an increased risk of cardiovascular adverse events. Therefore, the potential for cardiovascular risk should be considered when designing a treatment strategy for women with ER+ EBC, particularly for postmenopausal women with existing cardiovascular comorbidities.

Based on the known substantial incidence of existing cardiovascular disease in women, which is typically underrecognized, and the potential for cardiovascular-related adverse effects of breast cancer therapy, it is important to evaluate the cardiovascular status in women, especially those who are postmenopausal, who are receiving EBC treatment. In fact, recent data suggest that women with EBC are more likely to die of heart disease than recurrent cancer [2]. Thus, managing pre-existing cardiovascular disease or related risk factors prior to receiving treatment is of paramount importance. A multidisciplinary team approach to coordinate the management of patients with breast cancer would likely optimize clinical outcomes and help minimize the impact and risk of adverse effects [3]. This review summarizes the latest data regarding treatment-related cardiovascular adverse events in women with EBC and includes highlights and considerations for assessing baseline cardiovascular risk, follow-up, and management, as well as multidisciplinary strategies to optimize patient outcomes.


   TREATMENT OF ER+ EBC
Top
 Abstract
 Introduction
 Treatment of ER+ EBC
Overview of the Cardiovascular...
 Recommendations and Suggested...
 Conclusions
 Author Contributions
 References
 
After diagnosis by biopsy, patients with EBC (stage I, IIA, or IIB) may receive preoperative chemotherapy or undergo lumpectomy or total mastectomy with surgical staging of the sentinel and/or axillary lymph nodes [1]. All patients undergoing lumpectomy for locally invasive breast cancer undergo radiation therapy with treatment of the tumor bed, supraclavicular area, or internal mammary nodes, depending on the number of positive axillary lymph nodes. Radiation therapy may be omitted in patients undergoing a total mastectomy; however, this depends on the size of the tumor and number of positive lymph nodes. Tumors from patients with early invasive breast cancer are then tested for the presence of key predictive markers of response to therapy, including estrogen, progesterone, and HER-2 receptors.

Patients with ER+ tumors frequently receive a combination of adjuvant chemotherapy (depending on the tumor size and number of positive lymph nodes) and hormonal therapy. Patients with HER-2+ tumors >1 cm or with node-positive disease may also be given trastuzumab.

Radiation therapy, some types of chemotherapy, and trastuzumab have all been associated with an increased risk for cardiovascular disease [4–6]. Many women with EBC require multimodal treatment and receive a combination of these therapies, which may cumulatively increase their risk for cardiovascular complications [7]. The potential cardiovascular risks of hormonal therapy are still under investigation.

Because treatments such as aromatase inhibitors (AIs) deprive the patient of circulating estrogen, there was initial concern that antagonism of estrogen synthesis would negatively impact the cardioprotective effects of estrogen [8]; however, large randomized trials such as the Heart and Estrogen/Progestin Replacement Study, the Estrogen Replacement and Atherosclerosis trial, and the Women's Health Initiative (WHI) observational study did not support the cardioprotective effects of estrogen replacement therapy [9–11]. Taken together, these reports suggest that AIs and other estrogen-reducing therapies may not pose as substantial a risk as originally theorized.


   OVERVIEW OF THE CARDIOVASCULAR EFFECTS FROM BREAST CANCER TREATMENT CLINICAL TRIALS
Top
 Abstract
 Introduction
 Treatment of ER+ EBC
 Overview of the Cardiovascular...
Recommendations and Suggested...
 Conclusions
 Author Contributions
 References
 
Radiation
Radiation therapy for breast cancer is associated with an increased risk for cardiovascular disease long after radiotherapy. Cardiovascular mortality is highest in patients receiving radiation of the left breast [12]. In a study of >20,000 women with breast cancer diagnosed between 1971 and 1988, those receiving radiation of the left breast had a 25% higher cardiovascular mortality rate at ≥15 years after diagnosis than women who received radiation of the right breast [12]. Similarly, an analysis of 961 medical records from patients with EBC was conducted to evaluate long-term (median, 12 years postradiation therapy) radiation-associated coronary damage. That study showed that, among the 46 patients with left-sided and 36 patients with right-sided disease who had undergone cardiac stress testing, significantly more patients treated with left-sided radiation had stress test abnormalities (59% versus 8%, respectively; p = .001) [13]. Furthermore, an initial review of medical records from 961 patients with breast cancer revealed no difference in overall cardiac mortality at 10 years after radiation therapy; however, at 20 years, a higher rate of cardiac mortality and morbidity was observed in patients receiving irradiation of the left breast [14]. In contrast, analysis of data from the Surveillance, Epidemiology, and End Results (SEER)–Medicare database of >16,000 patients with breast cancer diagnosed between 1986 and 1993 revealed no difference in cardiac morbidity—including ischemic heart disease—between women with left- and right-sided breast cancer [15]. A later study of 4,414 breast cancer patients at a median follow-up of 17.7 years demonstrated that radiotherapy to either side of the mammary chain was correlated with a higher risk for cardiovascular disease, with an overall hazard ratio (HR) of 1.41 [16]. While the risk for myocardial infarction was lower in women treated after 1979 (due to the introduction of breast-conserving therapy), the risk of developing congestive heart failure (HF) persisted (HR, 2.66; 95% confidence interval [CI], 1.27–5.61). The risk for myocardial infarction was higher in women receiving irradiation of the left chest, regardless of treatment period or regimen (HR, 3.54; 95% CI, 1.13–11.1 versus no radiotherapy or negligible dose to the heart).

It is notable that the risk for death from ischemic heart disease associated with radiation for breast cancer has decreased substantially over time [17]. For example, Giordano et al. [4] divided the SEER 12 registry 1973–2000 dataset into three treatment eras and found that patients with left-side tumors treated with radiation between 1973 and 1979 had a higher cardiotoxicity rate than patients with right-side tumors. As a result, it appears that changes in techniques where radiation is administered tangentially, thereby minimizing cardiac exposure, ultimately reduce the potential cardiac toxicity [17]. However, during later eras, there was no difference between left- and right-sided radiation.

Anthracycline-Based Chemotherapy
Anthracycline-based regimens including epirubicin or doxorubicin are the standard of care for adjuvant chemotherapy in treating EBC. They are associated with a >12% lower recurrence rate of cancer and an 11%–16% lower mortality rate than with cyclophosphamide, methotrexate, and fluorouracil (CMF)-based regimens [18, 19]. The absolute difference in recurrence, breast cancer–specific mortality, and overall mortality between anthracycline-based and CMF-based regimens is about 4% at 10 years in favor of anthracycline-based therapy [19].

The length of time for which anthracycline-based therapies can be used is limited by their associated risk of developing life-threatening HF, cardiomyopathy, and tumor resistance [20–22]. The risk of anthracycline-induced HF increases significantly with increasing cumulative dose [20, 21, 23]. In addition, ongoing studies (e.g., the National Surgical Adjuvant Breast and Bowel Project [NSABP] B-36 trial and the Cancer and Leukemia Group B 40101 trial [24, 25]) and existing data do not support an additional benefit of high cumulative doses of anthracyclines in the adjuvant setting [22]. As a result, all current adjuvant regimens using anthracyclines typically do not exceed 360 mg/m2 [26].

Recent investigations indicate that previous methods for the detection of cardiac toxicity, primarily serial left ventricular ejection fraction (LVEF) measurements, may be substantially flawed and may not truly represent the incidence of cardiac toxicity. It is well established that a decrease in LVEF occurs when the tremendous compensatory ability of the myocardium has been impaired; therefore, a decline in LVEF is actually a marker of advanced damage [27]. Additionally, HF, a condition that can be challenging to diagnose during chemotherapy, frequently occurs even in a patient with a normal LVEF. As a result of these criticisms, there is interest in exploring the clinical utility of alternative measures of cardiac function. Several studies suggest that these potential biomarkers may give an early indication of cardiac toxicity and increased risk for a cardiac event. For example, elevations in the circulating levels of cardiac biomarkers such as troponin I, B-type natriuretic peptide (BNP), and N-terminal proBNP have shown promise as accurate predictors of cardiac toxicity [28–31]. Cardiac biomarkers may be best used as a mechanism to identify high-risk patients who are receiving chemotherapy or to more accurately predict cardiac toxicity [32]. Broad application of biomarkers as a less expensive, more accurate tool to monitor for cardiac toxicity is still under active investigation [33].

Certain cardioprotective medications have demonstrated benefit in ameliorating the cardiotoxic effects of anthracyclines and other high-dose chemotherapy [32, 34–37]. Reductions from baseline LVEF after chemotherapy indicative of cardiotoxicity were observed only in patients not receiving concomitant therapy with carvedilol [32], enalapril [34], and valsartan [35]. It is unclear whether prophylactic therapy with these or other cardioprotective agents will be helpful in preventing cardiac toxicity in certain high-risk patients receiving anthracyclines. There was significant interest in using dexrazoxane for cardioprotection during anthracycline chemotherapy. Dexrazoxane, an iron chelator initially believed to limit myocardial cell damage by scavenging reactive oxygen radicals produced during anthracycline therapy, has not been clearly established as beneficial. Although dexrazoxane is successful at reducing troponin release in children receiving anthracyclines, it has not substantially reduced clinical cardiac events [38]. Furthermore, this therapy is associated with myelosuppression and possibly secondary leukemia [36].

To mitigate the cardiotoxic risks associated with the anthracyclines, other studies are examining the efficacy of nonanthracycline-containing regimens in the adjuvant setting [39]. In one prospective, randomized clinical trial, four cycles of docetaxel and cyclophosphamide produced both longer disease-free survival (p = .018) and longer overall survival (p = .045), compared with four cycles of doxorubicin and cyclophosphamide in patients with EBC [40]. There is still considerable debate as to whether anthracycline therapy is an essential part of EBC treatment, but regardless, anthracyclines are still commonly used.

Trastuzumab
Trastuzumab significantly improves the survival of HER-2+, node-positive breast cancer patients and it is associated with an increased risk of cardiac dysfunction [6, 41]. An independent cardiac review and evaluation committee was established to assess the cardiovascular risk of trastuzumab in the clinical trials leading to U.S. Food and Drug Administration approval. This committee conducted a retrospective review of seven phase II and III clinical trials of trastuzumab in women with breast cancer. The analysis revealed a 3%–7% greater incidence of cardiac dysfunction associated with the use of trastuzumab monotherapy, but radiotherapy was not a significant risk factor [41]. When trastuzumab was given concomitantly with an anthracycline plus cyclophosphamide, the risk for cardiac dysfunction increased up to 27%, versus 8% for an anthracycline alone. Similarly, when trastuzumab was given concomitantly with paclitaxel, 13% of patients developed cardiac dysfunction, versus 1% for patients receiving paclitaxel alone. The long-term use of trastuzumab has been associated with a higher risk for cardiac toxicity in patients with metastatic breast cancer, although this toxicity is manageable and an acceptable risk in this setting [6]. Furthermore, cardiac dysfunction detected during trastuzumab therapy is frequently reversible when managed carefully with typical HF medications such as angiotensin-converting enzyme inhibitors and beta-blockers [42].

Lower rates of cardiac toxicity have been reported in the adjuvant setting. The risk for HF was in the range of 0.5%–4% in the four largest clinical trials that evaluated the efficacy and safety of trastuzumab-based chemotherapy in the adjuvant setting. The NSABP B-31 trial was a randomized trial in which >1,600 patients with node-positive, HER-2+ breast cancer received doxorubicin and cyclophosphamide followed by either paclitaxel alone or paclitaxel with trastuzumab. The study demonstrated a higher risk for HF following treatment with trastuzumab [43, 44]. Age, hypertension, and postdoxorubicin and cyclophosphamide LVEF values <54% were identified as risk factors for the development of HF.

The North Central Cancer Treatment Group phase III trial N9831 evaluated doxorubicin plus cyclophosphamide followed by weekly paclitaxel with or without trastuzumab in women with HER-2+ operable breast cancer [45]. That study showed that whereas postdoxorubicin and cyclophosphamide cardiac events were higher in treatment arms containing trastuzumab, the incidence was <4% of that in the control arms [45]. In addition, whereas other chemotherapeutic agents are not given concurrently with radiotherapy, the coadministration of trastuzumab and radiotherapy in the metastatic setting does not further increase the cardiotoxicities associated with radiotherapy alone at 1.5 years of follow-up [46]; however, because the effects of radiotherapy on cardiac function persist for many years, longer follow-up is needed to confirm this finding.

The Herceptin Adjuvant trial evaluated the use of sequential trastuzumab after at least four cycles of an anthracycline-containing regimen in 1,693 women with early-stage HER-2+ breast cancer. In that study, the rate of HF was 0.6% for patients receiving trastuzumab for 1 year [47, 48]; however, a major consideration is that the time between starting trastuzumab and completing anthracyclines was longer in this study (mean, 89 days) than in previously reported studies. This may, in part, explain the low incidence of cardiac toxicity detected, because patients may have had a longer time to recover from an anthracycline-related cardiac insult [49]. Furthermore, the LVEF had to be at least 55% after completion of adjuvant chemotherapy and prior to initiation of trastuzumab, suggesting that the patients in this study may have had more cardiac reserve prior to trastuzumab therapy. Exploratory data indicate that the early detection of cardiotoxicity associated with trastuzumab may be predicted by a doubling of the BNP level [50]. Twenty-seven percent of patients with cardiotoxicity, defined as a >15% decrease in LVEF or a 10%–15% decrease in LVEF to less than the institutional lower limit of normal, had a doubling of BNP, compared with 7% of controls. Because of the importance of prediction and early detection of treatment-related cardiotoxicities for the improvement of clinical outcomes, further study regarding the role of cardiac biomarkers is needed.

Both multigated acquisition (MUGA) scanning and echocardiography (echo) provide similar LVEF measurements [51] and are widely used in practice and in clinical trials for monitoring cardiac function in trastuzumab-treated patients. However, echo may be the preferred technique for cardiac monitoring because of additional structural hemodynamic information obtained by these studies as opposed to solely an LVEF measurement by MUGA. Moreover, because the cardiotoxicity of trastuzumab appears to be largely reversible [52], it is recommended that LVEF be re-evaluated every 12 weeks in patients receiving this therapy in the adjuvant setting.

In sum, anthracycline- and trastuzumab-based regimens have been associated with clinical efficacy and both have been linked to cardiac dysfunction. It is apparent that the mechanism for cardiac toxicity is distinctly different between these two therapies [53]; however the identification of toxicity and the optimal treatment of LV dysfunction is not [5]. It is also recognized that multiple factors may be responsible for cardiac dysfunction and all potential exacerbating factors should be identified and treated in these patients [7].

Hormonal Therapy

Cardiovascular Effects
It is thought that reduced estrogen levels during the hormonal treatment of women with EBC may increase the risk for cardiovascular disease. Initially, it was theorized that tamoxifen may be cardioprotective as a result of its estrogen agonist effects [54]; however, strong cardioprotective effects of tamoxifen have not been demonstrated. For example, a meta-analysis of data from the Early Breast Cancer Trialists' Collaborative Group showed that tamoxifen tended (p = .06) to lead to fewer cardiac deaths than with control treatment [55]. Another meta-analysis showed that tamoxifen treatment resulted in significantly fewer fatal myocardial infarctions than control treatment (although the effect was lost when one trial that had markedly different results from the others was excluded) [56]. The AIs commonly used in treating EBC do not appear to be highly associated with a higher risk for thromboembolic events and are not contraindicated in patients who are obese or hypertensive. Limited data suggest that the AIs (anastrozole, letrozole, and exemestane) may differ from tamoxifen in their cardiovascular effects (Table 1); however, comparing published data from randomized clinical trials must be cautiously considered because cardiovascular events were defined and evaluated differently across studies [57–61].


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  		Table 1. Number (%) of vascular events in breast cancer patients receiving AIs compared with tamoxifen or placebo

 
The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial compared 5 years of treatment with anastrozole, tamoxifen, or a combination of anastrozole plus tamoxifen in 9,366 women who had EBC [57]. The combination arm was discontinued after an initial analysis (median follow-up, 33 months) showed no additional benefit of the combination versus tamoxifen alone [57, 62]. At a median follow-up of 68 months (n = 6,186), there were no differences in the incidence of ischemic cardiovascular events, including angina, coronary artery disease, myocardial infarction, and myocardial ischemia, in patients treated with anastrozole (4%) or tamoxifen (3%; p = .1) [58]. Similarly, there were no significant differences in the incidence of cardiovascular-related deaths in patients receiving anastrozole (2%) or tamoxifen (1%). More patients receiving anastrozole developed hypertension (13%) than those receiving tamoxifen (11%; p = .04). Patients receiving anastrozole had fewer cerebrovascular (2% versus 3%, respectively; p = .03) and thromboembolic (3% versus 5%; p = .0004) events than patients receiving tamoxifen. The median follow-up of 100 months confirms these earlier findings and also shows no differences in the incidence of cardiovascular-related deaths in patients receiving anastrozole (2%) or tamoxifen (2%) [63].

Two large, randomized trials have compared the safety and efficacy of letrozole. The Breast International Group (BIG) 1–98 phase III study compared letrozole and tamoxifen in >8,000 women with EBC. Comparison of the monotherapy treatment arms in the BIG 1–98 study at a median follow-up time of 51 months revealed no differences in the incidence of cardiac events in patients who received letrozole versus tamoxifen (5.5% versus 5.0%; p = .48); however, in that trial, patients receiving letrozole had a significantly higher incidence of grade 3–5 cardiac events (3.0%) than those receiving tamoxifen (1.4; p < .001) [59, 64]. There were no differences between the rates of ischemic heart disease or cardiac failure between treatment groups; however, the incidence of other cardiovascular events was higher in patients receiving letrozole (p = .014) [59].

The National Cancer Institute of Canada Clinical Trials Group MA.17 trial compared a 5-year course of letrozole versus placebo in >5,000 women who completed 5 years of adjuvant tamoxifen treatment for breast cancer. In that study, the incidence of cardiovascular events was the same in patients receiving letrozole (5.8%) as in those receiving placebo (5.6%; p = .76) at a median follow-up of 30 months [60].

The Intergroup Exemestane Study evaluated the clinical benefit and long-term effects of switching to exemestane after 2–3 years of tamoxifen therapy in postmenopausal women with primary, ER+ breast cancer [65]. After a median follow-up of 55.7 months, the incidence of cardiovascular events did not differ between treatment groups; however, patients receiving exemestane had fewer thromboembolic events than those receiving tamoxifen (p = .004) [61]. No differences were observed in the incidence of myocardial infarction between treatment groups, although 71% of exemestane patients who had a myocardial infarction had a history of hypertension, versus only 32% of the corresponding tamoxifen patients.

Lipid Effects
Because elevations in total cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglycerides, and low levels of high-density lipoprotein cholesterol (HDL-C) are known risk factors for cardiovascular disease, it is important to evaluate the long-term effects of endocrine therapies on the lipid profiles of patients receiving these drugs [66]. The AIs and tamoxifen can significantly affect lipid levels. Tamoxifen significantly reduces serum cholesterol by 12% and LDL-C by 19%, with no change in HDL-C or triglyceride levels, perhaps via effects on lipoprotein lipase; however, studies in postmenopausal Japanese women with EBC have shown that tamoxifen raises triglyceride levels [54, 67, 68]. Like the cardiovascular effects of these drugs, the effects of AIs on lipids differ among agents, and vary among the individual studies. In the ATAC trial, anastrozole was associated with a greater incidence of hypercholesterolemia (9%) than with tamoxifen (3%; p < .0001), whereas other studies show no clear pattern of difference [58, 69]. Letrozole has mixed effects on total cholesterol, with one study showing an elevation in total cholesterol, compared with tamoxifen, but no difference compared with placebo [59, 60].

Data from the BIG 1–98 phase III study indicate that letrozole was associated with a higher incidence of hypercholesterolemia (50.6%) than with tamoxifen (24.5%; p < .001); however, the MA.17 study comparing letrozole with placebo after 5 years of tamoxifen revealed no differences in hypercholesterolemia among patients receiving letrozole or placebo (p = .79) [59, 60].

Studies of exemestane, on the other hand, revealed no significant differences in the incidence of hypercholesterolemia among women receiving exemestane (7.2%) versus tamoxifen (6.0%; p = .12), and a modest reduction in HDL-C and increase in LDL-C when compared with placebo [61, 70].

The Letrozole, Exemestane, and Anastrozole Pharmacodynamics trial compared the effects of all three of these AIs on lipid profiles in 90 healthy postmenopausal women [71]. Initial results showed that these three drugs have different effects on total cholesterol, triglycerides, the LDL-C:HDL-C ratio, HDL-C, and the apolipoprotein (Apo)B:ApoA1 ratio. Overall, anastrozole had a neutral effect on lipid values in this study; however, when compared with anastrozole, letrozole significantly increased triglyceride levels at week 12 (p = .037) and exemestane significantly increased the LDL-C:HDL-C ratio at week 12 (p = .048) and week 24 (p = .047) [71]. While these studies suggest that tamoxifen and the AIs may be involved in lipid metabolism, limitations of these studies include a lack of appropriate comparators (e.g., placebo), carryover effects of prior therapies, small sample sizes, and differences in trial designs that make meaningful interpretation of the data difficult (see summary in Table 2). Based on the available data, however, the demonstrable effects of lipid alterations do not appear to have a significant impact on clinical outcomes, especially because no notable cardiac events occurred. It is significant that the WHI trials, which evaluated the effects of hormone replacement therapy, concluded that changes in lipid profiles resulting from hormones are not a reliable predictor of cardiovascular events [72, 73].


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  		Table 2. Summary of clinical effects of AIs and tamoxifen on lipids

 

   RECOMMENDATIONS AND SUGGESTED INTERVENTIONS FOR ASSESSING AND MANAGING HIGH-RISK PATIENTS
Top
 Abstract
 Introduction
 Treatment of ER+ EBC
 Overview of the Cardiovascular...
 Recommendations and Suggested...
Conclusions
 Author Contributions
 References
 
Oncologists and cardiologists should remain vigilant regarding the risks for cardiovascular disease in patients receiving long-term adjuvant therapy for EBC. Although inconsistent and limited data may impede treatment decisions, a concerted effort must be made to educate the health care community involved in caring for breast cancer patients. It is important that oncologists understand the need to adequately assess cardiac function and vascular risk because many patients with EBC are more likely to die of heart disease than cancer [2, 74]. Similarly, education of cardiologists about the increased risk for cardiovascular events in the breast cancer patient population is also necessary. Oncologists and cardiologists should work together when possible [75] to ensure that women with breast cancer receive the necessary information to prevent cardiac events, as well as the appropriate treatment and rehabilitation if they develop cardiovascular disease or experience a cardiac event.

Based on our experience at the M. D. Anderson Cancer Center and our review of the literature, we suggest several recommendations for assessing and managing patients with EBC who are at high risk for a cardiovascular event (Table 3). Patients should be encouraged to follow standard guidelines for reducing cardiovascular risk [74]. Blood pressure control, lipid level reduction, and lifestyle modifications to include exercise and smoking cessation are suggested for the prevention and early identification of cardiovascular disease.


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  		Table 3. Recommendations and suggested interventions for the multidisciplinary management of cardiovascular risk in patients with EBC at high risk for cardiovascular events

 
A clinical endpoint for patients with breast cancer, particularly those at high risk for a cardiovascular event, should be the prevention and optimal management of cardiovascular risk factors (Table 3). A thorough history and baseline assessments should be conducted to determine the overall risk level. Because exposure to radiation, anthracycline-based therapies, and trastuzumab are all associated with adverse cardiac outcomes, including HF, physicians should remain cognizant of the potential for cardiovascular events during long-term follow-up. Based on an emerging body of literature and the fact that cardiac disease can be clinically silent, it is recommended that LVEF be assessed in any patient who is about to receive anthracyclines or has previously. Additionally, periodic (every 12 weeks) monitoring of cardiac function is suggested for those patients receiving trastuzumab in the adjuvant setting. Although there are no guidelines for biomarker monitoring of cardiac-related toxicity in breast cancer patients, both the literature and our experience suggest that there may be a prognostic value of biomarkers in identifying the high-risk patient and predicting the degree of LVEF reduction, especially in those patients receiving anthracyclines and perhaps trastuzumab [37].

It is important to critically evaluate all available and forthcoming data from clinical trials on the effects of AIs. To date, key trial data suggest some subtle differences among the AIs regarding cardiac and lipid abnormalities; however, there is neither sufficient nor available data from ongoing head-to-head studies to determine whether there are clear differences among these agents and if these results translate to clinical practice.

A multidisciplinary approach should be used to manage ER+ EBC patients with high cardiovascular risk. This approach involves the patient's primary care physician, oncologist, and cardiologist. The goals of the multidisciplinary management of the EBC patient are to improve clinical outcomes; maximize consistency, continuity, coordination, and cost-effectiveness of treatment; and foster better communication among clinicians [3]. Several studies evaluating the effectiveness of a multidisciplinary team approach for the management of patients with cancer reported increased survival following the introduction of the multidisciplinary management of patients [76–78]. Furthermore, increased communication among a patient's oncologist, primary care physician, and cardiologist will help ensure proper management of cardiovascular risk factors, appropriate follow-up care, and risk-reduction interventions for the prevention of cardiovascular events associated with the use of chemotherapeutic regimens commonly used for the treatment of EBC.


   CONCLUSIONS
Top
 Abstract
 Introduction
 Treatment of ER+ EBC
 Overview of the Cardiovascular...
 Recommendations and Suggested...
 Conclusions
Author Contributions
 References
 
Cardiovascular disease is the leading cause of death in women worldwide, with more than two million deaths annually [79]. Many adjuvant therapies for treating EBC are associated with an increased risk for cardiovascular events, particularly with long-term therapy. It is important for clinicians involved in the care of EBC patients to assess and manage the risk factors for cardiovascular disease. Overall, no significant differences in the risk for ischemic cardiovascular events have been reported between AIs and tamoxifen to date. Although variable effects on lipid levels have been observed with AIs, there has been no evidence to link these changes with clinical outcome. Furthermore, AIs may reduce the risk for venous thromboembolism and perhaps have a clinically beneficial effect on triglycerides. Greater awareness among primary care physicians, oncologists, and cardiologists of the cardiovascular risks associated with treating the EBC patient is needed. Improving cardiovascular outcomes in patients with EBC requires appropriate risk assessment, monitoring, and long-term follow-up care.


   AUTHOR CONTRIBUTIONS
Top
 Abstract
 Introduction
 Treatment of ER+ EBC
 Overview of the Cardiovascular...
 Recommendations and Suggested...
 Conclusions
 Author Contributions
References
 
Conception/design: Francisco J. Esteva, Daniel Lenihan

Data analysis: Francisco J. Esteva, Daniel Lenihan

Manuscript writing: Francisco J. Esteva, Daniel Lenihan

Final approval of manuscript: Francisco J. Esteva, Daniel Lenihan

We thank Mary Ellen Shepherd, Ph.D., and Brian Bass for providing writing support funded by AstraZeneca Pharmaceuticals LP. The technical-medical writers, Mary Ellen Shepherd and Brian Bass, from Health Learning Systems helped us organize the published literature and put together a first rough draft. Dr. Lenihan and Dr. Esteva revised the manuscript extensively to ensure its accuracy and balance.


   REFERENCES
Top
 Abstract
 Introduction
 Treatment of ER+ EBC
 Overview of the Cardiovascular...
 Recommendations and Suggested...
 Conclusions
 Author Contributions
 References
 

  1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Breast cancer. v. 1.2007. Available at http://www.nccn.org/professionals/physician_gls/PDF/breast.pdf. accessed January 4, 2007.
  2. Hanrahan EO, Gonzalez-Angulo AM, Giordano SH et al. Overall survival and cause-specific mortality of patients with stage T1a,bN0M0 breast carcinoma. J Clin Oncol 2007;25:4952–4960.[Abstract/Free Full Text]
  3. Fleissig A, Jenkins V, Catt S et al. Multidisciplinary teams in cancer care: Are they effective in the UK? Lancet Oncol 2006;7:935–943.[CrossRef][Medline]
  4. Giordano SH, Kuo YF, Freeman JL et al. Risk of cardiac death after adjuvant radiotherapy for breast cancer. J Natl Cancer Inst 2005;97:419–424.[Abstract/Free Full Text]
  5. Yeh ET, Tong AT, Lenihan DJ et al. Cardiovascular complications of cancer therapy: Diagnosis, pathogenesis, and management. Circulation 2004;109:3122–3131.[Abstract/Free Full Text]
  6. Guarneri V, Lenihan DJ, Valero V et al. Long-term cardiac tolerability of trastuzumab in metastatic breast cancer: The M.D. Anderson Cancer Center experience. J Clin Oncol 2006;24:4107–4115.[Abstract/Free Full Text]
  7. Jones LW, Haykowsky MJ, Swartz JJ et al. Early breast cancer therapy and cardiovascular injury. J Am Coll Cardiol 2007;50:1435–1441.[Abstract/Free Full Text]
  8. Grodstein F, Clarkson TB, Manson JE. Understanding the divergent data on postmenopausal hormone therapy. N Engl J Med 2003;348:645–650.[Free Full Text]
  9. Herrington DM, Reboussin DM, Brosnihan KB et al. Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. N Engl J Med 2000;343:522–529.[Abstract/Free Full Text]
  10. Hsia J, Langer RD, Manson JE et al. Conjugated equine estrogens and coronary heart disease: The Women's Health Initiative. Arch Intern Med 2006;166:357–365.[Abstract/Free Full Text]
  11. Grady D, Herrington D, Bittner V et al. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 2002;288:49–57.[Abstract/Free Full Text]
  12. Roychoudhuri R, Robinson D, Putcha V et al. Increased cardiovascular mortality more than fifteen years after radiotherapy for breast cancer: A population-based study. BMC Cancer 2007;7:9.[CrossRef][Medline]
  13. Correa CR, Litt HI, Hwang WT et al. Coronary artery findings after left-sided compared with right-sided radiation treatment for early-stage breast cancer. J Clin Oncol 2007;25:3031–3037.[Abstract/Free Full Text]
  14. Harris EE, Correa C, Hwang WT et al. Late cardiac mortality and morbidity in early-stage breast cancer patients after breast-conservation treatment. J Clin Oncol 2006;24:4100–4106.[Abstract/Free Full Text]
  15. Patt DA, Goodwin JS, Kuo YF et al. Cardiac morbidity of adjuvant radiotherapy for breast cancer. J Clin Oncol 2005;23:7475–7482.[Abstract/Free Full Text]
  16. Hooning MJ, Botma A, Aleman BM et al. Long-term risk of cardiovascular disease in 10-year survivors of breast cancer. J Natl Cancer Inst 2007;99:365–375.[Abstract/Free Full Text]
  17. Harris EE. Cardiac mortality and morbidity after breast cancer treatment. Cancer Control 2008;15:120–129.[Medline]
  18. Early Breast Cancer Trialists' Collaborative Group. Polychemotherapy for early breast cancer: An overview of the randomised trials. Lancet 1998;352:930–942.[CrossRef][Medline]
  19. Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials. Lancet 2005;365:1687–1717.[CrossRef][Medline]
  20. Von Hoff DD, Layard MW, Basa P et al. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 1979;91:710–717.[Abstract/Free Full Text]
  21. Ryberg M, Nielsen D, Skovsgaard T et al. Epirubicin cardiotoxicity: An analysis of 469 patients with metastatic breast cancer. J Clin Oncol 1998;16:3502–3508.[Abstract]
  22. Henderson IC, Berry DA, Demetri GD et al. Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 2003;21:976–983.[Abstract/Free Full Text]
  23. Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin: A retrospective analysis of three trials. Cancer 2003;97:2869–2879.[CrossRef][Medline]
  24. Comparison of Two Combination Chemotherapy Regimens in Treating Women With Breast Cancer. Available at http://www.clinicaltrials.gov/ct2/show/NCT00087178. accessed October 10, 2008.
  25. Combination Chemotherapy in Treating Women With Breast Cancer. Available at http://www.clinicaltrials.gov/ct2/show/NCT00041119. accessed October 10, 2008.
  26. Perez EA. TAC—a new standard in adjuvant therapy for breast cancer? N Engl J Med 2005;352:2346–2348.[Free Full Text]
  27. Ewer MS, Lenihan DJ. Left ventricular ejection fraction and cardiotoxicity: Is our ear really to the ground? J Clin Oncol 2008;26:1201–1203.[Free Full Text]
  28. Cardinale D, Sandri MT, Colombo A et al. Prognostic value of troponin I in cardiac risk stratification of cancer patients undergoing high-dose chemotherapy. Circulation 2004;109:2749–2754.[Abstract/Free Full Text]
  29. Lenihan DJ, Massey MR, Baysinger KB et al. Superior detection of cardiotoxicity during chemotherapy using biomarkers [abstract]. J Cardiac Fail 2007;13:S151.
  30. Ekstein S, Nir A, Rein AJ et al. N-terminal-proB-type natriuretic peptide as a marker for acute anthracycline cardiotoxicity in children. J Pediatr Hematol Oncol 2007;29:440–444.[Medline]
  31. Lenihan DJ, Massey MR, Baysinger K et al. Early detection of cardiotoxicity during chemotherapy using biomarkers [abstract]. J Clin Oncol 2007;25:19521.
  32. Kalay N, Basar E, Ozdogru I et al. Protective effects of carvedilol against anthracycline-induced cardiomyopathy. J Am Coll Cardiol 2006;48:2258–2262.[Abstract/Free Full Text]
  33. Carver JR, Schuster SJ, Glick JH. Doxorubicin cardiotoxicity in the elderly: Old drugs and new opportunities. J Clin Oncol 2008;26:3122–3124.[Free Full Text]
  34. Cardinale D, Colombo A, Sandri MT et al. Prevention of high-dose chemotherapy-induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition. Circulation 2006;114:2474–2481.[Abstract/Free Full Text]
  35. Nakamae H, Tsumura K, Terada Y et al. Notable effects of angiotensin II receptor blocker, valsartan, on acute cardiotoxic changes after standard chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone. Cancer 2005;104:2492–2498.[CrossRef][Medline]
  36. Tebbi CK, London WB, Friedman D et al. Dexrazoxane-associated risk for acute myeloid leukemia/myelodysplastic syndrome and other secondary malignancies in pediatric Hodgkin's disease. J Clin Oncol 2007;25:493–500.[Abstract/Free Full Text]
  37. Cardinale D. Reply to Letter to the Editor "Troponin I, cardiac ventricular dysfunction and causal toxicity of chemotherapy drugs", by L. Delval (Ann Oncol 2002;13: 1952–1953). Ann Oncol 2002;13:1952–1953.[Free Full Text]
  38. Lipshultz SE. Dexrazoxane for protection against cardiotoxic effects of anthracyclines in children. J Clin Oncol 1996;14:328–331.[Free Full Text]
  39. Jones SE, Savin MA, Holmes FA et al. Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer. J Clin Oncol 2006;24:5381–5387.[Abstract/Free Full Text]
  40. Jones S, Holmes F, O'Shaughnessy J et al. Extended follow-up and analysis by age of the US Oncology Adjuvant trial 9735: Docetaxel/cyclophosphamide is associated with an overall survival benefit compared to doxorubicin/cyclophosphamide and is well-tolerated in women 65 or older [abstract]. Breast Cancer Res Treat 2007;106:S5.
  41. Seidman A, Hudis C, Pierri MK et al. Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol 2002;20:1215–1221.[Abstract/Free Full Text]
  42. Ewer MS, Vooletich MT, Durand JB et al. Reversibility of trastuzumab-related cardiotoxicity: New insights based on clinical course and response to medical treatment. J Clin Oncol 2005;23:7820–7826.[Abstract/Free Full Text]
  43. Rastogi P, Jeong J, Geyer CE et al. Five year update of cardiac dysfunction on NSABP B-31, a randomized trial of sequential doxorubicin/cyclophosphamide (AC) paclitaxel (T) vs. AC T with trastuzumab (H). J Clin Oncol 2007;25:LBA513.
  44. Tan-Chiu E, Yothers G, Romond E et al. Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2-overexpressing breast cancer: NSABP B-31. J Clin Oncol 2005;23:7811–7819.[Abstract/Free Full Text]
  45. Perez EA, Suman VJ, Davidson NE et al. Cardiac safety analysis of doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in the North Central Cancer Treatment Group N9831 adjuvant breast cancer trial. J Clin Oncol 2008;26:1231–1238.[Abstract/Free Full Text]
  46. Halyard MY, Pisansky TM, Solin LJ et al. Adjuvant radiotherapy (RT) and trastuzumab in stage I-IIA breast cancer: Toxicity data from North Central Cancer Treatment Group phase III trial N9831 [abstract]. J Clin Oncol 2006;24:523.[Free Full Text]
  47. Suter TM, Procter M, van Veldhuisen DJ et al. Trastuzumab-associated cardiac adverse effects in the herceptin adjuvant trial. J Clin Oncol 2007;25:3859–3865.[Abstract/Free Full Text]
  48. Piccart-Gebhart MJ, Procter M, Leyland-Jones B et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005;353:1659–1672.[Abstract/Free Full Text]
  49. Ewer MS, Lenihan DJ. Is trastuzumab associated with adverse cardiac effects in patients with breast cancer? Nat Clin Pract Oncol 2008;5:192–193.[Medline]
  50. Kutteh LA, Hobday T, Jaffe A et al. A correlative study of cardiac biomarkers and left ventricular ejection fraction (LVEF) from N9831, a phase III randomized trial of chemotherapy and trastuzumab as adjuvant therapy for HER2-positive breast cancer [abstract]. J Clin Oncol 2007;25:579.[Abstract/Free Full Text]
  51. Godkar D, Bachu K, Dave B et al. Comparison and co-relation of invasive and noninvasive methods of ejection fraction measurement. J Natl Med Assoc 2007;99:1227–1228, 1231–1234.[Medline]
  52. Sengupta PP, Northfelt DW, Gentile F et al. Trastuzumab-induced cardiotoxicity: Heart failure at the crossroads. Mayo Clin Proc 2008;83:197–203.[Abstract/Free Full Text]
  53. Ewer MS, Lippman SM. Type II chemotherapy-related cardiac dysfunction: Time to recognize a new entity. J Clin Oncol 2005;23:2900–2902.[Free Full Text]
  54. Grey AB, Stapleton JP, Evans MC et al. The effect of the anti-estrogen tamoxifen on cardiovascular risk factors in normal postmenopausal women. J Clin Endocrinol Metab 1995;80:3191–3195.[Abstract]
  55. Buzdar A, Chlebowski R, Cuzick J et al. Defining the role of aromatase inhibitors in the adjuvant endocrine treatment of early breast cancer. Curr Med Res Opin 2006;22:1575–1585.[CrossRef][Medline]
  56. Braithwaite RS, Chlebowski RT, Lau J et al. Meta-analysis of vascular and neoplastic events associated with tamoxifen. J Gen Intern Med 2003;18:937–947.[CrossRef][Medline]
  57. Howell A, Cuzick J, Baum M et al. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet 2005;365:60–62.[CrossRef][Medline]
  58. Buzdar A, Howell A, Cuzick J et al.; ATAC Trialists' Group. Comprehensive side-effect profile of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: Long-term safety analysis of the ATAC trial. Lancet Oncol 2006;7:633–643.[CrossRef][Medline]
  59. Coates AS, Keshaviah A, Thürlimann B et al. Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: Update of study BIG 1–98. J Clin Oncol 2007;25:486–492.[Abstract/Free Full Text]
  60. Goss PE, Ingle JN, Martino S et al. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: Updated findings from NCIC CTG MA.17. J Natl Cancer Inst 2005;97:1262–1271.[Abstract/Free Full Text]
  61. Coombes RC, Kilburn LS, Snowdon CF et al. Survival and safety of exemestane versus tamoxifen after 2–3 years' tamoxifen treatment (Intergroup Exemestane Study): A randomised controlled trial. Lancet 2007;369:559–570.[CrossRef][Medline]
  62. Baum M, Budzar AU, Cuzick J et al.; ATAC Trialists' Group. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: First results of the ATAC randomised trial. Lancet 2002;359:2131–2139.[CrossRef][Medline]
  63. Forbes JF, Cuzick J, Buzdar A et al.; ATAC Trialists' Group. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol 2008;9:45–53.[CrossRef][Medline]
  64. Mouridsen H, Keshaviah A, Coates AS et al. Cardiovascular adverse events during adjuvant endocrine therapy for early breast cancer using letrozole or tamoxifen: Safety analysis of BIG 1–98 Trial. J Clin Oncol 2007;25:5715–5722.[Abstract/Free Full Text]
  65. Coombes RC, Hall E, Gibson LJ et al. Intergroup Exemestane Study. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 2004;350:1081–1092.[Abstract/Free Full Text]
  66. National Institutes of Health. Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III Final Report). Available at http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3_rpt.htm. accessed May 1, 2007.
  67. Hozumi Y, Kawano M, Saito T et al. Effect of tamoxifen on serum lipid metabolism. J Clin Endocrinol Metab 1998;83:1633–1635.[Abstract/Free Full Text]
  68. Sawada S, Sato K, Kusuhara M et al. Effect of anastrozole and tamoxifen on lipid metabolism in Japanese postmenopausal women with early breast cancer. Acta Oncol 2005;44:134–141.[CrossRef][Medline]
  69. Wojtacki J, Lesniewski-Kmak W, Pawlak W et al. Anastrozole therapy and lipid profile: An update [abstract]. Eur J Cancer Suppl 2004;2:142.
  70. Markopoulos C, Chrissochou M, Michailidou A et al. Effect of exemestane on the lipidemic profile of post-menopausal operable breast cancer patients following 5–7 years of adjuvant tamoxifen: Preliminary results of the ATENA substudy. Anticancer Drugs 2005;16:879–883.[CrossRef][Medline]
  71. McCloskey E, Eastell R, Lakner G et al. Initial results from the LEAP study: The first direct comparison of safety parameters between aromatase inhibitors in healthy postmenopausal women. Presented at the 28th Annual San Antonio Breast Cancer Symposium; December 8–11, 2005; San Antonio, Texas.
  72. Rossouw JE, Anderson GL, Prentice RL et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321–333.[Abstract/Free Full Text]
  73. Manson JE, Hsia J, Johnson KC et al. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med 2003;349:523–534.[Abstract/Free Full Text]
  74. Rosamond W, Flegal K, Friday G et al. American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2007 update: A report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2007;115:e69–e171.[Free Full Text]
  75. Lenihan DJ. Tyrosine kinase inhibitors: Can promising new therapy associated with cardiac toxicity strengthen the concept of teamwork? J Clin Oncol 2008;26:5154–5155.[Free Full Text]
  76. Forrest LM, McMillan DC, McArdle CS et al. An evaluation of the impact of a multidisciplinary team, in a single centre, on treatment and survival in patients with inoperable non-small-cell lung cancer. Br J Cancer 2005;93:977–978.[CrossRef][Medline]
  77. Birchall M, Bailey D, King P. South West Cancer Intelligence Service Head and Neck Tumour Panel. Effect of process standards on survival of patients with head and neck cancer in the south and west of England. Br J Cancer 2004;91:1477–1481.[Medline]
  78. Stephens MR, Lewis WG, Brewster AE et al. Multidisciplinary team management is associated with improved outcomes after surgery for esophageal cancer. Dis Esophagus 2006;19:164–171.[CrossRef][Medline]
  79. Yusuf S, Reddy S, Ounpuu S et al. Global burden of cardiovascular diseases: Part I: General considerations, the epidemiologic transition, risk factors, and impact of urbanization. Circulation 2001;104:2746–2753.[Abstract/Free Full Text]
  80. Forbes JF, Cuzick J, Buzdar A et al. for The Arimidex, Tamoxifen, Alone or in Combination (ATAC) Trialists' Group. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol 2008;9:45–53.[CrossRef][Medline]



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