Prospective surveillance and management of cardiac toxicity and health in breast cancer survivors†‡§¶
The articles in this supplement were commissioned based on presentations and deliberations at a Roundtable Meeting on a Prospective Model of Care for Breast Cancer Rehabilitation, held February 24-25, 2011, at the American Cancer Society National Home Office, in Atlanta, Georgia.
The opinions or views expressed in this supplement are those of the authors, and do not necessarily reflect the opinions or recommendations of the editors or the American Cancer Society
A Prospective Surveillance Model for Rehabilitation for Women with Breast Cancer, Supplement to cancer
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Breast cancer is commonly diagnosed in postmenopausal women, the majority of whom express 1 or more cardiovascular disease risk factors. Cardiovascular disease poses a significant competing risk for morbidity and mortality among nonmetastatic breast cancer survivors. Adjuvant systemic therapies may result in late-cardiac toxicity decades after treatment completion. The cumulative incidence of treatment-related cardiotoxic outcomes may be as high as 33% after some adjuvant breast cancer therapies. Breast cancer treatment–induced cardiotoxicity may manifest as cardiomyopathy, coronary ischemia, thromboembolism, arrhythmias and conduction abnormalities, and valvular and pericardial disease. Evidence indicates that preexisting cardiovascular conditions such as hypertension or left ventricular dysfunction may compound the adverse effects of cardiotoxic treatments. There are currently no published clinical practice guidelines that address ongoing cardiac surveillance for cardiotoxicity after breast cancer, and existing guidelines for monitoring and promoting cardiovascular health in older women are often not followed. The multidisciplinary prospective surveillance system proposed elsewhere in this supplement would allow for earlier detection of cardiotoxicity from treatment and may improve monitoring of cardiovascular health in the growing population of breast cancer survivors. Cancer 2012;118(8 suppl):. © 2012 American Cancer Society.
Advances in diagnosis and treatment of breast cancer have led to improved outcomes and an ever-expanding population of long-term breast cancer survivors currently estimated at 2.5 million in the United States alone.1, 2 Approximately 90% of the nearly 200,000 newly diagnosed patients in 2011 will be expected to live for 5 or more years.1, 2 Adjuvant therapies can potentially cause a wide range of acute and late cardiac complications.3, 4 In addition, diagnoses of breast cancer happen most commonly among postmenopausal women,5 the majority of whom have 1 or more cardiovascular disease (CVD) risk factors.6 Furthermore, there are published guidelines for monitoring cardiovascular health in women.7 The combined issues of common preexisting risk and the potential for adverse effects of treatment on the cardiovascular system implies that there may be merit to the establishment of multidisciplinary collaborative efforts to address potential adverse effects and improve cardiovascular health in breast cancer survivors.
The proposed prospective surveillance model, presented elsewhere in this issue of Cancer,8 promotes this type of multidisciplinary approach to managing cardiac toxicities and health in breast cancer survivors. The goal of this review is to understand the relative merits of such a model with a particular focus on early detection and management of cardiovascular outcomes in this population.
Preexisting Cardiovascular Risk in Breast Cancer Survivors
Cardiovascular disease and cancer share multiple risk factors, such as obesity, inactivity, and substance abuse (alcohol and cigarettes), and the incidence of both diseases increases as the population ages. In the Framingham Heart study, the overall lifetime risk for CVD approached 40% for women at age 50 years and increased proportionally to the increase in number of risk factors.9 Breast cancer is commonly diagnosed among women older than 50 years.2, 5 Population prevalence estimates for common CVD risk factors suggest that a significant proportion of women will have 1 or more cardiac risk factors at the time of breast cancer diagnosis.6 Furthermore, among breast cancer survivors 66 years and older, 29.2% were observed to have preexisting CVD or diabetes at the time of diagnosis.10
In an article presented at the American Society of Clinical Oncology (ASCO) Breast Cancer Symposium in 2009, 242 women from the ELPh (Exemestane Letrozole Pharmacogenetic) trial11 were evaluated as to their 10-year risk of CVD outcomes according to the Framingham CVD risk score.12 Independent of treatment, three-quarters of these breast cancer survivors had a risk of CVD at 10 years that was the same or greater than their risk of having a recurrence of breast cancer. Cardiovascular disease is a competing cause of morbidity and mortality among breast cancer survivors5, 13 that may adversely impact survival more than breast cancer itself.10, 14, 15
Any preexisting cardiovascular risk or diagnoses may be compounded by systemic adjuvant therapies with the potential for cardiac toxicity. Furthermore, the direct effects of adjuvant therapy on cardiac outcomes may be compounded by the indirect effects of therapy on changes in lifestyle behavior, a phenomenon that Jones and colleagues have termed “the multiple-hit hypothesis” for the observation of increased cardiovascular events among cancer survivors.16 In addition, any “protective effect” of menstruation in premenopausal women may be negated by treatment-related early menopause and the acceleration of cardiac risk. Research to separate the independent effect of cancer treatments on cardiovascular outcomes is challenging. A comparison of cancer survivors to similarly aged adults with no cancer history makes the debatable assumption that there are no physiologic differences between the cancer survivors and those with no cancer history that would bias such comparisons. Meanwhile, appropriate cardiac medical care of current breast cancer survivor requires knowledge of the treatment-related cardiovascular complications common to this growing population.
There are 2 potential foci for prospective cardiovascular surveillance in breast cancer survivors. First, among women exposed to adjuvant treatments associated with cardiotoxic effects, there is merit to ongoing surveillance for early detection and treatment of any possible cardiac damage. Second, regardless of whether a survivor has been exposed to potentially cardiotoxic adjuvant therapies, there are existing guidelines for monitoring cardiovascular health among women.7 There may be particular merit to ongoing surveillance for cardiovascular health among breast cancer survivors, given that the majority of breast cancer is diagnosed in an age range where preexisting CVD or increased CVD risk is likely to be present.6, 10
Prevalence of Treatment-Related Cardiovascular Complications in Breast Cancer Patients
Breast cancer treatment–induced cardiotoxicity may be manifested by cardiomyopathy, coronary ischemia, thromboembolism, arrhythmias and conduction abnormalities, and valvular and pericardial disease. The risk of breast cancer treatment–induced cardiotoxicity may be increased in patients with coexisting traditional risk factors for CVD, such as hypertension and hyperlipidemia.3, 17 Table 1 summarizes the cardiotoxic effects of chemotherapy agents used to treat breast cancer.
Table 1. Types of Cardiotoxic Effects, Causative Chemotherapy Agents, and Incidence Range From Published Literaturea
|Left ventricular dysfunction||Doxorubicin (Adriamycin)||3%-26%|
| ||Bevacizumab (Avastin)||2.3%|
|Venous thromboembolism||Cisplatin (Platinol-AQ)||8.5%|
Anthracyclines (daunorubicin, doxorubicin, idarubicin, and epirubicin) have been the cornerstone of breast cancer chemotherapy. The most common manifestation of anthracycline-induced cardiotoxicity is left ventricular dysfunction that may be systolic or diastolic, asymptomatic or symptomatic. Doxorubicin is the most commonly used and studied anthracycline. Its use is associated with dose-related cardiotoxicity, with a peak incidence occurring above a cumulative dose of 450 mg/m2.19 Recent evidence indicates that no safe threshold dose exists for anthracycline-induced cardiotoxicity and toxicity may occur even at a low cumulative dose, particularly among those with preexisting cardiovascular risk factors.20 A recent meta-analysis observed a 5.42-fold increased risk of clinical cardiotoxicity, 6.25-fold increased risk of subclinical cardiotoxicity, and a 4.94-fold increased risk of cardiac death among cancer patients treated with anthracyclines compared to those treated with non–anthracycline-based regimens.21 The incidence may be higher in older females. In one study, the 10-year prevalence of heart failure among breast cancer survivors aged 66 to 70 years was nearly 50% if they had had received anthracycline-based chemotherapy, 35% if they had had chemotherapy without anthracycline, and 27% if they had had no chemotherapy.22 This can be compared to the expected 10% prevalence among similarly aged women without a history of breast cancer.23 The large discrepancy in the prevalence of heart failure across women with versus those without a history of breast cancer is hypothesized to be related to an increase in cardiovascular risk factors and noncardiac toxicities of cancer and its treatments, because these may act synergistically with preexisting left ventricular dysfunction.23 This risk increases over time after treatment completion and underscores the need for ongoing surveillance guidelines for early diagnosis and treatment.17
Trastuzumab is the standard of care for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. It is associated with non–dose-related cardiac dysfunction that ranges from asymptomatic decreases in left ventricular ejection fraction (LVEF; in up to 17% of patients) to symptomatic heart failure (<4% incidence). Compared to anthracyclines that irreversibly damage myocardial structure, the mechanism of trastuzumab toxicity may be directly related to altered signaling pathways that, when interrupted, cause reversible, nonstructural myocardial dysfunction.3, 24-26 Trastuzumab-related cardiac dysfunction is almost always reversible and generally responds to standard heart failure treatment.
Hormonal therapies (tamoxifen and aromatase inhibitors)
Treatment for 5 years with tamoxifen or aromatase inhibitors (AIs) in the adjuvant setting has been effective in reducing the risk of breast cancer recurrence and death in both pre- and postmenopausal women with hormone-responsive breast cancer. The cardiovascular effects of these drugs differ. Tamoxifen consistently decreases low-density lipoprotein and total cholesterol levels among postmenopausal women.27 The data on AIs are less consistent and vary somewhat according to the AI used.28 There have been large trials that have shown aromatase inhibitors to either increase, decrease, or cause no changes in blood lipids.28 Part of the confusion arises from the head-to-head comparison of effects of AIs to tamoxifen, which makes it difficult to sort out whether changes in lipids or cardiac risk are due to a negative effect of AIs or the cardioprotective effect of tamoxifen. Tamoxifen is associated with an increased risk of arterial and venous thromboembolic disease but no statistically significant effect on myocardial infarction or overall cardiac death28; AIs do not appear to increase the risk of thromboembolic events and may even confer a small degree of protection. The overall incidence of negative cardiovascular outcomes in the adjuvant setting is generally low. For example, in the Breast International Group (BIG) 1-98 trial, overall incidence of cardiac adverse events was <5% for patients with breast cancer who were treated with an AI or tamoxifen.29
Adverse effects of radiation therapy (RT) on the heart have been observed in long-term survivors of breast cancer, with a latency of approximately 10 to 20 years. Radiation can cause a variety of cardiac diseases including coronary artery diseases, pericarditis, cardiomyopathy, valvular disease, and conduction abnormalities. The risk of radiation-induced heart disease (RIHD) appears to be highly dependent on the volume of heart exposed to radiation and the dose received by that volume. Older methods of delivering adjuvant RT, following either breast-conserving surgery or mastectomy, generally resulted in much more extensive incidental cardiac irradiation than is seen with current techniques. There is convincing evidence that patients irradiated with the older techniques suffered significant increases in cardiovascular morbidity and mortality. In the most recent Oxford Overview, for example, the risk of death due to heart disease was 27% higher in women treated with RT compared with unirradiated controls.30 However, with modern RT techniques, which have markedly reduced cardiac exposure, the risks of RIHD appear to have been markedly diminished.31-33 Although these studies of patients treated in the modern era are reassuring, they share a number of common limitations. Although the follow-up in these studies is substantial, it may not be sufficient given the 10- to 20-year latency for RIHD. Furthermore, these studies have not provided quantitative information on the dose or volume of cardiac irradiation, which would help define if a safe threshold for cardiac irradiation exists. Finally, these studies have not comprehensively evaluated the impact of concurrent CVD, coexistent classical risk factors for CVD (eg, hypertension, hyperlipidemia, and cigarette smoking), or coadministration of potentially cardiotoxic systemic therapies (eg, anthracyclines, trastuzumab) to these patients. In view of the potential adverse impact of low-dose cardiac exposure in these subsets of patients, prospective surveillance for CVD is critical in patients receiving adjuvant RT for breast cancer, and detailed clinical management guidelines should be established.
There are multiple ways in which treatment for breast cancer may affect cardiovascular risk over and above any existing pretreatment comorbid conditions. As with non–cancer survivors, long-term cardiovascular outcomes in breast cancer survivors may be improved by reduction of modifiable risk factors (eg, weight control, exercise, smoking cessation, and treatment of hypertension and hyperlipidemia) and by early detection and treatment of CVD that develops despite risk reduction efforts.7
Recommendations for Prospective Surveillance and Monitoring of Cardiovascular Health Among Breast Cancer Survivors
To date, there are no clinical practice guidelines specific to the posttreatment monitoring for cardiotoxicity or for cardiovascular health care of adult breast cancer survivors.
General consensus-based guidelines from The Children's Oncology Group were published in 2004 for the care and surveillance of survivors of pediatric cancers, stated as “A risk-based, exposure-related clinical practice guideline intended to promote earlier detection of and intervention for complications that may potentially arise as a result of treatment for pediatric malignancies.”34 The concept and methodology are relevant, but these guidelines are not fully applicable to adult breast cancer survivors.
In 2005, ASCO convened an expert panel to develop guideline recommendations for the ongoing surveillance and care of cardiotoxicity in adult survivors after cancer treatment. The charge to the panel was “to develop screening recommendations for chemotherapy- and radiotherapy-induced cardiac and pulmonary late effects.” Upon review, the ASCO Board of Directors decided that the quality of the available evidence did not warrant development of a clinical practice guideline. A clinical evidence review was published instead, in part to reveal the gaps in the evidence needed to support a clinical practice guideline on screening for cardiotoxicity among adult cancer survivors. There was agreement that the weight of the evidence indicated that the risk of treatment-related cardiovascular toxicity increases over time and may have a very long latency period. Potential tests that had been studied in the past for prospective surveillance of cardiotoxicity include serial endocardial biopsy, serial B-type natriuretic peptide (BNP) and troponin level measurement, multigated acquisition scanning, exercise testing, and the echocardiogram.17, 35-37 Among 251 breast cancer survivors treated with trastuzumab, troponin 1 successfully predicted which patients would develop cardiotoxicity.38 Additional studies are needed to further validate the usefulness of prospective surveillance for cardiotoxicity using any single test or a combination of tests.
In 2006, ASCO published updated breast cancer follow-up and management guidelines for survivors of adjuvant chemotherapy.40 There are specific detailed recommendations for breast cancer surveillance and follow-up, but there is no recommendation for cardiac risk surveillance and detection.
Some cancer centers have developed institution- or provider-based pathways for long-term cardiac surveillance for breast cancer survivors who were previously exposed to cardiotoxic treatments. For example, Carver et al outline a plan that begins monitoring for anthracycline- or radiation-derived cardiotoxicity beginning 5 years after treatment. The choice to begin at 5 years was based on the “bump” in the incidence of asymptomatic cardiac dysfunction observed around that time in a number of studies.41 The choice to conduct ongoing monitoring at 5-year intervals in asymptomatic survivors was based on observations that adverse cardiac outcomes continue to appear decades after treatment.41 Carver et al recommend a clinical history, physical examination, echocardiogram (or radionuclide angiogram), and electrocardiogram at 5 years after treatment for cancer survivors, with follow-up and additional testing according to findings of these screening activities. Graded exercise testing is not routinely recommended in the absence of a clinical suspicion for coronary artery disease.
The Abramson Cancer Center clinical approach to prospective surveillance and clinical management of trastuzumab-related cardiac dysfunction has also been published.25 In brief, patients are evaluated by a cardiologist before beginning trastuzumab treatment, and are monitored throughout treatment on a case-by-case basis, according to baseline findings and findings of ongoing monitoring. No posttreatment and/or long-term monitoring of cardiac function is recommended for those who are asymptomatic and who had no cardiac dysfunction during treatment. In women who are treated with anthracycline-based chemotherapy prior to trastuzumab, monitoring for cardiac dysfunction proceeds according to their guidelines for monitoring after anthracycline-based chemotherapy. Among trastuzumab-treated patients who develop cardiac dysfunction during treatment, ongoing treatment and monitoring is recommended as per the usual heart failure guidelines for patients with no cancer history.42 Symptomatic or asymptomatic patients with any abnormality of diastolic function and any reduction of LVEF below the lower limit of normal for the laboratory are treated with angiotensin-converting enzyme (ACE) inhibitors and beta-blockers.
The National Comprehensive Cancer Network guidelines for breast cancer adjuvant therapy suggest that cardiac monitoring should occur during the period of trastuzumab administration.43 No comments are made with regard to the need for ongoing monitoring after treatment is completed. In fact, review of the common sources for clinical practice guidelines in the United States, Canada, the United Kingdom, Europe, and Australia reveal no published guidelines on prospective surveillance, prevention, treatment, or rehabilitation of cardiac adverse effects of cancer therapy. The newly formed International CardiOncology Society has called for the development of such guidelines.44
In addition to the prospective surveillance of cancer treatment–related cardiovascular outcomes, breast cancer survivors are subject to the usual recommendations for cardiovascular health surveillance and prevention efforts as appropriate, given their non–cancer-related medical history. The American Heart Association has established guidelines for CVD prevention in women.7 These include the treatment of obesity, hypertension, and lipid abnormalities; smoking cessation; and increasing physical activity. Instituting a multidisciplinary prospective surveillance and rehabilitation system for breast cancer survivors, such as the one outlined in an accompanying article in this issue, would provide an obvious venue for this risk evaluation, ongoing surveillance, coaching for adherence, treatment recommendations, and possible referral to a cardiologist and cardiac rehabilitation.
Detection, Prevention, and Treatment of Cardiac Toxicity in Breast Cancer Survivors
Prevention of cancer treatment–related cardiac toxicity is primarily based on the recognition that adjuvant therapies have the potential for late cardiac toxicity. Vigilance is therefore required at every encounter in gathering information about subtle cardiac symptoms and performing a directed physical examination. Early detection leads to early treatment, and there is evidence that early treatment results in better outcomes.45 An integral part of detection and surveillance after breast cancer are recommendations for referral to supportive health care professionals (eg, cardiology, rehabilitation medicine, physical therapy).35, 36, 46-48 Although clinical signs and symptoms consistent with cardiac complications may be detected during prospective surveillance visits prior to the development of a life-threatening or disabling cardiac event, these may be insufficient to detect asymptomatic or symptomatic declines in LVEF. As reviewed above, there is emerging evidence that biomarkers (eg, troponin 1) and echocardiographic measurements (eg, longitudinal strain) may be useful for prospective surveillance of cardiotoxicity from adjuvant breast cancer treatments.38, 39 There is no peer-reviewed evidence regarding the appropriate timing to start such surveillance or the appropriate frequency of follow-up assessments. Until such evidence has been developed, there is merit to assessing symptoms, measuring biomarkers, and/or performing echocardiography prior to and then at some regular intervals after exposure to potentially cardiotoxic treatments. Appropriate timing may vary according to preexisting comorbid cardiopulmonary findings. There are preventive strategies during therapy for which benefit has been inconsistently reported.18 These include the measurement of biomarkers (troponin and BNP) with addition of an ACE inhibitor in patients who have elevated biomarkers during chemotherapy and the prophylactic use of ACE inhibitors and/or beta-blockers in “high-risk” patients (ie, those with preexisting cardiac disease or hypertension and the choice of using a non–anthracycline-based chemotherapy regimen).37, 49, 50 Addition of dexrazoxane as a cardioprotective agent has been recommended and has been shown effective in reducing the risk of cardiac toxicity when the cumulative dose of doxorubicin exceeds 350 mg/m2.51
For detection, prevention, and treatment to be effective, guidelines need to be implemented and are a critical component of the prospective surveillance and rehabilitation model proposed in this special issue of Cancer.
Progress in understanding and minimizing the impact of treatment-related cardiac toxicity requires the development of standardized measurement approaches for defining cardiac dysfunction that have high predictive validity for clinical outcomes. In today's environment of budgetary constraint, these measures must be subjected to rigorous cost-effectiveness evaluation. Existing guidelines for cardiac risk reduction must be tailored to breast cancer survivors. Finally, the efficacy of new technologies developed for screening and new methods for treatment of CVD in the general population must be evaluated in breast cancer survivors.
Additional areas recommended for future research include:
Collection of standardized incidence data in an effort similar to the Childhood Cancer Survivor Study.52
Prospective long-term studies that are designed to directly determine the efficacy of screening in asymptomatic cancer survivors.
Trials to determine whether drugs used for symptomatic congestive heart failure will also help patients with asymptomatic LVEF decline after chemotherapy.
Longitudinal, observational studies to more accurately predict which patients are at highest risk of developing treatment-related cardiotoxicity; these studies must include genomic testing to explain the variability of incidence and onset.
Novel mechanisms of action for new chemotherapy agents may present new mechanisms for cardiac damage. It has been hypothesized that the signaling pathways of tumor cells and cardiac cells may overlap enough for there to be cause for concern regarding the likelihood of cardiac damage from multiple proposed novel pathways of action for chemotherapy agents under development. As new pathways to treat disease are discovered, the potential impact on the cardiovascular system will need to be evaluated.53
Management plans and intervention strategies to reduce the burden of CVD in breast cancer survivors, regardless of cause, but including a focus on the use of prophylaxis or early intervention. The safety and efficacy of multiple risk factor interventions to reduce the burden of cardiovascular outcomes in breast cancer survivors remains to be established.
Modern treatment of breast cancer is a multidisciplinary effort and includes surgical, radiation, and medical oncologists as well as nonphysician support staff. It is now recognized that similar involvement of a multidisciplinary approach to survivor care is also needed. The observation that up to 33% of breast cancer survivors may experience a cardiotoxic treatment effect,7, 18 the high prevalence of preexisting CVD risk factors, and existing guidelines for promoting and maintaining cardiovascular health among women7 supports the proposal to institute a multidisciplinary systematic prospective surveillance model as presented elsewhere within this supplement.54
Support for this meeting and supplement were provided by the American Cancer Society through The Longaberger Company®, a direct selling company offering home products including handcrafted baskets made in Ohio, and the Longaberger Horizon of Hope® Campaign, which provided a grant to the American Cancer Society for breast cancer research and education.
CONFLICT OF INTEREST DISCLOSURE
The authors made no disclosure.