Approximately 50–60 % of patients newly diagnosed with breast cancer are women aged >65 years [41]. In examining 31,748 elderly women with early-stage breast cancer using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database , women who received any chemotherapy were 2.5 times more likely to develop cardiomyopathy than if they received no chemotherapy [42]. When looking specifically at anthracycline chemotherapy, the incidence of cardiotoxicity was 1.55 % for patients not receiving chemotherapy and 4.09 % for patients receiving anthracyclines (odds ratio, 3.51; 95 % confidence interval [CI], 2.63–4.69) in the first year after breast cancer diagnosis. After 5 years of follow-up, the cumulative incidence had increased to 4.97 % in patients not receiving chemotherapy and 10.23 % in patients receiving an anthracycline-containing regimen. In a follow-up study by Pinder et al. of 43,448 women ages 66–80 years with a diagnosis of breast cancer, 38 % of the group who had anthracycline exposure developed congestive heart failure by year 10 compared to 33 % in the non-anthracycline group and 29 % in the no-chemotherapy group [43]. Risk factors for the development of congestive heart failure in this patient population included advancing age, black race, use of trastuzumab, stage of cancer, and a personal history of hypertension, diabetes mellitus, coronary artery disease, peripheral vascular disease, and chronic obstructive pulmonary disease. Similarly, in an evaluation of the SEER-Medicare database looking at elderly women ages of 67 and 94 years (mean 76 years) between 2000 and 2007, the incidence of heart failure or cardiomyopathy 3 years after a breast cancer diagnosis was 20.2 % in those who received anthracyclines without trastuzumab [44].

In approximately a quarter of women with breast cancer , their tumors overexpress the human epidermal growth factor-2 (HER2) oncogene . In this case, trastuzumab is recommended. Trastuzumab is a monoclonal antibody that targets the human epidermal growth factor (HER2 or ErbB2). It is used in both the adjuvant and metastatic settings [45, 46]. Trastuzumab has been associated with type 2 cardiomyopathy, in which contractility loss occurs as opposed to cardiac myocyte death as is seen with the anthracyclines [47]. In the initial trials of trastuzumab in the metastatic setting, the incidence of cardiac dysfunction when trastuzumab was given alone, with paclitaxel, or with an anthracycline was 3–7 %, 13 %, and 27 %, respectively [46]. Subsequent trials in the adjuvant setting suggest the rates of grade 3 or 4 heart failure are 0–3.9 % in trastuzumab-treated patients as compared to 0–1.3 % in those not receiving trastuzumab [45]. In the PHARE trial, the rates were higher in those who received trastuzumab over 12 months versus 6 months (5.7 % vs. 1.9 %, p < 0.0001), demonstrating an association in terms of cardiotoxicity with more trastuzumab exposure [48].

In real-world evaluations of cardiac dysfunction and trastuzumab in the elderly population, the rates of cardiac dysfunction appear much higher than expected [44, 49–51]. Some of this may be explained by the fact that women in the clinical trials were typically younger and healthier. In one evaluation of the SEER-Medicare database looking at elderly women ages 67–94 years (mean 76 years) between 2000 and 2007, the incidence of heart failure or cardiomyopathy 3 years after a breast cancer diagnosis was 18.1 % in those with no chemotherapy, 30 % in those who received trastuzumab alone, and 41.9 % in those who received trastuzumab and anthracyclines [44]. In a subsequent retrospective population-based study of 12,500 women diagnosed with locoregional breast cancer treated in eight integrated health systems that looked at women with a mean age of 60 years and a median follow-up of 4.4 (2.6–6.9) years, the 5-year cumulative risk of heart failure for women who received anthracyclines and trastuzumab was 7.5 % in those less than 55 years, 11.4 % women ages 55–64 years, 35.6 % women ages 65–74 years, and 40.7 % in those over the age of 75 years [49]. In this analysis, the risk was not felt to be attributable to anthracyclines alone. While these analyses have limitations and may have some misclassification, it certainly appears that the elderly population is at a higher risk for cardiotoxicity both with anthracyclines and trastuzumab; this risk may also continue to increase even 10 years after the completion of therapy.

There are now several new agents used to treat HER2-positive breast cancers including lapatinib, pertuzumab, and trastuzumab emtansine. Lapatinib, an orally active tyrosine kinase inhibitor that affects both HER2 and the epidermal growth factor receptor, appears to have a safer cardiac profile than trastuzumab, even in those who have received prior anthracyclines [52]. Though age was not specifically evaluated as a risk factor, treatment-related cardiac events have occurred <1 % of the time [52, 53]. Cardiac toxicity also does not appear to be higher when lapatinib is given in conjunction with trastuzumab compared with when trastuzumab is given alone [54–58]. Trastuzumab emtansine (TDM-1) , an antibody drug conjugate composed of trastuzumab and a derivative of the antimitotic agent maytansine, and pertuzumab, a monoclonal antibody that binds to a different epitope of the HER2 extracellular domain than does trastuzumab, both approved by the Federal Drug Administration in 2012 and 2013, also do not appear to increase the rates of cardiac dysfunction. While neither long-term data nor geriatric-specific data are available, the early studies of TDM-1 and pertuzumab do not appear to increase the risk of cardiac dysfunction with rates of cardiomyopathy being 0–1.6 % [59–61]. In one study, combinations of pertuzumab in conjunction with anthracyclines appear safe from a cardiac perspective [62]. There is, however, limited follow-up available at this time. Finally, there are newer clinical trials published looking at the use of trastuzumab with less combination chemotherapy. Tolaney et al. demonstrated excellent clinical outcomes in using 12 weekly doses of paclitaxel with trastuzumab followed by every-3-week trastuzumab to complete 12 months [63]. This regimen appears safe and effective and, given there is less systemic combination chemotherapy, has the potential for less cardiac toxicity. Long-term cardiac follow-up is warranted.

In addition to the cardiac concerns from doxorubicin and trastuzumab-based therapies in breast cancer patients, approximately three-fourths of breast cancer cases are hormone-responsive tumors, in which endocrine therapy using tamoxifen or aromatase inhibitors will be prescribed. Aromatase inhibitors have been shown to reduce both disease recurrence and breast cancer-related mortality in women with ER-positive, early disease [64]. The major clinical trials that have examined the efficacy and safety of the aromatase inhibitors include the Arimidex, Tamoxifen, Alone, or in Combination (ATAC) study [64], the Breast International Group (BIG 1–98) [65], and the Intergroup Exemestane Study (IES) [66]. In these studies, the use of aromatase inhibitors was associated with higher rates of hypertension, hypercholesterolemia, angina pectoris, and ischemic cardiovascular disease [66–68]. After 33 months of follow-up of the ATAC trial, there were 2.3 % ischemic cardiovascular disease events, 0.8 % myocardial infarction, and 1.7 % angina rates associated with the aromatase inhibitor anastrazole compared to 1.9 %, 0.8 %, and 1.0 % rates, respectively, with tamoxifen [69]. In the BIG 1–98 trial, cardiac event rates were 4.1 % at 25.8 months and 5.5 % at 51 months with letrozole compared to 3.8 and 5.0 % with tamoxifen [70]. In the exemestane study, the incidence of ischemic cardiovascular disease was higher for exemestane (9.9 %) compared with tamoxifen (8.6 %) [66]. Two recent meta-analyses have suggested a small increase in cardiovascular events in patients taking AIs as compared to those on tamoxifen [68, 71]. In women with a history of cardiovascular disease, the use of anastrazole was associated with a 17 % incidence of cardiac events; this ultimately resulted in a black-box warning of anastrazole for those with a history of cardiovascular disease. These studies were not specifically in elderly women; however, the median age in the ATAC trial at the time of the 10-year analysis was 72 years and was similar in the other trials in which postmenopausal women were enrolled. Given women are now taking adjuvant endocrine therapy for not only 5 years but up to 10 years and are using aromatase inhibitors in the chemoprevention setting [72], there is concern about the long-term effects of aromatase inhibitors on the vascular system. It is important for clinicians to monitor lipids and other cardiovascular risk factors while on adjuvant endocrine therapy.

Risk factors for the development of non-Hodgkin lymphoma (NHL ) have been identified and are not specific for age. However, age, specifically over 60 years, was the most important factor independently associated with outcome. An advanced age resulted in lower response rates and a decrease in survival [73].

From a therapy perspective, the standard approach to diffuse large B-cell lymphoma, one of the most common subtypes of NHL , is a combination of chemotherapy using anthracyclines. In a large analysis of the elderly using the SEER database, 9438 patients with DLBCL were evaluated [74]. Despite doxorubicin being a backbone of chemotherapy for those with diffuse large B-cell lymphoma, only 42 % received doxorubicin. Any doxorubicin use was associated with a 29 % increase in risk of CHF; CHF risk was associated with an increased number of doxorubicin claims, increasing age, prior heart disease, comorbidities, diabetes, and hypertension [74]. This was also confirmed in another study looking at early-stage diffuse large B-cell lymphoma, regardless of whether individuals received radiation therapy [75].

While alternative non-anthracycline-containing regimens have been studied in prospective studies, these combinations of therapy resulted in lower complete response rates and shorter survival compared with anthracycline-containing regimens [76, 77]. The substitution of liposomal doxorubicin has also been studied in the elderly. In these small studies, it appears to be an acceptable alternative, even in those with known cardiac disease in which ejection fractions remained stable [78]. However, the follow-up of these patients was limited. In those patients with an absolute contraindication to anthracycline in which their ejection fraction is below 30 %, there are non-anthracycline-containing regimens that could be considered, such as CEPP (B) [79]. Consideration of the use of an angiotensin-converting enzyme inhibitor or beta-blocker concomitantly with chemotherapy could be considered as will be discussed below .

Ewing sarcoma typically occurs in young adults, while other types of sarcoma such as leiomyosarcomas tend to occur in older adults, in which anthracyclines and platinums are the backbone of therapy. Little literature exists on the cardiac impact of these treatment regimens on elderly patients with sarcomas. A number of sarcoma regimens substitute liposomal doxorubicin for standard doxorubicin, thus theoretically reducing the cardiac damage seen from this class of drugs. Monitoring left ventricular ejection fraction is still recommended when any anthracycline is recommended. Similarly, while the platinum chemotherapy drugs are known to cause endothelial dysfunction in childhood cancer survivors, it is unclear whether this complication applies to the elderly.

Tyrosine kinase inhibitors have been studied in the treatment of some subtypes of sarcoma, including leiomyosarcomas [80]. Tyrosine kinase inhibitors have been associated with a small increase in congestive heart risk. The overall incidence of all-grade and high-grade CHF associated with tyrosine kinase inhibitors was 3.2 % (95 % CI 1.8 %, 5.8 %) and 1.4 % (95 % CI 0.9 %, 2.3 %), respectively, in a recent meta-analysis of over 10,000 patients [81]. Age did not appear to be associated with increased risk, nor did tumor subtype.

Finally, sarcomas and lymphomas can manifest as cardiac tumors.

Ovarian cancer is the leading mortality of gynecologic cancers. More than half of these cases occur in women over the age of 65 years, with the primary treatment consisting of debulking surgery and postoperative chemotherapy with platinum and paclitaxel chemotherapies. Despite the disease occurring primarily in elderly women, in an analysis of all Southwestern Oncology Group trials of 16,396 patients in 164 trials in the 1990s, only 30 % of those individuals in the trials were over the age of 65 years [3]. Similarly, in another analysis of elderly women with ovarian cancer using the SEER registries, 9 % of the women in clinical trials using new therapies were over the age of 75 years. Elderly women are underrepresented in clinical trials [82]. Elderly women also appear to have poorer outcomes than their younger counterparts with only half receiving standard platinum chemotherapy, regardless of comorbidity [83].

From a cardiac perspective, the primary risk for elderly women with ovarian cancer consists of their surgical risk and then their chemotherapy exposure. The platinum and paclitaxel regimens are not known to be particularly cardiotoxic at any age . There are studies suggesting the platinum chemotherapies can cause endothelial dysfunction and can result in increased clotting risks [84, 85]; however, these features are not unique to the elderly population. In recurrent ovarian cancer, chemotherapy consisting of bevacizumab, liposomal doxorubicin, gemcitabine, and topotecan can be utilized. It appears the risk of hypertension and arterial thrombosis may be increased in the elderly [86]. For liposomal doxorubicin, it appears that doses up to 550 mg/m² are safe from a cardiac perspective [87]. When administered at modified doses of 45 mg/m² every 4 weeks, no cardiac toxicity has been observed [88]. In these studies, however, no description of the impact on the elderly was outlined [88]. In similar analyses, frequent determinations of LVEF, as routinely done for other anthracyclines, did not appear to have any clinical value in patient follow-up. In these studies though, the median age was 53 years; it is thus difficult to conclude what monitoring is necessary in the elderly receiving prolonged liposomal doxorubicin [89, 90].

Lung cancer, bladder cancer, and colon cancer are all common cancers for which the prevalence increases as the population ages. Traditionally cardiotoxic medications such as anthracyclines and trastuzumab are not typically used in these cancers. Platinum therapies , known to increase clotting risk and endothelial dysfunction, may be used. In many of these diseases, further work with selective tyrosine kinase inhibitors as well as vascular endothelial-growth factor inhibitors continue are being studied. Many of these medications, particularly bevacizumab and regorafenib, are known to cause hypertension. Additionally, multiple new agents have been approved recently for melanoma including BRAF inhibitors vemurafenib and dabrafenib. Both of these medications are known to cause QT prolongation [91]. Hypertension and QT prolongation are side effects not unique to the aging population. However, as individuals age, it is also more likely that they may have hypertension or be on concurrent medications that may result in arrhythmias. As a result, monitoring for side effects remains vital in the care of these patients. Further ongoing work is being done evaluating the association between many of these targeted therapies and incident heart failure.

Hematopoietic stem cell transplantation (HSCT ) is a potential cure for various hematologic malignancies, which carries a risk of treatment-related complications and mortality. To lower these risks, reduced intensity conditioning regimens have now been adapted, allowing older patients up to the age of 70 years to become eligible for stem cell transplantation.

Currently available data suggest that cardiac complications from HSCT are infrequent, occurring <1 % of the time [92]. However, the median age of patients in this study was 22 years [92], and it is likely that older patients will have a higher incidence of cardiac complications. The geriatric patient often presents with comorbidities indicating that a complete geriatric assessment may be beneficial. There are little data available on the role of CGAs in the hematopoietic stem cell transplantation population. Through the HSCT-specific comorbidity index , a cardiac comorbidity (defined as the presence of coronary artery disease, congestive heart failure, myocardial infarction, or an ejection fraction <50 %) is considered as a low-risk comorbidity. Further, recent data suggests that those with an ejection fraction <50 % can still be eligible for HSCT, and patients with borderline left ventricular systolic dysfunction can safely undergo HSCT without alterations in overall survival or treatment-related complications [93].

Surveillance during and after potentially cardiotoxic therapy is critical because early detection and treatment of cardiac dysfunction can prevent further cardiotoxicity and improve cardiac outcomes [139]. The earlier the onset of treatment, the better will be the results. An asymptomatic decrease in left ventricular ejection fraction is universally accepted as an indication for treatment with angiotensin-converting enzyme inhibitors and beta-blockers. While data are not available specifically for the elderly, it is likely that these treatments are equally effective in them.

While age is considered an important risk factor for cardiotoxicity, surveillance recommendations are generally not tailored to the elderly. The International Society of Geriatric Oncology recommends regular monitoring of the left ventricular ejection fraction by echocardiography or multiple-gated acquisition scan after every two to three cycles of anthracyclines in patients age 70 years or older [40]. They also recommend consideration of liposomal formulations, prolonged infusions, or use of dexrazoxane if there is a decrease of more than 10 % in left ventricular ejection fraction, even if it remains within the normal range. This recommendation applies especially to patients with hypertension, diabetes, or coronary artery disease [40].

Cardiac monitoring with echocardiography or radionuclide ventriculography (multiple-gated acquisition [MUGA] scans) is the standard of care among patients receiving trastuzumab-based chemotherapy. The National Comprehensive Cancer Network (NCCN) guidelines recommend cardiac monitoring at baseline and at 3, 6, and 9 months after initiating trastuzumab therapy. In a recent study from the SEER-Medicare and the Texas Cancer Registry-Medicare-linked databases, the patterns of cardiac monitoring of 2203 patients aged 66 or older with breast cancer who were treated with adjuvant trastuzumab-based chemotherapy were studied [140]. The investigators found that 64 % of the patients had inadequate monitoring, defined as the absence of a baseline (within 4 months before first trastuzumab dose) cardiac evaluation (with echocardiogram or MUGA scan) and subsequent follow-up cardiac evaluation at least every 4 months while receiving trastuzumab therapy [140]. Because trastuzumab-related cardiotoxicity is reversible, efforts to improve the adequacy of cardiac monitoring are needed, particularly in the elderly.

Consideration should be given to cumulative radiation exposure and the risk of secondary cancers with the use of MUGA scans for surveillance. Guidelines such as those from the International Society of Geriatric Oncology and the United Kingdom National Cancer Research Institute for cardiac monitoring after trastuzumab therapy recommend the use of the same imaging modality throughout the course of treatment [40, 141]. A breast cancer patient receiving adjuvant trastuzumab therapy is recommended to undergo cardiac monitoring before starting treatment, every 3 months during and upon completion of treatment, and every 6 months for at least 2 years following completion of therapy [142]. More frequent monitoring is recommended if trastuzumab is withheld for a significant drop in left ventricular ejection fraction [142]. With 12 months of adjuvant trastuzumab therapy as the standard of care, this translates into a minimum of nine studies. With an average typical effective ionizing radiation dose of 8 mSv per multiple-gated acquisition scan [143, 144], the use of multiple-gated acquisition scans would result in a cumulative effective dose of 72 mSv. Based on published estimates of the radiation-related cancer risk from technetium-99 m myocardial perfusion studies [145], a 50-year-old female who undergoes nine multiple-gated acquisition scans would be estimated to have a lifetime risk of 0.64 % for a radiation-related secondary cancer. While the risk in the elderly is lower than this estimate due to the lower overall life expectancy, it is not an insignificant risk considering the excellent survival rates for patients diagnosed with breast cancer today—a 5-year relative survival rate of 89 % and a 10-year relative survival rate of 82 % [146]. To avoid this risk, echocardiography and cardiac magnetic resonance imaging should be considered as the imaging modalities for surveillance.

Serum cardiac biomarkers , such as N-terminal prohormone brain natriuretic peptide and troponin, are being studied for the early detection of cardiotoxicity, but further investigation is needed before they can be recommended for clinical use [147].

There is a need for systematic research and evidence-based guidelines on the risk prediction models, early biomarkers of toxicity, monitoring, surveillance, and treatment of older patients with cancer receiving potentially cardiotoxic therapy. There are several ongoing studies looking at the impact of comprehensive geriatric assessments on cancer care. The results of these studies will be extremely valuable in determining how to best risk-stratify and treat elderly patients with cancer while preserving their quality of life and functional outcomes. Increasing recruitment of older patients to cancer trials by eliminating an upper age limit to clinical trial eligibility and mandating adequate representation of the elderly is also important in determining how new therapies will impact our aging population.