Steven M. Ewer

Cardiotoxicity of anticancer treatments: what the cardiologist needs to know

Cardiotoxicity of anticancer treatments has become an increasingly important clinical problem faced by cardiologists. Left ventricular systolic dysfunction and heart failure generate the most concern, but clinical features and prognosis vary considerably depending on the causative agent. Anthracycline-related cardiomyopathy differs fundamentally from effects associated with newer targeted agents, such as trastuzumab. Other forms of cardiovascular disease that occur as a result of cancer treatment include hypertension, thromboembolic disease, pericardial disease, arrhythmia, and myocardial ischemia. The approach to cardiovascular disease in patients with cancer is often different from that in the general population, not only because of distinct underlying mechanisms and clinical features of their heart disease, but also because of the potential ongoing need for additional cancer treatment as well as the altered duration of anticipated survival. In an effort to maximize both quality of life and survival, cardiologists and oncologists should collaborate with the aim of balancing the risks of cardiotoxicity with the benefits of oncologic therapy.

Cardiotoxicity profile of trastuzumab.

Trastuzumab is a monoclonal antibody that targets the human epidermal growth factor receptor tyrosine kinase HER2/ErbB2. This agent has shown a highly significant antitumour effect for patients with HER2-positive breast cancer, and is now considered part of the standard regimens for the treatment of this disease in both the metastatic and adjuvant setting.Cardiotoxicity has been associated with trastuzumab, and this issue has now been studied and documented in a number of adjuvant trials for which data have now been released. Cardiotoxicity has been shown to be potentiated when the agent is used concurrently or sequentially with an anthracycline, and this has limited the use of trastuzumab in some patients. Determining the overall impact of trastuzumab is further complicated by the administration of other cardiotoxic agents such as the taxanes and cyclophosphamide as well as by pre-existing cardiac disease.The incidence of severe congestive heart failure (New York Heart Association class III or IV) was 0–3.9% in the trastuzumab arms versus 0–1.3% in the control arms in the five major randomized adjuvant trials. Only one cardiac death was related to trastuzumab whereas two cardiac deaths occurred in the control arms. Ejection fraction decline of ≥10% or 15% was reported in 3–34% of trastuzumab recipients in these trials.Patients affected by trastuzumab-related cardiotoxicity do not exhibit the cellular death and distinctive ultrastructural myocardial changes seen on electron microscopy with anthracycline-induced cardiotoxicity. The cardiotoxicity of trastuzumab also differs from traditional chemotherapy-induced cardiotoxicity in that it appears to be at least partially reversible, not related to the cumulative dose, and re-challenge is generally tolerated.There remain a number of uncertainties regarding the diagnosis and management of trastuzumab-related cardiotoxicity. While no formal guidelines or consensus statements exist at present regarding cardiac monitoring during use of trastuzumab, proposed recommendations include a careful assessment of ejection fraction prior to initiating trastuzumab, avoidance of concurrent administration of trastuzumab with anthracyclines, and regular monitoring of symptoms and cardiac function during and for several years after therapy. Increased vigilance is appropriate for higher risk patients.

Cardiotoxicity of anticancer treatments

Patients with cancer can experience adverse cardiovascular events secondary to the malignant process itself or its treatment. Patients with cancer might also have underlying cardiovascular illness, the consequences of which are often exacerbated by the stress of the tumour growth or its treatment. With the advent of new treatments and subsequent prolonged survival time, late effects of cancer treatment can become clinically evident decades after completion of therapy. The hearts extensive energy reserve and its ability to compensate for reduced function add to the complexity of diagnosis and timely initiation of therapy. Additionally, modern oncological treatment regimens often incorporate multiple agents whose deleterious cardiac effects might be additive or synergistic. Treatment-related impairment of cardiac contractility can be either transient or irreversible. Furthermore, cancer treatment is associated with life-threatening arrhythmia, ischaemia, infarction, and damage to cardiac valves, the conduction system, or the pericardium. Awareness of these processes has gained prominence with the arrival of strategies to monitor and to prevent or to mitigate the effects of cardiovascular damage. A greater understanding of the mechanisms of injury can prolong the lives of those cured of their malignancy, but left with potentially devastating cardiac sequelae.

Returns to physician human capital: Evidence from patients randomized to physician teams

Physicians play a major role in determining the cost and quality of healthcare, yet estimates of these effects can be confounded by patient sorting. This paper considers a natural experiment where nearly 30,000 patients were randomly assigned to clinical teams from one of two academic institutions. One institution is among the top medical schools in the U.S., while the other institution is ranked lower in the distribution. Patients treated by the two programs have similar observable characteristics and have access to a single set of facilities and ancillary staff. Those treated by physicians from the higher ranked institution have 10-25% less expensive stays than patients assigned to the lower ranked institution. Health outcomes are not related to the physician team assignment. Cost differences are most pronounced for serious conditions, and they largely stem from diagnostic-testing rates: the lower ranked program tends to order more tests and takes longer to order them.

Prospective Evaluation of Sunitinib-Induced Cardiotoxicity in Patients with Metastatic Renal Cell Carcinoma

Purpose: To prospectively evaluate cardiotoxicity risk with sunitinib in metastatic renal cell carcinoma (mRCC) routine clinical practice using comprehensive echocardiography and biomarker phenotyping. Experimental Design: In a multicenter prospective study of 90 patients with mRCC, echocardiography and biomarkers of cardiovascular injury and stress were quantified at baseline, 3.5, 15, and 33 weeks following sunitinib initiation. These “on-drug” visits corresponded to cycles 1, 3, and 6, respectively. Left ventricular (LV) dysfunction was defined as an absolute decline in LV ejection fraction (LVEF) by ≥10% to a value of <50%. Conditional survival analyses predicted the risk of LV dysfunction. Linear mixed-effects models estimated changes in LVEF, high-sensitivity Troponin I (hsTnI), and B-type natriuretic peptide (BNP) over time. Results: The predicted risk of LV dysfunction by cycle 6 was 9.7% (95% confidence interval, 3%–17%). The majority of events occurred in the first treatment cycle. This risk diminished to 5% and 2% in patients who had not experienced dysfunction by the completion of cycles 1 and 3, respectively. All evaluable patients who experienced LV dysfunction had subsequent improvement in LVEF with careful management. Six patients (6.7%) developed hsTnI elevations >21.5 pg/mL, and 11 additional patients (12.2%) developed BNP elevations >100 pg/mL. These elevations similarly tended to occur early and resolved over time. Conclusions: On average, patients with mRCC receiving sunitinib exhibit modest declines in LVEF and nonsignificant changes in hsTnI and BNP. However, approximately 9.7% to 18.9% of patients develop more substantive abnormalities. These changes occur early and are largely recoverable with careful management. Clin Cancer Res; 23(14); 3601–9. ©2017 AACR.

The anthracycline–trastuzumab interaction: a lesson in not jumping to confusion

A group of oncologists and cardiologists met in Maui, Hawaii in July 1998 for a consensus conference to discuss the treatment of breast cancer with trastuzumab [1]. Trastuzumab had proven to be highly effective in the treatment of HER-2 positive breast cancer, a form of the disease that heretofore had the reputation for being resistant to conventional therapy and which carried a poor prognosis. In that respect, trastuzumab was considered a ‘breakthrough’ agent. Unfortunately, early reports found an unexpected incidence of both symptomatic (19%) and total (27%) cardiac events that included asymptomatic declines in ejection fraction [2].

Longitudinal Assessment of Vascular Function With Sunitinib in Patients With Metastatic Renal Cell Carcinoma

Background: Sunitinib, used widely in metastatic renal cell carcinoma, can result in hypertension, left ventricular dysfunction, and heart failure. However, the relationships between vascular function and cardiac dysfunction with sunitinib are poorly understood. Methods and Results: In a multicenter prospective study of 84 metastatic renal cell carcinoma patients, echocardiography, arterial tonometry, and BNP (B-type natriuretic peptide) measures were performed at baseline and at 3.5, 15, and 33 weeks after sunitinib initiation, correlating with sunitinib cycles 1, 3, and 6. Mean change in vascular function parameters and 95% confidence intervals were calculated. Linear regression models were used to estimate associations between vascular function and left ventricular ejection fraction, longitudinal strain, diastolic function (E/e′), and BNP. After 3.5 weeks of sunitinib, mean systolic blood pressure increased by 9.5 mm Hg (95% confidence interval, 2.0–17.1; P=0.02) and diastolic blood pressure by 7.2 mm Hg (95% confidence interval, 4.3–10.0; P<0.001) across all participants. Sunitinib resulted in increases in large artery stiffness (carotid–femoral pulse wave velocity) and resistive load (total peripheral resistance and arterial elastance; all P<0.05) and changes in pulsatile load (total arterial compliance and wave reflection). There were no statistically significant associations between vascular function and systolic dysfunction (left ventricular ejection fraction and longitudinal strain). However, baseline total peripheral resistance, arterial elastance, and aortic impedance were associated with worsening diastolic function and filling pressures over time. Conclusions: In patients with metastatic renal cell carcinoma, sunitinib resulted in early, significant increases in blood pressure, arterial stiffness, and resistive and pulsatile load within 3.5 weeks of treatment. Baseline vascular function parameters were associated with worsening diastolic but not systolic function.

Trastuzumab cardiotoxiciy: the age-old balance of risk and benefit

The cardiac sequelae of trastuzumab administration has been the subject of considerable concern dating back to the original report noting a 27% incidence of ejection fraction declines and 19% of clinical heart failure (Slamon et al, 2001). Although this trial continues to be cited, these high incidences have never been subsequently encountered. As knowledge regarding how trastuzumab affects the heart expands, new questions arise. These questions run the gamut from whether trastuzumab truly exhibits primary cardiotoxicity to whether zealous monitoring of ejection fraction every 3 months offers any quantifiable benefit to patients in the form of furthering early intervention to delay overt cardiotoxicity (Davies et al, 2016; Ewer and Swain, 2016). Some findings regarding trastuzumab cardiotoxicity are sufficiently clear and have been observed over sufficiently long periods that they can, at least for the present, be taken as established facts. Trastuzumab is associated with cardiomyopathic events; these events are indisputably different from the primary toxicity seen with anthracyclines that destroy myocytes in a cumulative dose-related fashion. The mechanism or mechanisms of trastuzumab-associated cardiotoxicity are different; the structural changes seen with agents that show primary toxicity are absent, and there is increasing evidence that observed declines following administration of this agent are often, albeit not always, reversible (Ewer and Lippman, 2005). We now also have sufficient experience in treating patients with metastatic disease to understand that for many, albeit not all, the drug can be given for long periods of time without untoward cardiac events (Tripathy et al, 2004). The mechanisms for what does occur in the heart are probably more complex than have been appreciated. Trastuzumab, as a monoclonal antibody that affects tyrosine kinase pathways, initially was not considered a likely agent for cardiotoxicity, and yet cardiac effects were clearly noted. One established mechanism involves interference with myocyte repair (de Korte et al, 2007). Damaged myocytes are less likely to recover in the presence of trastuzumab, offering a possible explanation of the reason higher levels of toxicity are noted when trastuzumab is given concurrently or immediately following an anthracycline (Ewer and Ewer, 2010). When the time interval between the two agents is sufficiently long so that cell damage from the anthracycline has resolved, trastuzumab-associated events are almost as low as is the case when an anthracycline has not been given (Suter et al, 2007). We also recognise that some patients experience declines in their ejection fraction or experience overt heart failure after trastuzumab exposure. Are these events because of inherited predisposition, acquired sensitivity to the drug, some enhanced underlying myocyte injury for which cell repair is impaired, overzealous monitoring in the face of imperfect methods of determining ejection fraction, or some other as yet unexplored mechanism? Trastuzumab has had a major impact on the treatment of HER-2-positive breast cancer. The agent is used in both the metastatic and adjuvant setting. Although patients with metastatic disease are often treated to progression or intolerance, the optimal duration of treatment in the adjuvant setting is not, or at least not yet, certain. The HERA trial looked at 1 vs 2 years of administration and found that the additional year offered no oncological advantage; however, more cardiac events were noted among the 2-year when compared with the 1-year cohort (20.4% vs 16.3%; Goldhirsch et al, 2013). Interference with cell repair could offer a plausible, albeit unproven, explanation. It is in the context of these observations that we can explore the findings of Earl et al (2016) reported in this issue of British Journal of Cancer. In this highly important and timely initiative to determine if 6 months of trastuzumab is oncologically inferior to the usual 12 months of exposure, the Persephone trial was undertaken; cardiac function is a secondary end point of this trial, and is appropriately reported ahead of efficacy data that may take considerable time to be ripe for analysis. The researchers took an approach to cardiac events that may have been overinclusive in that a new or altered cardiac medication prescribed during the 12 months after starting trastuzumab was considered sufficient for positive adjudication; overinclusion, if it

Enigmas regarding the true extent and impact of tyrosine kinase inhibitor-related cardiotoxicity

Cardiac sequelae of anticancer treatment remains a major concern among both oncologists and cardiologists caring for patients treated with potentially cardiotoxic regimens. While the toxicity of anthracyclines is well understood to destroy myocytes, the scenario with regard to newer agents, both monoclonal antibodies and small-molecule tyrosine kinase inhibitors, is substantially different. This article differentiates the toxicity of agents that directly destroy myocytes (type I agents) from those that are associated with cardiac damage more indirectly (type II agents). Some mechanistic considerations regarding type II toxicity, albeit not categorically proven, are presented.