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Cardio-oncological management of patients
Seminars in Oncology 46 (2019) 408–413
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Seminars in Oncology journal homepage: www.elsevier.com/locate/seminoncol
Cardio-oncological management of patients ✩ Daniela M. Cardinale a, Ana Barac b, Adam Torbicki c, Bijoy K. Khandheria d, Daniel Lenihan e, Giorgio Minotti f,∗ a
Cardioncology Unit, European Institute of Oncology, Milan, Italy Georgetown University, MedStar Heart and Vascular Institute, Washington DC Institute of Tuberculosis and Lung Diseases, Warsaw, Poland d Aurora St. Luke’s Medical Centers, Milwaukee, WI e Cardio-Oncology Center of Excellence, Washington University in St Louis, St. Louis, MO f Department of Medicine, Campus Bio-Medico University, Rome, Italy b c
a r t i c l e
i n f o
Article history: Received 10 January 2019 Accepted 11 November 2019
Keywords: Cancer drugs Cardiovascular toxicity Imaging Risk Prevention Treatment
a b s t r a c t Session III of the Second International Colloquium on Cardio-Oncology focused on the diagnosis, management, and prevention of cardiovascular toxicity of cancer drugs. With a large menu of biomarkers and imaging modalities available to the cardio oncologist, there continues to be no consensus regarding the best use of each modality alone and in combination and whether we can actually prevent early and late cardiotoxicity using these tests to guide a preventive strategy. It has become increasingly clear that early diagnosis and intervention leads to less late cardiotoxicity and fewer cardiac-related events. This can be accomplished by taking a thorough history and performing a goal directed physical examination coupled with use of biomarkers and imaging studies. This session attempted to provide rationale for a current and integrated approach to these issues. © 2019 Elsevier Inc. All rights reserved.
Session summary Session III of the Second International Colloquium on CardioOncology, chaired by Drs. Torbicki (Warsaw, Poland) and Khandheria (Wisconsin, MI), focused on the diagnosis, management, and prevention of cardiovascular toxicity of cancer drugs along with the directed use of biomarkers (troponin) and imaging techniques. With a large menu of these modalities available to the cardio oncologist, there continues to be no consensus regarding the best use of each modality alone and in combination and whether we can actually prevent early and late cardiotoxicity using these tests to guide a preventive strategy. This session attempts to provide a rationale for the current approach to these issues.
✩ Based on presentations and extended abstracts submitted to Session 3 of the Second International Colloquium on Cardio-Oncology, held in Krakow (Poland). ∗ Corresponding author. Department of Medicine, Campus Bio-Medico University, Viale Alvaro del Portillo 21, 00128 Rome, Italy. E-mail address: [email protected] (G. Minotti).
https://doi.org/10.1053/j.seminoncol.2019.11.002 0093-7754/© 2019 Elsevier Inc. All rights reserved.
Cardiotoxicity–Unresolved issue regarding monitoring and prevention strategies This session opened with a presentation entitled “Turning cardio-oncological management to a continuum of early and late events” by Dr. Cardinale from the European Institute of Oncology in Milan, Italy. Dr. Cardinale mentioned that over the past 20 years, the remarkable breakthroughs of cancer treatments have led to a significant decline in mortality for many forms of cancer. However, this result has been achieved at a price in terms of cardiovascular side effects. In some cases, cardiotoxicity has had an impact on the clinical effectiveness of the cancer therapy, independent of the cancer prognosis, and thus an impact on the patient’s survival and quality of life [1–3]. The most clinically impacting manifestation of cardiotoxicity, feared both by cardiologists and by oncologists, is the development of left ventricular dysfunction. It is probable that cardiotoxicity is a unique and continuous phenomenon that starts with myocardial cell injury, followed by a progressive decline in left ventricular ejection fraction (LVEF) and/or global longitudinal strain (GLS, TEXT BOX 1) that, if disregarded and not treated, progressively leads to overt heart failure [2] as illustrated in Fig. 1. We can identify car-
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diotoxicity at each of these steps, depending on the diagnostic tool we use.
Start of chemotherapy
Hours/Days/Weeks
TEXT BOX 1. Global longitudinal strain (GLS). As with left ventricular ejection fraction (LVEF), a measure of global longitudinal strain (GLS) provides information on left ventricular systolic function/dysfunction. GLS is derived from “speckle tracking” and can objectively and reliably assess systolic function. Echocardiographic global longitudinal strain (GLS) has been recommended as a means to follow patients with cancer at risk of chemotherapy-related left ventricular (LV) systolic dysfunction. The American College of Cardiology notes the following pragmatic points: 1. GLS expresses percent change in longitudinal shortening: change in length-baseline length 2. GLS varies with age, sex, and LV loading conditions, rendering definitions of what constitutes an “abnormal GLS” difficult. However, in adults, GLS <16% is abnormal, 16%–18% is borderline and >18% is normal. Note: GLS is expressed as a negative number. 3. Softwares from different manufacturers derive GLS differently. Common features involve view selection, defining end-systole, tracing the myocardium, assessing tracking quality, and integration. 4. Different aspects of strain can be displayed differently. Waveform displays can illustrate contraction delay and temporal dispersion in multiple myocardial segments. Parametric displays can illustrate spatial dispersion through the cardiac cycle. 5. Common errors in assessing GLS include errors in triggering, and errors in the definition of the ROI (region of interest). Adapted from American College of Cardiology. [https://www.acc.org/latest- in- cardiology/ten- points- toremember/2018/08/10/11/01/assessment- of- left- ventricularglobal- longitudinal- strain]
At present, we can identify cardiotoxicity in a preclinical phase, long before the onset of symptoms of heart failure, long before evidence of a fall in the LVEF (Fig. 1). Most data refer to biochemical markers such as troponins and strain echocardiography, but often– still today–cardiotoxicity is detected only when symptoms of heart failure occur [1–3]. According to recent publications neither cardiac imaging, measurement of biomarkers nor primary preventive drug interventions are recommended in a patient without pre-existing cardiac risk factors [4,5]. The reasons why cardiac monitoring is not recommended by international oncological guidelines in low risk patients–ie, those without cardiovascular risk factors or a previous history of cardiac disease–include medicalization, the possibility of causing stress and anxiety, and increasing health care costs [4,5]. In daily clinical practice, cardiotoxicity can be detected as an asymptomatic drop in LVEF. However, a diagnosis of cardiotoxicity based on the onset of symptoms of decompensation or on evidence of an asymptomatic decrease in the LVEF is a diagnosis that has been made very late in its course, precluding any form of effective prevention [6]. Moreover, very often at that phase cardiac damage is progressive, and no longer reversible [6]. In a prospective study that included 2625 patients with some followed for more than 15 years, it was recognized that in most patients cardiotoxicity can be detected in a preclinical state with 98% of these patients identified at a mean of 3.5 months. In addition,
Myocardial cell injury
Increase in troponin
Myocardial deformation
Decrease in GLS
409
Months Asymptomatic cardiotoxicity
Decrease in LVEF
Years Overt cardiotoxicity
HF symptoms
Fig. 1. Pathobiologic continuum of cardiotoxicity from asymptomatic increases in troponin and echocardiographic indices to clinically symptomatic heart failure. GLS, global longitudinal strain; LVEF, left ventricular ejection fraction. Reprinted from reference [3]. With permission from springer nature.
the treatment of symptomatic and/or asymptomatic left ventricular dysfunction, diagnosed early through strict cardiac monitoring, enabled the recovery of systolic function in more than 80% of patients [7]. However, full recovery to a prechemotherapy LVEF value was achieved in only 11% of patients. In most patients who improved with normalization of cardiac function, the final LVEF value was still significantly below the baseline value. This suggests that the diagnosis of cardiotoxicity must be made earlier. The role of troponins as early markers of cardiotoxicity has been extensively studied [2,4,5,8]. Increases in troponin during chemotherapy allows for an accurate stratification of cardiac risk after the end of therapy: patients without an increase of troponin do not develop left ventricular dysfunction, and have a very low incidence of cardiac events. On the other hand, patients who show an increase in troponin–especially if the increase is persistent–have a high risk of developing left ventricular dysfunction, and major cardiac events [8]. The possibility of identifying patients at high risk of cardiotoxicity on the basis of troponin monitoring offers the opportunity to institute targeted preventive therapies. Enalapril, started after the first troponin rise and continued for a year, was able to prevent the development of left ventricular dysfunction and cardiac events after chemotherapy [9]. However, troponin changes might be detected at various time intervals after chemotherapy administration, possibly due to different kinetics of troponin release in response to different treatment schedules. As a result, repeated blood samples are necessary to capture its rise. This may represent a limitation of a preventive approach based on troponin values in clinical practice. Primary prevention–extended to all patients due to receive cardiotoxic chemotherapy–may overcome this limitation [10]. The aim of the International CardioOncology Society-one trial, the first multicenter, randomized trial of the Italian branch of the International CardioOncology Society [11], was to evaluate prospectively whether enalapril started in all patients prior to the beginning of chemotherapy could prevent troponin elevation and subsequent development of cardiac dysfunction, compared to a strategy that started enalapril only after evidence of troponin elevation during chemotherapy (TEXT BOX 2). The principal result of this study was that the two strategies emerged as equally effective in preventing left ventricular dysfunction and major cardiac events, supporting the effectiveness of using enalapril to prevent anthracyclineinduced left ventricular dysfunction, regardless of the strategy used [10].
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TEXT BOX 2. Anthracycline-induced cardiotoxicity: A multicenter randomized trial comparing two strategies for guiding prevention with enalapril: The International CardioOncology Society-one trial (ICOS-ONE). [Cardinale et al., Eur J Cancer 2018; 94:126-137] Hypothesis Will preventive treatment with enalapril further increase the benefit from the use of enalapril reported for cancer patients with troponin elevation. Methods: Controlled, open-label trial Patients randomly assigned to either: • Prevention arm: Enalapril started before chemotherapy or • Troponin-triggered arm: Enalapril started only in patients with increase in troponin during or after chemotherapy Results: 273 patients, 88% were women, mean age 51 ± 12 years 76% had breast cancer; epirubicin and doxorubicin most commonly prescribed Median cumulative doses: • Epirubicin: 360 [270–360] mg/m2 • Doxorubicin: 240 [240–240] mg/m2 Incidence of troponin elevation: • Prevention arm: 23% • Troponin-triggered arm: 26% (P= .50) Cardiotoxicity: Three patients (1.1%)–two in prevention, one in the troponin-triggered group–developed left ventricular dysfunction defined as 10% point reduction of LVEF, with values lower than 50% Conclusions: “Low cumulative doses of anthracyclines in adult patients with low cardiovascular risk can raise troponins, without differences between the two strategies of giving enalapril. Considering a benefit of enalapril in the prevention of LV dysfunction, a troponin-triggered strategy may be more convenient.”
So, which prevention strategy should we prefer? What are the pros and cons of the two approaches? A “secondary” prevention approach where the use of enalapril is triggered by a rise in troponin has the disadvantage that it requires repeated blood samples to detect an increase in troponin. However, there are several advantages including: (i) enalapril is administered only to selected high-risk patients (20%, not 100%); (ii) only select patients need careful blood pressure monitoring as the dose of enalapril is increased; (iii) only high-risk patients are exposed to possible enalapril-induced side effects, and not patients less prone to develop cardiotoxicity, who do not require any cardioprotective therapy; (iv) low risk patients–ie, those whose troponin levels do not increase–do not undergo long-term monitoring with expensive imaging methods, with a better cost-benefit ratio, and reduced medicalization, distress, anxiety, and costs [6,10]. Imaging options: Perils, challenges and opportunities In her presentation entitled “Imaging: the essential and the superfluous”, Dr. Ana Barac (Washington, DC) continued the discussion with a focus on imaging. She began with a historical perspective of the routine use of imaging in cancer patients that began in the 1970s, following the initial observation of cardiac toxicity with high cumulative doses of anthracyclines. Assessment of LVEF using equilibrium radionuclide angiography, more widely known as MUGA (multigated blood pool imaging), prior to initiation and during the administration of anthracyclines became part of clinical oncology practice in the 1980s [12,13]. The premise of routine imaging was to detect asymptomatic declines in LVEF as a marker of cardiac injury and provide safety recommendations for anthracy-
Table 1 Cardiac imaging in clinical cardio-oncology: echocardiogram, CMR, PET-CT. Essential tools for cardiac assessment before, during and after cancer treatment. • Differential diagnosis of LV dysfunction → Ischemia → Infiltrative disease (amyloid) → Myocarditis → Stress induced cardiomyopathy, sepsis → Cancer treatment-related cardiotoxicity • RV assessment • Valvular disease • Pericardial disease • Cardiac masses
cline administration. In patients with normal cardiac function, defined as a LVEF >50% based on the normal ranges using MUGA, anthracyclines could be administered, however, reassessment of LVEF was recommended after a cumulative doxorubicin dose of 250–300 mg/m2 had been administered and prior to each subsequent cycle of anthracycline-containing chemotherapy after a cumulative dose of 450 mg/m2 had reached [13]. In patients with abnormal cardiac function at baseline and/or those with significant declines in LVEF, avoidance and/or discontinuation of anthracyclines was recommended. From this early use, the cardiac imaging needs for patients with cancer have increased with advances in imaging modalities that now include echocardiography, cardiac magnetic resonance (CMR, cardiac), and Positron Emission Tomography-Computed Tomography (PET-CT) scanning. Additionally there has been an increase in the number of cancer drugs with associated off-target cardiac effects, beyond cancer treatment-related cardiotoxicity, ie, reductions in LVEF, that require cardiac assessment at every stage of cancer diagnosis, treatment, and survivorship (Table 1). Until the introduction of the HER2-targeted monoclonal antibody, trastuzumab, in the early 20 0 0s, anthracyclines were the only oncology drug class that required routine cardiac imaging prior to or during administration. In the seminal trial of patients with metastatic HER2-positive breast cancer, treated by trastuzumab in combination with anthracycline, trastuzumab demonstrated clinical benefit with a lower risk of death at 1 year and improved survival, however, with cardiac dysfunction and symptomatic New York Heart Association class III and IV heart failure occurring in up to 27% of patients [14]. To improve the safety of its administration, all subsequent trials of trastuzumab in early breast cancer incorporated routine cardiac imaging before and during trastuzumab administration [15]. Indeed, with administering trastuzumab after the anthracycline and implementing holding and stopping rules based on LVEF changes, the incidence of symptomatic heart failure was significantly reduced and LVEF assessment was incorporated in the recommendations of regulatory agencies and ultimately the drug label of most HER2- targeted therapies [16]. In parallel, since 1970s cardiac monitoring has evolved with development of advanced modalities including echocardiography and CMR, and with investigations of new approaches to predict and prevent cardiotoxicity. Serial monitoring of cardiac function in patients undergoing trastuzumab therapy has brought focus to specific needs in this patient population, including reproducibility and accuracy of LVEF assessment (coefficient of variation and reproducibility 10%–12%), challenges with comparing LVEF values across different techniques, as well as the limitations of LVEF as a single measure of cardiac function. Advances in cardiac monitoring, applied early-on in patients with a diagnosis of cancer, include myocardial strain using speckletracking echocardiography (TEXT BOX 1), 3-D echocardiography as well as native tissue characterization using CMR. Professional
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Table 2 Trials assessing primary cardioprotection in breast cancer.
Study population
Study design
Primary outcome [Endpoint] Results
Fig. 2. Cardiac Magnetic Resonance (CMR) imaging of a patient with a diagnosis of melanoma treated with an immune check point inhibitor and showing a mass in intraventricular septum. SSFP, steady-state free precession; LGE, late gadolinium enhancement.
organizations have taken note and a number of recent statements provide recommendations on cardiac imaging in this population [17–19]. Consider a brief case history that reflects the complexity of cardio oncology care and the unique critical role of imaging in diagnosis, decision making and outcome surveillance. A 49 year old male first diagnosed with ocular melanoma at age 23 years was treated initially with radiation. Nine years later at the age of 32, a solitary right pulmonary nodule was resected, pathology consistent with melanoma, and he was enrolled in a phase 1 vaccine study. At the age of 36, he was then found to have metastases to the right middle and at the age of 42 to the left lower lobe. He now presented with a 2.5 cm PET-avid lesion involving the intraventricular septum and a new 1.5 cm left lung lesion. The risk of resection was considered as excessive and he was treated with immune checkpoint inhibitor therapy with an excellent clinical response. CMR images are presented in Fig. 2. This case illustrates the use and benefit of imaging not initially envisioned in the 1990s. However, the current use of cardiac imaging in patients with cancer presents perils, challenges, and opportunities that include: 1. A lack of clear guidelines for the monitoring of cardiac toxicities– Routine cardiac imaging, including assessment of baseline cardiac function, is presently limited to patients receiving anthracyclines and HER2-targeted therapies. Much less, if anything, is known about cardiac and cardiovascular injury associated with other classes of cancer therapeutics. Of particular interest are the inhibitors of vascular endothelial growth factor (VEGF), a drug class known to cause hypertension and less often symptomatic heart failure, and immune checkpoint inhibitors that may result in myocarditis, an infrequent but highly morbid complication. Cardiac imaging in patients treated with these therapies is pursued only if and when patients develop clinical symptoms and in these cases, the lack of baseline imaging lim-
PRADA [21] [2016]
MANTICORE [22] [2017]
• N = 130
• N = 94
• N = 200
• All epirubicin
• All trastuzumab
• All doxorubicin
• 22% trastuzumab 2 × 2, metoprolol, candesartan, placebo Changes in LVEF by CMR at 10-64 weeks In intention-totreat analysis overall decline in LVEF was 2.6% (95% CI 1.5, 3.8) in the placebo group and 0.8% (95% CI −0.4, 1.9) (P value for betweengroup difference: 0.026). No effect of metoprolol on the overall decline in LVEF was observed
• 12%–33% anthracycline 1:1:1 bisoprolol, perindopril, placebo
Changes in LVEDV by CMR at 1 year
Perindopril and bisoprolol were well tolerated and protected against cancer therapy-related declines in LVEF [attenuated in bisoprolol-treated patients (−1 ± 5%) relative to the perindopril (−3 ± 4%) and placebo (−5 ± 5%) groups (P = .001)]. However, trastuzumabmediated left ventricular remodeling - the primary outcome was not prevented by perindopril or bisoprolol [LVEDV increased with perindopril (+7 ± 14 mL/m2 ), bisoprolol (+8 mL ± 9 mL/m2 ), and placebo (+4 ± 11 mL/m2 ; P = .36)]
CECCY [23] [2018]
1:1 carvedilol and placebo
Reduction in Echo LVEF>10% at 6 months Carvedilol had no impact on the incidence of early onset of LVEF reduction (13.5% v 14.5% for placebo and carvedilol, respectively). However, the use of carvedilol resulted in a significant reduction in troponin. I levels (P = .003) and diastolic dysfunction (P = .039).
Abbreviations: LVEDV, left ventricular end-diastolic volume; CMR, cardiac magnetic resonance; LVEF, left ventricular ejection fraction.
its our ability to assess the contribution of the cancer therapy to changes in cardiac function and the development of heart failure. This may have important repercussions as regards a patients’ safety and our ability to reinitiate cancer treatment. 2. Concerns about excessive monitoring–In patients receiving HER2targeted therapeutics, concern has been raised about overuse of imaging that is not justified in all patients, has not been shown to improve outcomes and may lead to additional unnecessary testing and adverse oncology outcomes including treatment interruption [20]. More recent trials evaluating the use of cardioprotection in breast cancer patients (Prada, Manticore, CECCY) have demonstrated inconclusive results for neurohumoral inhibition started at the time breast cancer treatment is initiated to prevent LV dysfunction in patients receiving HER2-targeted therapies, as well as a very low risk of cardiac events, pointing to the need to include higher-risk patients as well as longer follow-up times [21–23]. The study characteristics are reported in Table 2. 3. The need to gather data in the context of clinical trials–The inclusion of monitoring into clinical trials that enroll patients with a diagnosis of cancer needs to expand beyond the traditional focus on a single (LVEF) value as the only measure of cardiovascular risk. This approach will create an opportunity to
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Fig. 3. Modified and adapted by the authors from the definitions of heart failure (HF) stages according to the American Heart Association.
increase our understanding of the different mechanisms of cardiovascular injury and help create imaging phenotypes specific to cancer therapeutics. Echocardiographic myocardial strain and tissue characterization by CMR represent examples of advanced imaging techniques ready for clinical investigations [24–26]. Global longitudinal strain (GLS, TEXT BOX 1), a parameter derived from echocardiography based on speckle tracking that can detect myocardial injury earlier than a decrease in LVEF can be detected by 2-D echocardiography, has been used as a tool for diagnosis and risk stratification to detect subclinical myocardial injury and is being studied as a tool to guide cardioprotective strategies [17,27]. Advances in the treatment of many cancers continues to increase survivorship and continues to change the paradigm of cancer as an acute disease with high mortality into the one of manageable and often chronic disease. In that setting, cardiac imaging is tasked with improving baseline cardiovascular risk stratification, providing accurate diagnosis of cancer-treatment related toxicity and guiding management during and after cancer treatment. While the historic use of LVEF assessment as a single imaging “yes or no” criteria for administration of select cancer therapies clearly falls short of this standard, advances in cardiovascular imaging offers an opportunity to develop collaboration and design trials focused on improved oncology and cardiovascular outcomes. Primary and secondary prevention Dr. Lenihan (St. Louis, MO) began by defining primary and secondary prevention using the AHA/ACC stages of heart failure guidelines as a platform. Noting that all patients who receive potentially cardiotoxic chemotherapy are at Stage A–at risk for heart failure but without structural heart disease or symptoms of heart failure– primary prevention in this population includes a heart healthy lifestyle and risk factor prevention as appropriate to prevent evolution to Stage B where there is known structural heart disease that requires secondary prevention strategies. The latter include renin-angiotensin system inhibitors and beta blockers. The stages of heart failure are illustrated in Fig. 3. Trastuzumab has been shown to have survival benefit in women with HER2 positive breast cancers [28]. The increase in survival comes at a cost, ie, an increase in asymptomatic and symptomatic decreases in LVEF. The results of the PRADA trial [21] where candesartan but not metoprolol was shown to be modestly cardioprotective (primary prevention) in women with HER2 positive breast cancer when given prior to trastuzumab chemotherapy, is an example of primary prevention. A major question is whether left ventricular dysfunction be prevented? There is inconsistent evidence that the use of traditional heart failure medications including angiotensin converting enzyme (ACE)-inhibitors, angiotensin receptor antagonists, beta blockers (carvedilol, bisoprolol, metoprolol) alone or in combination with
ACE/angiotensin receptor antagonists, spironolactone, and statins can prevent the emergence of left ventricular dysfunction when used in a primary prevention strategy. Ky et al. showed that early increases in multiple biomarkers can predict subsequent cardiac toxicity in patients with a diagnosis of breast cancer treated with doxorubicin, taxanes, and trastuzumab [29]. Moreover, as discussed above, early detection and treatment based on troponin elevation can lead to recovery of function and a decrease in MACEs (major adverse cardiac events) [7]. Yoon and colleagues reviewed a series of patients receiving potential cardiotoxic chemotherapy and found that many cancer survivors are not receiving treatment consistent with heart failure guidelines. This presents a substantial opportunity for collaboration between oncologists and cardiologists to improve the care of these cancer patients [30]. From a cancer treatment delivery standpoint, patients are more likely to have cardiac testing if they are receiving anthracycline-based chemotherapy or trastuzumab compared to other chemotherapies [31] and oncologists are more likely to withhold potentially cancer effective treatment when patients are symptomatic and have a measured LVEF <50% [32]. To improve cancer and cardiac outcomes, the role for collaborative cardio-oncology care was stressed. Cardiac toxicity beyond anthracyclines and HER-2-targeted therapies: Agents targeting VEGF, the proteasome, and cellular immunity The problem goes beyond the occurrence of cardiomyopathy with anthracyclines and HER-2 antagonists. A new definition of cardiotoxicity must include structural changes [valvular heart disease, pericardial inflammation, effusion, constriction, and tamponade], electrical abnormalities [arrhythmias, conduction disease, QT prolongation], metabolic abnormalities [hyperglycemia, hyperlipidemia], and vascular disease [accelerated atherosclerosis, hypertension, arterial and venous thrombosis, and pulmonary hypertension]). The discussion then shifted to other classes of antineoplastic agents and their effect on the vascular system. It is recognized that many chemotherapeutic drugs in addition to their direct anticancer effects, have potent antiangiogenic activity [32]. Amongst small molecule tyrosine kinase inhibitors (TKIs), those with antiVEGF properties are associated with hypertension and heart failure. These drugs have emerged as critical therapies for renal cell cancer, nonsmall cell lung cancer and a variety of other solid tumors [33]. This highlights the need for careful and frequent monitoring of blood pressure and most importantly, a baseline assessment of cardiac risk factors that should be optimally managed prior to treatment initiation and throughout the treatment course (primary prevention). Of interest, some data in patients with renal cell carcinoma treated with anti-VEGF directed TKI therapy, suggests concurrent treatment with statins not only effectively lowers lipids but can also improve overall survival [34]. As had been discussed by Dr. Carver in his presentation in Session II [35], another class of drugs that have off target cardiac effects are the proteosome inhibitors. They have emerged as cornerstones in the treatment of multiple myeloma, reducing mortality, and extending the frequency and duration of remissions [36– 41]. Immune checkpoint inhibitors have achieved important survival benefit in metastatic melanoma, nonsmall cell lung cancer, and bladder cancer. By activating the immune system, and the patient’s own immunocompetence, they provide a novel and exciting approach to cancer treatment. However, they have off target immune-mediated effects in all organ systems, including the heart. Myocarditis with lymphocyte infiltration has been described [42], as illustrated by Dr. Moslehi in his presentation in Session I [43]. However, not every patient receiving an immune checkpoint inhibitor who presents with cardiac symptoms has an immune complication and thus:
D.M. Cardinale, A. Barac and A. Torbicki et al. / Seminars in Oncology 46 (2019) 408–413 Table 3 Marching orders for cardio-oncology. 1. Define how to detect CV toxicity (including vascular toxicity) in the most judicious and effective manner 2. Describe, by reporting clinical outcomes in the broadest possible populations, what are the best clinical approaches to identified CV toxicity (not just left ventricular dysfunction) 3. Commit to training and education of medical professionals at all levels in order to refine the knowledge base that is required for the optimal management of CV disease in patients being treated or previously treated for cancer
1. It is critical to have a thorough cardiovascular assessment prior to the initiation of immune checkpoint inhibitor therapy–but equally important for all potentially toxic chemotherapy. This is the core tenet of primary prevention. 2. Vigilance in monitoring for myocarditis is essential–patients should be questioned about possible cardiac symptoms–this is the pathway to secondary prevention. 3. Patients being treated with immune checkpoint inhibitors should have troponin levels monitored regularly. This session concluded with marching orders for cardiooncology as presented in Table 3. Declaration of Competing Interest No conflict of interest to declare. References [1] Biasillo G, Cipolla CM, Cardinale D. Cardio-oncology: gaps in knowledge, goals, advances, and educational efforts. Curr Oncol Rep 2017;19:55. [2] Curigliano G, Cardinale D, Dent S, et al. Cardiotoxicity of anticancer treatments: epidemiology, detection, and management. CA Cancer J Clin 2016;66:309–25. [3] Cardinale D, Biasillo G, Cipolla CM. Curing cancer, saving the heart: a challenge that cardioncology should not miss. Curr Cardiol Rep 2016;18:51. [4] Armenian SH, Lacchetti C, Barac A, et al. Prevention and monitoring of cardiac dysfunction in survivors of adult cancers: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2017;35:893–911. [5] Levis BE, Binkley PF, Shapiro CL. Cardiotoxic effects of anthracycline-based therapy: what is the evidence and what are the potential harms? Lancet Oncol 2017;18:e445–56. [6] Colombo A, Cipolla CM, Beggiato M, et al. Cardiac toxicity of anticancer agents. Curr Cardiol Rep 2013;15:362. [7] Cardinale D, Colombo A, Bacchiani G, et al. Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy. Circulation 2015;131:1981–8. [8] Cardinale D, Biasillo G, Salvatici M, et al. Using biomarkers to predict and to prevent cardiotoxicity of cancer therapy. Expert Rev Mol Diagn 2017;17:245–56. [9] 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;114:2474–81. [10] Cardinale D, Ciceri F, Latini R, et al. Anthracycline-induced cardiotoxicity: a multicenter randomised trial comparing two strategies for guiding prevention with enalapril: The International CardioOncology Society-one trial. Eur J Cancer 2018;94:126–37. [11] Minotti G. The International Cardioncology Society-ONE trial: not all that glitters is for cardioncologists only. Eur J Cancer 2018;97:27–9. [12] Alexander J, Dainiak N, Berger HJ, et al. Serial assessment of doxorubicin cardiotoxicity with quantitative radionuclide angiocardiography. N Engl J Med 1979;300:278–83. [13] Schwartz RG, McKenzie WB, Alexander J, et al. Congestive heart failure and left ventricular dysfunction complicating doxorubicin therapy. Seven-year experience using serial radionuclide angiocardiography. Am J Med 1987;82:1109–18. [14] Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;344:783–92. [15] Seidman A, Hudis C, Pierri MK, et al. Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol 2002;20:1215–21. [16] Kenigsberg B, Wellstein A, Barac A. Left ventricular dysfunction in cancer treatment: is it relevant? JACC Heart Fail 2018;6:87–95.
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Cardiac surveillance guidelines for trastuzumab-containing therapy in early-stage breast cancer: getting to the heart of the matter. J Clin Oncol 2016;34:1030–3. [21] Gulati G, Heck SL, Ree AH, et al. Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA): a 2×2 factorial, randomized, placebo– controlled, double-blind clinical trial of candesartan and metoprolol. Eur Heart J 2016;37:1671–80. [22] Pituskin E, Mackey JR, Koshman S, et al. Multidisciplinary approach to novel therapies in cardio-oncology research (MANTICORE 101-Breast): a randomized trial for the prevention of trastuzumab-associated cardiotoxicity. J Clin Oncol 2017;35:870–7. [23] Avila MS, Ayub-Ferreira SM, de Barros Wanderley MR Jr, et al. Carvedilol for prevention of chemotherapy related cardiotoxicity. J Am Coll Cardiol 2018;71:2281–90. [24] Jordan JH, Castellino SM, Meléndez GC, et al. Left ventricular mass change after anthracycline chemotherapy. Circ Heart Fail 2018;11:e004560. [25] Narayan HK, Finkelman B, French B, et al. Detailed echocardiographic phenotyping in breast cancer patients: associations with ejection fraction decline, recovery, and heart failure symptoms over 3 years of follow-up. Circulation 2017;135:1397–412. [26] Neilan TG, Coelho-Filho OR, Pena-Herrera D, et al. Left ventricular mass in patients with cardiomyopathy after treatment with anthracyclines. Am J Cardiol 2012;110:1679–86. [27] Negishi T, Thavendiranathan P, Negishi K, et al. Rationale and design of the strain surveillance of chemotherapy for improving cardiovascular outcomes: the SUCCOUR Trial. JACC Cardiovasc Imaging 2018;11:1098–105. [28] Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 2011;365:1273–83. [29] Ky B, Putt M, Sawaya H, et al. Early increases in multiple biomarkers predict subsequent cardiotoxicity in patients with breast cancer treated with doxorubicin, taxanes, and trastuzumab. J Am Col Cardiol 2014;63:809–16. [30] Yoon GJ, Telli ML, Kao DP, et al. Left ventricular dysfunction in patients receiving cardiotoxic cancer therapies: are clinicians responding optimally? J Am Coll Cardiol 2010;56:1644–50. [31] Jovenaux L, Cautela J, Resseguier N, et al. Practices in management of cancer treatment-related cardiovascular toxicity: a cardio-oncology survey. Int J Cardiol 2017;241:387–92. [32] Kirchmair R, Walter DH, Ii M, et al. Antiangiogenesis mediates cisplatin-induced peripheral neuropathy: attenuation or reversal by local vascular endothelial growth factor gene therapy without augmenting tumor growth. Circulation 2005;111:2662–70. [33] Hall PS, Harshman LC, Srinivas S, et al. The frequency and severity of cardiovascular toxicity from targeted therapy in advanced renal cell carcinoma patients. J Am Coll Cardiol-Heart Fail 2013;1:72–8. [34] McKay RR, Lin X, Albiges L. Statins and survival outcomes in patients with metastatic renal cell carcinoma. Eur J Cancer 2016;52:155–62. [35] Breccia M, Carver JR, Szmit S, et al. Mechanisms and clinical course of cardiovascular toxicity of cancer treatment. II. Hematology. Sem Oncol 2019 (in press). [36] Willis MS, Patterson C. Proteotoxicity and cardiac dysfunction. New Eng J Med 2013;368:455–64. [37] Dick LR, Fleming PE. Building on bortezomib: second-generation proteasome inhibitors as anti-cancer therapy. Drug Discov Today 2010;15:243–8. [38] Grandin EW, Ky B, Cornell RF, et al. Patterns of cardiac toxicity associated with irreversible proteasome inhibition in the treatment of multiple myeloma. J Card Fail 2015;21:138–44. [39] Stewart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med 2015;372:142–52. [40] Cornell RF, Ky B, Weiss BM, et al. Prospective study of cardiac events during proteasome inhibitor therapy for relapsed multiple myeloma. J Clin Oncol 2019;37:1946–55. [41] Li W, Cornell RF, Lenihanet D, et al. Cardiovascular complications of novel multiple myeloma treatments. Circulation 2016;133:908–12. [42] Johnson DB, Balko JM, Compton ML, et al. Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med 2016;375:1749–55. [43] Yeh ET, Ewer MS, Moslehi J, et al. Mechanisms and clinical course of cardiovascular toxicity of cancer treatment. I. Oncology. Sem Oncol 2019 (in press).
Contents lists available at ScienceDirect
Seminars in Oncology journal homepage: www.elsevier.com/locate/seminoncol
Cardio-oncological management of patients ✩ Daniela M. Cardinale a, Ana Barac b, Adam Torbicki c, Bijoy K. Khandheria d, Daniel Lenihan e, Giorgio Minotti f,∗ a
Cardioncology Unit, European Institute of Oncology, Milan, Italy Georgetown University, MedStar Heart and Vascular Institute, Washington DC Institute of Tuberculosis and Lung Diseases, Warsaw, Poland d Aurora St. Luke’s Medical Centers, Milwaukee, WI e Cardio-Oncology Center of Excellence, Washington University in St Louis, St. Louis, MO f Department of Medicine, Campus Bio-Medico University, Rome, Italy b c
a r t i c l e
i n f o
Article history: Received 10 January 2019 Accepted 11 November 2019
Keywords: Cancer drugs Cardiovascular toxicity Imaging Risk Prevention Treatment
a b s t r a c t Session III of the Second International Colloquium on Cardio-Oncology focused on the diagnosis, management, and prevention of cardiovascular toxicity of cancer drugs. With a large menu of biomarkers and imaging modalities available to the cardio oncologist, there continues to be no consensus regarding the best use of each modality alone and in combination and whether we can actually prevent early and late cardiotoxicity using these tests to guide a preventive strategy. It has become increasingly clear that early diagnosis and intervention leads to less late cardiotoxicity and fewer cardiac-related events. This can be accomplished by taking a thorough history and performing a goal directed physical examination coupled with use of biomarkers and imaging studies. This session attempted to provide rationale for a current and integrated approach to these issues. © 2019 Elsevier Inc. All rights reserved.
Session summary Session III of the Second International Colloquium on CardioOncology, chaired by Drs. Torbicki (Warsaw, Poland) and Khandheria (Wisconsin, MI), focused on the diagnosis, management, and prevention of cardiovascular toxicity of cancer drugs along with the directed use of biomarkers (troponin) and imaging techniques. With a large menu of these modalities available to the cardio oncologist, there continues to be no consensus regarding the best use of each modality alone and in combination and whether we can actually prevent early and late cardiotoxicity using these tests to guide a preventive strategy. This session attempts to provide a rationale for the current approach to these issues.
✩ Based on presentations and extended abstracts submitted to Session 3 of the Second International Colloquium on Cardio-Oncology, held in Krakow (Poland). ∗ Corresponding author. Department of Medicine, Campus Bio-Medico University, Viale Alvaro del Portillo 21, 00128 Rome, Italy. E-mail address: [email protected] (G. Minotti).
https://doi.org/10.1053/j.seminoncol.2019.11.002 0093-7754/© 2019 Elsevier Inc. All rights reserved.
Cardiotoxicity–Unresolved issue regarding monitoring and prevention strategies This session opened with a presentation entitled “Turning cardio-oncological management to a continuum of early and late events” by Dr. Cardinale from the European Institute of Oncology in Milan, Italy. Dr. Cardinale mentioned that over the past 20 years, the remarkable breakthroughs of cancer treatments have led to a significant decline in mortality for many forms of cancer. However, this result has been achieved at a price in terms of cardiovascular side effects. In some cases, cardiotoxicity has had an impact on the clinical effectiveness of the cancer therapy, independent of the cancer prognosis, and thus an impact on the patient’s survival and quality of life [1–3]. The most clinically impacting manifestation of cardiotoxicity, feared both by cardiologists and by oncologists, is the development of left ventricular dysfunction. It is probable that cardiotoxicity is a unique and continuous phenomenon that starts with myocardial cell injury, followed by a progressive decline in left ventricular ejection fraction (LVEF) and/or global longitudinal strain (GLS, TEXT BOX 1) that, if disregarded and not treated, progressively leads to overt heart failure [2] as illustrated in Fig. 1. We can identify car-
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diotoxicity at each of these steps, depending on the diagnostic tool we use.
Start of chemotherapy
Hours/Days/Weeks
TEXT BOX 1. Global longitudinal strain (GLS). As with left ventricular ejection fraction (LVEF), a measure of global longitudinal strain (GLS) provides information on left ventricular systolic function/dysfunction. GLS is derived from “speckle tracking” and can objectively and reliably assess systolic function. Echocardiographic global longitudinal strain (GLS) has been recommended as a means to follow patients with cancer at risk of chemotherapy-related left ventricular (LV) systolic dysfunction. The American College of Cardiology notes the following pragmatic points: 1. GLS expresses percent change in longitudinal shortening: change in length-baseline length 2. GLS varies with age, sex, and LV loading conditions, rendering definitions of what constitutes an “abnormal GLS” difficult. However, in adults, GLS <16% is abnormal, 16%–18% is borderline and >18% is normal. Note: GLS is expressed as a negative number. 3. Softwares from different manufacturers derive GLS differently. Common features involve view selection, defining end-systole, tracing the myocardium, assessing tracking quality, and integration. 4. Different aspects of strain can be displayed differently. Waveform displays can illustrate contraction delay and temporal dispersion in multiple myocardial segments. Parametric displays can illustrate spatial dispersion through the cardiac cycle. 5. Common errors in assessing GLS include errors in triggering, and errors in the definition of the ROI (region of interest). Adapted from American College of Cardiology. [https://www.acc.org/latest- in- cardiology/ten- points- toremember/2018/08/10/11/01/assessment- of- left- ventricularglobal- longitudinal- strain]
At present, we can identify cardiotoxicity in a preclinical phase, long before the onset of symptoms of heart failure, long before evidence of a fall in the LVEF (Fig. 1). Most data refer to biochemical markers such as troponins and strain echocardiography, but often– still today–cardiotoxicity is detected only when symptoms of heart failure occur [1–3]. According to recent publications neither cardiac imaging, measurement of biomarkers nor primary preventive drug interventions are recommended in a patient without pre-existing cardiac risk factors [4,5]. The reasons why cardiac monitoring is not recommended by international oncological guidelines in low risk patients–ie, those without cardiovascular risk factors or a previous history of cardiac disease–include medicalization, the possibility of causing stress and anxiety, and increasing health care costs [4,5]. In daily clinical practice, cardiotoxicity can be detected as an asymptomatic drop in LVEF. However, a diagnosis of cardiotoxicity based on the onset of symptoms of decompensation or on evidence of an asymptomatic decrease in the LVEF is a diagnosis that has been made very late in its course, precluding any form of effective prevention [6]. Moreover, very often at that phase cardiac damage is progressive, and no longer reversible [6]. In a prospective study that included 2625 patients with some followed for more than 15 years, it was recognized that in most patients cardiotoxicity can be detected in a preclinical state with 98% of these patients identified at a mean of 3.5 months. In addition,
Myocardial cell injury
Increase in troponin
Myocardial deformation
Decrease in GLS
409
Months Asymptomatic cardiotoxicity
Decrease in LVEF
Years Overt cardiotoxicity
HF symptoms
Fig. 1. Pathobiologic continuum of cardiotoxicity from asymptomatic increases in troponin and echocardiographic indices to clinically symptomatic heart failure. GLS, global longitudinal strain; LVEF, left ventricular ejection fraction. Reprinted from reference [3]. With permission from springer nature.
the treatment of symptomatic and/or asymptomatic left ventricular dysfunction, diagnosed early through strict cardiac monitoring, enabled the recovery of systolic function in more than 80% of patients [7]. However, full recovery to a prechemotherapy LVEF value was achieved in only 11% of patients. In most patients who improved with normalization of cardiac function, the final LVEF value was still significantly below the baseline value. This suggests that the diagnosis of cardiotoxicity must be made earlier. The role of troponins as early markers of cardiotoxicity has been extensively studied [2,4,5,8]. Increases in troponin during chemotherapy allows for an accurate stratification of cardiac risk after the end of therapy: patients without an increase of troponin do not develop left ventricular dysfunction, and have a very low incidence of cardiac events. On the other hand, patients who show an increase in troponin–especially if the increase is persistent–have a high risk of developing left ventricular dysfunction, and major cardiac events [8]. The possibility of identifying patients at high risk of cardiotoxicity on the basis of troponin monitoring offers the opportunity to institute targeted preventive therapies. Enalapril, started after the first troponin rise and continued for a year, was able to prevent the development of left ventricular dysfunction and cardiac events after chemotherapy [9]. However, troponin changes might be detected at various time intervals after chemotherapy administration, possibly due to different kinetics of troponin release in response to different treatment schedules. As a result, repeated blood samples are necessary to capture its rise. This may represent a limitation of a preventive approach based on troponin values in clinical practice. Primary prevention–extended to all patients due to receive cardiotoxic chemotherapy–may overcome this limitation [10]. The aim of the International CardioOncology Society-one trial, the first multicenter, randomized trial of the Italian branch of the International CardioOncology Society [11], was to evaluate prospectively whether enalapril started in all patients prior to the beginning of chemotherapy could prevent troponin elevation and subsequent development of cardiac dysfunction, compared to a strategy that started enalapril only after evidence of troponin elevation during chemotherapy (TEXT BOX 2). The principal result of this study was that the two strategies emerged as equally effective in preventing left ventricular dysfunction and major cardiac events, supporting the effectiveness of using enalapril to prevent anthracyclineinduced left ventricular dysfunction, regardless of the strategy used [10].
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TEXT BOX 2. Anthracycline-induced cardiotoxicity: A multicenter randomized trial comparing two strategies for guiding prevention with enalapril: The International CardioOncology Society-one trial (ICOS-ONE). [Cardinale et al., Eur J Cancer 2018; 94:126-137] Hypothesis Will preventive treatment with enalapril further increase the benefit from the use of enalapril reported for cancer patients with troponin elevation. Methods: Controlled, open-label trial Patients randomly assigned to either: • Prevention arm: Enalapril started before chemotherapy or • Troponin-triggered arm: Enalapril started only in patients with increase in troponin during or after chemotherapy Results: 273 patients, 88% were women, mean age 51 ± 12 years 76% had breast cancer; epirubicin and doxorubicin most commonly prescribed Median cumulative doses: • Epirubicin: 360 [270–360] mg/m2 • Doxorubicin: 240 [240–240] mg/m2 Incidence of troponin elevation: • Prevention arm: 23% • Troponin-triggered arm: 26% (P= .50) Cardiotoxicity: Three patients (1.1%)–two in prevention, one in the troponin-triggered group–developed left ventricular dysfunction defined as 10% point reduction of LVEF, with values lower than 50% Conclusions: “Low cumulative doses of anthracyclines in adult patients with low cardiovascular risk can raise troponins, without differences between the two strategies of giving enalapril. Considering a benefit of enalapril in the prevention of LV dysfunction, a troponin-triggered strategy may be more convenient.”
So, which prevention strategy should we prefer? What are the pros and cons of the two approaches? A “secondary” prevention approach where the use of enalapril is triggered by a rise in troponin has the disadvantage that it requires repeated blood samples to detect an increase in troponin. However, there are several advantages including: (i) enalapril is administered only to selected high-risk patients (20%, not 100%); (ii) only select patients need careful blood pressure monitoring as the dose of enalapril is increased; (iii) only high-risk patients are exposed to possible enalapril-induced side effects, and not patients less prone to develop cardiotoxicity, who do not require any cardioprotective therapy; (iv) low risk patients–ie, those whose troponin levels do not increase–do not undergo long-term monitoring with expensive imaging methods, with a better cost-benefit ratio, and reduced medicalization, distress, anxiety, and costs [6,10]. Imaging options: Perils, challenges and opportunities In her presentation entitled “Imaging: the essential and the superfluous”, Dr. Ana Barac (Washington, DC) continued the discussion with a focus on imaging. She began with a historical perspective of the routine use of imaging in cancer patients that began in the 1970s, following the initial observation of cardiac toxicity with high cumulative doses of anthracyclines. Assessment of LVEF using equilibrium radionuclide angiography, more widely known as MUGA (multigated blood pool imaging), prior to initiation and during the administration of anthracyclines became part of clinical oncology practice in the 1980s [12,13]. The premise of routine imaging was to detect asymptomatic declines in LVEF as a marker of cardiac injury and provide safety recommendations for anthracy-
Table 1 Cardiac imaging in clinical cardio-oncology: echocardiogram, CMR, PET-CT. Essential tools for cardiac assessment before, during and after cancer treatment. • Differential diagnosis of LV dysfunction → Ischemia → Infiltrative disease (amyloid) → Myocarditis → Stress induced cardiomyopathy, sepsis → Cancer treatment-related cardiotoxicity • RV assessment • Valvular disease • Pericardial disease • Cardiac masses
cline administration. In patients with normal cardiac function, defined as a LVEF >50% based on the normal ranges using MUGA, anthracyclines could be administered, however, reassessment of LVEF was recommended after a cumulative doxorubicin dose of 250–300 mg/m2 had been administered and prior to each subsequent cycle of anthracycline-containing chemotherapy after a cumulative dose of 450 mg/m2 had reached [13]. In patients with abnormal cardiac function at baseline and/or those with significant declines in LVEF, avoidance and/or discontinuation of anthracyclines was recommended. From this early use, the cardiac imaging needs for patients with cancer have increased with advances in imaging modalities that now include echocardiography, cardiac magnetic resonance (CMR, cardiac), and Positron Emission Tomography-Computed Tomography (PET-CT) scanning. Additionally there has been an increase in the number of cancer drugs with associated off-target cardiac effects, beyond cancer treatment-related cardiotoxicity, ie, reductions in LVEF, that require cardiac assessment at every stage of cancer diagnosis, treatment, and survivorship (Table 1). Until the introduction of the HER2-targeted monoclonal antibody, trastuzumab, in the early 20 0 0s, anthracyclines were the only oncology drug class that required routine cardiac imaging prior to or during administration. In the seminal trial of patients with metastatic HER2-positive breast cancer, treated by trastuzumab in combination with anthracycline, trastuzumab demonstrated clinical benefit with a lower risk of death at 1 year and improved survival, however, with cardiac dysfunction and symptomatic New York Heart Association class III and IV heart failure occurring in up to 27% of patients [14]. To improve the safety of its administration, all subsequent trials of trastuzumab in early breast cancer incorporated routine cardiac imaging before and during trastuzumab administration [15]. Indeed, with administering trastuzumab after the anthracycline and implementing holding and stopping rules based on LVEF changes, the incidence of symptomatic heart failure was significantly reduced and LVEF assessment was incorporated in the recommendations of regulatory agencies and ultimately the drug label of most HER2- targeted therapies [16]. In parallel, since 1970s cardiac monitoring has evolved with development of advanced modalities including echocardiography and CMR, and with investigations of new approaches to predict and prevent cardiotoxicity. Serial monitoring of cardiac function in patients undergoing trastuzumab therapy has brought focus to specific needs in this patient population, including reproducibility and accuracy of LVEF assessment (coefficient of variation and reproducibility 10%–12%), challenges with comparing LVEF values across different techniques, as well as the limitations of LVEF as a single measure of cardiac function. Advances in cardiac monitoring, applied early-on in patients with a diagnosis of cancer, include myocardial strain using speckletracking echocardiography (TEXT BOX 1), 3-D echocardiography as well as native tissue characterization using CMR. Professional
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Table 2 Trials assessing primary cardioprotection in breast cancer.
Study population
Study design
Primary outcome [Endpoint] Results
Fig. 2. Cardiac Magnetic Resonance (CMR) imaging of a patient with a diagnosis of melanoma treated with an immune check point inhibitor and showing a mass in intraventricular septum. SSFP, steady-state free precession; LGE, late gadolinium enhancement.
organizations have taken note and a number of recent statements provide recommendations on cardiac imaging in this population [17–19]. Consider a brief case history that reflects the complexity of cardio oncology care and the unique critical role of imaging in diagnosis, decision making and outcome surveillance. A 49 year old male first diagnosed with ocular melanoma at age 23 years was treated initially with radiation. Nine years later at the age of 32, a solitary right pulmonary nodule was resected, pathology consistent with melanoma, and he was enrolled in a phase 1 vaccine study. At the age of 36, he was then found to have metastases to the right middle and at the age of 42 to the left lower lobe. He now presented with a 2.5 cm PET-avid lesion involving the intraventricular septum and a new 1.5 cm left lung lesion. The risk of resection was considered as excessive and he was treated with immune checkpoint inhibitor therapy with an excellent clinical response. CMR images are presented in Fig. 2. This case illustrates the use and benefit of imaging not initially envisioned in the 1990s. However, the current use of cardiac imaging in patients with cancer presents perils, challenges, and opportunities that include: 1. A lack of clear guidelines for the monitoring of cardiac toxicities– Routine cardiac imaging, including assessment of baseline cardiac function, is presently limited to patients receiving anthracyclines and HER2-targeted therapies. Much less, if anything, is known about cardiac and cardiovascular injury associated with other classes of cancer therapeutics. Of particular interest are the inhibitors of vascular endothelial growth factor (VEGF), a drug class known to cause hypertension and less often symptomatic heart failure, and immune checkpoint inhibitors that may result in myocarditis, an infrequent but highly morbid complication. Cardiac imaging in patients treated with these therapies is pursued only if and when patients develop clinical symptoms and in these cases, the lack of baseline imaging lim-
PRADA [21] [2016]
MANTICORE [22] [2017]
• N = 130
• N = 94
• N = 200
• All epirubicin
• All trastuzumab
• All doxorubicin
• 22% trastuzumab 2 × 2, metoprolol, candesartan, placebo Changes in LVEF by CMR at 10-64 weeks In intention-totreat analysis overall decline in LVEF was 2.6% (95% CI 1.5, 3.8) in the placebo group and 0.8% (95% CI −0.4, 1.9) (P value for betweengroup difference: 0.026). No effect of metoprolol on the overall decline in LVEF was observed
• 12%–33% anthracycline 1:1:1 bisoprolol, perindopril, placebo
Changes in LVEDV by CMR at 1 year
Perindopril and bisoprolol were well tolerated and protected against cancer therapy-related declines in LVEF [attenuated in bisoprolol-treated patients (−1 ± 5%) relative to the perindopril (−3 ± 4%) and placebo (−5 ± 5%) groups (P = .001)]. However, trastuzumabmediated left ventricular remodeling - the primary outcome was not prevented by perindopril or bisoprolol [LVEDV increased with perindopril (+7 ± 14 mL/m2 ), bisoprolol (+8 mL ± 9 mL/m2 ), and placebo (+4 ± 11 mL/m2 ; P = .36)]
CECCY [23] [2018]
1:1 carvedilol and placebo
Reduction in Echo LVEF>10% at 6 months Carvedilol had no impact on the incidence of early onset of LVEF reduction (13.5% v 14.5% for placebo and carvedilol, respectively). However, the use of carvedilol resulted in a significant reduction in troponin. I levels (P = .003) and diastolic dysfunction (P = .039).
Abbreviations: LVEDV, left ventricular end-diastolic volume; CMR, cardiac magnetic resonance; LVEF, left ventricular ejection fraction.
its our ability to assess the contribution of the cancer therapy to changes in cardiac function and the development of heart failure. This may have important repercussions as regards a patients’ safety and our ability to reinitiate cancer treatment. 2. Concerns about excessive monitoring–In patients receiving HER2targeted therapeutics, concern has been raised about overuse of imaging that is not justified in all patients, has not been shown to improve outcomes and may lead to additional unnecessary testing and adverse oncology outcomes including treatment interruption [20]. More recent trials evaluating the use of cardioprotection in breast cancer patients (Prada, Manticore, CECCY) have demonstrated inconclusive results for neurohumoral inhibition started at the time breast cancer treatment is initiated to prevent LV dysfunction in patients receiving HER2-targeted therapies, as well as a very low risk of cardiac events, pointing to the need to include higher-risk patients as well as longer follow-up times [21–23]. The study characteristics are reported in Table 2. 3. The need to gather data in the context of clinical trials–The inclusion of monitoring into clinical trials that enroll patients with a diagnosis of cancer needs to expand beyond the traditional focus on a single (LVEF) value as the only measure of cardiovascular risk. This approach will create an opportunity to
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Fig. 3. Modified and adapted by the authors from the definitions of heart failure (HF) stages according to the American Heart Association.
increase our understanding of the different mechanisms of cardiovascular injury and help create imaging phenotypes specific to cancer therapeutics. Echocardiographic myocardial strain and tissue characterization by CMR represent examples of advanced imaging techniques ready for clinical investigations [24–26]. Global longitudinal strain (GLS, TEXT BOX 1), a parameter derived from echocardiography based on speckle tracking that can detect myocardial injury earlier than a decrease in LVEF can be detected by 2-D echocardiography, has been used as a tool for diagnosis and risk stratification to detect subclinical myocardial injury and is being studied as a tool to guide cardioprotective strategies [17,27]. Advances in the treatment of many cancers continues to increase survivorship and continues to change the paradigm of cancer as an acute disease with high mortality into the one of manageable and often chronic disease. In that setting, cardiac imaging is tasked with improving baseline cardiovascular risk stratification, providing accurate diagnosis of cancer-treatment related toxicity and guiding management during and after cancer treatment. While the historic use of LVEF assessment as a single imaging “yes or no” criteria for administration of select cancer therapies clearly falls short of this standard, advances in cardiovascular imaging offers an opportunity to develop collaboration and design trials focused on improved oncology and cardiovascular outcomes. Primary and secondary prevention Dr. Lenihan (St. Louis, MO) began by defining primary and secondary prevention using the AHA/ACC stages of heart failure guidelines as a platform. Noting that all patients who receive potentially cardiotoxic chemotherapy are at Stage A–at risk for heart failure but without structural heart disease or symptoms of heart failure– primary prevention in this population includes a heart healthy lifestyle and risk factor prevention as appropriate to prevent evolution to Stage B where there is known structural heart disease that requires secondary prevention strategies. The latter include renin-angiotensin system inhibitors and beta blockers. The stages of heart failure are illustrated in Fig. 3. Trastuzumab has been shown to have survival benefit in women with HER2 positive breast cancers [28]. The increase in survival comes at a cost, ie, an increase in asymptomatic and symptomatic decreases in LVEF. The results of the PRADA trial [21] where candesartan but not metoprolol was shown to be modestly cardioprotective (primary prevention) in women with HER2 positive breast cancer when given prior to trastuzumab chemotherapy, is an example of primary prevention. A major question is whether left ventricular dysfunction be prevented? There is inconsistent evidence that the use of traditional heart failure medications including angiotensin converting enzyme (ACE)-inhibitors, angiotensin receptor antagonists, beta blockers (carvedilol, bisoprolol, metoprolol) alone or in combination with
ACE/angiotensin receptor antagonists, spironolactone, and statins can prevent the emergence of left ventricular dysfunction when used in a primary prevention strategy. Ky et al. showed that early increases in multiple biomarkers can predict subsequent cardiac toxicity in patients with a diagnosis of breast cancer treated with doxorubicin, taxanes, and trastuzumab [29]. Moreover, as discussed above, early detection and treatment based on troponin elevation can lead to recovery of function and a decrease in MACEs (major adverse cardiac events) [7]. Yoon and colleagues reviewed a series of patients receiving potential cardiotoxic chemotherapy and found that many cancer survivors are not receiving treatment consistent with heart failure guidelines. This presents a substantial opportunity for collaboration between oncologists and cardiologists to improve the care of these cancer patients [30]. From a cancer treatment delivery standpoint, patients are more likely to have cardiac testing if they are receiving anthracycline-based chemotherapy or trastuzumab compared to other chemotherapies [31] and oncologists are more likely to withhold potentially cancer effective treatment when patients are symptomatic and have a measured LVEF <50% [32]. To improve cancer and cardiac outcomes, the role for collaborative cardio-oncology care was stressed. Cardiac toxicity beyond anthracyclines and HER-2-targeted therapies: Agents targeting VEGF, the proteasome, and cellular immunity The problem goes beyond the occurrence of cardiomyopathy with anthracyclines and HER-2 antagonists. A new definition of cardiotoxicity must include structural changes [valvular heart disease, pericardial inflammation, effusion, constriction, and tamponade], electrical abnormalities [arrhythmias, conduction disease, QT prolongation], metabolic abnormalities [hyperglycemia, hyperlipidemia], and vascular disease [accelerated atherosclerosis, hypertension, arterial and venous thrombosis, and pulmonary hypertension]). The discussion then shifted to other classes of antineoplastic agents and their effect on the vascular system. It is recognized that many chemotherapeutic drugs in addition to their direct anticancer effects, have potent antiangiogenic activity [32]. Amongst small molecule tyrosine kinase inhibitors (TKIs), those with antiVEGF properties are associated with hypertension and heart failure. These drugs have emerged as critical therapies for renal cell cancer, nonsmall cell lung cancer and a variety of other solid tumors [33]. This highlights the need for careful and frequent monitoring of blood pressure and most importantly, a baseline assessment of cardiac risk factors that should be optimally managed prior to treatment initiation and throughout the treatment course (primary prevention). Of interest, some data in patients with renal cell carcinoma treated with anti-VEGF directed TKI therapy, suggests concurrent treatment with statins not only effectively lowers lipids but can also improve overall survival [34]. As had been discussed by Dr. Carver in his presentation in Session II [35], another class of drugs that have off target cardiac effects are the proteosome inhibitors. They have emerged as cornerstones in the treatment of multiple myeloma, reducing mortality, and extending the frequency and duration of remissions [36– 41]. Immune checkpoint inhibitors have achieved important survival benefit in metastatic melanoma, nonsmall cell lung cancer, and bladder cancer. By activating the immune system, and the patient’s own immunocompetence, they provide a novel and exciting approach to cancer treatment. However, they have off target immune-mediated effects in all organ systems, including the heart. Myocarditis with lymphocyte infiltration has been described [42], as illustrated by Dr. Moslehi in his presentation in Session I [43]. However, not every patient receiving an immune checkpoint inhibitor who presents with cardiac symptoms has an immune complication and thus:
D.M. Cardinale, A. Barac and A. Torbicki et al. / Seminars in Oncology 46 (2019) 408–413 Table 3 Marching orders for cardio-oncology. 1. Define how to detect CV toxicity (including vascular toxicity) in the most judicious and effective manner 2. Describe, by reporting clinical outcomes in the broadest possible populations, what are the best clinical approaches to identified CV toxicity (not just left ventricular dysfunction) 3. Commit to training and education of medical professionals at all levels in order to refine the knowledge base that is required for the optimal management of CV disease in patients being treated or previously treated for cancer
1. It is critical to have a thorough cardiovascular assessment prior to the initiation of immune checkpoint inhibitor therapy–but equally important for all potentially toxic chemotherapy. This is the core tenet of primary prevention. 2. Vigilance in monitoring for myocarditis is essential–patients should be questioned about possible cardiac symptoms–this is the pathway to secondary prevention. 3. Patients being treated with immune checkpoint inhibitors should have troponin levels monitored regularly. This session concluded with marching orders for cardiooncology as presented in Table 3. Declaration of Competing Interest No conflict of interest to declare. References [1] Biasillo G, Cipolla CM, Cardinale D. Cardio-oncology: gaps in knowledge, goals, advances, and educational efforts. Curr Oncol Rep 2017;19:55. [2] Curigliano G, Cardinale D, Dent S, et al. Cardiotoxicity of anticancer treatments: epidemiology, detection, and management. CA Cancer J Clin 2016;66:309–25. [3] Cardinale D, Biasillo G, Cipolla CM. Curing cancer, saving the heart: a challenge that cardioncology should not miss. Curr Cardiol Rep 2016;18:51. [4] Armenian SH, Lacchetti C, Barac A, et al. Prevention and monitoring of cardiac dysfunction in survivors of adult cancers: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2017;35:893–911. [5] Levis BE, Binkley PF, Shapiro CL. Cardiotoxic effects of anthracycline-based therapy: what is the evidence and what are the potential harms? Lancet Oncol 2017;18:e445–56. [6] Colombo A, Cipolla CM, Beggiato M, et al. Cardiac toxicity of anticancer agents. Curr Cardiol Rep 2013;15:362. [7] Cardinale D, Colombo A, Bacchiani G, et al. Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy. Circulation 2015;131:1981–8. [8] Cardinale D, Biasillo G, Salvatici M, et al. Using biomarkers to predict and to prevent cardiotoxicity of cancer therapy. Expert Rev Mol Diagn 2017;17:245–56. [9] 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;114:2474–81. [10] Cardinale D, Ciceri F, Latini R, et al. Anthracycline-induced cardiotoxicity: a multicenter randomised trial comparing two strategies for guiding prevention with enalapril: The International CardioOncology Society-one trial. Eur J Cancer 2018;94:126–37. [11] Minotti G. The International Cardioncology Society-ONE trial: not all that glitters is for cardioncologists only. Eur J Cancer 2018;97:27–9. [12] Alexander J, Dainiak N, Berger HJ, et al. Serial assessment of doxorubicin cardiotoxicity with quantitative radionuclide angiocardiography. N Engl J Med 1979;300:278–83. [13] Schwartz RG, McKenzie WB, Alexander J, et al. Congestive heart failure and left ventricular dysfunction complicating doxorubicin therapy. Seven-year experience using serial radionuclide angiocardiography. Am J Med 1987;82:1109–18. [14] Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;344:783–92. [15] Seidman A, Hudis C, Pierri MK, et al. Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol 2002;20:1215–21. [16] Kenigsberg B, Wellstein A, Barac A. Left ventricular dysfunction in cancer treatment: is it relevant? JACC Heart Fail 2018;6:87–95.
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