Controversies in the Definition of Cardiotoxicity: Do We Care?
Cardiotoxicity Incidence and Impact
Cancer survival rates have improved significantly in recent decades due to advancement in detection and treatment. For example, breast-cancer-specific mortality decreased by 24% between 1990 and 2000,1 and mortality rates for non-Hodgkin's lymphoma and leukemia fell by 2.5% and 1% each year, respectively, from 2003 to 2012.2 Similarly, the mortality for childhood cancers has declined more than 50% between 1975 and 1977 to the current era.2 Unfortunately, many of the drugs used to treat cancer can cause cardiac complications that could alter quality of life and decrease lifespan. Cardiovascular disease is the major competing cause of mortality now in elderly women diagnosed with breast cancer, with a 30% increased standardised incidence ratio of cardiovascular events, particularly heart failure (HF).3 Although the reason for this is multifactorial and includes decreased physical activity, radiotherapy, and increased ischemic heart disease due to vascular risk factors, it is thought to be at least partially driven by the direct cardiotoxic effects of chemotherapy agents.4
Although cardiotoxicity from cancer therapy can include coronary artery disease, cardiac arrhythmias, conduction abnormalities, and HF, the largest controversy is in the definition of cancer-therapy-related cardiomyopathy and HF. This article focuses on the latter. Drugs most commonly associated with HF include the anthracyclines and, to a lesser degree, biologic agents such as epidermal growth factor receptor inhibitors.5 The true incidence of cardiomyopathy and HF from cancer therapy is difficult to define and varies depending on the cancer treatment regimen, doses, and whether the data are from clinical trials or cohort studies. Although clinical trials are not representative of routine clinical practice, there has been concern that incidences from cohort studies are an overestimate. In the modern era, with restrictions on maximal anthracycline dose and careful cardiac monitoring, overt clinical HF and cardiac death occur in <2.5% of treated patients.6 However, a significant proportion of patients experience asymptomatic deterioration in left ventricular ejection fraction (LVEF) (5.1-18.6%),7-10 which in the context of cardiotoxicity is associated with a higher incidence of cardiac events at follow-up.11,12 We also know from the Framingham cohort13 and more recent data14 that mild left ventricular systolic dysfunction itself is associated with a 4.6- to 4.8-fold higher risk of subsequent symptomatic HF and a 1.6-fold higher risk of mortality.
Types of Cardiotoxicity
Suter and Ewer15,16 proposed a pathophysiological system to identify drugs that have the potential for irreversible (type I) cardiac damage, such as anthracyclines, versus reversible (type II) cardiac damage, such as monoclonal antibodies. This proposed strategy was based on retrospective analysis of patients with cancer with HF after chemotherapy. Despite there being some molecular basis for these distinctions,16-18 this concept is controversial. Recent work from Cardinale et al.11 demonstrated that initiation of cardioprotective medications after a traditional diagnosis of type I anthracycline cardiotoxicity was associated with at least partial recovery of cardiac function in 82% of patients followed prospectively. Several sources have also called into question the reversibility of type II trastuzumab-induced cardiotoxicity, with prospective and retrospective data showing a significant portion of these patients having sustained decrements in LVEF.19-21
Ejection-Fraction-Based Diagnosis of Cardiotoxicity
Definition of Cardiotoxicity
The definition of cardiotoxicity has significant practical implications for how patients are managed. Unfortunately, there is no universal definition of cardiotoxicity. The definitions used in the clinical trials differ, but all thematically define cardiotoxicity by a serial decline in LVEF. Various organizations have defined cardiotoxicity differently using different threshold changes in LVEF (Table 1).
Table 1: Definitions of Cardiotoxicity
|
Definition |
Modality of Measurement |
Chemotherapy Agents |
Comments |
Alexander et al.22 |
Mild: Decline in LVEF > 10% |
Multigated acquisition (MUGA) scan |
Anthracycline |
|
Schwartz et al.23 |
Decline in LVEF > 10% to final LVEF < 50% |
MUGA scan |
Anthracycline |
|
Cardiac Review and Evaluation Committee24 |
1. Cardiomyopathy characterized by a decrease in LVEF globally or more severe in the septum |
MUGA scan and echocardiogram |
Trastuzumab +/- Anthracycline |
|
Common Terminology Criteria for Adverse Events, version 4.03 ( HF, left ventricular dysfunction)56 |
|
Not defined |
N/A |
Other definitions included such as troponin and clinical HF |
American Society of Echocardiography and European Association of Cardiovascular Imaging24 |
≥10% decline in LVEF to final LVEF < 53% |
Echocardiography; two-dimensional (2D) and three-dimensional (3D) contrast, cardiac magnetic resonance imaging, MUGA scan |
N/A |
First guideline to include global longitudinal strain >15% |
The earliest definition of cardiotoxicity during cancer treatment is from the work by Alexander et al.22 in which moderate cardiotoxicity due to doxorubicin was defined as a >15% fall in LVEF to <45% using serial MUGA scans. The largest MUGA-based study to date defined cardiotoxicity from anthracyclines as a >10% fall in LVEF to <50%.23 Subsequently, during the review of trastuzumab treatment trials, the Cardiac Review and Evaluation Committee24 defined cardiotoxicity as an asymptomatic reduction in LVEF by ≥10% or a symptomatic reduction of ≥5% to <55% (Table 1). More recently, the American Society of Echocardiography Consensus document defined cardiotoxicity as an LVEF drop ≥10% to a value of <53%.25 Despite the common thread of sequential screening via cardiac imaging studies to identify cardiotoxicity, it is not clear which of these definitions should be adopted or whether one is more specific than the other for future development of clinical HF. Also, the frequency of cardiac screening during cancer treatment is not clear. The European Society for Medical Oncology working guidelines group,26 the American Society of Echocardiography,25 and the UK National Cancer Research Institute27 do offer flow charts and recommendations to direct screening, but these are not evidenced based and not universally adopted.28 The need for baseline cardiac assessment including assessment of LVEF prior to the initiation of potentially cardiotoxic chemotherapy is similarly controversial. Although the European Society for Medical Oncology26 and the American Society of Echocardiography25 would recommend basal evaluation of cardiac function prior to initiation, it is far from a universal practice. This is especially true prior to the initiation of anthracycline-based chemotherapy and less so with trastuzumab-based therapy where regional funding issues may drive increased rates of basal LVEF assessment.
Method of Detection of Cardiotoxicity
There is also controversy regarding the best method to follow LVEF during cancer treatment (Table 2). It is important that the diagnostic modality used has the accuracy and reproducibility to reliably identify a true change in LVEF. MUGA scan is one potential modality for screening. It has a low inter- and intra-observer variability (<5%), and the values obtained correlate well with cardiac magnetic resonance imaging (CMRI) and 3D echocardiography.23,29-30 The disadvantage of MUGA is the potential for repeat exposure to 5-10 mSv of radiation at each time point.31 However, whether this level of radiation exposure is clinically significant is controversial for effective doses of <100 mSv, with many debating the concept of cumulative biologic effects of multiple low-dose exposures (linear no-threshold relationship).32,33
Table 2: Utility of Methods for Assessment of Cardiotoxicity
|
2D Echocardio-graphy |
3D Echocardio-graphy |
Global Longitudinal Strain |
MUGA |
CMRI |
Troponin I |
Cost |
Low |
Low |
Low |
Medium |
Medium |
Very low |
Availability |
++++ |
+++ |
+++ |
+++ |
++ |
+++ |
Reproducibility* |
++ |
+++ |
+++ |
+++ |
++++ |
++++ |
Radiation |
Nil |
Nil |
Nil |
5-10 mSv |
Nil |
Nil |
Detection of subclinical toxicity |
Low |
Low |
High |
Low |
Medium |
High |
Additional diagnostic utility |
Structural information, valvular heart disease, pericardial disease, diastolic function |
|
|
|
Tissue characterization, |
Has high negative predictive value when combined with global longitudinal strain. |
* Inter/intra observer variability |
Echocardiography has gained popularity as a technique to serially follow patients during chemotherapy. 3D echocardiography is more accurate and reproducible than 2D echocardiography for the measurement of LVEF and has the best temporal reproducibility during cancer therapy.34-37 The latter is particularly important given the fact that LVEF changes as small as 10% are commonly used to define cardiotoxicity. If 2D techniques are used, careful attention to image acquisition and post-processing along with liberal use of contrast agents can help improve reproducibility.
CMRI is widely considered the reference method for measurement of left ventricular volumes and LVEF. There is currently very limited work on the routine use of CMRI for cardiotoxicity screening.38,39 However, previous work has demonstrated that CMRI may be better able to identify small changes in LVEF during treatment.40,41 At present, perhaps the best use of CMRI is when image quality is suboptimal or when there are discrepancies in the degree of fall in LVEF between different modalities. Unfortunately, measurements of LVEF via different imaging modalities are not interchangeable.29,30,42 For this reason, it is suggested that serial comparisons over time be made with the same modality using the technique with the greatest experience and best reproducibility at each center.
Screening in Survivors
There is also controversy about the best approach to screening cancer survivors for cardiovascular complications. There is a lack of evidence-based recommendations on appropriate timing of screening (or the criteria to define cardiotoxicity). Although the European Society for Medical Oncology guidelines26 provide recommendations for long-term cardiac screening and the Children's Oncology Group43 makes some recommendations in childhood cancer survivors, the American Society of Clinical Oncology Cancer Survivorship Expert Panel deemed the lack of evidence from prospective sources insufficient to support practice guidelines to direct screening.44 The best cardiac imaging method to identify cardiotoxicity in survivors is also not clear. In pediatric cancer survivors, Armstrong45 found a high correlation between CMRI and 3D echocardiography but demonstrated that both 2D and 3D echocardiography have reduced sensitivity to identify LVEF < 50%. There is a developing interest in using myocardial strain measurements to identify subclinical left ventricular dysfunction; however, the type of strain measure, the threshold values, and the clinical relevance of these findings is unknown.46-51
Myocardial-Strain-Based Diagnosis of Cardiotoxicity
The measurement of LVEF is a relatively insensitive tool for the diagnosis of cardiotoxicity during the early stage, when therapeutic interventions may have their largest impact. This is because the myocardium may be able to tolerate significant damage before exhaustion of the compensatory mechanism, resulting in overt systolic dysfunction. Myocardial strain, which measures myocardial deformation, has been considered as a potential measure to identify early subclinical myocardial injury (i.e., myocardial changes prior to a fall in LVEF or symptomatic HF).
A recent systematic review46 reported the sensitivity and specificity of early reduction in deformation indices such as strain and strain rate for the prediction of subsequent reduction in LVEF or development of HF. The most studied parameter to identify subclinical injury during cancer treatment is global longitudinal strain. The degree of change in strain that predicts later cardiotoxicity differs between studies and varies between 10 and 15%.46 Early studies demonstrated that relative reduction in global longitudinal strain of 10-11% at 3 or 6 months during treatment predicts subsequent cardiotoxicity in women treated with trastuzumab with or without anthracyclines for breast cancer.52 An absolute global longitudinal strain value of <20.5% at 6 months during trastuzumab therapy in women with breast cancer52 and <19% at 3 months in women treated with anthracyclines followed by trastuzumab has also been shown to predict cardiotoxicity.53 However, due to variability in strain measurements, differences in strain values between vendors, and analysis software, serial measurements of global longitudinal strain appear to be more useful for predicting early cardiotoxicity. The American Society of Echocardiography is the first society to suggest a threshold change in global longitudinal strain by >15% during cancer treatment to define cardiotoxicity;25 however, this threshold is different from those identified in several published studies.46 Therefore, the most specific threshold to identify subclinical myocardial injury remains controversial. Furthermore, it is also not evident whether interventions based on isolated falls in myocardial strain prevent subsequent left ventricular dysfunction or HF. A multi-centre, randomized controlled trial (SUCCOUR [Strain Surveillance During Chemotherapy for Improving Cardiovascular Outcomes], trial ID: ACTRN12614000341628) is currently investigating this approach.
Serum Biomarker-Based Diagnosis of Cardiotoxicity
Multiple studies have shown that measurement of troponin I after initiation of chemotherapy has utility in predicting occurrence and severity of cardiotoxicity in both patients treated with anthracyclines12 and patients on combined chemotherapy regimens that include trastuzumab.19,54
Sawaya et al. has shown that a significant increase in troponin I (>30 ng/mL) among patients with HER-2-positive breast cancer treated with sequential anthracycline with trastuzumab was predictive of subsequent cardiotoxicity. Interestingly, the study also found that when combined with global longitudinal strain, troponin I measurements had a negative predictive value of 91% for the future development of cardiotoxicity.53 More pronounced cardiotoxicity appears to be associated with both the earlier rise in troponin (within 72 hours) and persisting troponin positivity (persisting up to 1 month post-treatment has an 85% sensitivity for development of major cardiac events). In addition, a persistent absence of troponin release has a 99% negative predictive value for cardiotoxicity.12,55
Despite the above, the literature has not clearly defined the optimal troponin assay to use, the threshold for risk prediction, the timing of measurements in relationship to chemotherapy, or troponin's prognostic utility with biologic agents whose presumptive mechanism of cardiotoxicity may not result from cell death. The 2012 European Society for Medical Oncology guidelines26 recommended troponin testing at baseline and after each chemotherapy session (level of evidence III). The 2014 American Society of Echocardiography25 guidelines recommend baseline troponin at the initiation of both type I and type II chemotherapy agents and the measurement of troponin before and 24 hours after each chemotherapy cycle to aid in detection of subclinical cardiotoxicity. Ultimately, given their reproducibility and relative lack of expense, cardiac biomarkers may become an important part of the diagnostic armamentarium for cardiotoxicity when their utility is better defined.
Conclusion
Multiple controversies exist in the definition of cardiotoxicity related to cancer therapy. A universal definition of cardiotoxicity with established prognostic value is needed. The optimal timing of screening during cancer therapy and in survivors and the best modality to identify reduction in ventricular function will need to be established. With growing interest in the use of myocardial strain to identify subclinical myocardial injury, a threshold change that has prognostic value will need to be defined. Whether interventions based on a change in strain alters prognosis will need to be defined. Although serum biomarkers may be ideal to detect early cardiac injury, the timing of measurements, the assays to use, and the prognostic implication of biomarker-based intervention will need to be established. In an era when cancer therapy is extremely effective and survivorship issues are considered even at the start of cancer therapy, it is prudent for oncologists and cardiologists to work together to resolve the controversies in the diagnosis of cardiotoxicity. This is required prior to consideration of interventions that can minimize or eliminate the risk of cardiac disease in cancer survivors.
References
- Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010;60:277-300.
- Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 2015;65:5-29.
- Hooning MJ, Botma A, Aleman BM, et al. Long-term risk of cardiovascular disease in 10-year survivors of breast cancer. J Natl Cancer Inst 2007;99:365-75.
- Jones LW, Haykowsky MJ, Swartz JJ, Douglas PS, Mackey JR. Early breast cancer therapy and cardiovascular injury. J Am Coll Cardiol 2007;50:1435-41.
- Yeh ET, Bickford CL. Cardiovascular complications of cancer therapy: incidence, pathogenesis, diagnosis, and management. J Am Coll Cardiol 2009;53:2231-47.
- Wang L, Tan TC, Halpern EF, et al. Major cardiac events and the value of echocardiographic evaluation in patients receiving anthracycline-based chemotherapy. Am J Cardiol 2015;116:442-6.
- Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer 2003;97:2869-79.
- Tan-Chiu E, Yothers G, Romond E, et al. Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2-overexpressing breast cancer: NSABP B-31. J Clin Oncol 2005;23:7811-9.
- Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 2011;365:1273-83.
- Perez EA, Suman VJ, Davidson NE, et al. Cardiac safety analysis of doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in the North Central Cancer Treatment Group N9831 adjuvant breast cancer trial. J Clin Oncol 2008;26:1231-8.
- Cardinale D, Colombo A, Bacchiani G, et al. Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy. Circulation 2015;131:1981-8.
- Cardinale D, Sandri MT, Colombo A, et al. Prognostic value of troponin I in cardiac risk stratification of cancer patients undergoing high-dose chemotherapy. Circulation 2004;109:2749-54.
- Wang TJ, Evans JC, Benjamin EJ, Levy D, LeRoy EC, Vasan RS. Natural history of asymptomatic left ventricular systolic dysfunction in the community. Circulation 2003;108:977-82.
- Echouffo-Tcheugui JB, Ergou S, Butler J, Yancy CW, Fonarow GC. Assessing the risk of progression from asymptomatic left ventricular dysfunction to overt heart failure: a systematic overview and meta-analysis. JACC Heart Fail 2016;4:237-48.
- Suter TM, Ewer MS. Cancer drugs and the heart: importance and management. Eur Heart J 2013;34:1102-11.
- Ewer MS, Lippman SM. Type II chemotherapy-related cardiac dysfunction: time to recognize a new entity. J Clin Oncol 2005;23:2900-2.
- Zhang S, Liu X, Bawa-Khalfe T, et al. Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nat Med 2012;18:1639-42.
- Friedman MA, Bozdech MJ, Billingham ME, Rider AK. Doxorubicin cardiotoxicity. Serial endomyocardial biopsies and systolic time intervals. JAMA 1978;240:1603-6.
- Cardinale D, Colombo A, Torrisi R, et al. Trastuzumab-induced cardiotoxicity: clinical and prognostic implications of troponin I evaluation. J Clin Oncol 2010;28:3910-6.
- Telli ML, Hunt SA, Carlson RW, Guardino AE. Trastuzumab-related cardiotoxicity: calling into question the concept of reversibility. J Clin Oncol 2007;25:3525-33.
- Wadhwa D, Fallah-Rad N, Grenier D. Trastuzumab mediated cardiotoxicity in the setting of adjuvant chemotherapy for breast cancer: a retrospective study. Breast Cancer Res Treat 2009;117:357-64.
- 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.
- 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.
- Seidman A, Hudis C, Pierri MK, et al. Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol 2002;20:1215-21.
- Plana JC, Galderisi M, Barac A, et al. Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 2014;27:911-39.
- Cirigliano G, Cardinale D, Suter T, et al. Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy: ESMO clinical practice guidelines. Ann Oncol 2012;23:vvii55-66.
- Jones AL, Barlow M, Barrett-Lee PJ, et al. Management of clinical health in trastuzumab-treated patients with breast cancer: updated United Kingdom National Cancer Research Institute recommendations for monitoring. Br J Cancer 2009;100:684-92.
- Chavez-MacGregor M, Niu J, Zhang N, et al. Cardiac monitoring during adjuvant trastuzumab-based chemotherapy among older patients with breast cancer. J Clin Oncol 2015;33:2176-83.
- Bellenger NG, Burgess MI, Ray SG, et al. Comparison of left ventricular ejection fraction and volumes in heart failure by echocardiography, radionuclide ventriculography and cardiovascular magnetic resonance; are they interchangeable? Eur Heart J 2000;21:1387-96.
- Mogelvang J, Stokholm KH, Saunamaki K, et al. Assessment of left ventricular volumes by magnetic resonance in comparison with radionuclide angiography, contrast angiography and echocardiography. Eur Heart J 1992;13:1677-83.
- Brenner DJ, Hall EJ. Computed tomography—an increasing source of radiation exposure. N Engl J Med 2007;357:2277-84.
- Little MP, Wakeford R, Tawn EJ, Bouffler SD, Berrington de Gonzalez A. Risks associated with low doses and low dose rates of ionizing radiation: why linearity may be (almost) the best we can do. Radiology 2009;251:6-12.
- Tubiana M, Feinendegen LE, Yang C, Kaminski JM. The linear no-threshold relationship is inconsistent with radiation biologic and experimental data. Radiology 2009;251:13-22.
- Jenkins C, Moir S, Chan J, Rakhit D, Haluska B, Marwick TH. Left ventricular volume measurement with echocardiography: a comparison of left ventricular opacification, three-dimensional echocardiography, or both with magnetic resonance imaging. Eur Heart J 2009;30:98-106.
- Badano LP, Boccalini F, Murau D, et al. Current clinical applications of transthoracic three-dimensional echocardiography. J Cardiovasc Ultrasound 2012;20:1-22.
- Walker J, Bhullar N, Fallah-Rad N, et al. Role of three-dimensional echocardiography in breast cancer: comparison with two-dimensional echocardiography, multiple-gated acquisition scans, and cardiac magnetic resonance imaging. J Clin Oncol 2010;28:3429-36.
- Thavendiranathan P, Grant AD, Negishi T, Plana JC, Popovic ZB, Marwick TH. Reproducibility of echocardiographic techniques for sequential assessment of left ventricular ejection fraction and volumes: application to patients undergoing cancer chemotherapy. J Am Coll Cardiol 2013;61:77-84.
- Thavendiranathan P, Wintersperger BJ, Flamm SD, Marwick TH. Cardiac MRI in the assessment of cardiac injury and toxicity from cancer chemotherapy: a systematic review. Circ Cardiovasc Imaging 2013;6:1080-91.
- Kongbundansuk S, Hundley WG. Noninvasive imaging of cardiovascular injury related to the treatment of cancer. JACC Cardiovasc Imaging 2014;7:824-38.
- Grover S, Leong DP, Chakrabarty A, et al. Left and right ventricular effects of anthracycline and trastuzumab chemotherapy: a prospective study using novel cardiac imaging and biochemical markers. Int J Cardiol 2013;168:5465-7.
- Drafts BC, Twomley KM, D'Agostino R Jr, et al. Low to moderate dose anthracycline-based chemotherapy is associated with early noninvasive imaging evidence of subclinical cardiovascular disease. JACC Cardiovasc Imaging 2013;6:877-85.
- Bellenger NG, Davies LC, Francis JM, Coats AJ, Pennell DJ. Reduction in sample size for studies of remodeling in heart failure by the use of cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2000;2:271-8.
- Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers (Children's Oncology Group website). 2014. Available at: http://www.survivorshipguidelines.org/. Accessed February 2016.
- Carver JR, Shapiro CL, Ng A, et al. American Society of Clinical Oncology clinical evidence review ont eh ongoing care of adult cancer survivors: cardiac and pulmonary late effects. J Clin Oncol 2007;25:3991-4008.
- Armstrong GT, Plana JC, Zhang N, et al. Screening adult survivors of childhood cancer for cardiomyopathy: comparison of echocardiography and cardiac magnetic resonance imaging. J Clin Oncol 2012;30:2876-84.
- Thavendiranathan P, Poulin F, Lim KD, Plana JC, Woo A, Marwick TH. Use of myocardial strain imaging by echocardiography for the early detection of cardiotoxicity in patients during and after cancer chemotherapy: a systematic review. J Am Coll Cardiol 2014;63:2751-68.
- Lipshultz SE, Cochran TR, Wilkinson JD. Screening for long-term cardiac status during cancer treatment. Circ Cardiovasc Imaging 2012;5:555-8.
- Ho E, Brown A, Barrett P, et al. Subclinical anthracycline- and trastuzumab-induced cardiotoxicity in the long-term follow-up of asymptomatic breast cancer survivors: a speckle tracking echocardiographic study. Heart 2010;96:701-7.
- Yu W, Li SN, Chan GC, Ha SY, Wong SJ, Cheung YF. Transmural strain and rotation gradient in survivors of childhood cancers. Eur Heart J Cardiovasc Imaging 2013;14:175-82.
- Yu HK, Yu W, Cheuk DK, Wong SJ, Chan GC, Cheung YF. New three-dimensional speckle-tracking echocardiography identifies global impairment of left ventricular mechanics with a high sensitivity in childhood cancer survivors. J Am Soc Echocardiogr 2013;26:846-52.
- Cheung YF, Li SN, Chan GC, Wong SJ, Ha SY. Left ventricular twisting and untwisting motion in childhood cancer survivors. Echocardiography 2011;28:738-45.
- Negishi K, Negishi T, Hare JL, Haluska BA, Plana JC, Marwick TH. Independent and incremental value of deforamtion indices for prediction of trastuzumab-induced cardiotoxicity. J Am Soc Echocardiogr 2013;26:493-8.
- Sawaya H, Sebag IA, Plana JC, et al. Assessment of echocardiography and biomarkers for the extended prediction of cardiotoxicity in patients treated with anthracyclines, taxanes, and trastuzumab. Circ Cardiovasc Imaging 2012;5:596-603.
- 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 Coll Cardiol 2014;63:809-16.
- 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;11:2474-81.
- Common Terminology Criteria for Adverse Events (CTCAE) (U.S Department of Health and Human Services website). 2010. Available at: http://evs.nci.nih.gov/ftp1/CTCAE. Accessed February 2016.
Keywords: Cardiotoxicity, Anthracyclines, Antibodies, Monoclonal, Arrhythmias, Cardiac, Biological Factors, Biological Products, Breast Neoplasms, Cardiomyopathies, Cell Death, Cohort Studies, Coronary Artery Disease, Doxorubicin, Echocardiography, Echocardiography, Three-Dimensional, Heart Diseases, Heart Failure, Heart Valve Diseases, Leukemia, Lymphoma, Non-Hodgkin, Magnetic Resonance Imaging, Medical Oncology, Myocardium, Receptor, Epidermal Growth Factor, Receptor, ErbB-2, Risk Factors, Stroke Volume, Survival Rate, Troponin I, Ventricular Dysfunction, Left, Ventricular Function
< Back to Listings