Journal of the Practice of Cardiovascular Sciences

REVIEW ARTICLE
Year
: 2017  |  Volume : 3  |  Issue : 2  |  Page : 82--93

Cancer therapy-induced cardiotoxicity: Review and algorithmic approach toward evaluation


K Purkayastha1, Rachna Seth1, Sandeep Seth2, Alex R Lyon3,  
1 Department of Pediatrics, AIIMS, New Delhi, India
2 Department of Cardiology, AIIMS, New Delhi, India
3 Department of Cardiology, Royal Brompton Hospital and Imperial College London, London, United Kingdom

Correspondence Address:
Rachna Seth
Department of Pediatrics, Oncology Division, AIIMS, New Delhi
India

Abstract

In pediatric cancer, the overall 5-year survival has increased to more than 80%, but these improvements in cancer outcomes have come at the cost of increased morbidity and mortality. These can occur during or early after treatment, and in others may occur many years after cancer treatment is completed. Survivors of childhood cancers are at an increased risk of developing congestive heart failure and premature death due to cardiac causes (coronary artery disease, stroke, and congestive heart failure). There is a strong dose-dependent relationship between anthracycline chemotherapy exposure and risk of congestive heart failure, and the risk is increased in those who have been exposed to chest radiation. Early detection of myocardial injury, prevention of myocardial dysfunction, strategies to promote quick recovery of myocardial function in case of injury, and monitoring for delayed effects of cancer therapy are areas which both oncologists as well as cardiologists looking after cancer patients need to understand. A subspecialty of cardio-oncology has emerged to allow more focus in these areas.



How to cite this article:
Purkayastha K, Seth R, Seth S, Lyon AR. Cancer therapy-induced cardiotoxicity: Review and algorithmic approach toward evaluation.J Pract Cardiovasc Sci 2017;3:82-93


How to cite this URL:
Purkayastha K, Seth R, Seth S, Lyon AR. Cancer therapy-induced cardiotoxicity: Review and algorithmic approach toward evaluation. J Pract Cardiovasc Sci [serial online] 2017 [cited 2019 Dec 11 ];3:82-93
Available from: http://www.j-pcs.org/text.asp?2017/3/2/82/218807


Full Text



 Introduction



The improvement and advances in diagnostics and management of childhood cancers have resulted in tremendous improvements in survival. In pediatric cancer populations, the overall 5-year survival has increased to more than 80%. However, these improvements in cancer outcomes have come at the cost of increased morbidity and mortality. These can occur in some patients during or early after cancer treatment, and in others the late effects may occur many years after cancer treatment is completed.[1]

The cumulative incidence of severe or life-threatening chronic health disorders exceeds 40% for survivors of childhood cancer who are still alive beyond 30 years after primary diagnosis. These chronic health disorders include second malignant neoplasms, endocrine disorders, cardiopulmonary dysfunction, cardiovascular (CV) complications, renal dysfunction, and neurosensory impairment.[2],[3] Compared with the general population, survivors of childhood cancers are at a 15-fold increased risk of developing congestive heart failure [2] and at a 7-fold increased risk of premature death due to cardiac causes (coronary artery disease, stroke, and congestive heart failure). There is a strong dose-dependent relationship between anthracycline chemotherapy exposure and risk of congestive heart failure, and the risk is further increased in those who have been exposed to chest radiation. The developing heart in children appears particularly sensitive to anthracycline and radiation-induced cardiotoxicity compared to adult patients, partly as resident cardiac stem cells, and the creation of new cardiomyocytes during growth is perturbed by anthracyclines.

Cardiotoxicity is one of the most dreaded complications of cancer therapy today. Cardiotoxicity has the potential to limit active cancer treatment, but can also present years after the treatment is completed in survivors. Early detection of myocardial injury, prevention of myocardial dysfunction, strategies to promote quick recovery of myocardial function in case of injury, and monitoring for delayed effects of cancer therapy are areas which both oncologists as well as cardiologists looking after cancer patients need to understand. A subspecialty of cardio-oncology has emerged to allow more focus in these areas.[4] Cardiotoxicity can vary and include arrhythmias, myocarditis, pericarditis, myocardial infarction (MI), and heart failure. Based on the onset, the World Health Organization guidelines classify the cardiac toxicities as acute, subacute, and chronic. The cardiotoxicity caused by the anticancer therapy varies. Depending on the nature and dose of the treatment, the duration from treatment to detection and the underlying CV risk factors, either irreversible or reversible myocardial dysfunction, may vary.

 Anthracyclines



Anthracyclines are commonly used antineoplastic drugs, effective against malignancies such as leukemia, lymphoma, and many solid cancers. The incidence of congestive heart failure is <5% with cumulative anthracycline exposure of <250 mg/m2; approaches 10% at doses between 250 mg/m2 and 600 mg/m2 and exceeds 30% for doses higher than 600 mg/m2 for survivors of childhood cancer.[4],[5],[6],[7],[8] Nearly 60% of all survivors of childhood cancer have had exposure to anthracycline chemotherapy, or chest radiation, or both.[1],[9]

Acute toxicity, which may arise during the cycles of chemotherapy or in the days to weeks following completion of the treatment course. It may be detectable as rises in cardiac troponin (Tn), reduction in global longitudinal strain, diastolic dysfunction, and in more severe cases, a reduction in left ventricular ejection fraction (LVEF). The various abnormalities can be detected by measuring B-type natriuretic peptide (BNP) elevation and ventricular functionEarly toxicity, which may occur within weeks or months and is often dose related. The commonly recorded toxicities are ventricular dysfunction and heart failure. The incidence can vary from 1% to 18%. In a recent large series of 2625 patients receiving anthracycline-containing chemotherapy, a 9% incidence of cardiotoxicity (defined at >10% reduction in LVEF and below 50%) was reported, with 98% cases detectable in the first 12 months following completion of treatmentLate toxicity, which might take years to develop and is always dose related. The late effects are mainly characterized by LV systolic failure, diastolic failure, reduced cardiac contractility, ventricular dysfunction, and heart failure.[9]

In a retrospective Childhood Cancer Survivor Study cohort of 10,724 patients, 5 years' survivors had an increased risk of cardiotoxicity and related mortality, which was due to the anthracycline chemotherapy and radiotherapy and was dose dependent.[10],[11],[12],[13],[14],[15]

Other chemotherapy agents that have cardiotoxic side effects include cyclophosphamide, ifosfamide, cytarabine, cisplatin, pactitaxel, fluorouracil, and amsacrine. Despite some guidelines for evaluation of cardiotoxicity for anthracyclines and trastuzumab exist, there are no specific guidelines for monitoring patients treated with chemotherapy excluding anthracyclines. These drugs include cyclophosphamide, cytarabine, cisplatin, and tyrosine kinase inhibitors [Table 1].[16],[17],[18]{Table 1}

 Radiotherapy



Radiation plays an important role in inducing cardiotoxicity, especially after radiotherapy directed to the chest. The intensity of cardiotoxicity is greatest for patients receiving radiation at a younger age for childhood malignancies, Hodgkin's lymphoma, early-stage breast cancer, and lung and esophageal cancers. Radiation-induced cardiotoxicity is generally progressive and complex. The risk of cardiotoxicity usually arises if the dose is >30–35 Gy, dose per fraction >2 Gy, younger age, time of exposure is prolonged, and used with chemotherapies.[19]

The spectrum of radiation-induced cardiotoxicity includes:

Acute pericarditis and symptomatic or asymptomatic chronic pericardial effusion appears usually 6–12 months after radiotherapyMyocarditis and congestive heart failure, valvular stenosis, and fibrosis of the conduction systemArteritis of the endothelium of coronary arteries appears 10–15 years after radiotherapy.

The factors that increase the risk of developing postradiation cardiotoxicity are the volume of heart exposed to radiation, total and fractionated dose administered, duration of follow-up, and age at administration.

 Risk Factors and Incidence



Cancer treatment primarily comprises chemotherapy, radiation, and surgery: chemotherapy and radiation contribute significantly to cardiotoxicity. Not all cancer patients develop cardiotoxicity, there are many factors which influence the cancer therapy-induced cardiotoxicity [Figure 1].{Figure 1}

The nature of toxicity varies with different drugs [20] and also varies with the cumulative doses [Table 2].{Table 2}

 Mechanisms of Cardiotoxicity



The possible mechanisms of cardiotoxicity of various cardiotoxic drugs are depicted in [Table 3]. however, the most studied chemotherapy is the anthracycline-induced cardiotoxicity [Figure 2].{Figure 2}{Table 3}

 Evaluation Of Cardiotoxicity



Patients receiving therapy that has potential cardiotoxicity [24] require close monitoring during therapy for acute toxic effects and after therapy for occurrence of acute cardiac effects. The goal of monitoring during therapy is to identify the early signs of cardiotoxicity to modify a patient's therapeutic plan so that the risk of further development of cardiac disease is decreased. These modifications have to be balanced with the risks of decreasing antitumor effects that may result from drug modification. Posttherapy patients may require lifelong monitoring for late cardiotoxic effects, especially if they have received high doses of anthracyclines and/or mediastinal radiation [Table 4].{Table 4}

As the complete cascade of cardiotoxicity varies from days to months and years, long-term follow-up of the patients becomes necessary. Many techniques are being tried for early detection of cardiotoxicity [Table 5]. The current guidelines emphasize measuring the baseline risk assessment including measurement of cardiac function and cardiac biomarkers, followed by regular surveillance for patients at high risk or receiving high-risk treatments. Various options are available to assess for cardiotoxicity [Table 4] depending on the particular clinical concern [Table 2]. A number of techniques are available for detecting cardiomyopathy, ranging from echocardiography to biochemical markers to magnetic resonance imaging scan as listed in [Table 5] and [Table 6].[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42],[43],[44],[45],[46],[47]{Table 5}{Table 6}

Echocardiography is preferred in pediatric patients, due to lack of ionizing radiation.[34] Multigated acquisition (MUGA) can be used as an alternative to echocardiography. A clinical trial on 28 non-Hodgkin's lymphoma patients receiving cumulative doxorubicin dose of 200 mg/m 2 by Nousiainen et al. found that the sensitivity and specificity of MUGA scan were 90% and 72%, respectively, in predicting the development of heart failure. The endomyocardial biopsy is invasive and evaluates the ultrastructural alterations. It was previously applied, but with the increasing use of noninvasive imaging and biomarkers, its role is limited. It may be helpful in borderline cases, although sensitivity is variable.

Various studies by Cardinale et al. support the use of measuring TnI using the conventional assay in patients with advanced neoplasia and breast cancer treated with high-dose chemotherapy. In one of the studies by Cardinale et al., 703 patients received high-dose chemotherapy, and TnI evaluation was done periodically at initiation, 12, 24, 36, and 72 h after the chemotherapy and then 1 month after, and prior to start of the next chemotherapy cycle. The group where TnI values were high at both early and late time points had the highest risk of cardiotoxicity and greatest reduction in LVEF over 3 years. Other studies by Auner et al., Lipshultz et al., and Kilickap et al. have shown the use of TnI in blood cancers, leukemia, and advanced neoplasia, respectively, treated with high dose of chemotherapy.

In a multicentric cohort study, PREDICT, 586 patients enrolled received anthracycline as a chemotherapy. The assessment of cardiac parameters was done at baseline, before each chemotherapy cycle, and at 6 and 12 months. At baseline or during chemotherapy or follow-up, 17% had a BNP >100 pg/ml and 41% had a TnI >0.05 ng/ml. Of all patients, 63 (11%) suffered a CV event. Statistically BNP >100 pg/ml was associated with cardiotoxicity, whereas the values of TnI were not conclusive.

For prediction of short-term cardiotoxicity arising as a result of chemotherapy-induced cardiotoxicity, TnI and natriuretic peptides have been preferred.[48] The use of BNP and TnI is supported in the PREDICT study, 830 adult patients receiving anthracycline across 24 community oncology programs likely to end by December 2017.[49] The blood sampling for predictive biomarkers was done at baseline, before start of each cycle, 6 months after starting chemotherapy, and 12 months after completion of chemotherapy. At any of the time points, the BNP >200 pg/ml and TnI >0.4 ng/ml are considered to be related to cardiotoxicity.

Several novel parameters such as serum homocysteine levels, myeloperoxidase (MPO), apolipoprotein a, and C-reactive protein have been tested. Generally, these are not suitable for routine practice.[47] MPO may have potential with high-sensitivity Tn in trastuzumab-induced cardiotoxicity[Figure 3].[50]{Figure 3}

 Prevention



Cardiotoxicity limits the efficient use of antineoplastic treatments. There are various measures [51],[52] by which the cardiotoxicity can be minimized or prevented [Figure 4] and [Table 7]. Cardinale et al. reported that elevation in TnI can be correlated with the decrease in ventricular ejection fraction. In a randomized trial conducted by Cardinale et al., 114 adult patients treated with high-dose chemotherapy with an increased TnI value were randomized to enalapril or usual care.[52] Tn rise predicted reduction in LVEF, and patients receiving enalapril following a rise in Tn were prevented from the future reduction in LVEF.{Figure 4}{Table 7}

In a cohort of breast cancer patients from a large US center, 106 patients already treated with beta-blockers at the time of cancer diagnosis had a third of the detectable heart failure compared to a matched control group in a retrospective propensity-matched study.[60]

In the study, preventiOn of left Ventricular dysfunction with Enalapril and caRvedilol in patients submitted to intensive ChemOtherapy for the treatment of Malignant hEmopathies (OVERCOME)[61] was conducted in ninety patients with various hematological malignancies. All the patients receiving high-dose chemotherapy were grouped in two fractions, one fraction of patients received enalapril and carvedilol, while the other half served as controls. The LVEF was measured before and after the chemotherapy using cardiac magnetic resonance (CMR) and echocardiography. The patients receiving enalapril and carvedilol had no reduction in their LVEF, whereas a significant decrease was observed in the control groups.[61]

The Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy (PRADA) trial was a 2 × 2 factorial randomized controlled trial (RCT) enrolling 120 women with breast cancer at relatively low risk of cardiotoxicity (prior CV disease or current use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers excluded) and received a daily dose of the ARBs candesartan which showed very less changes in LVEF from the baseline and placebo controls. However, there were no significant group differences in LVEF changes between the patients receiving 100 mg daily of the beta-blocker metoprolol succinate versus placebo.[62]

Dexrazoxane (ICRF-187) is the only drug approved by the US Food and Drug Administration (FDA) for the prevention of anthracycline-related cardiotoxicity. Dexrazoxane acts by chelating redox-active iron and preventing reactive oxygen species formation and also interfering with the interaction between doxorubicin and Top2B. A Cochrane meta-analysis recently concluded that it was effective in reducing the incidence of anthracycline-induced heart failure in pediatric oncology patients without an increased risk of second malignancy or compromise in the efficacy of treating the primary malignancy. It has had a recent revision of its license by EMEA to reflect the long-term follow-up analyses.

3-hydroxy-3-methyl-glutaryl CoA reductase inhibitors (statins) may be cardioprotective due to their antioxidant and anti-inflammatory properties. Mechanistically, they also reduce the topoisomerase II beta-mediated DNA damage, induced due to impaired Ras-related C3 botulinum toxin substrate-1 signaling.

 Aiims Data on Cardiotoxicity



We did a preliminary analysis of our data for the past 2 years (2015–2017). In 2 years, 715 new patients of different childhood cancers were enrolled. Of these, acute lymphoblastic leukemia (ALL) constituted 20%, acute myeloid leukemia (AML) 6%, and Hodgkin's lymphoma (HL) 11%.

The cumulative doses of anthracyclines received were as follows:

ALL 75–200 mg/m 2 depending on the risk stratification of ALL (standard, intermediate, and high risk)AML 300 mg/m 2HL 200–300 mg/m 2 depending on the number of chemotherapy cycles.

Anthracyclines used comprised daunorubicin and doxorubicin for ALL, daunorubicin for AML, and doxorubicin for HL. Other cardiotoxic drugs such as mitoxantrone, cytosine arabinoside, cyclophosphamide, and imatinib were also used to treat the hematological malignancies and compounded anthracycline cardiotoxicity. Radiation as a mode of treatment was used for HL patients if the disease was bulky at presentation/residual disease was documented on imaging after the chemotherapy course.

Cardiac dysfunction as measured by decline in ejection fraction to <50% during chemotherapy was seen as follows:

AML (25%)HL (3.7%)ALL (2%).

There was one patient each of Down syndrome in the ALL and AML groups and both these patients had myocardial dysfunction. One child with ALL was detected to have cardiac dysfunction prior to starting chemotherapy on baseline evaluation. It is also to be noted that sepsis (febrile neutropenia) was more severe in AML as compared to ALL and HL which could have precipitated cardiac decompensation in a predisposed heart.

A multidisciplinary approach and association between cardiologists and oncologists is very necessary for deciding the best treatment regimen and recommend the preventive strategies that can prevent the cardiotoxicity induced by various chemotherapy regimens in our cancer patients. This has led to the emergence of specialist cardio-oncology services to provide specialist advice and management.

 Conclusion



The survival rate of cancer patients in both developed and developing countries has greatly increased in the past decade. The substantial improvement in survival is due in part to the development of new cancer therapies. The different classes of the drugs exert varying CV toxicities. The treatment drugs most commonly associated with cardiotoxicity are anthracyclines, Trastuzumab, and radiotherapy. It can be hypothesized that with the growing efficacy and survivorship the incidence of cardiotoxicity induced by cancer therapy will increase in the future. Heart exposure to radiation, particularly in combination with anthracycline chemotherapy, is known to give rise to severe cardiotoxicities which may vary from asymptomatic changes to cardiac function on echocardiogram or echocardiography to severe toxicities leading to heart failure, acute MI, and death. The cancer therapies are known to give rise to early and late cardiotoxicities, which can be reversible or irreversible based on the nature and dose of the treatment. The chronic cardiotoxicities are known to compromise with the cancer treatment.

Standard practice involves occasional assessment of LVEF and responding with a significant fall in LVEF, for example, >10% fall and below 50%. Surveillance strategies using modern cardiac imaging and cardiac biomarkers may detect early changes in cardiac function and should be considered to consider implementing early preventative strategies and prevent reduction in LVEF. Newer techniques such as LV speckle tracking and deformation analysis are becoming increasingly employed. In complex cases, CMR can be used to confirm cardiac dysfunction and assess for the presence of fibrosis or infarction.

Prevention of cardiotoxicities induced by cancer therapy, an early sensitive marker as an indication of cardiac impairment, would be beneficial in improving the prognosis and the quality of life in cancer patients. The cardiac biomarkers including TnI, T, BNP, and NT-pro-BNP have different advantages and disadvantages, and cardiac TnI has been reported widely in major studies by Cardinale et al.[52] Growing evidence supports the use of high-sensitivity Tn assays, but more research is required to confirm the optimal timing of measurement.

Various cardioprotective strategies exist depending on the age of the patient, nature of cancer drugs prescribed, and the baseline CV risk of the patient. The FDA-approved drug, dexrazoxane, has been reported to be useful in anthracycline-induced cardiotoxicity in adult and pediatric populations, although the range of evidence in adult cancer populations is limited. The meta-analysis of nine clinical trials suggests that dexrazoxane is protective against anthracycline-induced cardiotoxicity. ACE inhibitors and beta-blockers are effective in treating heart failure with reduced LVEF, and in high-risk patients, post-MI. Two of the recent studies “OVERCOME” and “PRADA” have shown that the reductions in the LVEF can be prevented by the use of ACE inhibitors and beta-blockers. Using these cardioprotective strategies in appropriately selected patients as preventive measure will hopefully minimize the cardiotoxicities and related mortality, but this requires clarification in prospective RCTs. Closer collaborations between oncologists and cardiologists will lead to a more accurate management of cardiotoxicities induced by cancer therapies.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1Ferlay J, Parkin DM, Steliarova-Foucher E. Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer 2010;46:765-81.
2Iliescu C, Grines CL, Herrmann J, Yang EH, Cilingiroglu M, Charitakis K, et al. SCAI expert consensus statement: Evaluation, management, and special considerations of cardio-oncology patients in the cardiac catheterization laboratory (Endorsed by the Cardiological Society of India, and Sociedad Latino Americana de Cardiologıa Intervencionista). Catheter Cardiovasc Interv 2016;87:895-9.
3de Haas EC, Oosting SF, Lefrandt JD, Wolffenbuttel BH, Sleijfer DT, Gietema JA, et al. The metabolic syndrome in cancer survivors. Lancet Oncol 2010;11:193-203.
4Seth R, Singh A, Yadav M. Cardio-oncology: An emerging concept. J Pract Cardiovasc Sci 2015;1:99.
5Smith LA, Cornelius VR, Plummer CJ, Levitt G, Verrill M, Canney P, et al. Cardiotoxicity of anthracycline agents for the treatment of cancer: Systematic review and meta-analysis of randomised controlled trials. BMC Cancer 2010;10:337.
6Gianni L, Herman EH, Lipshultz SE, Minotti G, Sarvazyan N, Sawyer DB, et al. Anthracycline cardiotoxicity: From bench to bedside. J Clin Oncol 2008;26:3777-84.
7Ewer MS, Vooletich MT, Durand JB, Woods ML, Davis JR, Valero V, et al. Reversibility of trastuzumab-related cardiotoxicity: New insights based on clinical course and response to medical treatment. J Clin Oncol 2005;23:7820-6.
8WHO model list of essential medicines. 19th ed. WHO; 2015. Available from: http://www.who.int/medicines/publications/essentialmedicines/EML2015. [Last accessed on 2017 May 08].
9Zhang S, Liu X, Bawa-Khalfe T, Lu LS, Lyu YL, Liu LF, et al. Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nat Med 2012;18:1639-42.
10Albini A, Pennesi G, Donatelli F, Cammarota R, De Flora S, Noonan DM, et al. Cardiotoxicity of anticancer drugs: The need for cardio-oncology and cardio-oncological prevention. J Natl Cancer Inst 2010;102:14-25.
11Mertens AC, Liu Q, Neglia JP, Wasilewski K, Leisenring W, Armstrong GT, et al. Cause-specific late mortality among 5-year survivors of childhood cancer: The Childhood Cancer Survivor Study. J Natl Cancer Inst 2008;100:1368-79.
12Reulen RC, Winter DL, Frobisher C, Lancashire ER, Stiller CA, Jenney ME, et al. Long-term cause-specific mortality among survivors of childhood cancer. JAMA 2010;304:172-9.
13Mulrooney DA, Yeazel MW, Kawashima T, Mertens AC, Mitby P, Stovall M, et al. Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: Retrospective analysis of the Childhood Cancer Survivor Study cohort. BMJ 2009;339:b4606.
14Brouwer CA, Postma A, Vonk JM, Zwart N, van den Berg MP, Bink-Boelkens MT, et al. Systolic and diastolic dysfunction in long-term adult survivors of childhood cancer. Eur J Cancer 2011;47:2453-62.
15Armstrong GT, Oeffinger KC, Chen Y, Kawashima T, Yasui Y, Leisenring W, et al. Modifiable risk factors and major cardiac events among adult survivors of childhood cancer. J Clin Oncol 2013;31:3673-80.
16Landier W, Bhatia S, Eshelman DA, Forte KJ, Sweeney T, Hester AL, et al. Development of risk-based guidelines for pediatric cancer survivors: The Children's Oncology Group long-term follow-up guidelines from the Children's Oncology Group Late Effects Committee and Nursing Discipline. J Clin Oncol 2004;22:4979-90.
17Raschi E, Vasina V, Ursino MG, Boriani G, Martoni A, De Ponti F, et al. Anticancer drugs and cardiotoxicity: Insights and perspectives in the era of targeted therapy. Pharmacol Ther 2010;125:196-218.
18Viale PH, Yamamoto DS. Cardiovascular toxicity associated with cancer treatment. Clin J Oncol Nurs 2008;12:627-38.
19Curigliano G, Cardinale D, Suter T, Plataniotis G, de Azambuja E, Sandri MT, et al. Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy: ESMO Clinical Practice Guidelines. Ann Oncol 2012;23 Suppl 7:vii155-66.
20Florescu M, Cinteza M, Vinereanu D. Chemotherapy-induced cardiotoxicity. Mædica 2013;8:59-67.
21Kratz F, Warnecke A, Schmid B, Chung DE, Gitzel M. Prodrugs of anthracyclines in cancer chemotherapy. Curr Med Chem 2006;13:477-523.
22Schuchter LM, Hensley ML, Meropol NJ, Winer EP; American Society of Clinical Oncology Chemotherapy and Radiotherapy Expert Panel. 2002 update of recommendations for the use of chemotherapy and radiotherapy protectants: Clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol 2002;20:2895-903.
23Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005;353:1659-72.
24Reinbolt RE, Patel R, Pan X, Timmers CD, Pilarski R, Shapiro CL, et al. Risk factors for anthracycline-associated cardiotoxicity. Support Care Cancer 2016;24:2173-80.
25Seidman A, Hudis C, Pierri MK, Shak S, Paton V, Ashby M, et al. Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol 2002;20:1215-21.
26Ureña PE, Lamas GA, Mitchell G, Flaker GC, Smith SC Jr., Wackers FJ, et al. Ejection fraction by radionuclide ventriculography and contrast left ventriculogram. A tale of two techniques. SAVE investigators. Survival and ventricular enlargement. J Am Coll Cardiol 1999;33:180-5.
27Evaluation of Myocardial Changes During BReast Adenocarcinoma Therapy to Detect Cardiotoxicity Earlier with MRI (EMBRACE-MRI). Available from: https://www.clinicaltrials.gov/ct2/show/NCT02306538. [Last accessed on 2017 May 05].
28Billingham ME, Mason JW, Bristow MR, et al. Anthracycline cardiomyopathy monitored by morphologic changes. Cancer Treat Rep 1978;62:865-72.
29Assessment of Cardiotoxicity by Cardiac Magnetic Resonance (CMR) in Breast Cancer Patients Receiving Trastuzumab. Assessment of Cardiotoxicity by Cardiac MRI Versus MUGA Scans in Breast Cancer Patients Receiving Trastuzumab. Available from: https://www.clinicaltrials.gov/ct2/show/NCT01022086. [Last accessed on 2017 May 05].
30Thavendiranathan P, Poulin F, Lim KD, Plana JC, Woo A, Marwick TH, et al. 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.
31Mitani I, Jain D, Joska TM, Burtness B, Zaret BL. Doxorubicin cardiotoxicity: Prevention of congestive heart failure with serial cardiac function monitoring with equilibrium radionuclide angiocardiography in the current era. J Nucl Cardiol 2003;10:132-9.
32Wagner A, Mahrholdt H, Holly TA, Elliott MD, Regenfus M, Parker M, et al. Contrast-enhanced MRI and routine single photon emission computed tomography (SPECT) perfusion imaging for detection of subendocardial myocardial infarcts: An imaging study. Lancet 2003;361:374-9.
33Jellis CL, Kwon DH. Myocardial T1 mapping: Modalities and clinical applications. Cardiovasc Diagn Ther 2014;4:126-37.
34Wieczorek SJ, Wu AH, Christenson R, Krishnaswamy P, Gottlieb S, Rosano T, et al. Arapid B-type natriuretic peptide assay accurately diagnoses left ventricular dysfunction and heart failure: A multicenter evaluation. Am Heart J 2002;144:834-9.
35Sicari R, Nihoyannopoulos P, Evangelista A, Kasprzak J, Lancellotti P, Poldermans D, et al. Stress echocardiography expert consensus statement: European Association of Echocardiography (EAE) (a registered branch of the ESC). Eur J Echocardiogr 2008;9:415-37.
36de Geus-Oei LF, Mavinkurve-Groothuis AM, Bellersen L, Gotthardt M, Oyen WJ, Kapusta L, et al. Scintigraphic techniques for early detection of cancer treatment-induced cardiotoxicity. J Nucl Med 2011;52:560-71.
37Steinherz LJ, Graham T, Hurwitz R, Sondheimer HM, Schwartz RG, Shaffer EM, et al. Guidelines for cardiac monitoring of children during and after anthracycline therapy: Report of the Cardiology Committee of the Childrens Cancer Study Group. Pediatrics 1992;89:942-9.
38Borlaug BA, Paulus WJ. Heart failure with preserved ejection fraction: Pathophysiology, diagnosis, and treatment. Eur Heart J 2011;32:670-9.
39Paulus WJ, Tschöpe C, Sanderson JE, Rusconi C, Flachskampf FA, Rademakers FE, et al. How to diagnose diastolic heart failure: A consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur Heart J 2007;28:2539-50.
40Marwick TH, Raman SV, Carrió I, Bax JJ. Recent developments in heart failure imaging. JACC Cardiovasc Imaging 2010;3:429-39.
41Paterson DI, OMeara E, Chow BJ, Ukkonen H, Beanlands RS. Recent advances in cardiac imaging for patients with heart failure. Curr Opin Cardiol 2011;26:132-43.
42Rudski LG, Lai WW, Afilalo J, Hua L, Handschumacher MD, Chandrasekaran K, et al. Guidelines for the echocardiographic assessment of the right heart in adults: A report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography. J Am Soc Echocardiogr 2010;23:685-713.
43Dokainish H, Nguyen JS, Bobek J, Goswami R, Lakkis NM. Assessment of the American Society of Echocardiography-European Association of Echocardiography guidelines for diastolic function in patients with depressed ejection fraction: An echocardiographic and invasive haemodynamic study. Eur J Echocardiogr 2011;12:857-64.
44Kirkpatrick JN, Vannan MA, Narula J, Lang RM. Echocardiography in heart failure: Applications, utility, and new horizons. J Am Coll Cardiol 2007;50:381-96.
45Lancellotti P, Moura L, Pierard LA, Agricola E, Popescu BA, Tribouilloy C, et al. European Association of Echocardiography recommendations for the assessment of valvular regurgitation. Part 2: Mitral and tricuspid regurgitation (native valve disease). Eur J Echocardiogr 2010;11:307-32.
46Lancellotti P, Tribouilloy C, Hagendorff A, Moura L, Popescu BA, Agricola E, et al. European Association of Echocardiography recommendations for the assessment of valvular regurgitation. Part 1: Aortic and pulmonary regurgitation (native valve disease). Eur J Echocardiogr 2010;11:223-44.
47Popescu BA, Andrade MJ, Badano LP, Fox KF, Flachskampf FA, Lancellotti P, et al. European Association of Echocardiography recommendations for training, competence, and quality improvement in echocardiography. Eur J Echocardiogr 2009;10:893-905.
48Nagueh SF, Bhatt R, Vivo RP, Krim SR, Sarvari SI, Russell K, et al. Echocardiographic evaluation of hemodynamics in patients with decompensated systolic heart failure. Circ Cardiovasc Imaging 2011;4:220-7.
49Ewald B, Ewald D, Thakkinstian A, Attia J. Meta-analysis of B type natriuretic peptide and N-terminal pro B natriuretic peptide in the diagnosis of clinical heart failure and population screening for left ventricular systolic dysfunction. Intern Med J 2008;38:101-13.
50Ky B, Putt M, Sawaya H, French B, Januzzi JL Jr., Sebag IA, 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.
51Qureshi W, Khalid F. Prevention is better than Cure – Preventing chemotherapy induced cardiomyopathy. J Cardiol Clin Res 2013;1:1006.
52Cardinale D, Sandri MT, Colombo A, Colombo N, Boeri M, Lamantia G, et al. Prognostic value of troponin I in cardiac risk stratification of cancer patients undergoing high-dose chemotherapy. Circulation 2004;109:2749-54.
53Legha SS, Benjamin RS, Mackay B, Ewer M, Wallace S, Valdivieso M, et al. Reduction of doxorubicin cardiotoxicity by prolonged continuous intravenous infusion. Ann Intern Med 1982;96:133-9.
54Lipshultz SE, Scully RE, Lipsitz SR, Sallan SE, Silverman LB, Miller TL, et al. Assessment of dexrazoxane as a cardioprotectant in doxorubicin-treated children with high-risk acute lymphoblastic leukaemia: Long-term follow-up of a prospective, randomised, multicentre trial. Lancet Oncol 2010;11:950-61.
55Speyer JL, Green MD, Zeleniuch-Jacquotte A, Wernz JC, Rey M, Sanger J, et al. ICRF-187 permits longer treatment with doxorubicin in women with breast cancer. J Clin Oncol 1992;10:117-27.
56Cardinale D, Colombo A, Sandri MT, Lamantia G, Colombo N, Civelli M, et al. Prevention of high-dose chemotherapy-induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition. Circulation 2006;114:2474-81.
57Li L, Takemura G, Li Y, Miyata S, Esaki M, Okada H, et al. Preventive effect of erythropoietin on cardiac dysfunction in doxorubicin-induced cardiomyopathy. Circulation 2006;113:535-43.
58Li K, Sung RY, Huang WZ, Yang M, Pong NH, Lee SM, et al. Thrombopoietin protects against in vitro and in vivo cardiotoxicity induced by doxorubicin. Circulation 2006;113:2211-20.
59Neilan TG, Jassal DS, Scully MF, Chen G, Deflandre C, McAllister H, et al. Iloprost attenuates doxorubicin-induced cardiac injury in a murine model without compromising tumour suppression. Eur Heart J 2006;27:1251-6.
60Seicean S, Seicean A, Alan N, Plana JC, Budd GT, Marwick TH, et al. Cardioprotective effect of β-adrenoceptor blockade in patients with breast cancer undergoing chemotherapy: Follow-up study of heart failure. Circ Heart Fail 2013;6:420-6.
61Bosch X, Rovira M, Sitges M, Domènech A, Ortiz-Pérez JT, de Caralt TM, et al. Enalapril and carvedilol for preventing chemotherapy-induced left ventricular systolic dysfunction in patients with malignant hemopathies: The OVERCOME trial (preventiOn of left Ventricular dysfunction with Enalapril and caRvedilol in patients submitted to intensive ChemOtherapy for the treatment of Malignant hEmopathies). J Am Coll Cardiol 2013;61:2355-62.
62Leger KJ, Cushing-Haugen K, Hansen JA, Fan W, Leisenring WM, Martin PJ, et al. Clinical and genetic determinants of cardiomyopathy risk among hematopoietic cell transplantation survivors. Biol Blood Marrow Transplant 2016;22:1094-101.