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 Table of Contents  
Year : 2017  |  Volume : 3  |  Issue : 2  |  Page : 82-93

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

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

Date of Web Publication20-Nov-2017

Correspondence Address:
Rachna Seth
Department of Pediatrics, Oncology Division, AIIMS, New Delhi
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jpcs.jpcs_33_17

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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.

Keywords: Cardio-oncology, cardiotoxicity, chemotherapy, childhood cancer

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 2023 Jun 4];3:82-93. Available from: https://www.j-pcs.org/text.asp?2017/3/2/82/218807

  Introduction Top

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 Top

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 function
  • Early 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 treatment
  • Late 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: The chemotherapeutics are known to cause cardiotoxicity of various pathophysiology and degrees

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  Radiotherapy Top

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 radiotherapy
  • Myocarditis and congestive heart failure, valvular stenosis, and fibrosis of the conduction system
  • Arteritis 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 Top

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: Risk factors associated with varied progression of chemotherapy-induced cardiotoxicity.

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The nature of toxicity varies with different drugs [20] and also varies with the cumulative doses [Table 2].
Table 2: Cardiotoxicity: Spectrum

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  Mechanisms of Cardiotoxicity Top

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: Illustration of the possible pathways by which anthracyclines can cause cardiotoxicity. Na+: Sodium ion, GSSG: Oxidized glutathione, K+: Potassium ion, O2: Oxygen-free radical, Ca2+: Calcium ion, HO: Hydroxy-free radical, P: Phosphate, ROS: Reactive oxygen species, MAPK: Mitogen-activated protein kinase, TOPO II: Topoisomerase-II, SOD: Superoxide dismutase, ERB: Estrogen receptor beta, GSH: Reduced glutathione, ONOO: Peroxynitrite.

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Table 3: Mechanisms of drug-induced cardiotoxicity

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  Evaluation Of Cardiotoxicity Top

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: Cardiomyopathy risk groups (based on treatment exposure)

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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: The various techniques for predicting chemotherapy-induced cardiotoxicity

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Table 6: Algorithm for long-term follow-up for cardiotoxicity

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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: Algorithm for monitoring of cancer patients receiving anthracycline chemotherapy.

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  Prevention Top

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: Strategies to prevent the cancer therapy-induced cardiotoxicity.

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Table 7: The use of various cardioprotective techniques, best suited against the chemotherapies

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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 Top

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 2
  • HL 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 Top

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.

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Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]

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